Patent Publication Number: US-2023137382-A1

Title: Methods for treating hypercholesterolemia

Description:
SEQUENCE LISTING 
     The present application is being filed along with a Sequence Listing in electronic format. The Sequence Listing is provided as a file entitled 201155 Sequence Listing.xml, created on Nov. 4, 2022 which is 616.1 Kb in size. The information in the electronic format of the sequence listing is incorporated herein by reference in its entirety. 
     FIELD OF THE INVENTION 
     Methods are provided for lowering LDL-C levels in an individual having elevated LDL-C levels. Such methods are further useful to treat hypercholesterolemia, and to reduce the risk of coronary heart disease. 
     BACKGROUND 
     Atherosclerosis is a complex, polygenic disease of arterial degeneration that can lead to coronary heart disease (CHD). In Western societies, complications arising from atherosclerosis are the most common causes of death. Several risk factors for CHD have been well-established, and include elevated low density lipoprotein-cholesterol (LDL-C), low levels of high density lipoprotein cholesterol (HDL-C), cigarette smoking, hypertension, age, and family history of early CHD. Given the abundant clinical data and epidemiological studies indicating that lowering LDL-C is beneficial for the prevention of adverse coronary events, the primary target of pharmacological intervention in the treatment and prevention of CHD is lowered LDL-C. 
     In individuals with autosomal dominant hypercholesterolemia (ADH), elevated LDL-C levels have been linked to mutations in the genes encoding LDL-receptor (LDL-R), apolipoprotein B (apoB), or proprotein convertase subtilisin/kexin type 9 (PCSK9) (Abifadel et al., Nat. Genet., 2003, 34:154-156). The PCSK9 gene (also known as FH3; NARC1; NARC-1; and HCHOLA3) was mapped to Chromosome 1 at location 1p32.3. PCSK9 was identified as a third locus associated with ADH when gain-of-function mutations in PCSK9 were found to be linked to elevated LDL-C levels. ApoB-100 participates in the intracellular assembly and secretion of triglyceride-rich lipoproteins and is a ligand for the LDL-R. PCSK9 is proposed to reduce LDL-R expression levels in the liver. Reduced LDL-R expression results in reduced hepatic uptake of circulating apoB containing lipoproteins, which in turn leads to elevated cholesterol. 
     Familial hypercholesterolemia (FH) is caused by hundreds of different mutations in the LDL-R, and is phenotypically characterized by elevated plasma LDL-C levels and deposits of LDL-C in tendons, skin and arteries, leading to premature cardiovascular disease. Homozygous and heterozygous mutations in the LDL-R are associated with FH. Likewise, heterozygous and homozygous mutations in the ligand-binding domain of PCSK9 are associated with the FH phenotype. Mutations in this gene have been associated with a third form of autosomal dominant FH. 
     In mice genetically deficient in PCSK9, a marked increase in LDL-R expression and increased plasma LDL clearance rate were observed. Conversely, overexpression in mice of wild-type PCSK9, or certain PCSK9 mutants, promotes decreased LDL-R expression and elevated LDL-C levels. 
     SUMMARY OF THE INVENTION 
     Provided herein are methods for the treatment of hypercholesterolemia and/or atherosclerosis, as well as methods for the reduction of elevated LDL-C levels and CHD risk. Methods for treating hypercholesterolemia comprise administering to an individual an antisense compound targeted to a PCSK9 nucleic acid. In such methods, an antisense compound targeted to a PCSK9 nucleic acid may be targeted to sequences as set forth in GENBANK® Accession No. NM_174936.2, nucleotides 25475000 to 25504000 of GENBANK® Accession No. NT_032977.8, or GENBANK® Accession No. AK124635.1. 
     Methods for treating and/or preventing atherosclerosis comprise administering to an individual an antisense compound targeted to a PCSK9 nucleic acid. Methods for reducing LDL-C levels comprise administering to an individual an antisense compound targeted to a PCSK9 nucleic acid. Methods for reducing CHD risk comprise administering to an individual an antisense compound targeted to a PCSK9 nucleic acid. Such methods may comprise the administration of a therapeutically effective amount of an antisense compound targeted to a PCSK9 nucleic acid. 
     Methods are provided for reducing LDL-C levels in an individual having elevated LDL-C levels, comprising administering to the individual a therapeutically effective amount of an antisense oligonucleotide targeted to a PCSK9 nucleic acid, thereby reducing LDL-C levels. Also provided are methods for reducing LDL-C levels in an individual comprising selecting an individual having elevated LDL-C levels, and administering to the individual a therapeutically effective amount of an antisense compound targeted to a PCSK9 nucleic acid, and additionally monitoring LDL-cholesterol levels. Further provided are methods for treating atherosclerosis in an individual, comprising selecting an individual diagnosed with atherosclerosis, administering to the individual a therapeutically effective amount of an antisense compound targeted to a PCSK9 nucleic acid, and monitoring atherosclerosis. Also provided are methods for reducing coronary heart disease risk, comprising selecting an individual having elevated LDL-C levels and one or more additional indicators of coronary heart disease, administering to the individual a therapeutically effective amount of an antisense compound targeted to a PCSK9 nucleic acid, and monitoring LDL-C levels. Additionally provided are methods for treating hypercholesterolemia, comprising administering to an individual diagnosed with hypercholesterolemia a therapeutically effective amount of an antisense oligonucleotide targeted to a PCSK9 nucleic acid, thereby reducing cholesterol levels. 
     Further provided is a use of an effective amount of one or more of the disclosed antisense compounds for treating atherosclerosis or hypercholesterolemia in an individual in need of such treatment. Also provided is a use of an effective amount of one or more of the disclosed antisense compounds for reducing LDL-C levels or reducing CHD risk in an individual in need of such treatment. Also provided is the use of one or more of the disclosed antisense compounds in the manufacture of a medicament for the treatment of atherosclerosis or hypercholesterolemia. Further provided is the use of one or more of the disclosed antisense compounds in the manufacture of a medicament for reducing LDL-C levels or for reducing CHD risk. 
     In any of the methods provided, a PCSK9 nucleic acid may be the sequence set forth in SEQ ID NO: 1. Thus, the antisense compound may be targeted to a PCSK9 nucleic acid as set forth in SEQ ID NO: 1. 
     Any of the methods provided herein may further comprise monitoring LDL-C levels. 
     An individual may be selected for administration of an antisense compound targeted to a PCSK9 nucleic acid when the individual exhibits an LDL-C level above 100 mg/dL, above 130 mg/dL, above 160 mg/dL, or above 190 mg/dL. Administration of an antisense compound targeted to a PCSK9 nucleic acid may result in an LDL-C level below 190 mg/dL, below 160 mg/dL, below 130 mg/dL, below 100 mg/dL, below 70 mg/dL, or below 50 mg/dL. 
     In any of the aforementioned methods, administration of the antisense compound may comprise parenteral administration. The parenteral administration may further comprise subcutaneous or intravenous administration. 
     In any of the methods provided herein, the antisense compound may have least 80%, at least 90%, or at least 95% complementarity to SEQ ID NO: 1. Alternatively, the antisense compound may have 100% complementarity to SEQ ID NO: 1. 
     The antisense compounds provided herein and employed in any of the described methods may be 8 to 80 subunits in length, 12 to 50 subunits in length, 12 to 30 subunits in length, 15 to 30 subunits in length, 18 to 24 subunits in length, 19 to 22 subunits in length, or 20 subunits in length. Further, the antisense compounds employed in any of the described methods may be antisense oligonucleotides 8 to 80 nucleotides in length, 12 to 50 nucleotides in length, 12 to 30 nucleotides in length 15 to 30 nucleotides in length, 18 to 24 nucleotides in length, 19 to 22 nucleotides in length, or 20 nucleotides in length. 
     In any of the methods provided, the antisense compound may be an antisense oligonucleotide. Moreover, the antisense oligonucleotide may be a gapmer antisense oligonucleotide. The gapmer antisense oligonucleotide may comprise a gap segment of ten 2′-deoxynucleotides positioned between wing segments of five 2′-MOE nucleotides. The gapmer antisense oligonucleotide may be a gap-widened antisense oligonucleotide, comprising a gap segment of fourteen 2′-deoxynucleotides positioned between wing segments of three 2′-MOE nucleotides. 
     In any of the methods provided, the antisense compounds may have at least one modified internucleoside linkage. Additionally, each internucleoside linkage may be a phosphorothioate internucleoside linkage. Each cytosine may be a 5-methyl cytosine. 
     Also provided herein are antisense compounds targeted to a PCSK9 nucleic acid. Further provided are antisense oligonucleotides targeted to a PCSK9 nucleic acid. The antisense compounds, including antisense oligonucleotides, may be targeted to PCSK9 nucleic acids, which include the sequences as set forth in GENBANK® Accession No. NM_174936.2, nucleotides 25475000 to 25504000 of GENBANK® Accession No. NT_032977.8, or GENBANK® Accession No. AK124635.1. The antisense compounds, including antisense oligonucleotides, may have at least 70%, at least 80%, at least 90%, or at least 95% complementarity to a PCSK9 nucleic acid. The antisense compounds, including antisense oligonucleotides, may have 99% complementarity to a PCSK9 nucleic acid. The antisense compounds, including antisense oligonucleotides, may have 100% complementarity to a PCSK9 nucleic acid. For any of the antisense compounds provided, including antisense oligonucleotides, the PCSK9 nucleic acid may be the sequence set forth in SEQ ID NO: 1. 
     Antisense compounds targeted to a PCSK9 nucleic acid may be 8 to 80 subunits in length, 12 to 50 subunits in length, 12 to 30 subunits in length, 15 to 30 subunits in length, 18 to 24 subunits in length, 19 to 22 subunits in length, or 20 subunits in length. Antisense oligonucleotides targeted to a PCSK9 nucleic acid may be 8 to 80 nucleotides in length, 12 to 50 nucleotides in length, 12 to 30 nucleotides in length, 15 to 30 nucleotides in length, 18 to 24 nucleotides in length, 19 to 22 nucleotides in length, or 20 nucleotides in length. 
     Moreover, the antisense compound may be a gapmer antisense oligonucleotide. The gapmer antisense oligonucleotide may comprise a gap segment of ten 2′-deoxynucleotides positioned between wing segments of five 2′-MOE nucleotides. The gapmer antisense oligonucleotide may be a gap-widened antisense oligonucleotide, comprising a gap segment of fourteen 2′-deoxynucleotides positioned between wing segments of three 2′-MOE nucleotides. 
     Antisense compounds, including antisense oligonucleotides, targeted to a PCSK9 nucleic acid may have at least one modified internucleoside linkage. Additionally, each internucleoside linkage may be a phosphorothioate internucleoside linkage. Each cytosine may be a 5-methyl cytosine. 
     Antisense compounds, including antisense oligonucleotides, targeted to a PCSK9 nucleic acid may have at least one modified nucleoside. In certain embodiments, a modified nucleoside is a sugar-modified nucleoside. In certain such embodiments, the sugar-modified nucleosides can further comprise a natural or modified heterocyclic base moiety and/or a natural or modified internucleoside linkage and may include further modifications independent from the sugar modification. In certain embodiments, a sugar modified nucleoside is a 2′-modified nucleoside, wherein the sugar ring is modified at the 2′ carbon from natural ribose or 2′-deoxy-ribose. 
     In certain embodiments, a 2′ modified nucleoside has a 2′-F, 2′-OCH 2  (2′-OMe) or a 2′-O(CH 2 ) 2 —OCH 3  (2′-O-methoxyethyl or 2′-MOE) substituent group 
     In certain embodiments, a 2′-modified nucleoside has a bicyclic sugar moiety. In certain such embodiments, the bicyclic sugar moiety is a D sugar in the alpha configuration. In certain such embodiments, the bicyclic sugar moiety is a D sugar in the beta configuration. In certain such embodiments, the bicyclic sugar moiety is an L sugar in the alpha configuration. In certain such embodiments, the bicyclic sugar moiety is an L sugar in the beta configuration. 
     In certain embodiments, the bicyclic sugar moiety comprises a bridge group between the 2′ and the 4′-carbon atoms. In certain such embodiments, the bridge group comprises from 1 to 8 linked biradical groups. In certain embodiments, the bicyclic sugar moiety comprises from 1 to 4 linked biradical groups. In certain embodiments, the bicyclic sugar moiety comprises 2 or 3 linked biradical groups. In certain embodiments, the bicyclic sugar moiety comprises 2 linked biradical groups. In certain embodiments, a linked biradical group is selected from —O—, —S—, —N(R1)-, —C(R1)(R2)-, —C(R1)=C(R1)-, —C(R1)=N—, —C(═NR1)-, —Si(R1)(R2)-, —S(═O)2-, —S(═O)—, —C(═O)— and —C(═S)—; where each R1 and R2 is, independently, H, hydroxyl, C1-C12 alkyl, substituted C1-C12 alkyl, C2-C12 alkenyl, substituted C2-C12 alkenyl, C2-C12 alkynyl, substituted C2-C12 alkynyl, C5-C20 aryl, substituted C5-C20 aryl, a heterocycle radical, a substituted hetero-cycle radical, heteroaryl, substituted heteroaryl, C5-C7 alicyclic radical, substituted C5-C7 alicyclic radical, halogen, substituted oxy (—O—), amino, substituted amino, azido, carboxyl, substituted carboxyl, acyl, substituted acyl, CN, thiol, substituted thiol, sulfonyl (S(═O)2-H), substituted sulfonyl, sulfoxyl (S(═O)—H) or substituted sulfoxyl; and each substituent group is, independently, halogen, C1-C12 alkyl, substituted C1-C12 alkyl, C2-C12 alkenyl, substituted C2-C12 alkenyl, C2-C12 alkynyl, substituted C2-C12 alkynyl, amino, substituted amino, acyl, substituted acyl, C1-C12 aminoalkyl, C1-C12 aminoalkoxy, substituted C1-C12 aminoalkyl, substituted C1-C12 aminoalkoxy or a protecting group. 
     In some embodiments, the bicyclic sugar moiety is bridged between the 2′ and 4′ carbon atoms with a biradical group selected from —O—(CH2)p-, —O—CH2-, —O—CH2CH2-, —O—CH(alkyl)-, —NH—(CH2)p-, —N(alkyl)-(CH2)p-, —O—CH(alkyl)-, —(CH(alkyl))-(CH2)p-, —NH—O—(CH2)p-, —N(alkyl)-O—(CH2)p-, or —O—N(alkyl)-(CH 2 )p-, wherein p is 1, 2, 3, 4 or 5 and each alkyl group can be further substituted. In certain embodiments, p is 1, 2 or 3. 
     In one aspect, each of said bridges is, independently, —[C(R1)(R2)]n-, —[C(R1)(R2)]n-O—, —C(R1R2)-N(R1)-O— or —C(R1R2)-O—N(R1)-. In another aspect, each of said bridges is, independently, 4′-(CH2)3-2′, 4′-(CH2)2-2′, 4′-CH2-O-2′, 4′-(CH2)2-O-2′, 4′-CH2-O—N(R1)-2′ and 4′-CH2-N(R1)-O-2′- wherein each R1 is, independently, H, a protecting group or C1-C12 alkyl. 
     The present disclosure further discloses subsets of the antisense compounds above that show superior properties relating to pharmacodynamics and/or pharmacokinetics, among other properties. Exemplary antisense compounds reduce PCSK9 expression in a cultured cell model system, e.g., Hep3B cells, cynomolgus monkey hepatocytes, or human primary hepatocytes. In particular embodiments, antisense compounds reduce PCSK9 expression in a dose-dependent manner in a cell culture system, where the antisense compounds have an IC 50  in the nanomolar range. 
     Exemplary antisense compounds also reduce the expression of a PCSK9 nucleic acid in an animal model, such as a transgenic mouse that expresses a human PCSK9 nucleic acid (HuPCSK9Tg mice). In particular embodiments, antisense compounds include those that reduce PCSK9 express in an animal model with a physiology that correlates closely with humans, such as monkey, e.g., the cynomolgus monkey. 
     Exemplary antisense compounds display minimal side effects. Side effects include responses to the administration of the antisense compound unrelated to the targeting of a PCSK9 nucleic acid, such as an inflammatory response in the host individual. Exemplary antisense compounds are well tolerated by the host individual. Tolerability may be determined though histological analysis of various cell types, and includes examination of such markers as cytoplasmic swelling from multifocal apoptosis in liver cells, follicular hyperplasia in spleen cells, macrophage infiltration, and the like. In particular embodiments, antisense compounds produce minimal signs of host intolerance. 
     Exemplary antisense compounds further display favorable pharmacokinetics. In particular embodiments, antisense compounds accumulate at a relatively high ratio in the liver versus other sensitive organs, such as kidneys. In particular embodiments, antisense compounds exhibit relatively high half-lives in relevant biological fluids or tissues, e.g., liver tissue, reflecting higher stability and resistance to nucleases, for example. 
     In particular embodiments, antisense compounds target identical sequences in human and animal PCSK9 sequences. In other embodiments, antisense compounds target PCSK9 sequences without a known single nucleotide polymorphism (SNP), have a high relative G-content, have minimal secondary structure, have greatly reduced effets on the host&#39;s serum chemistry, body weight, or histopathology, compared to other antisense compounds, and/or induce a minimal adverse immunohistocompatibility reaction. 
     In a particular embodiment, the antisense compound is selected from the group of Isis 405881, Isis 399819, Isis 395165, Isis 405879, Isis 406008, Isis 405891, Isis 395186, Isis 405988, Isis 405994, Isis 406023, Isis 395187, Isis 395185, Isis 406033, Isis 405923, Isis 399900, Isis 405995, Isis 405991, Isis 406005, Isis 399793, and Isis 395152. The aforementioned antisense compounds effectively repress PCSK9 expression in a Hep3B cell culture system. In another embodiment, antisense compounds effectively inhibit PCSK9 expression with a low IC 50  in a battery of cell culture systems. Exemplary antisense compounds include those selected from the group of Isis 395165, Isis 395185, Isis 395186, Isis 395187, Isis 405879, Isis 405881, Isis 405891, Isis 405988, Isis 405994, and Isis 406008. In yet another embodiment, antisense compounds exhibit minimal or no adverse histopathological effects when administered at particularly high doses to an individual. Exemplary antisense compounds include those selected from the group consisting of Isis 395185, Isis 395186, Isis 395187, Isis 405879, Isis 405891, and Isis 405988. In yet another embodiment, antisense compounds affect therapeutic end-points, e.g., reduction of plasma LDL-C, liver TG, or liver PCSK9 mRNA, in an animal model. Exemplary antisense compounds include Isis 405879. In yet another embodiment, antisense compounds display combinations of the characteristics above and reduce liver PCSK9 mRNA expression in an animal model with high efficiency, e.g., Isis 405879. 
     Definitions 
     Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by on of skill in the art to which the invention(s) belong. 
     Unless specific definitions are provided, the nomenclature utilized in connection with, and the procedures and techniques of, analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein are those well known and commonly used in the art. Standard techniques may be used for chemical synthesis, chemical analysis, pharmaceutical preparation, formulation and delivery, and treatment of subjects. Certain such techniques and procedures may be found for example in “Antisense Drug Technology: Principles, Strategies, and Applications.” by Stanley Crooke, Boca Raton: Taylor &amp; Francis Group, 2008; “Carbohydrate Modifications in Antisense Research” Edited by Sangvi and Cook, American Chemical Society, Washington D.C., 1994; and “Remington&#39;s Pharmaceutical Sciences,” Mack Publishing Co., Easton, Pa., 18th edition, 1990; and which is hereby incorporated by reference for any purpose. Where permitted, all patents, patent applications, published applications and publications, GENBANK sequences, websites and other published materials referred to throughout the entire disclosure herein, unless noted otherwise, are incorporated by reference in their entirety. All of the GENBANK® Accession Nos. along with their associated sequence and structural data pertaining to such sequences including gene organization and structural elements and SNP information that may be found in sequence databases such as the National Center for Biotechnology Information (NCBI) are incorporated herein by reference in their entirety. In the event that there is a plurality of definitions for terms herein, those in this section prevail. Where reference is made to a URL or other such identifier or address, it is understood that such identifiers can change and particular information on the internet can come and go, but equivalent information can be found by searching the internet. Reference thereto evidences the availability and public dissemination of such information. 
     A “pharmaceutical composition” means a mixture of substances suitable for administering to an individual. For example, a pharmaceutical composition may comprise an antisense oligonucleotide and a sterile aqueous solution. 
     “Administering” means providing a pharmaceutical agent to an individual, and includes, but is not limited to administering by a medical professional and self-administering. 
     “Individual” means a human or non-human animal selected for treatment or therapy. 
     “Duration” means the period of time during which an activity or event continues. In certain embodiments, the duration of treatment is the period of time during which doses of a pharmaceutical agent are administered. 
     “Parenteral administration,” means administration through injection or infusion. Parenteral administration includes, but is not limited to, subcutaneous administration, intravenous administration, or intramuscular administration. 
     “Subcutaneous administration” means administration just below the skin. “Intravenous administration” means administration into a vein. 
     “Dose” means a specified quantity of a pharmaceutical agent provided in a single administration. In certain embodiments, a dose may be administered in two or more boluses, tablets, or injections. For example, in certain embodiments, where subcutaneous administration is desired, the desired dose requires a volume not easily accommodated by a single injection. In such embodiments, two or more injections may be used to achieve the desired dose. In certain embodiments, a dose may be administered in two or more injections to minimize injection site reaction in a individual. 
     “Dosage unit” means a form in which a pharmaceutical agent is provided. In certain embodiments, a dosage unit is a vial containing lyophilized antisense oligonucleotide. In certain embodiments, a dosage unit is a vial containing reconstituted antisense oligonucleotide. 
     “Pharmaceutical agent” means a substance provides a therapeutic benefit when administered to a individual. For example, in certain embodiments, an antisense oligonucleotide targeted to PCSK9 is pharmaceutical agent. 
     “Diluent” means an ingredient in a composition that lacks pharmacological activity, but is pharmaceutically necessary or desirable. For example, in drugs that are injected the diluent may be a liquid, e.g., saline solution. 
     “Active pharmaceutical ingredient” means the substance in a pharmaceutical composition that provides a desired effect. 
     “Pharmaceutically acceptable carrier” means a medium or diluent that does not interfere with the structure of the oligonucleotide. Certain of such carriers enable pharmaceutical compositions to be formulated as, for example, tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspension and lozenges for the oral ingestion by a subject. 
     “Therapeutically effective amount” means an amount of a pharmaceutical agent that provides a therapeutic benefit to an individual. In certain embodiments, a therapeutically effective amount of antisense compound targeted to a PCSK9 nucleic acid is an amount that decreases LDL-C in the individual. 
     “Hypercholesterolemia” means a condition characterized by elevated serum cholesterol. 
     “Hyperlipidemia” means a condition characterized by elevated serum lipids. 
     “Hypertriglyceridemia” means a condition characterized by elevated serum triglyceride levels. 
     “Non-familial hypercholesterolemia” means a condition characterized by elevated serum cholesterol that is not the result of a single gene mutation. 
     “Polygenic hypercholesterolemia” means a condition characterized by elevated cholesterol that results from the influence of a variety of genetic factors. In certain embodiments, polygenic hypercholesterolemia may be exacerbated by dietary intake of lipids. 
     “Familial hypercholesterolemia (FH)” means an autosomal dominant metabolic disorder characterized by a mutation in the LDL-receptor (LDL-R) gene, markedly elevated LDL-C and premature onset of atherosclerosis. A diagnosis of familial hypercholesterolemia is made when an individual meets one or more of the following criteria: genetic testing confirming 2 mutated LDL-receptor genes; genetic testing confirming one mutated LDL-receptor gene; document history of untreated serum LDL-cholesterol greater than 500 mg/dL; tendinous and/or cutaneous xanthoma prior to age 10 years; or, both parents have documented elevated serum LDL-cholesterol prior to lipid-lowering therapy consistent with heterozygous familial hypercholesterolemia. 
     “Homozygous familial hypercholesterolemia” or “HoFH” means a condition characterized by a mutation in both maternal and paternal LDL-R genes. 
     “Heterozygous familial hypercholesterolemia” or “HeFH” means a condition characterized by a mutation in either the maternal or paternal LDL-R gene. 
     “Mixed dyslipidemia” means a condition characterized by elevated serum cholesterol and elevated serum triglycerides. 
     “Diabetic dyslipidemia” or “Type II diabetes with dyslipidemia” means a condition characterized by Type II diabetes, reduced HDL-C, elevated serum triglycerides, and elevated small, dense LDL particles. 
     “CHD risk equivalents,” means indicators of clinical atherosclerotic disease that confer a high risk for coronary heart disease, and include clinical coronary heart disease, symptomatic carotid artery disease, peripheral arterial disease, and/or abdominal aortic aneurysm. 
     “Metabolic syndrome” means a condition characterized by a clustering of lipid and non-lipid cardiovascular risk factors of metabolic origin. In certain embodiments, metabolic syndrome is identified by the presence of any 3 of the following factors: waist circumference of greater than 102 cm in men or greater than 88 cm in women; serum triglyceride of at least 150 mg/dL; HDL-C less than 40 mg/dL in men or less than 50 mg/dL in women; blood pressure of at least 130/85 mmHg; and fasting glucose of at least 110 mg/dL. 
     “Non-alcholic fatty liver disease (NAFLD)” means a condition characterized by fatty inflammation of the liver that is not due to excessive alcohol use (for example, alcohol consumption of over 20 g/day). In certain embodiments, NAFLD is related to insulin resistance and the metabolic syndrome. 
     “Non-alcoholic steatohepatitis (NASH)” means a condition characterized by inflammation and the accumulation of fat and fibrous tissue in the liver, that is not due to excessive alcohol use. NASH is an extreme form of NAFLD. 
     “Major risk factors” mean factors that contribute to a high risk for coronary heart disease, and include without limitation cigarette smoking, hypertension, low HDL-C, family history of coronary heart disease, and age. 
     “CHD risk factors” mean CHD risk equivalents and major risk factors. 
     “Coronary heart disease (CHD)” means a narrowing of the small blood vessels that supply blood and oxygen to the heart, which is often a result of atherosclerosis. 
     “Reduced coronary heart disease risk” means a reduction in the likelihood that an individual will develop coronary heart disease. In certain embodiments, a reduction in coronary heart disease risk is measured by an improvement in one or more CHD risk factors, for example, a decrease in LDL-C levels. 
     “Atherosclerosis” means a hardening of the arteries affecting large and medium-sized arteries and is characterized by the presence of fatty deposits. The fatty deposits are called “atheromas” or “plaques,” which consist mainly of cholesterol and other fats, calcium and scar tissue, and damage the lining of arteries. 
     “History of coronary heart disease” means the occurrence of clinically evident coronary heart disease in the medical history of an individualor a individual&#39;s family member. 
     “Early onset coronary heart disease” means a diagnosis of coronary heart disease prior to age 50. 
     “Statin intolerant individual” means an individualwho as a result of statin therapy experiences one or more of creatine kinase increases, liver function test abnormalities, muscle aches, or central nervous system side effects. 
     “Efficacy” means the ability to produce a desired effect. For example, efficacy of a lipid-lowering therapy may be reduction in the concentration of one or more of LDL-C, VLDL-C, IDL-C, non-HDL-C, ApoB, lipoprotein(a), or triglycerides. 
     “Acceptable safety profile” means a pattern of side effects that is within clinically acceptable limits. 
     “Side effects” means physiological responses attributable to a treatment other than desired effects. In certain embodiments, side effects include, without limitation, injection site reactions, liver function test abnormalities, renal function abnormalities, liver toxicity, renal toxicity, central nervous system abnormalities, and myopathies. For example, increased aminotransferase levels in serum may indicate liver toxicity or liver function abnormality. For example, increased bilirubin may indicate liver toxicity or liver function abnormality. 
     “Injection site reaction” means inflammation or abnormal redness of skin at a site of injection in an individual. 
     “Individual compliance” means adherence to a recommended or prescribed therapy by an individual. 
     “Lipid-lowering therapy” means a therapeutic regimen provided to an individual to reduce one or more lipids in a individual. In certain embodiments, a lipid-lowering therapy is provide to reduce one or more of ApoB, total cholesterol, LDL-C, VLDL-C, IDL-C, non-HDL-C, triglycerides, small dense LDL particles, and Lp(a) in a individual. 
     “Lipid-lowering agent” means a pharmaceutical agent provided to an individual to achieve a lowering of lipids in the individual. For example, in certain embodiments, a lipid-lowering agent is provided to an individualto reduce one or more of ApoB, LDL-C, total cholesterol, and triglycerides. 
     “LDL-C target” means an LDL-C level that is desired following lipid-lowering therapy. 
     “Comply” means the adherence with a recommended therapy by a individual. 
     “Recommended therapy” means a therapeutic regimen recommended by a medical professional for the treatment, amelioration, or prevention of a disease. 
     “Low LDL-receptor activity” means LDL-receptor activity that is not sufficiently high to maintain clinically acceptable levels of LDL-C in the bloodstream. 
     “Cardiovascular outcome” means the occurrence of major adverse cardiovascular events. 
     “Improved cardiovascular outcome” means a reduction in the occurrence of major adverse cardiovascular events, or the risk thereof. Examples of major adverse cardiovascular events include, without limitation, death, reinfarction, stroke, cardiogenic shock, pulmonary edema, cardiac arrest, and atrial dysrhythmia. 
     “Surrogate markers of cardiovascular outcome” means indirect indicators of cardiovascular events, or the risk thereof. For example, surrogate markers of cardiovascular outcome include carotid intimal media thickness (CIMT). Another example of a surrogate marker of cardiovascular outcome includes atheroma size. Atheroma size may be determined by intravascular ultrasound (IVUS). Surrogate markers also include increased HDL-cholesterol, or any combination of the markers above. 
     “Increased HDL-C” means an increase in serum HDL-C in an individualover time. 
     “Lipid-lowering” means a reduction in one or more serum lipids in an individual over time. 
     “Co-administration” means administration of two or more pharmaceutical agents to a individual. The two or more pharmaceutical agents may be in a single pharmaceutical composition, or may be in separate pharmaceutical compositions. Each of the two or more pharmaceutical agents may be administered through the same or different routes of administration. Co-administration encompasses administration in parallel or sequentially. 
     “Administered concomitantly” refers to the administration of two agents at the same therapeutic time frame, in any manner in which the pharmacological effects of both are manifest in the patient at the same time. Concomitant administration does not require that both agents be administered in a single pharmaceutical composition, in the same dosage form, or by the same route of administration. 
     “Therapeutic lifestyle change” means dietary and lifestyle changes intended to lower cholesterol and reduce the risk of developing heart disease, and includes recommendations for dietary intake of total daily calories, total fat, saturated fat, polyunsaturated fat, monounsaturated fat, carbohydrate, protein, cholesterol, insoluble fiber, as well as recommendations for physical activity. 
     “Statin” means a pharmaceutical agent that inhibits the activity of HMG-CoA reductase. 
     “HMG-CoA reductase inhibitor” means a pharmaceutical agent that acts through the inhibition of the enzyme HMG-CoA reductase. 
     “Cholesterol absorption inhibitor” means a pharmaceutical agent that inhibits the absorption of exogenous cholesterol obtained from diet. 
     “LDL apheresis” means a form of apheresis by which LDL-C is removed from blood. Typically, a individual&#39;s blood is removed from a vein, and separated into red cells and plasma. LDL-C is filtered out of the plasma prior to return of the plasma and red blood cells to the individual. 
     “MTP inhibitor” means a pharmaceutical agent that inhibits the enzyme microsomal triglyceride transfer protein. 
     “Low density lipoprotein-cholesterol (LDL-C)” means cholesterol carried in low density lipoprotein particles. Concentration of LDL-C in serum (or plasma) is typically quantified in mg/dL or nmol/L. “Serum LDL-C” and “plasma LDL-C” mean LDL-C in the serum and plasma, respectively. 
     “Very low density lipoprotein-cholesterol (VLDL-C)” means cholesterol associated with very low density lipoprotein particles. Concentration of VLDL-C in serum (or plasma) is typically quantified in mg/dL or nmol/L. “Serum VLDL-C” and “plasma VLDL-C” mean VLDL-C in the serum or plasma, respectively. 
     “Intermediate low density lipoprotein-cholesterol (IDL-C)” means cholesterol associated with intermediate density lipoprotein. Concentration of IDL-C in serum (or plasma) is typically quantified in mg/dL or nmol/L. “Serum IDL-C” and “plasma IDL-C” mean IDL-C in the serum or plasma, respectively. 
     “Non-high density lipoprotein-cholesterol (Non-HDL-C)” means cholesterol associated with lipoproteins other than high density lipoproteins, and includes, without limitation, LDL-C, VLDL-C, and IDL-C. 
     “High density lipoprotein-C(HDL-C)” means cholesterol associated with high density lipoprotein particles. Concentration of HDL-C in serum (or plasma) is typically quantified in mg/dL or nmol/L. “Serum HDL-C” and “plasma HDL-C” mean HDL-C in the serum and plasma, respectively. 
     “Total cholesterol” means all types of cholesterol, including, but not limited to, LDL-C, HDL-C, IDL-C and VLDL-C. Concentration of total cholesterol in serum (or plasma) is typically quantified in mg/dL or nmol/L. 
     “Lipoprotein(a)” or “Lp(a)” means a lipoprotein particle that is comprised of LDL-C, an apolipoprotein(a) particle, and an apolipoproteinB-100 particle. 
     “ApoA1” means apolipoprotein-A1 protein in serum. Concentration of ApoA1 in serum is typically quantified in mg/dL or nmol/L. 
     “ApoB:ApoA1 ratio” means the ratio of ApoB concentration to ApoA1 concentration. 
     “ApoB-containing lipoprotein” means any lipoprotein that has apolipoprotein B as its protein component, and is understood to include LDL, VLDL, IDL, and lipoprotein(a). 
     “Small LDL particle” means a subclass of LDL particles characterized by a smaller, denser size compared to other LDL particles. In certain embodiments, large LDL particles are 23-27 nm in diameter. In certain embodiments, intermediate LDL particles are 21.2-23 nm in diameter. In certain embodiments, small LDL particles are 18-21.2 nm in diameter. In certain embodiments, particle size is measured by nuclear magnetic resonance analysis. 
     “Small VLDL particle” means a subclass of VLDL particles characterized by a smaller, denser size compared to other VLDL particles. In certain embodiments, large VLDL particles are greater than 60 nm in diameter. In certain embodiments, medium VLDL particles are 35-60 nm in diameter. In certain embodiments, small VLDL particles are 27-35 nm in diameter. In certain embodiments, particle size is measured by nuclear magnetic resonance analysis. 
     “Triglycerides” means lipids that are the triesters of glycerol. “Serum triglycerides” mean triglycerides present in serum. “Liver triglycerides” mean triglycerides present in liver tissue. 
     “Serum lipids” mean cholesterol and triglycerides in the serum. 
     “Elevated total cholesterol” means total cholesterol at a concentration in an individual at which lipid-lowering therapy is recommended, and includes, without limitation, elevated LDL-C”, “elevated VLDL-C,” “elevated IDL-C,” and “elevated non-HDL-C.” In certain embodiments, total cholesterol concentrations of less than 200 mg/dL, 200-239 mg/dL, and greater than 240 mg/dL are considered desirable, borderline high, and high, respectively. In certain embodiments, LDL-C concentrations of 100 mg/dL, 100-129 mg/dL, 130-159 mg/dL, 160-189 mg/dL, and greater than 190 mg/dL are considered optimal, near optimal/above optimal, borderline high, high, and very high, respectively. 
     “Elevated triglyceride” means concentrations of triglyceride in the serum or liver at which lipid-lowering therapy is recommended, and includes “elevated serum triglyceride” and “elevated liver triglyceride.” In certain embodiments, serum triglyceride concentration of 150-199 mg/dL, 200-499 mg/dL, and greater than or equal to 500 mg/dL is considered borderline high, high, and very high, respectively. 
     “Elevated small LDL particles” means a concentration of small LDL particles in an individual at which lipid-lowering therapy is recommended. 
     “Elevated small VLDL particles” means a concentration of small VLDL particles in an individual at which lipid-lowering therapy is recommended. 
     “Elevated lipoprotein(a)” means a concentration of lipoprotein(a) in an individual at which lipid-lowering therapy is recommended. 
     “Low HDL-C” means a concentration of HDL-C in an individual at which lipid-lowering therapy is recommended. In certain embodiments lipid-lowering therapy is recommended when low HDL-C is accompanied by elevations in non-HDL-C and/or elevations in triglyceride. In certain embodiments, HDL-C concentrations of less than 40 mg/dL are considered low. In certain embodiments, HDL-C concentrations of less than 50 mg/dL are considered low. 
     “ApoB” means apolipoprotein B-100 protein. Concentration of ApoB in serum (or plasma) is typically quantified in mg/dL or nmol/L. “Serum ApoB” and “plasma ApoB” mean ApoB in the serum and plasma, respectively. 
     “LDL/HDL ratio” means the ratio of LDL-C to HDL-C. 
     “Oxidized-LDL” or “Ox-LDL-C” means LDL-C that is oxidized following exposure to free radicals. 
     “Individual having elevated LDL-C levels” means an individual who has been identified by a medical professional (e.g., a physician) as having LDL-C levels near or above the level at which therapeutic intervention is recommended, according to guidelines recognized by medical professionals. Such an individual may also be considered “in need of treatment” to decrease LDL-C levels. 
     “Individual having elevated apoB-100 levels” means an individual who has been identified as having apoB-100 levels near or above the level at which therapeutic intervention is recommended, according to guidelines recognized by medical professionals. Such an individual may also be considered “in need of treatment” to decrease apoB-100 levels. 
     “Treatment of elevated LDL-C levels” means administration of an antisense compound targeted to a PCSK9 nucleic acid to an individual having elevated LDL-C levels. 
     “Treatment of atherosclerosis” means administration of an antisense compound targeted to a PCSK9 nucleic acid to an individual who, based upon a physician&#39;s assessment, has or is likely to have atherosclerosis. “Prevention of atherosclerosis” means administration of an antisense compound targeted to a PCSK9 nucleic acid to an individual who, based upon a physician&#39;s assessment, is susceptible to atherosclerosis. 
     “Ameliorate” means to make better or improve a detrimental condition in an individual. 
     “Target nucleic acid,” “target RNA,” “target RNA transcript” and “nucleic acid target” all mean any nucleic acid capable of being targeted by antisense compounds. 
     “PCSK9 nucleic acid” means any nucleic acid encoding PCSK9. For example, in certain embodiments, a PCSK9 nucleic acid includes, without limitation, a DNA sequence encoding PCSK9, an RNA sequence transcribed from DNA encoding PCSK9, and an mRNA sequence encoding PCSK9. “PCSK9 mRNA” means an mRNA encoding a PCSK9 protein. 
     “Targeting” means the process of design and selection of an antisense compound that will specifically hybridize to a target nucleic acid and induce a desired effect. 
     “Targeted” means having a nucleobase sequence that will allow specific hybridization of an antisense compound to a target nucleic acid to induce a desired effect. In certain embodiments, a desired effect is reduction of a target nucleic acid. In certain such embodiments, a desired effect is reduction of PCSK9 mRNA. 
     “Antisense inhibition” means reduction of a target nucleic acid levels in the presence of an antisense compound complementary to a target nucleic acid compared to target nucleic acid levels in the absence of the antisense compound. 
     “Target region” means a fragment of a target nucleic acid to which one or more antisense compounds is targeted. 
     “Target segment” means the sequence of nucleotides of a target nucleic acid to which an antisense compound is targeted. “5′ target site” refers to the 5′-most nucleotide of a target segment. “3′ target site” refers to the 3′-most nucleotide of a target segment. 
     “Active target region” means a target region to which one or more active antisense compounds is targeted. “Active antisense compounds” means antisense compounds that reduce target nucleic acid levels. 
     “Hybridization” means the annealing of complementary nucleic acid molecules. In certain embodiments, complementary nucleic acid molecules include, but are not limited to, an antisense compound and a nucleic acid target. In certain such embodiments, complementary nucleic acid molecules include, but are not limited to, an antisense oligonucleotide and a nucleic acid target 
     “Stringent hybridization conditions” means conditions under which a nucleic acid molecule, such as an antisense compound, will hybridize to a target nucleic acid sequence, but to a minimal number of other sequences. 
     “Specifically hybridizable” means an antisense compound that hybridizes to a target nucleic acid to induce a desired effect, while exhibiting minimal or no effects on non-target nucleic acids. 
     “Complementarity” means the capacity for pairing between nucleobases of a first nucleic acid and a second nucleic acid. 
     “Fully complementary” means each nucleobase of a first nucleic acid is capable of pairing with each nucleobase of a second nucleic acid. In certain embodiments, a first nucleic acid is an antisense compound and a target nucleic acid is a second nucleic acid. In certain such embodiments, an antisense oligonucleotide is a first nucleic acid and a target nucleic acid is a second nucleic acid. 
     “Non-complementary nucleobase” means a nucleobase of first nucleic acid that is not capable of pairing with the corresponding nucleobase of a target nucleic acid. “Mismatch” a nucleobase of first nucleic acid that is not capable of pairing with the corresponding nucleobase of a target nucleic acid. 
     “Portion” means a defined number of contiguous (i.e., linked) nucleobases. In certain embodiments, a portion is a defined number of contiguous nucleobases of a target nucleic acid. In certain embodiments, a portion is a defined number of contiguous nucleobases of an antisense compound. 
     “Oligomeric compound” means a polymer of linked monomeric subunits which is capable of hybridizing to at least a region of an RNA molecule. 
     “Antisense compound” means an oligomeric compound that is is capable of undergoing hybridization to a target nucleic acid through hydrogen bonding. 
     “Oligonucleotide” means a polymer of linked nucleosides each of which can be modified or unmodified, independent one from another. 
     “Oligonucleoside” means an oligonucleotide in which the internucleoside linkages do not contain a phosphorus atom. 
     “Unmodified nucleotide” means a nucleotide composed of naturally occurring nucleobases, sugar moieties and internucleoside linkages. In certain embodiments, an unmodified nucleotide is an RNA nucleotide (i.e., β-D-ribonucleosides) or a DNA nucleotide (i.e., β-D-deoxyribonucleoside). 
     “Antisense oligonucleotide” means a single-stranded oligonucleotide having a nucleobase sequence that permits hybridization to a corresponding region of a target nucleic acid. 
     “Motif” means the pattern of unmodified and modified nucleosides in an antisense compound. 
     “Chimeric antisense compound” means an antisense compound that has at least 2 chemically distinct regions, each region having a plurality of subunits. 
     A “gapmer” means an antisense compound in which an internal position having a plurality of nucleotides that supports RNaseH cleavage is positioned between external regions having one or more nucleotides that are chemically distinct from the nucleosides of the internal region. 
     A “gap segment” means the plurality of nucleotides that make up the internal region of a gapmer. 
     A “wing segment” means the external region of a gapmer. 
     “Gap-widened” means an antisense compound has a gap segment of 12 or more contiguous 2′-deoxyribonucleotides positioned between 5′ and 3′ wing segments having from one to six nucleotides having modified sugar moieties. 
     “Nucleoside” means a nucleobase linked to a sugar. 
     “Nucleobase” means a heterocyclic base moiety capable of pairing with a base of another nucleic acid. 
     “Nucleotide” means a nucleoside having a phosphate group covalently linked to the sugar portion of the nucleoside. 
     “Nucleobase sequence” means the order of contiguous nucleobases independent of any sugar, linkage, and/or nucleobase modification. 
     “Modified nucleotide” means a nucleotide having, independently, a modified sugar moiety, modified internucleoside linkage, or modified nucleobase. 
     “Modified nucleoside” means a nucleotide having, independently, a modified sugar moiety or modified nucleobase. 
     “Contiguous nucleobases” means nucleobases immediately adjacent to each other. 
     “Modified oligonucleotide” means an oligonucleotide comprising a modified internucleoside linkage, a modified sugar, and/or a modified nucleobase. 
     “Single-stranded modified oligonucleotide” means a modified oligonucleotide which is not hybridized to a complementary strand. 
     “Internucleoside linkage” refers to the chemical bond between nucleosides. 
     “Linked nucleoside” means adjacent nucleosides which are bonded together. 
     “Linked deoxynucleoside” means a nucleic acid base (A, G, C, T, U) substituted by deoxyribose linked by a phosphate ester to form a nucleotide. 
     “Naturally occurring internucleoside linkage” means a 3′ to 5′ phosphodiester linkage. 
     “Modified internucleoside linkage” means substitution and/or any change from a naturally occurring internucleoside bond. In certain instances, the modified internucleoside linkage refers to a phosphodiester internucleoside bond. 
     “Phosphorothioate linkage” means a linkage between nucleosides where the phosphodiester bond is modified by replacing one of the non-bridging oxygen atoms with a sulfur atom. A phosphorothioate linkage is a modified internucleoside linkage. 
     “Modified sugar moiety” means substitution and/or any change from a natural sugar moiety. For the purposes of this disclosure, a “natural sugar moiety” is a sugar moiety found in DNA (2′-H) or RNA (2′-OH). 
     “Modified sugar” refers to a substitution and/or any change from a natural sugar. 
     “Bicyclic sugar” means a furosyl ring modified by the bridging of the two non-geminal ring atoms. A bicyclic sugar is a modified sugar. 
     “Modified nucleobase” means any nucleobase other than adenine, cytosine, guanine, thymidine, or uracil. An “unmodified nucleobase” means the purine bases adenine (A) and guanine (G), and the pyrimidine bases thymine (T), cytosine (C) and uracil (U). 
     “Modified sugar moiety” means a sugar moiety having a substitution and/or any change from a natural sugar moiety. 
     “Natural sugar moiety” means a sugar moiety found in DNA (2′-H) or RNA (2′-OH). 
     “2′-O-methoxyethyl sugar moiety” means a 2′-substituted furosyl ring having a 2′-O(CH2) 2 —OCH 3  (2′-O-methoxyethyl or 2′-MOE) substituent group. 
     “2′-O-methoxyethyl nucleotide” means a nucleotide comprising a 2′-O-methoxyethyl modified sugar moiety. 
     “2′-O-methoxyethyl” refers to an O-methoxy-ethyl modification of the 2′ position of a furosyl ring. A 2′-O-methoxyethyl modified sugar is a modified sugar. 
     “Bicyclic nucleic acid sugar moiety” means a furosyl ring modified by the bridging of two non-geminal ring atoms. 
     “5-methylcytosine” means a cytosine modified with a methyl group attached to the 5′ position. A 5-methylcytosine is a modified nucleobase. 
     “Prodrug” means a therapeutic agent that is prepared in an inactive form that is converted to an active form (i.e., drug) within the body or cells thereof by the action of endogenous enzymes or other chemicals and/or conditions. 
     “Pharmaceutically acceptable salts” means physiologically and pharmaceutically acceptable salts of antisense compounds, i.e., salts that retain the desired biological activity of the parent oligonucleotide and do not impart undesired toxicological effects thereto. 
     “Salts” refers to physiologically and pharmaceutically acceptable salts of antisense compounds, i.e., salts that retain the desired biological activity of the parent oligonucleotide and do not impart undesired toxicological effects thereto. 
     “Cures” means a method or course that restores health or a prescribed treatment for an illness. 
     “Slows progression” means decrease in the development of the said disease. 
     “Cap structure” or “terminal cap moiety” means chemical modifications, which have been incorporated at either terminus of an antisense compound. 
     “ISIS 301012” means a lipid-lowering agent that is an antisense oligonucleotide having the sequence “GCCTCAGTCTGCTTCGCACC” (SEQ ID NO: 457), where each internucleoside linkage is a phosphorothioate internucleoside linkage, each cytosine is a 5-methylcytosine, nucleotides 6-15 are 2′-deoxynucleotides, and nucleotides 1-5 and 16-20 are 2′-O-methoxyethyl nucleotides. ISIS 301012 does not target PCSK9. It is used herein as a non-PCSK9 control. 
    
    
     
       BRIEF DESCRIPTION OF THE FIGURES 
         FIG.  1    depicts the location of PCSK9 mRNA target sequences of exemplary antisense compounds. 
         FIG.  2    depicts the results of a five-point dose response experiment with exemplary antisense compounds in HEK-293 cells. The antisense compounds are identified by Isis number. The bars from left to right represent PCSK9 expression in relative units at 0 nM, 25 nM, 50 nM, 100 nM, 200 nM, and 300 nM antisense oligonucleotides. 
         FIG.  3    depicts the results of a five-point dose response experiment with exemplary antisense compounds in cyno primary hepatocytes. The antisense compounds are identified by Isis number. The bars from left to right represent PCSK9 expression in relative units at 300 nM, 150 nM, 50 nM, 25 nM, and 10 nM antisense oligonucleotides. Control values are shown in the rightmost two bars. 
         FIG.  4    depicts a reduction of murine PCSK9 mRNA expression (relative units) in the liver of h-apoB/CETP transgenic mice when administered Isis 394816. Isis 394816 was administered by intraperitoneal injection for 6 weeks at a dosing regimen of 20 mg/kg/wk or 50 mg/kg/wk. Isis 329993 was administered at 50 mg/kg/wk as a control. 
         FIG.  5   , Panel A, depicts inhibition of plasma LDL-C (mg/dL) in mice administered Isis 394816 at 20 mg/kg/wk or 50 mg/kg/wk.  FIG.  5   , Panel B, depicts inhibition of liver TG (mg/gram) in mice administered Isis 394816 at 20 mg/kg/wk or 50 mg/kg/wk. 
         FIG.  6    depicts the dose-dependent inhibition (relative units) of liver PCSK9 mRNA, plasma LDL-C, and liver TG in response to the indicated doses of Isis 394816. 
         FIG.  7    depicts a correlation between LDL-C lowering and PCSK9 mRNA inhibition, using the data from  FIG.  6   . 
         FIG.  8    depicts the accumulation of exemplary antisense compounds in rat tissues (μg/g tissue) following administration of antisense compounds. The antisense compounds are identified by Isis number. The bars from left to right represent antisense compound accumulation in kidney and liver. 
         FIG.  9    depicts the accumulation of the identified antisense compounds in tissues (μg/g tissue) following administration to a cyno monkey. Accumulation at each dosing concentration (15 mg/kg and 30 mg/kg) is shown in cyno kidney (left side bar) and cyno liver (right side bar). 
         FIG.  10    depicts PCSK9 mRNA levels (relative units) following administration of the identified antisense compounds to a cyno monkey. Results are shown at each dosing concentration (15 mg/kg and 30 mg/kg). 
         FIG.  11    depicts hepatic PCSK9 mRNA levels (relative units) detected by Northern analysis. Cyno monkeys were administered Isis 405879 (“BMS-844421”) at a dose of 15 mg/kg or 30 mg/kg. 
         FIG.  12    depicts plasma LDL-C levels (mg/dL) following administration of Isis 405879 (labeled “BMS-844421”) at a dose of 15 mg/kg or 30 mg/kg. Left side bars represent baseline levels of LDL-C in control animals; right side bars represent LDL-C following administration of antisense compounds. 
         FIG.  13    depicts the ratio of plasma HDL/LDL following administration of Isis 405879 (labeled “BMS-844421”) at a dose of 15 mg/kg or 30 mg/kg. Left side bars represent baseline HDL/LDL in control animals; right side bars represent HDL/LDL following administration of antisense compounds. 
         FIG.  14    depicts the effect of BMS-844421 and control ASOs on liver human PCSK9 mRNA in transgenic mice (6 wk). 
         FIG.  15    depicts the effect of BMS-844421 and control ASOs on plasma levels of human PCSK9 protein in transgenic mice (6 wk). 
         FIG.  16    depicts plasma hPCSK9 at baseline ( FIG.  16 A ), 3 wk ( FIG.  16 B ), and 6 wk ( FIG.  16 C ) treatment. 
         FIG.  17    depicts the BMS-844421 dose response for plasma hPCSK9 levels in transgenic mice at 6 weeks (wk). 
         FIG.  18    depicts the BMS-844421 dose response for liver mRNA and plasma protein (hPCSK9). 
         FIG.  19    depicts the dose response for plasma hPCSK9 in male and female transgenic mice. 
         FIG.  20    depicts the dose response for liver hPCSK9 mRNA in male versus female transgenic mice. 
         FIG.  21    depicts the effect of the ASOs on liver endogenous PCSK9 mRNA in the transgenic mouse after 6 weeks of administration. The numbers following the hyphens provide the mg ASO/kg body weight dose of each ASO. For example, “844421-30” is the data for BMS-84421 administered to test animals at 30 mg/kg. 
         FIG.  22    depicts the effect of ASOs on liver endogenous HMGCoA reductase mRNA in the transgenic mouse after 6 weeks of administration. 
         FIG.  23    depicts LDLR protein concentration following a 6 wk ASO treatment, as assayed by a Western blot. 
         FIG.  24    depicts the quantification of the Western blot shown in  FIG.  23   . The LDLR band is normalized to a transferring receptor (TR) band, as observed using anti-LDLR and anti-TR antibodies, respectively. 
         FIG.  25    depicts the Liver PCSK9 mRNA concentration in cyno monkeys after 13 weeks of treatment. The numbers in parentheses are administered doses in mg/kg. 
         FIG.  26    depicts the concentration of BMS-844421 in the liver of cyno monkeys after 13 weeks of treatment. 
         FIG.  27    depicts the average serum LDL-C levels in the cyno monkey study. The numbers in parentheses are administered doses in mg/kg. 
         FIG.  28 A  depicts the pharmacodynamic responses in serum lipid assays for the cyno 2.5 and 5 wk ASO studies, as displayed in a scatterplot of individual animal data.  FIG.  28 B  depicts the average ratio of HDL/LDL in BMS-844421-treated cynos at 2.5 and 5 wk. The numbers in parentheses in  FIG.  28 B  are administered doses in mg/kg. 
         FIG.  29    depicts downregulation of PCSK9 target in cyno monkeys at 13 wk in the toxicology study of liver mRNA and plasma PCSK9. 
     
    
    
     DETAILED DESCRIPTION 
     Overview 
     Elevated levels of LDL-cholesterol (HDL-C) are recognized as a major independent risk factor for coronary heart disease (CHD). Even in individuals undergoing aggressive treatment with currently available cholesterol-lowering agents to reduce LDL-cholesterol (LDL-C) levels, coronary events still occur, and elevated LDL-C levels remain a major risk factor for coronary heart disease in these individuals. Furthermore, many individuals undergoing LDL-lowering therapy do not reach their target LDL-C levels, and thus remain at risk for CHD. Accordingly, there is a need for additional LDL-C lowering agents. 
     The antisense compounds and methods provided herein are useful for the treatment of hypercholesterolemia. Treatment of hypercholesterolemia encompasses a therapeutic regimen that results in a clinically desirable outcome. For example, the antisense compounds and methods provided herein are useful for the treatment of elevated cholesterol, such as elevated LDL-C. In addition, the antisense compounds and methods provided herein may be used to reduce the risk of CHD, in individuals exhibiting one or more risk factors for CHD. Furthermore, the antisense compounds and methods provided herein may be used to treat and/or prevent atherosclerosis. 
     As illustrated herein, administration of an antisense oligonucleotide targeted to PCSK9 to animals fed a high-fat diet (an experimental model of hyperlipidemia) resulted in antisense inhibition of PCSK9, upregulation of the LDL-R, reduction of LDL-C levels, and reduction of liver triglycerides. Thus, it is demonstrated that in an experimental model of hyperlipidemia, antisense inhibition of PCSK9 results in lowering LDL-C levels. Accordingly, provided herein are methods for the treatment of reducing LDL-C levels through the administration of an antisense compound targeted to a PCSK9 nucleic acid. Increased LDL-C levels are considered a risk factor for CHD, and are also linked to atherosclerosis. Accordingly, also provided herein are methods for the reduction of CHD risk, and for the prevention and/or treatment of atherosclerosis. Also provided herein are methods for the treatment of conditions characterized by elevated liver triglycerides, such as hepatic steatosis. 
     In a particular embodiment, methods comprise the use of antisense compounds targeted to particularly advantageous sequences within a PCSK9 nucleic acid. The PCSK9 target sequences are selected on the basis of superior results shown in one or more selection criteria. The presently disclosed antisense compounds all exhibit high in vitro efficacy, determined using a battery of cell models to measure antisense regulation of PCSK9 expression. Further, preferred antisense compounds exhibit relatively high in vivo efficacy, determined using a transgenic mouse model that expresses human PCSK9 or a cynomolgus (“cyno”) monkey model. The antisense compound ISIS 405879 (SEQ ID NO: 248) displays superior results in suppressing PCSK9 mRNA expression in the liver of a host individual. 
     The present antisense compounds are tolerated to different extents when administered to a host individual. Increased tolerability can depend on a number of factors, including, but not limited to, the nucleotide sequence of the antisense compound, chemical modifications to the nucleotides, the particular motif of unmodified and modified nucleosides in the antisense compound, or combinations thereof. Antisense compounds that exhibit increased or superior tolerability are particularly preferred in the present methods. The present antisense compounds also can show different pharmacokinetic properties, depending on their nucleotide sequence, chemical modifications, motifs, or combinations thereof. Particularly preferred antisense compounds also exhibit favorable pharmacokinetics when administered to a host individual. 
     Certain Indications 
     In certain embodiments, the invention provides methods of treating an individual comprising administering one or more pharmaceutical compositions of the present invention. In certain embodiments, the individual has hypercholesterolemia, mixed dyslipidemia, atherosclerosis, a risk of developing atherosclerosis, coronary heart disease, a history of coronary heart disease, early onset coronary heart disease, acute coronary syndrome, one or more risk factors for coronary heart disease, type II diabetes, type II diabetes with dyslipidemia, dyslipidemia, hypertriglyceridemia, hyperlipidemia, hyperfattyacidemia, hepatic steatosis, non-alcoholic steatohepatitis, or non-alcoholic fatty liver disease. 
     Guidelines for lipid-lowering therapy were established in 2001 by Adult Treatment Panel III (ATP III) of the National Cholesterol Education Program (NCEP), and updated in 2004 (Grundy et al., Circulation, 2004, 110, 227-239). The guidelines include obtaining a complete lipoprotein profile, typically after a 9 to 12 hour fast, for determination of LDL-C, total cholesterol, and HDL-C levels. According to the most recently established guidelines, LDL-C levels of 130-159 mg/dL, 160-189 mg/dL, and greater than or equal to 190 mg/dL are considered borderline high, high, and very high, respectively. Total cholesterol levels of 200-239 and greater than or equal to 240 mg/dL are considered borderline high and high, respectively. HDL-C levels of less than 40 mg/dL are considered low. 
     In certain embodiments, the individual has been identified as in need of lipid-lowering therapy. In certain such embodiments, the individual has been identified as in need of lipid-lowering therapy according to the guidelines established in 2001 by Adult Treatment Panel III (ATP III) of the National Cholesterol Education Program (NCEP), and updated in 2004 (Grundy et al., Circulation, 2004, 110, 227-239). In certain such embodiments, the individual in need of lipid-lowering therapy has LDL-C above 190 mg/dL. In certain such embodiments, the individual in need of lipid-lowering therapy has LDL-C above 160 mg/dL. In certain such embodiments, the individual in need of lipid-lowering therapy has LDL-C above 130 mg/dL. In certain such embodiments, the individual in need of lipid-lowering therapy has LDL-C above 100 mg/dL. In certain such embodiments, the individual in need of lipid-lowering therapy should maintain LDL-C below 160 mg/dL. In certain such embodiments, the individual in need of lipid-lowering therapy should maintain LDL-C below 130 mg/dL. In certain such embodiments, the individual in need of lipid-lowering therapy should maintain LDL-C below 100 mg/dL. In certain such embodiments, the individual should maintain LDL-C below 70 mg/dL or even below 50 mg/dL. 
     In certain embodiments, the invention provides methods for reducing ApoB in an individual. In certain embodiments, the invention provides methods for reducing ApoB-containing lipoprotein in an individual. In certain embodiments, the invention provides methods for reducing LDL-C in an individual. In certain embodiments, the invention provides methods for reducing VLDL-C in an individual. In certain embodiments, the invention provides methods for reducing IDL-C in an individual. In certain embodiments, the invention provides methods for reducing non-HDL-C in an individual. In certain embodiments the invention provides methods for reducing Lp(a) in an individual. In certain embodiments, the invention provides methods for reducing serum triglyceride in an individual. In certain embodiments, the invention provides methods for reducing liver triglyceride in an individual. In certain embodiments, the invention provides methods for reducing Ox-LDL-C in an individual. In certain embodiments, the invention provides methods for reducing small LDL particles in an individual. In certain embodiments, the invention provides methods for reducing small VLDL particles in an individual. In certain embodiments, the invention provides methods for reducing phospholipids in an individual. In certain embodiments, the invention provides methods for reducing oxidized phospholipids in an individual. 
     In certain embodiments, the methods provided by the present invention do not lower HDL-C. In certain embodiments, the methods provided by the present invention do not result in accumulation of lipids in the liver. 
     In one embodiment are methods for decreasing LDL-C levels, or alternatively methods for treating hypercholesterolemia, by administering to an individual suffering from elevated LDL-C levels a therapeutically effective amount of an antisense compound targeted to a PCSK9 nucleic acid. In another embodiment, a method of decreasing LDL-C levels comprises selecting an individual in need of a decrease in LDL-C levels, and administering to the individual a therapeutically effective amount of an antisense compound targeted to a PCSK9 nucleic acid. In a further embodiment, a method of reducing coronary heart disease risk includes selecting an individual having elevated LDL-C levels and one or more additional indicators of coronary heart disease risk, and administering to the individual a therapeutically effective amount of an antisense compound targeted to a PCSK9 nucleic acid. 
     In other embodiments, the LDL-C level is from 100-129 mg/dL, from 130 to 159 mg/dL, from 160-189 mg/dL, or greater than or equal to 190 mg/dL. 
     In one embodiment, administration of a therapeutically effective amount of an antisense compound targeted to a PCSK9 nucleic acid is accompanied by monitoring of LDL-C levels in the serum of an individual, to determine an individual&#39;s response to administration of the antisense compound. An individual&#39;s response to administration of the antisense compound is used by a physician to determine the amount and duration of therapeutic intervention. 
     In one embodiment, administration of an antisense compound targeted to a PCSK9 nucleic acid results in LDL-C levels below 190 mg/dL, below 160 mg/dL, below 130 mg/dL, below 100 mg/dL, below 70 mg/dL, or below 50 mg/dL. In another embodiment, administration of an antisense compound targeted to a PCSK9 nucleic acid decreases LDL-C by at least 15%, by at least 25%, by at least 50%, by at least 60%, by at least 70%, by at least 75%, by at least 80%, by at least 85%, by at least 90%, or by at least 95%. 
     An individual having elevated LDL-C levels may also exhibit reduced HDL-C levels and/or elevated total cholesterol levels. Accordingly, in one embodiment a therapeutically effective amount of an antisense compound targeted to a PCSK9 nucleic acid is administered to an individual having elevated LDL-C levels, who also has reduced HDL-C levels and/or elevated total cholesterol levels. 
     Individuals having elevated LDL-C levels may also exhibit elevated triglyceride levels. Accordingly, in one embodiment a therapeutically effective amount of an antisense compound targeted to a PCSK9 nucleic acid is administered to an individual having elevated LDL-C levels, and also having elevated triglyceride levels. 
     Atherosclerosis can lead to coronary heart disease, stroke, or peripheral vascular disease. Elevated LDL-C levels are considered a risk factor in the development and progression of atherosclerosis. Accordingly, in one embodiment, a therapeutically effective amount of an antisense compound targeted to a PCSK9 nucleic acid is administered to an individual having atherosclerosis. In a further embodiment, a therapeutically effective amount of antisense compound targeted to a PCSK9 nucleic acid is administered to an individual susceptible to atherosclerosis. Atherosclerosis is assessed directly through routine imaging techniques such as, for example, ultrasound imaging techniques that reveal carotid intimomedial thickness. Accordingly, treatment and/or prevention of atherosclerosis further include monitoring atherosclerosis through routine imaging techniques. In one embodiment, administration of an antisense compound targeted to a PCSK9 nucleic acid leads to a lessening of the severity of atherosclerosis, as indicated by, for example, a reduction of carotid intimomedial thickness in arteries. 
     Measurements of cholesterol, lipoproteins and triglycerides are obtained using serum or plasma collected from an individual. Methods of obtaining serum or plasma samples are routine, as are methods of preparation of the serum samples for analysis of cholesterol, triglycerides, and other serum markers. 
     A physician may determine the need for therapeutic intervention for individuals in cases where more or less aggressive LDL-lowering therapy is needed. The practice of the methods herein may be applied to any altered guidelines provided by the NCEP, or other entities that establish guidelines for physicians used in treating any of the diseases or conditions listed herein, for determining coronary heart disease risk and diagnosing metabolic syndrome. 
     In one embodiment, administration of an antisense compound targeted to a PCSK9 nucleic acid is parenteral administration. Parenteral administration may be intravenous or subcutaneous administration. Accordingly, in another embodiment, administration of an antisense compound targeted to a PCSK9 nucleic acid is intravenous or subcutaneous administration. Administration may include multiple doses of an antisense compound targeted to a PCSK9 nucleic acid. 
     In certain embodiments, a pharmaceutical composition comprising an antisense compound targeted to PCSK9 is for use in therapy. In certain embodiments, the therapy is the reduction of LDL-C, ApoB, VLDL-C, IDL-C, non-HDL-C, Lp(a), serum triglyceride, liver triglyceride, Ox-LDL-C, small LDL particles, small VLDL, phospholipids, or oxidized phospholipids in an individual. In certain embodiments, the therapy is the treatment of hypercholesterolemia, mixed dyslipidemia, atherosclerosis, a risk of developing atherosclerosis, coronary heart disease, acute coronary syndrome, a history of coronary heart disease, early onset coronary heart disease, one or more risk factors for coronary heart disease, type II diabetes, type II diabetes with dyslipidemia, dyslipidemia, hypertriglyceridemia, hyperlipidemia, hyperfattyacidemia, hepatic steatosis, non-alcoholic steatohepatitis, or non-alcoholic fatty liver disease. In additional embodiments, the therapy is the reduction of CHD risk. In certain aspects, the therapy is prevention of atherosclerosis. In certain embodiments, the therapy is the prevention of coronary heart disease. 
     In certain embodiments, a pharmaceutical composition comprising an antisense compound targeted to PCSK9 is used for the preparation of a medicament for reducing LDL-C, ApoB, VLDL-C, IDL-C, non-HDL-C, Lp(a), serum triglyceride, liver triglyceride, Ox-LDL-C, small LDL particles, small VLDL, phospholipids, or oxidized phospholipids in an individual. In certain embodiments pharmaceutical composition comprising an antisense compound targeted to PCKS9 is used for the preparation of a medicament for reducing coronary heart disease risk. In certain embodiments, an antisense compound targeted to PCSK9 is used for the preparation of a medicament for the treatment of hypercholesterolemia, mixed dyslipidemia, atherosclerosis, a risk of developing atherosclerosis, coronary heart disease, a history of coronary heart disease, early onset coronary heart disease, one or more risk factors for coronary heart disease, type II diabetes, type II diabetes with dyslipidemia, dyslipidemia, hypertriglyceridemia, hyperlipidemia, hyperfattyacidemia, hepatic steatosis, non-alcoholic steatohepatitis, or non-alcoholic fatty liver disease. 
     Certain Combination Therapies 
     In certain embodiments, one or more pharmaceutical compositions of the present invention are co-administered with one or more other pharmaceutical agents. In certain embodiments, such one or more other pharmaceutical agents are designed to treat the same disease or condition as the one or more pharmaceutical compositions of the present invention. In certain embodiments, such one or more other pharmaceutical agents are designed to treat a different disease or condition as the one or more pharmaceutical compositions of the present invention. In certain embodiments, such one or more other pharmaceutical agents are designed to treat an undesired effect of one or more pharmaceutical compositions of the present invention. In certain embodiments, one or more pharmaceutical compositions of the present invention are co-administered with another pharmaceutical agent to treat an undesired effect of that other pharmaceutical agent. In certain embodiments, one or more pharmaceutical compositions of the present invention and one or more other pharmaceutical agents are administered at the same time. In certain embodiments, one or more pharmaceutical compositions of the present invention and one or more other pharmaceutical agents are administered at different times. In certain embodiments, one or more pharmaceutical compositions of the present invention and one or more other pharmaceutical agents are prepared together in a single formulation. In certain embodiments, one or more pharmaceutical compositions of the present invention and one or more other pharmaceutical agents are prepared separately. For example, a composition may comprise a pharmaceutical agent for separate, sequential, or simultaneous administration with an antisense compound. 
     In certain embodiments, pharmaceutical agents that may be co-administered with a pharmaceutical composition of the present invention include lipid-lowering agents or LXR agonists. In certain such embodiments, pharmaceutical agents that may be co-administered with a pharmaceutical composition of the present invention include, but are not limited to atorvastatin, simvastatin, rosuvastatin, and ezetimibe. In certain such embodiments, the lipid-lowering agent is administered prior to administration of a pharmaceutical composition of the present invention. In certain such embodiments, the lipid-lowering agent is administered following administration of a pharmaceutical composition of the present invention. In certain such embodiments the lipid-lowering agent is administered at the same time as a pharmaceutical composition of the present invention. In certain such embodiments the dose of a co-administered lipid-lowering agent is the same as the dose that would be administered if the lipid-lowering agent was administered alone. In certain such embodiments the dose of a co-administered lipid-lowering agent is lower than the dose that would be administered if the lipid-lowering agent was administered alone. In certain such embodiments the dose of a co-administered lipid-lowering agent is greater than the dose that would be administered if the lipid-lowering agent was administered alone. 
     In certain embodiments, a co-administered lipid-lowering agent is a HMG-CoA reductase inhibitor. In certain such embodiments the HMG-CoA reductase inhibitor is a statin. In certain such embodiments, the statin is selected from, for example, atorvastatin, simvastatin, pravastatin, fluvastatin, and rosuvastatin. 
     In certain embodiments, a co-administered lipid-lowering agent is a cholesterol absorption inhibitor. In certain such embodiments, cholesterol absorption inhibitor is ezetimibe. 
     In certain embodiments, a co-administered lipid-lowering agent is a co-formulated HMG-CoA reductase inhibitor and cholesterol absorption inhibitor. In certain such embodiments the co-formulated lipid-lowering agent is ezetimibe/simvastatin. 
     In certain embodiments, a co-administered lipid-lowering agent is a microsomal triglyceride transfer protein inhibitor (MTP inhibitor). 
     In certain embodiments, a co-administered lipid-lowering agent is an oligonucleotide targeted to ApoB. 
     In certain embodiments, a co-administered pharmaceutical agent is a bile acid sequestrant. In certain such embodiments, the bile acid sequestrant is selected from cholestyramine, colestipol, and colesevelam. 
     In certain embodiments, a co-administered pharmaceutical agent is a nicotinic acid. In certain such embodiments, the nicotinic acid is selected from immediate release nicotinic acid, extended release nicotinic acid, and sustained release nicotinic acid. 
     In certain embodiments, a co-administered pharmaceutical agent is a fibric acid. In certain such embodiments, a fibric acid is selected from gemfibrozil, fenofibrate, clofibrate, bezafibrate, and ciprofibrate. 
     Further examples of pharmaceutical agents that may be co-administered with a pharmaceutical composition of the present invention include, but are not limited to, corticosteroids, including but not limited to prednisone; LXR agonists; immunoglobulins, including, but not limited to intravenous immunoglobulin (IVIg); analgesics (e.g., acetaminophen); anti-inflammatory agents, including, but not limited to non-steroidal anti-inflammatory drugs (e.g., ibuprofen, COX-1 inhibitors, and COX-2, inhibitors); salicylates; antibiotics; antivirals; antifungal agents; antidiabetic agents (e.g., biguanides, glucosidase inhibitors, insulins, sulfonylureas, and thiazolidenediones); adrenergic modifiers; diuretics; hormones (e.g., anabolic steroids, androgen, estrogen, calcitonin, progestin, somatostan, and thyroid hormones); immunomodulators; muscle relaxants; antihistamines; osteoporosis agents (e.g., biphosphonates, calcitonin, and estrogens); prostaglandins, antineoplastic agents; psychotherapeutic agents; sedatives; poison oak or poison sumac products; antibodies; and vaccines. 
     In certain embodiments, the pharmaceutical compositions of the present invention may be administered in conjunction with a lipid-lowering therapy. In certain such embodiments, a lipid-lowering therapy is therapeutic lifestyle change. In certain such embodiments, a lipid-lowering therapy is LDL apheresis. 
     Antisense Compounds 
     Oligomeric compounds include, but are not limited to, oligonucleotides, oligonucleosides, oligonucleotide analogs, oligonucleotide mimetics, antisense compounds, antisense oligonucleotides, and siRNAs. An oligomeric compound may be “antisense” to a target nucleic acid, meaning that is is capable of undergoing hybridization to a target nucleic acid through hydrogen bonding. 
     In certain embodiments, an antisense compound has a nucleobase sequence that, when written in the 5′ to 3′ direction, comprises the reverse complement of the target segment of a target nucleic acid to which it is targeted. In certain such embodiments, an antisense oligonucleotide has a nucleobase sequence that, when written in the 5′ to 3′ direction, comprises the reverse complement of the target segment of a target nucleic acid to which it is targeted. 
     In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid is 8 to 80, 12 to 50, 12 to 30 or 15 to 30 subunits in length. In other words, antisense compounds are from 8 to 80, 12 to 50, 12 to 30 or 15 to 30 linked subunits. In certain such embodiments, the antisense compounds are 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 subunits in length. 
     In certain embodiments, an antisense oligonucleotide targeted to a PCSK9 nucleic acid is 12 to 30 nucleotides in length. In certain such embodiments, an antisense oligonucleotide targeted to a PCSK9 nucleic acid is 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides in length. 
     In certain embodiment, an antisense compound targeted to a PCSK9 nucleic acid is 15 to 30 subunits in length. In other words, antisense compounds are from 15 to 30 linked subunits. In certain such embodiments, the antisense compounds are 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 subunits in length. 
     In certain embodiments, an antisense oligonucleotide targeted to a PCSK9 nucleic acid is 15 to 30 nucleotides in length. In certain such embodiments, an antisense oligonucleotide targeted to a PCSK9 nucleic acid is 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides in length. 
     In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid is 18 to 24 subunits in length. In other words, antisense compounds are from 18 to 24 linked subunits. In one embodiment, the antisense compounds are 18, 19, 20, 21, 22, 23, or 24 subunits in length. 
     In certain embodiments, an antisense oligonucleotide targeted to a PCSK9 nucleic acid is 18 to 24 nucleotides in length. In certain such embodiments, an antisense oligonucleotide targeted to a PCSK9 nucleic acid is 18, 19, 20, 21, 22, 23, or 24 nucleotides in length. 
     In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid is 19 to 22 subunits in length. In other words, antisense compounds are from 19 to 22 linked subunits. This embodies antisense compounds of 19, 20, 21, or 22 subunits in length. 
     In certain embodiments, an antisense oligonucleotide targeted to a PCSK9 nucleic acid is 19 to 22 nucleotides in length. In certain such embodiments, an antisense oligonucleotide targeted to a PCSK9 nucleic acid is 19, 20, 21, or 22 nucleotides in length. 
     In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid is 20 subunits in length. In certain such embodiments, antisense compounds are 20 linked subunits in length. 
     In certain embodiments, an antisense oligonucleotide targeted to a PCSK9 nucleic acid is 20 nucleotides in length. In certain such embodiments, an antisense oligonucleotide targeted to an PCSK9 nucleic acid is 20 linked nucleotides in length. 
     In certain embodiments, antisense compounds target a range of a PCSK9 nucleic acid. In certain embodiment, such compounds contain at least an 8 nucleotide core sequence in common. In certain embodiments, such compounds sharing at least an 8 nucleotide core sequence target a region identified herein. 
     In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid may target the following nucleotide regions of SEQ ID NO: 1: 294-317, 406-440, 406-526, 410-436, 410-499, 446-526, 545-581, 591-619, 591-704, 591-743, 595-622, 600-626, 600-639, 600-670, 601-628, 602-628, 603-630, 611-636, 620-647, 638-665, 648-674, 657-684, 705-743, 782-810, 821-859, 835-859, 835-917, 835-942, 860-887, 860-899, 860-909, 860-917, 869-895, 878-905, 888-909, 923-952, 960-1034, 960-1173, 960-986, 967-991, 970-1023, 970-1064, 970-1117, 970-996, 977-1004, 985-1011, 989-1016, 992-1019, 997-1024, 997-1024, 998-1025, 999-1026, 1000-1027, 1001-1028, 1002-1029, 1003-1029, 1004-1029, 1005-1029, 1006-1029, 1007-1034, 1036-1061, 1045-1072, 1076-1096, 1088-1115, 1098-1123, 1200-1251, 1210-1237, 1219-1245, 1228-1251, 1273-1444, 1295-1316, 1318-1345, 1328-1354, 1337-1361, 1344-1371, 1354-1377, 1380-1406, 1389-1416, 1400-1426, 1409-1434, 1465-1491, 1465-1602, 1474-1499, 1482-1519, 1513-1540, 1523-1549, 1526-1602, 1526-1624, 1532-1558, 1541-1568, 1552-1579, 1560-1587, 1561-1589, 1564-1591, 1565-1592, 1566-1592, 1567-1592, 1570-1597, 1571-1599, 1605-1706, 1628-1706, 1640-1666, 1672-1698, 1681-1706, 1735-1761, 1735-1765, 1740-1765, 1849-1876, 1849-1879, 1850-1877, 1851-1877, 1852-1878, 1852-1879, 1853-1879, 1854-1879, 1905-1955, 1915-1942, 1916-1943, 1917-1944, 1918-1945, 1919-1946, 1920-1939, 1920-1947, 1921-1948, 1922-1949, 1923-1950, 1924-1951, 1925-1952, 1926-1952, 1927-1952, 1928-1955, 1962-2059, 2040-2126, 2100-2126, 2100-2139, 2100-2206, 2101-2126, 2305-2332, 2305-2354, 2306-2333, 2307-2334, 2308-2334, 2309-2334, 2310-2334, 2410-2434, 2504-2528, 2509-2528, 2582-2625, 2606-2668, 2828-2855, 2832-2851, 2900-2927, 2900-2929, 2902-2927, 2983-3007, 2983-3013, 3227-3252, 3227-3456, 3472-3496, or 3543-3569. 
     In certain embodiments, antisense compounds target a range of a PCSK9 nucleic acid. In certain embodiment, such compounds contain at least an 8 nucleotide core sequence in common. In certain embodiments, such compounds sharing at least an 8 nucleotide core sequence targets the following nucleotide regions of SEQ ID NO: 1: 294-317, 406-440, 406-526, 410-436, 410-499, 446-526, 545-581, 591-619, 591-704, 591-743, 595-622, 600-626, 600-639, 600-670, 601-628, 602-628, 603-630, 611-636, 620-647, 638-665, 648-674, 657-684, 705-743, 782-810, 821-859, 835-859, 835-917, 835-942, 860-887, 860-899, 860-909, 860-917, 869-895, 878-905, 888-909, 923-952, 960-1034, 960-1173, 960-986, 967-991, 970-1023, 970-1064, 970-1117, 970-996, 977-1004, 985-1011, 989-1016, 992-1019, 997-1024, 997-1024, 998-1025, 999-1026, 1000-1027, 1001-1028, 1002-1021, 1002-1029, 1003-1029, 1004-1029, 1005-1029, 1006-1029, 1007-1034, 1036-1061, 1045-1072, 1076-1096, 1088-1115, 1098-1123, 1200-1251, 1210-1237, 1219-1245, 1228-1251, 1273-1444, 1295-1316, 1318-1345, 1328-1354, 1337-1361, 1344-1371, 1354-1377, 1380-1406, 1389-1416, 1400-1426, 1409-1434, 1465-1491, 1465-1602, 1474-1499, 1482-1519, 1513-1540, 1523-1549, 1526-1602, 1526-1624, 1532-1558, 1541-1568, 1552-1579, 1560-1587, 1561-1589, 1564-1591, 1565-1592, 1566-1592, 1567-1592, 1570-1597, 1571-1599, 1605-1706, 1628-1706, 1640-1666, 1672-1698, 1681-1706, 1735-1761, 1735-1765, 1740-1765, 1849-1876, 1849-1879, 1850-1877, 1851-1877, 1852-1878, 1852-1879, 1853-1879, 1854-1879, 1905-1955, 1915-1942, 1916-1943, 1917-1944, 1918-1945, 1919-1946, 1920-1939, 1920-1947, 1921-1948, 1922-1949, 1923-1950, 1924-1951, 1925-1952, 1926-1952, 1927-1952, 1928-1955, 1962-2059, 2040-2126, 2100-2126, 2100-2139, 2100-2206, 2101-2126, 2305-2332, 2305-2354, 2306-2333, 2307-2334, 2308-2334, 2309-2334, 2310-2334, 2410-2434, 2504-2528, 2509-2528, 2582-2625, 2606-2668, 2828-2855, 2832-2851, 2900-2927, 2900-2929, 2902-2927, 2983-3007, 2983-3013, 3227-3252, 3227-3456, 3472-3496, or 3543-3569. 
     In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid may target the following nucleotide regions of SEQ ID NO: 2: 2274-2400, 2274-2575, 2433-2570, 2433-2579, 2549-2575, 2552-2579, 2585-2638, 2605-2638, 3056-3075, 4150-5159, 4306-4325, 5590-5618, 5667-5686, 6444-6463, 6482-6518, 6492-6518, 6528-6555, 6528-6623, 6534-6561, 6535-6562, 6536-6563, 6537-6563, 6538-6565, 6539-6565, 6540-6567, 6541-6567, 6542-6569, 6546-6573, 6557-6584, 6575-6602, 6585-6611, 6594-6621, 6596-6623, 6652-6671, 7099-7118, 7556-7584, 8836-8855, 8948-8967, 9099-9118, 9099-9168, 9130-9168, 9207-9233, 9207-9235, 9209-9235, 10252-10271, 10633-10652, 11308-11491, 12715-12734, 12928-12947, 13681-13700, 13746-13779, 13816-13847, 13903-13945, 13977-14141, 14179-14198, 14267-14286, 14397-14423, 14441-14460, 14494-14513, 14494-14543, 14524-14543, 14601-14650, 14670-14700, 14675-14700, 14801-14828, 14877-14912, 14877-14915, 14877-14973, 14916-14943, 14916-14973, 14925-14951, 14934-14963, 14946-14973, 14979-14998, 15254-15280, 15254-15328, 15264-15290, 15279-15305, 15291-15318, 15292-15319, 15293-15320, 15294-15321, 15294-15321, 15295-15322, 15296-15323, 15297-15323, 15298-15323, 15299-15323, 15300-15323, 15301-15328, 15330-15355, 15330-15490, 15339-15366, 15358-15490, 16134-16153, 16668-16687, 17267-17286, 18377-18427, 18561-18580, 18591-18618, 18591-18646, 18591-18668, 18695-18746, 18705-18730, 18709-18736, 18719-18746, 19203-20080, 19931-19952, 19954-19981, 19964-19990, 19973-19999, 19982-20009, 19992-20016, 20016-20042, 20025-20052, 20036-20062, 20045-20070, 20100-20119, 20188-20207, 20624-20650, 20624-20759, 20629-20804, 20633-20660, 20635-20781, 20643-20662, 20657-20676, 20670-20697, 20680-20706, 20683-20781, 20689-20715, 20698-20725, 20709-20736, 20717-20744, 20718-20745, 20719-20746, 20720-20747, 20721-20748, 20722-20749, 20727-20752, 20735-20759, 20762-21014, 20785-21014, 21082-21107, 21082-21152, 21091-21114, 21118-21144, 21127-21152, 21181-21209, 21181-21211, 21183-21211, 21481-21500, 21589-21608, 21692-21719, 22000-22227, 22096-22115, 22096-22223, 22096-22311, 22133-22160, 22133-22163, 22134-22161, 22135-22162, 22136-22163, 22137-22163, 22138-22163, 22189-22239, 22199-22226, 22199-22227, 22200-22227, 22201-22228, 22202-22229, 22203-22230, 22204-22231, 22205-22232, 22206-22233, 22207-22234, 22208-22235, 22209-22236, 22210-22236, 22210-22239, 22211-22236, 22212-22239, 22292-22311, 23985-24054, 24035-24134, 24095-24121, 24858-24877, 24907-24926, 25413-25432, 25994-26013, 26112-26139, 26112-26161, 26112-27303, 26113-26140, 26114-26141, 26115-26141, 26116-26141, 26117-26141, 26117-26475, 26118-26141, 26120-26141, 26132-26151, 26142-26161, 26217-26241, 26311-26335, 26389-26432, 26456-26576, 26635-26662, 26707-26734, 26707-26736, 26790-26820, 27034-27263, 27279-27303, or 27350-27376. 
     In certain embodiments, antisense compounds target a range of a PCSK9 nucleic acid. In certain embodiment, such compounds contain at least an 8 nucleotide core sequence in common. In certain embodiments, such compounds sharing at least an 8 nucleotide core sequence targets the following nucleotide regions of SEQ ID NO: 2: 2274-2400, 2274-2575, 2433-2570, 2433-2579, 2549-2575, 2552-2579, 2585-2638, 2605-2638, 3056-3075, 4150-5159, 4306-4325, 5590-5618, 5667-5686, 6444-6463, 6482-6518, 6492-6518, 6528-6555, 6528-6623, 6534-6561, 6535-6562, 6536-6563, 6537-6563, 6538-6565, 6539-6565, 6540-6567, 6541-6567, 6542-6569, 6546-6573, 6557-6584, 6575-6602, 6585-6611, 6594-6621, 6596-6623, 6652-6671, 7099-7118, 7556-7584, 8836-8855, 8948-8967, 9099-9118, 9099-9168, 9130-9168, 9207-9233, 9207-9235, 9209-9235, 10252-10271, 10633-10652, 11308-11491, 12715-12734, 12928-12947, 13681-13700, 13746-13779, 13816-13847, 13903-13945, 13977-14141, 14179-14198, 14267-14286, 14397-14423, 14441-14460, 14494-14513, 14494-14543, 14524-14543, 14601-14650, 14670-14700, 14675-14700, 14801-14828, 14877-14912, 14877-14915, 14877-14973, 14916-14943, 14916-14973, 14925-14951, 14934-14963, 14946-14973, 14979-14998, 15254-15280, 15254-15328, 15264-15290, 15279-15305, 15291-15318, 15292-15319, 15293-15320, 15294-15321, 15294-15321, 15295-15322, 15296-15323, 15297-15323, 15298-15323, 15299-15323, 15300-15323, 15301-15328, 15330-15355, 15330-15490, 15339-15366, 15358-15490, 16134-16153, 16668-16687, 17267-17286, 18377-18427, 18561-18580, 18591-18618, 18591-18646, 18591-18668, 18695-18746, 18705-18730, 18709-18736, 18719-18746, 19203-20080, 19931-19952, 19954-19981, 19964-19990, 19973-19999, 19982-20009, 19992-20016, 20016-20042, 20025-20052, 20036-20062, 20045-20070, 20100-20119, 20188-20207, 20624-20650, 20624-20759, 20629-20804, 20633-20660, 20635-20781, 20643-20662, 20657-20676, 20670-20697, 20680-20706, 20683-20781, 20689-20715, 20698-20725, 20709-20736, 20717-20744, 20718-20745, 20719-20746, 20720-20747, 20721-20748, 20722-20749, 20727-20752, 20735-20759, 20762-21014, 20785-21014, 21082-21107, 21082-21152, 21091-21114, 21118-21144, 21127-21152, 21181-21209, 21181-21211, 21183-21211, 21481-21500, 21589-21608, 21692-21719, 22000-22227, 22096-22115, 22096-22223, 22096-22311, 22133-22160, 22133-22163, 22134-22161, 22135-22162, 22136-22163, 22137-22163, 22138-22163, 22189-22239, 22199-22226, 22199-22227, 22200-22227, 22201-22228, 22202-22229, 22203-22230, 22204-22231, 22205-22232, 22206-22233, 22207-22234, 22208-22235, 22209-22236, 22210-22236, 22210-22239, 22211-22236, 22212-22239, 22292-22311, 23985-24054, 24035-24134, 24095-24121, 24858-24877, 24907-24926, 25413-25432, 25994-26013, 26112-26139, 26112-26161, 26112-27303, 26113-26140, 26114-26141, 26115-26141, 26116-26141, 26117-26141, 26117-26475, 26118-26141, 26120-26141, 26132-26151, 26142-26161, 26217-26241, 26311-26335, 26389-26432, 26456-26576, 26635-26662, 26707-26734, 26707-26736, 26790-26820, 27034-27263, 27279-27303, or 27350-27376. 
     In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid may target the following nucleotide regions of SEQ ID NO: 3: 220-253, 290-321, 377-419, 451-615, 653-672, 741-760, 871-897, 915-934, 968-1017, 1075-1124, 1075-1174, 1144-1174, 1275-1302, 1315-1341, 1351-1389, 1351-1447, 1365-1439, 1390-1417, 1390-1429, 1390-1439, 1399-1425, 1408-1435, 1420-1447, 1453-1482, 1490-1516, 1490-1564, 1500-1526, 1515-1541, 1527-1553, 1527-1554, 1528-1554, 1529-1555, 1529-1556, 1530-1556, 1530-1557, 1531-1557, 1532-1558, 1533-1559, 1534-1559, 1535-1559, 1536-1559, 1537-1564, 1566-1602, 1566-1681, 1606-1626, 1618-1645, 1626-1653, 1684-1703, 1730-1781, 1740-1767, 1749-1775, 1758-1781, 1820-1847, 1820-1877, 1822-2198, 1830-1856, 1839-1865, 1840-1867, 1898-1924, 1898-2035, 1903-2127, 1907-1934, 1911-1938, 1946-1971, 1954-1980, 1959-2035, 1959-2057, 1963-1988, 1967-2035, 1972-1999, 1982-2008, 1991-2018, 1993-2019, 1995-2022, 1996-2023, 1997-2024, 1998-2025, 1999-2025, 2000-2025, 2009-2035, 2038-2139, 2061-2139, 2073-2099, 2078-2104, 2105-2131, 2112-2139, 2168-2198, 2170-2177, 2245-2284, 2295-2394, 2355-2381, 2355-2394, 2405-2461, 2560-2587, 2560-2609, 2561-2588, 2562-2589, 2563-2589, 2564-2589, 2565-2589, 2566-2589, 2567-2589, 2568-2589, 2665-2689, 2759-2783, 2837-2880, 2904-2923, 3005-3024, 3005-3174, 3083-3110, 3155-3184, 3238-3268, 3482-3711, 3727-3751, or 3798-3824. 
     In certain embodiments, antisense compounds target a range of a PCSK9 nucleic acid. In certain embodiment, such compounds contain at least an 8 nucleotide core sequence in common. In certain embodiments, such compounds sharing at least an 8 nucleotide core sequence targets the following nucleotide regions of SEQ ID NO: 3: 220-253, 290-321, 377-419, 451-615, 653-672, 741-760, 871-897, 915-934, 968-1017, 1075-1124, 1075-1174, 1144-1174, 1275-1302, 1315-1341, 1351-1389, 1351-1447, 1365-1439, 1390-1417, 1390-1429, 1390-1439, 1399-1425, 1408-1435, 1420-1447, 1453-1482, 1490-1516, 1490-1564, 1500-1526, 1515-1541, 1527-1553, 1527-1554, 1528-1554, 1529-1555, 1529-1556, 1530-1556, 1530-1557, 1531-1557, 1532-1558, 1533-1559, 1534-1559, 1535-1559, 1536-1559, 1537-1564, 1566-1602, 1566-1681, 1606-1626, 1618-1645, 1626-1653, 1684-1703, 1730-1781, 1740-1767, 1749-1775, 1758-1781, 1820-1847, 1820-1877, 1822-2198, 1830-1856, 1839-1865, 1840-1867, 1898-1924, 1898-2035, 1903-2127, 1907-1934, 1911-1938, 1946-1971, 1954-1980, 1959-2035, 1959-2057, 1963-1988, 1967-2035, 1972-1999, 1982-2008, 1991-2018, 1993-2019, 1995-2022, 1996-2023, 1997-2024, 1998-2025, 1999-2025, 2000-2025, 2009-2035, 2038-2139, 2061-2139, 2073-2099, 2078-2104, 2105-2131, 2112-2139, 2168-2198, 2170-2177, 2245-2284, 2295-2394, 2355-2381, 2355-2394, 2405-2461, 2560-2587, 2560-2609, 2561-2588, 2562-2589, 2563-2589, 2564-2589, 2565-2589, 2566-2589, 2567-2589, 2568-2589, 2665-2689, 2759-2783, 2837-2880, 2904-2923, 3005-3024, 3005-3174, 3083-3110, 3155-3184, 3238-3268, 3482-3711, 3727-3751, or 3798-3824. 
     In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid may target the following nucleotide regions of SEQ ID NO: 1: 320-405, 441-445, 527-544, 582-590, 744-781, 811-820, 918-922, 953-959, 1034-1036, 1152-1153, 1174-1199, 1251-1272, 1445-1464, 1603-1604, 1625-1627, 1707-1734, 1766-1811, 1832-1848, 1880-1904, 1956-1961, 1982-1939, 2030-2039, 2060-2099, 2140-2149, 2170-2186, 2207-2304, 2355-2409, 2435-2503, 2529-2581, 2626-2648, 2669-2749, 2770-2827, 2856-2876, 2891-2899, 2930-2982, 3014-3226, 3253-3436, 3457-3471, or 3497-3542. 
     In certain embodiments, antisense compounds target a range of a PCSK9 nucleic acid. In certain embodiment, such compounds contain at least an 8 nucleotide core sequence in common. In certain embodiments, such compounds sharing at least an 8 nucleotide core sequence targets the following nucleotide regions of SEQ ID NO: 1: 320-405, 441-445, 527-544, 582-590, 744-781, 811-820, 918-922, 953-959, 1034-1036, 1152-1153, 1174-1199, 1251-1272, 1445-1464, 1603-1604, 1625-1627, 1707-1734, 1766-1811, 1832-1848, 1880-1904, 1956-1961, 1982-1939, 2030-2039, 2060-2099, 2140-2149, 2170-2186, 2207-2304, 2355-2409, 2435-2503, 2529-2581, 2626-2648, 2669-2749, 2770-2827, 2856-2876, 2891-2899, 2930-2982, 3014-3226, 3253-3436, 3457-3471, or 3497-3542. 
     In certain embodiments, a shortened or truncated antisense compound targeted to a PCSK9 nucleic acid has a single subunit deleted from the 5′ end (5′ truncation), or alternatively from the 3′ end (3′ truncation). A shortened or truncated antisense compound targeted to a PCSK9 nucleic acid may have two subunits deleted from the 5′ end, or alternatively may have two subunits deleted from the 3′ end, of the antisense compound. Alternatively, the deleted nucleosides may be dispersed throughout the antisense compound, for example, in an antisense compound having one nucleoside deleted from the 5′ end and one nucleoside deleted from the 3′ end. 
     When a single additional subunit is present in a lengthened antisense compound, the additional subunit may be located at the 5′ or 3′ end of the antisense compound. When two are more additional subunits are present, the added subunits may be adjacent to each other, for example, in an antisense compound having two subunits added to the 5′ end (5′ addition), or alternatively to the 3′ end (3′ addition), of the antisense compound. Alternatively, the added subunits may be dispersed throughout the antisense compound, for example, in an antisense compound having one subunit added to the 5′ end and one subunit added to the 3′ end. 
     It is possible to increase or decrease the length of an antisense compound, such as an antisense oligonucleotide, and/or introduce mismatch bases without eliminating activity. For example, in Woolf et al. (Proc. Natl. Acad. Sci. USA 89:7305-7309, 1992), a series of antisense oligonucleotides 13-25 nucleobases in length were tested for their ability to induce cleavage of a target RNA in an oocyte injection model. Antisense oligonucleotides 25 nucleobases in length with 8 or 11 mismatch bases near the ends of the antisense oligonucleotides were able to direct specific cleavage of the target mRNA, albeit to a lesser extent than the antisense oligonucleotides that contained no mismatches. Similarly, target specific cleavage was achieved using 13 nucleobase antisense oligonucleotides, including those with 1 or 3 mismatches. 
     Gautschi et al (J. Natl. Cancer Inst. 93:463-471, March 2001) demonstrated the ability of an oligonucleotide having 100% complementarity to the bcl-2 mRNA and having 3 mismatches to the bcl-xL mRNA to reduce the expression of both bcl-2 and bcl-xL in vitro and in vivo. Furthermore, this oligonucleotide demonstrated potent anti-tumor activity in vivo. 
     Maher and Dolnick (Nuc. Acid. Res. 16:3341-3358, 1988) tested a series of tandem 14 nucleobase antisense oligonucleotides, and a 28 and 42 nucleobase antisense oligonucleotides comprised of the sequence of two or three of the tandem antisense oligonucleotides, respectively, for their ability to arrest translation of human DHFR in a rabbit reticulocyte assay. Each of the three 14 nucleobase antisense oligonucleotides alone was able to inhibit translation, albeit at a more modest level than the 28 or 42 nucleobase antisense oligonucleotides. 
     PCT/US2007/068404 describes incorporation of chemically-modified high-affinity nucleotides into short antisense compounds about 8-16 nucleobases in length and that such compounds are useful in the reduction of target RNAs in animals with increased potency and improved therapeutic index. 
     In certain embodiments, antisense compounds targeted to a PCSK9 nucleic acid are short antisense compounds. In certain embodiments, such short antisense compounds are oligonucleotide compounds. In certain embodiments, such short antisense compounds are about 8 to 16, preferably 9 to 15, more preferably 9 to 14, more preferably 10 to 14 nucleotides in length and comprises a gap region flanked on each side by a wing, wherein each wing independently consists of 1 to 3 nucleotides. Preferred motifs include but are not limited to wing—deoxy gap—wing motifs selected from 3-10-3, 2-10-3, 2-10-2, 1-10-1, 2-8-2, 1-8-1, 3-6-3 or 1-6-1. 
     Antisense compounds targeted to a PCSK9 nucleic acid are synthesized in vitro and do not include antisense compositions of biological origin, or genetic vector constructs designed to direct the in vivo synthesis of antisense molecules. 
     In certain embodiments, an antisense compound is targeted to a region of a PCSK9 nucleic acid that does not contain a single nucleotide polymorphism (SNPs). In certain embodiments, an antisense compound is targeted to a region of a PCSK9 nucleic acid that does contain a single nucleotide polymorph (SNPs). A single nucleotide polymorphism refers to polymorphisms that are the result of a single nucleotide alteration or the existence of two or more alternative sequences which can be, for example, different allelic forms of a gene. A polymorphism may comprise one or more base changes including, for example, an insertion, a repeat, or a deletion. In certain embodiments, an antisense oligonucleotide targeted to a PCSK9 nucleic acid overlaps with a SNP at the following positions: 428, 432, 449, 996, 1011, 1044, 1317, 1565, 1617, 1618, 1671, 1711, 1722, 1836, 1911. In certain embodiments, the compounds provided herein that target a region of a PCSK9 nucleic acid that contains one or more SNPs will contain the appropriate base substitution, insertion, repeat or deletion such that the compound is fully complementary to the altered PCSK9 nucleic acid sequence. 
     A subgroup of these antisense compounds were selected for further characterization, based on the ability of the selected antisense compounds to inhibit PCSK9 expression selectively and effectively in cell culture assays, set forth in the Examples. The antisense compounds selected for further evaluation are listed in Table 1. The 5′ and 3′ boundaries of the PCSK9 target sequence are shown for each antisense compound, with reference to the nucleotide positions of SEQ ID NO: 1. 
     “Motif” in Table 1 refers to the use of chemically modified nucleosides at the 5′ and 3′ ends of the antisense compounds. In a “5-10-5” motif, for example, five chemical modified nucleosides at both the 5′ and 3′ ends flank ten unmodified nucleosides in the center of the antisense compound. As disclosed in more detail below, modified nucleosides may make the antisense compounds more resistant to nucleases, among other things, which generally improves the pharmacodynamic and pharmacokinetic properties of the antisense compounds when administered to an individual. 
     Table 1 further discloses the nucleobase sequence of the antisense compounds. In certain embodiments, an antisense compound has a nucleobase sequence that, when written in the 5′ to 3′ direction, comprises the reverse complement of the target segment of a target nucleic acid to which it is targeted. 
     
       
         
           
               
               
               
               
               
               
             
               
                 TABLE 1 
               
               
                   
               
               
                   
                 5′ 
                 3′ 
                   
                   
                 SEQ 
               
               
                 Isis 
                 Target 
                 Target 
                   
                   
                 ID 
               
               
                 No. 
                 Site 
                 Site 
                 Sequence 5′-3′ 
                 Motif 
                 NO 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 405881 
                 1005 
                 1024 
                 CACCCTTGGCCACGCCGGCA 
                 5-10-5 
                 250 
               
               
                   
               
               
                 399819 
                 2509 
                 2528 
                 CCCACTCAAGGGCCAGGCCA 
                 5-10-5 
                 65 
               
               
                   
               
               
                 395165 
                 1004 
                 1023 
                 ACCCTTGGCCACGCCGGCAT 
                 5-10-5 
                 28 
               
               
                   
               
               
                 405879 
                 1002 
                 1021 
                 CCTTGGCCACGCCGGCATCC 
                 5-10-5 
                 248 
               
               
                   
               
               
                 406008 
                 602 
                 621 
                 CTTGGTGAGGTATCCCCGGC 
                 5-10-5 
                 188 
               
               
                   
               
               
                 405891 
                 1567 
                 1586 
                 TCCTCAGGGAACCAGGCCTC 
                 5-10-5 
                 352 
               
               
                   
               
               
                 395186 
                 2100 
                 2119 
                 CTTTGCATTCCAGACCTGGG 
                 5-10-5 
                 60 
               
               
                   
               
               
                 405988 
                 1854 
                 1873 
                 GGCAGCACCTGGCAATGGCG 
                 5-10-5 
                 381 
               
               
                   
               
               
                 405994 
                 1928 
                 1947 
                 GCAGTGGACACGGGTCCCCA 
                 5-10-5 
                 400 
               
               
                   
               
               
                 406023 
                 787 
                 806 
                 TGGTATTCATCCGCCCGGTA 
                 5-10-5 
                 212 
               
               
                   
               
               
                 395187 
                 2310 
                 2329 
                 GGCAGCAGATGGCAACGGCT 
                 5-10-5 
                 62 
               
               
                   
               
               
                 395185 
                 1920 
                 1939 
                 CACGGGTCCCCATGCTGGCC 
                 5-10-5 
                 59 
               
               
                   
               
               
                 406033 
                 967 
                 986 
                 CCTGCCAGGTGGGTGCCATG 
                 5-10-5 
                 237 
               
               
                   
               
               
                 405923 
                 1295 
                 1314 
                 GGCATTGGTGGCCCCAACTG 
                 5-10-5 
                 288 
               
               
                   
               
               
                 399900 
                 1569 
                 1588 
                 GGTCCTCAGGGAACCAGGCC 
                 3-14-3 
                 50 
               
               
                   
               
               
                 405995 
                 1930 
                 1949 
                 TGGCAGTGGACACGGGTCCC 
                 5-10-5 
                 402 
               
               
                   
               
               
                 405991 
                 1922 
                 1941 
                 GACACGGGTCCCCATGCTGG 
                 5-10-5 
                 394 
               
               
                   
               
               
                 406005 
                 559 
                 578 
                 CGGGCAGTGCGCTCTGACTG 
                 5-10-5 
                 180 
               
               
                   
               
               
                 399793 
                 417 
                 436 
                 CCTCGGAACGCAAGGCTAGC 
                 5-10-5 
                 8 
               
               
                   
               
               
                 395152 
                 410 
                 429 
                 ACGCAAGGCTAGCACCAGCT 
                 5-10-5 
                 7 
               
               
                   
               
            
           
         
       
     
     Antisense Compound Motifs 
     In certain embodiments, antisense compounds targeted to a PCSK9 nucleic acid have chemically modified subunits arranged in patterns, or motifs, to confer to the antisense compounds properties such as enhanced the inhibitory activity, increased binding affinity for a target nucleic acid, or resistance to degradation by in vivo nucleases. 
     Chimeric antisense compounds typically contain at least one region modified so as to confer increased resistance to nuclease degradation, increased cellular uptake, increased binding affinity for the target nucleic acid, and/or increased inhibitory activity. A second region of a chimeric antisense compound may serve as a substrate for the cellular endonuclease RNase H, which cleaves the RNA strand of an RNA:DNA duplex. 
     Antisense compounds having a gapmer motif are considered chimeric antisense compounds. In a gapmer an internal position having a plurality of nucleotides that supports RNaseH cleavage is positioned between external regions having a plurality of nucleotides that are chemically distinct from the nucleosides of the internal region. In the case of an antisense oligonucleotide having a gapmer motif, the gap segment generally serves as the substrate for endonuclease cleavage, while the wing segments comprise modified nucleosides. The regions of a gapmer are differentiated by the types of sugar moieties comprising each distinct region. The types of sugar moieties that are used to differentiate the regions of a gapmer may in some embodiments include β-D-ribonucleosides, β-D-deoxyribonucleosides, 2′-modified nucleosides (such 2′-modified nucleosides may include 2′-MOE, and 2′-O—CH 3 , among others), and bicyclic sugar modified nucleosides (such bicyclic sugar modified nucleosides may include those having a 4′-(CH2)n-O-2′ bridge, where n=1 or n=2). In general, each distinct region comprises uniform sugar moieties. The wing-gap-wing motif is frequently described as “X-Y-Z”, where “X” represents the length of the 5′ wing region, “Y” represents the length of the gap region, and “Z” represents the length of the 3′ wing region. 
     In some embodiments, an antisense compound targeted to a PCSK9 nucleic acid has a gap-widened motif. In other embodiments, an antisense oligonucleotide targeted to a PCSK9 nucleic acid has a gap-widened motif. 
     The gap-widened antisense oligonucleotides described herein may have various wing-gap-wing motifs selected from: 1-16-1, 2-15-1, 1-15-2, 1-14-3, 3-14-1, 2-14-2, 1-13-4, 4-13-1, 2-13-3, 3-13-2, 1-12-5, 5-12-1, 2-12-4, 4-12-2, 3-12-3, 1-11-6, 6-11-1, 2-11-5, 5-11-2, 3-11-4, 4-11-3, 1-17-1, 2-16-1, 1-16-2, 1-15-3, 3-15-1, 2-15-2, 1-14-4, 4-14-1, 2-14-3, 3-14-2, 1-13-5, 5-13-1, 2- 13-4, 4-13-2, 3-13-3, 1-12-6, 6-12-1, 2-12-5, 5-12-2, 3-12-4, 4-12-3, 1-11-7, 7-11-1, 2-11-6, 6-11-2, 3-11-5, 5-11-3, 4-11-4, 1-18-1, 1-17-2, 2-17-1, 1-16-3, 1-16-3, 2-16-2, 1-15-4, 4-15-1, 2-15-3, 3-15-2, 1-14-5, 5-14-1, 2-14-4, 4-14-2, 3-14-3, 1-13-6, 6-13-1, 2-13-5, 5-13-2, 3-13-4, 4-13-3, 1-12-7, 7- 12-1, 2-12-6, 6-12-2, 3-12-5, 5-12-3, 4-12-4, 1-11-8, 8-11-1, 2-11-7, 7-11-2, 3-11-6, 6-11-3, 4-11-5, 5-11-4, 1-18-1, 1-17-2, 2-17-1, 1-16-3, 3-16-1, 2-16-2, 1-15-4, 4-15-1, 2-15-3, 3-15-2, 1-14-5, 2-14-4, 4 2, 3-14-3, 1-13-6, 6-13-1, 2-13-5, 5-13-2, 3-13-4, 4-13-3, 1-12-7, 7-12-1, 2-12-6, 6-12-2, 3- 12-5, 5-12-3, 4-12-4, 1-11-8, 8-11-1, 2-11-7, 7-11-2, 3-11-6, 6-11-3, 4-11-5, 5-11-4, 1-19-1, 1-18-2, 2-18-1, 1-17-3, 3-17-1, 2-17-2, 1-16-4, 4-16-1, 2-16-3, 3-16-2, 1-15-5, 2-15-4, 4-15-2, 3-15-3, 1-14-6, 6 1, 2-14-5, 5-14-2, 3-14-4, 4-14-3, 1-13-7, 7-13-1, 2-13-6, 6-13-2, 3-13-5, 5-13-3, 4-13-4, 1- 12-8, 8-12-1, 2-12-7, 7-12-2, 3-12-6, 6-12-3, 4-12-5, 5-12-4, 2-11-8, 8-11-2, 3-11-7, 7-11-3, 4-11-6, 6-11-4, 5-11-5, 1-20-1, 1-19-2, 2-19-1, 1-18-3, 3-18-1, 2-18-2, 1-17-4, 4-17-1, 2-17-3, 3-17-2, 1-16-5, 2-16-4, 4-16-2, 3-16-3, 1-15-6, 6-15-1, 2-15-5, 5-15-2, 3-15-4, 4-15-3, 1-14-7, 7-14-1, 2-14-6, 6- 14-2, 3-14-5, 5-14-3, 4-14-4, 1-13-8, 8-13-1, 2-13-7, 7-13-2, 3-13-6, 6-13-3, 4-13-5, 5-13-4, 2-12-8, 8-12-2, 3-12-7, 7-12-3, 4-12-6, 6-12-4, 5-12-5, 3-11-8, 8-11-3, 4-11-7, 7-11-4, 5-11-6, 6-11-5, 1-21-1, 1-20-2, 2-20-1, 1-20-3, 3-19-1, 2-19-2, 1-18-4, 4-18-1, 2-18-3, 3-18-2, 1-17-5, 2-17-4, 4-17-2, 3- 17-3, 1-16-6, 6-16-1, 2-16-5, 5-16-2, 3-16-4, 4-16-3, 1-15-7, 7-15-1, 2-15-6, 6-15-2, 3-15-5, 5-15-3, 4-15-4, 1-14-8, 8-14-1, 2-14-7, 7-14-2, 3-14-6, 6-14-3, 4-14-5, 5-14-4, 2-13-8, 8-13-2, 3-13-7, 7-13-3, 4-13-6, 6-13-4, 5-13-5, 1-12-10, 10-12-1, 2-12-9, 9-12-2, 3-12-8, 8-12-3, 4-12-7, 7-12-4, 5-12-6, 6-12-5, 4-11-8, 8-11-4, 5-11-7, 7-11-5, 6-11-6, 1-22-1, 1-21-2, 2-21-1, 1-21-3, 3-20-1, 2-20-2, 1-19-4, 4-19-1, 2-19-3, 3-19-2, 1-18-5, 2-18-4, 4-18-2, 3-18-3, 1-17-6, 6-17-1, 2-17-5, 5-17-2, 3-17-4, 4- 17-3, 1-16-7, 7-16-1, 2-16-6, 6-16-2, 3-16-5, 5-16-3, 4-16-4, 1-15-8, 8-15-1, 2-15-7, 7-15-2, 3-15-6, 6-15-3, 4-15-5, 5-15-4, 2-14-8, 8-14-2, 3-14-7, 7-14-3, 4-14-6, 6-14-4, 5-14-5, 3-13-8, 8-13-3, 4-13-7, 7-13-4, 5-13-6, 6-13-5, 4-12-8, 8-12-4, 5-12-7, 7-12-5, 6-12-6, 5-11-8, 8-11-5, 6-11-7, or 7-11-6. In certain preferred embodiments, a gap-widened motif includes, but is not limited to, 2-13-5, 3-14-3, 3-14-4 gapmer motif. 
     In one embodiment, a gap-widened antisense oligonucleotide targeted to a PCSK9 nucleic acid has a gap segment of fourteen 2′-deoxyribonucleotides positioned between wing segments of three chemically modified nucleosides. In one embodiment, the chemical modification comprises a 2′-sugar modification. In another embodiment, the chemical modification comprises a 2′-MOE sugar modification. 
     In one embodiment, antisense compounds targeted to a PCSK9 nucleic acid possess a 5-10-5 gapmer motif. 
     Target Nucleic Acids, Target Regions and Nucleotide Sequences 
     Nucleotide sequences that encode PCSK9 include, without limitation, the following: GENBANK® Accession No. NM_174936.2, first deposited with GENBANK® on Jun. 1, 2003, and incorporated herein as SEQ ID NO: 1; nucleotides 25475000 to 25504000 of GENBANK® Accession No. NT_032977.8, first deposited with GENBANK® on Feb. 26, 2006, and incorporated herein as SEQ ID NO: 2; and GENBANK® Accession No. AK124635.1, first deposited with GENBANK® on Sep. 8, 2003, and incorporated herein as SEQ ID NO: 3. 
     It is noted that some portions of these nucleotide sequences share identical sequence. For example, portions of SEQ ID NO: 1 are identical to portions of SEQ ID NO: 2; portions of SEQ ID NO: 1 are identical to portions of SEQ ID NO: 3; and portions of SEQ ID NO: 2 are identical to portions of SEQ ID NO: 3. Accordingly, antisense compounds targeted to SEQ ID NO: 1 may also target SEQ ID NO: 2 and/or SEQ ID NO: 3; antisense compounds targeted to SEQ ID NO: 2 may also target SEQ ID NO: 1 and/or SEQ ID NO: 3; and antisense compounds targeted to SEQ ID NO: 3 may also target SEQ ID NO: 1 and/or SEQ ID NO: 2. Examples of such antisense compounds are shown in the following tables. 
     In certain embodiments, antisense compounds target a PCSK9 nucleic acid having the sequence of GENBANK® Accession No. NM_174936.2, first deposited with GENBANK® on Jun. 1, 2003, and incorporated herein as SEQ ID NO: 1. In certain such embodiments, an antisense oligonucleotide targets SEQ ID NO: 1. In certain such embodiments, an antisense oligonucleotide that is targeted to SEQ ID NO: 1 is at least 90% complementary to SEQ ID NO: 1. In certain such embodiments, an antisense oligonucleotide that is targeted to SEQ ID NO: 1 is at least 95% complementary to SEQ ID NO: 1. In certain such embodiments, an antisense oligonucleotide that is targeted to SEQ ID NO: 1 is 100% complementary to SEQ ID NO: 1. In certain embodiments, an antisense oligonucleotide targeted to SEQ ID NO: 1 comprises a nucleotide sequence selected from the nucleotide sequences set forth in Table 2. 
     
       
         
           
               
             
               
                 TABLE 2 
               
             
            
               
                   
               
               
                 Nucleotide sequences targeted to NM_174936.2 
               
               
                 (SEQ ID NO: 1) 
               
            
           
           
               
               
               
               
            
               
                   
                 5′ Target 
                 3′ Target 
                   
               
               
                   
                 Site on 
                 Site on 
                   
               
               
                 SEQ ID 
                 SEQ ID 
                 SEQ ID 
                   
               
               
                 NO 
                 NO: 1 
                 NO: 1 
                 Sequence (5′-3′) 
               
               
                   
               
            
           
           
               
               
               
               
            
               
                 4 
                 135 
                 154 
                 GCGCGGAATCCTGGCTGGGA 
               
               
                   
               
               
                 5 
                 242 
                 261 
                 GAGGAGACCTAGAGGCCGTG 
               
               
                   
               
               
                 159 
                 294 
                 313 
                 GCCTGGAGCTGACGGTGCCC 
               
               
                   
               
               
                 160 
                 298 
                 317 
                 GACCGCCTGGAGCTGACGGT 
               
               
                   
               
               
                 6 
                 300 
                 319 
                 AGGACCGCCTGGAGCTGACG 
               
               
                   
               
               
                 162 
                 406 
                 425 
                 AAGGCTAGCACCAGCTCCTC 
               
               
                   
               
               
                 163 
                 407 
                 426 
                 CAAGGCTAGCACCAGCTCCT 
               
               
                   
               
               
                 164 
                 408 
                 427 
                 GCAAGGCTAGCACCAGCTCC 
               
               
                   
               
               
                 165 
                 409 
                 428 
                 CGCAAGGCTAGCACCAGCTC 
               
               
                   
               
               
                 7 
                 410 
                 429 
                 ACGCAAGGCTAGCACCAGCT 
               
               
                   
               
               
                 166 
                 411 
                 430 
                 AACGCAAGGCTAGCACCAGC 
               
               
                   
               
               
                 167 
                 412 
                 431 
                 GAACGCAAGGCTAGCACCAG 
               
               
                   
               
               
                 168 
                 413 
                 432 
                 GGAACGCAAGGCTAGCACCA 
               
               
                   
               
               
                 169 
                 414 
                 433 
                 CGGAACGCAAGGCTAGCACC 
               
               
                   
               
               
                 8 
                 417 
                 436 
                 CCTCGGAACGCAAGGCTAGC 
               
               
                   
               
               
                 170 
                 421 
                 440 
                 TCCTCCTCGGAACGCAAGGC 
               
               
                   
               
               
                 171 
                 446 
                 465 
                 GTGCTCGGGTGCTTCGGCCA 
               
               
                   
               
               
                 172 
                 466 
                 485 
                 TGGAAGGTGGCTGTGGTTCC 
               
               
                   
               
               
                 9 
                 480 
                 499 
                 CCTTGGCGCAGCGGTGGAAG 
               
               
                   
               
               
                 173 
                 482 
                 501 
                 ATCCTTGGCGCAGCGGTGGA 
               
               
                   
               
               
                 174 
                 484 
                 503 
                 GGATCCTTGGCGCAGCGGTG 
               
               
                   
               
               
                 175 
                 488 
                 507 
                 CCACGGATCCTTGGCGCAGC 
               
               
                   
               
               
                 176 
                 507 
                 526 
                 CGTAGGTGCCAGGCAACCTC 
               
               
                   
               
               
                 177 
                 545 
                 564 
                 TGACTGCGAGAGGTGGGTCT 
               
               
                   
               
               
                 178 
                 555 
                 574 
                 CAGTGCGCTCTGACTGCGAG 
               
               
                   
               
               
                 179 
                 557 
                 576 
                 GGCAGTGCGCTCTGACTGCG 
               
               
                   
               
               
                 180 
                 559 
                 578 
                 CGGGCAGTGCGCTCTGACTG 
               
               
                   
               
               
                 10 
                 561 
                 580 
                 GGCGGGCAGTGCGCTCTGAC 
               
               
                   
               
               
                 181 
                 562 
                 581 
                 CGGCGGGCAGTGCGCTCTGA 
               
               
                   
               
               
                 182 
                 591 
                 610 
                 ATCCCCGGCGGGCAGCCTGG 
               
               
                   
               
               
                 183 
                 595 
                 614 
                 AGGTATCCCCGGCGGGCAGC 
               
               
                   
               
               
                 184 
                 597 
                 616 
                 TGAGGTATCCCCGGCGGGCA 
               
               
                   
               
               
                 185 
                 598 
                 617 
                 GTGAGGTATCCCCGGCGGGC 
               
               
                   
               
               
                 186 
                 599 
                 618 
                 GGTGAGGTATCCCCGGCGGG 
               
               
                   
               
               
                 11 
                 600 
                 619 
                 TGGTGAGGTATCCCCGGCGG 
               
               
                   
               
               
                 187 
                 601 
                 620 
                 TTGGTGAGGTATCCCCGGCG 
               
               
                   
               
               
                 188 
                 602 
                 621 
                 CTTGGTGAGGTATCCCCGGC 
               
               
                   
               
               
                 189 
                 603 
                 622 
                 TCTTGGTGAGGTATCCCCGG 
               
               
                   
               
               
                 190 
                 604 
                 623 
                 ATCTTGGTGAGGTATCCCCG 
               
               
                   
               
               
                 191 
                 605 
                 624 
                 GATCTTGGTGAGGTATCCCC 
               
               
                   
               
               
                 12 
                 606 
                 625 
                 GGATCTTGGTGAGGTATCCC 
               
               
                   
               
               
                 192 
                 607 
                 626 
                 AGGATCTTGGTGAGGTATCC 
               
               
                   
               
               
                 193 
                 609 
                 628 
                 GCAGGATCTTGGTGAGGTAT 
               
               
                   
               
               
                 194 
                 611 
                 630 
                 ATGCAGGATCTTGGTGAGGT 
               
               
                   
               
               
                 195 
                 613 
                 632 
                 ACATGCAGGATCTTGGTGAG 
               
               
                   
               
               
                 13 
                 615 
                 634 
                 AGACATGCAGGATCTTGGTG 
               
               
                   
               
               
                 196 
                 617 
                 636 
                 GAAGACATGCAGGATCTTGG 
               
               
                   
               
               
                 14 
                 620 
                 639 
                 ATGGAAGACATGCAGGATCT 
               
               
                   
               
               
                 197 
                 628 
                 647 
                 AGAAGGCCATGGAAGACATG 
               
               
                   
               
               
                 198 
                 638 
                 657 
                 GAAGCCAGGAAGAAGGCCAT 
               
               
                   
               
               
                 15 
                 646 
                 665 
                 TTCACCAGGAAGCCAGGAAG 
               
               
                   
               
               
                 199 
                 648 
                 667 
                 TCTTCACCAGGAAGCCAGGA 
               
               
                   
               
               
                 16 
                 651 
                 670 
                 TCATCTTCACCAGGAAGCCA 
               
               
                   
               
               
                 200 
                 653 
                 672 
                 ACTCATCTTCACCAGGAAGC 
               
               
                   
               
               
                 201 
                 655 
                 674 
                 CCACTCATCTTCACCAGGAA 
               
               
                   
               
               
                 202 
                 657 
                 676 
                 CGCCACTCATCTTCACCAGG 
               
               
                   
               
               
                 203 
                 659 
                 678 
                 GTCGCCACTCATCTTCACCA 
               
               
                   
               
               
                 204 
                 661 
                 680 
                 AGGTCGCCACTCATCTTCAC 
               
               
                   
               
               
                 205 
                 663 
                 682 
                 GCAGGTCGCCACTCATCTTC 
               
               
                   
               
               
                 206 
                 665 
                 684 
                 CAGCAGGTCGCCACTCATCT 
               
               
                   
               
               
                 207 
                 667 
                 686 
                 TCCAGCAGGTCGCCACTCAT 
               
               
                   
               
               
                 208 
                 685 
                 704 
                 GGCAACTTCAAGGCCAGCTC 
               
               
                   
               
               
                 17 
                 705 
                 724 
                 CCTCGATGTAGTCGACATGG 
               
               
                   
               
               
                 209 
                 724 
                 743 
                 GCAAAGACAGAGGAGTCCTC 
               
               
                   
               
               
                 210 
                 782 
                 801 
                 TTCATCCGCCCGGTACCGTG 
               
               
                   
               
               
                 211 
                 784 
                 803 
                 TATTCATCCGCCCGGTACCG 
               
               
                   
               
               
                 18 
                 785 
                 804 
                 GTATTCATCCGCCCGGTACC 
               
               
                   
               
               
                 212 
                 787 
                 806 
                 TGGTATTCATCCGCCCGGTA 
               
               
                   
               
               
                 213 
                 789 
                 808 
                 GCTGGTATTCATCCGCCCGG 
               
               
                   
               
               
                 214 
                 791 
                 810 
                 GGGCTGGTATTCATCCGCCC 
               
               
                   
               
               
                 215 
                 821 
                 840 
                 ATACACCTCCACCAGGCTGC 
               
               
                   
               
               
                 216 
                 832 
                 851 
                 GTGTCTAGGAGATACACCTC 
               
               
                   
               
               
                 19 
                 835 
                 854 
                 CTGGTGTCTAGGAGATACAC 
               
               
                   
               
               
                 217 
                 837 
                 856 
                 TGCTGGTGTCTAGGAGATAC 
               
               
                   
               
               
                 20 
                 840 
                 859 
                 GTATGCTGGTGTCTAGGAGA 
               
               
                   
               
               
                 21 
                 860 
                 879 
                 GATTTCCCGGTGGTCACTCT 
               
               
                   
               
               
                 218 
                 862 
                 881 
                 TCGATTTCCCGGTGGTCACT 
               
               
                   
               
               
                 219 
                 863 
                 882 
                 CTCGATTTCCCGGTGGTCAC 
               
               
                   
               
               
                 220 
                 864 
                 883 
                 CCTCGATTTCCCGGTGGTCA 
               
               
                   
               
               
                 221 
                 865 
                 884 
                 CCCTCGATTTCCCGGTGGTC 
               
               
                   
               
               
                 22 
                 866 
                 885 
                 GCCCTCGATTTCCCGGTGGT 
               
               
                   
               
               
                 222 
                 867 
                 886 
                 TGCCCTCGATTTCCCGGTGG 
               
               
                   
               
               
                 223 
                 868 
                 887 
                 CTGCCCTCGATTTCCCGGTG 
               
               
                   
               
               
                 224 
                 869 
                 888 
                 CCTGCCCTCGATTTCCCGGT 
               
               
                   
               
               
                 225 
                 870 
                 889 
                 CCCTGCCCTCGATTTCCCGG 
               
               
                   
               
               
                 226 
                 874 
                 893 
                 ATGACCCTGCCCTCGATTTC 
               
               
                   
               
               
                 227 
                 876 
                 895 
                 CCATGACCCTGCCCTCGATT 
               
               
                   
               
               
                 228 
                 878 
                 897 
                 GACCATGACCCTGCCCTCGA 
               
               
                   
               
               
                 23 
                 880 
                 899 
                 GTGACCATGACCCTGCCCTC 
               
               
                   
               
               
                 229 
                 882 
                 901 
                 CGGTGACCATGACCCTGCCC 
               
               
                   
               
               
                 230 
                 884 
                 903 
                 GTCGGTGACCATGACCCTGC 
               
               
                   
               
               
                 231 
                 886 
                 905 
                 AAGTCGGTGACCATGACCCT 
               
               
                   
               
               
                 232 
                 888 
                 907 
                 CGAAGTCGGTGACCATGACC 
               
               
                   
               
               
                 24 
                 890 
                 909 
                 CTCGAAGTCGGTGACCATGA 
               
               
                   
               
               
                 233 
                 898 
                 917 
                 GGCACATTCTCGAAGTCGGT 
               
               
                   
               
               
                 25 
                 923 
                 942 
                 GTGGAAGCGGGTCCCGTCCT 
               
               
                   
               
               
                 234 
                 933 
                 952 
                 TGGCCTGTCTGTGGAAGCGG 
               
               
                   
               
               
                 235 
                 960 
                 979 
                 GGTGGGTGCCATGACTGTCA 
               
               
                   
               
               
                 236 
                 963 
                 982 
                 CCAGGTGGGTGCCATGACTG 
               
               
                   
               
               
                 237 
                 967 
                 986 
                 CCTGCCAGGTGGGTGCCATG 
               
               
                   
               
               
                 26 
                 970 
                 989 
                 ACCCCTGCCAGGTGGGTGCC 
               
               
                   
               
               
                 238 
                 972 
                 991 
                 CCACCCCTGCCAGGTGGGTG 
               
               
                   
               
               
                 27 
                 975 
                 994 
                 TGACCACCCCTGCCAGGTGG 
               
               
                   
               
               
                 239 
                 977 
                 996 
                 GCTGACCACCCCTGCCAGGT 
               
               
                   
               
               
                 240 
                 985 
                 1004 
                 TCCCGGCCGCTGACCACCCC 
               
               
                   
               
               
                 241 
                 989 
                 1008 
                 GGCATCCCGGCCGCTGACCA 
               
               
                   
               
               
                 242 
                 992 
                 1011 
                 GCCGGCATCCCGGCCGCTGA 
               
               
                   
               
               
                 243 
                 997 
                 1016 
                 GCCACGCCGGCATCCCGGCC 
               
               
                   
               
               
                 244 
                 998 
                 1017 
                 GGCCACGCCGGCATCCCGGC 
               
               
                   
               
               
                 245 
                 999 
                 1018 
                 TGGCCACGCCGGCATCCCGG 
               
               
                   
               
               
                 246 
                 1000 
                 1019 
                 TTGGCCACGCCGGCATCCCG 
               
               
                   
               
               
                 247 
                 1001 
                 1020 
                 CTTGGCCACGCCGGCATCCC 
               
               
                   
               
               
                 248 
                 1002 
                 1021 
                 CCTTGGCCACGCCGGCATCC 
               
               
                   
               
               
                 249 
                 1003 
                 1022 
                 CCCTTGGCCACGCCGGCATC 
               
               
                   
               
               
                 28 
                 1004 
                 1023 
                 ACCCTTGGCCACGCCGGCAT 
               
               
                   
               
               
                 447 
                 1004 
                 1023 
                 ACCCTTGGTCACGCCGGCAT 
               
               
                   
               
               
                 250 
                 1005 
                 1024 
                 CACCCTTGGCCACGCCGGCA 
               
               
                   
               
               
                 251 
                 1006 
                 1025 
                 GCACCCTTGGCCACGCCGGC 
               
               
                   
               
               
                 252 
                 1007 
                 1026 
                 GGCACCCTTGGCCACGCCGG 
               
               
                   
               
               
                 253 
                 1008 
                 1027 
                 TGGCACCCTTGGCCACGCCG 
               
               
                   
               
               
                 254 
                 1009 
                 1028 
                 CTGGCACCCTTGGCCACGCC 
               
               
                   
               
               
                 255 
                 1010 
                 1029 
                 GCTGGCACCCTTGGCCACGC 
               
               
                   
               
               
                 256 
                 1015 
                 1034 
                 CGCATGCTGGCACCCTTGGC 
               
               
                   
               
               
                 257 
                 1036 
                 1055 
                 CAGTTGAGCACGCGCAGGCT 
               
               
                   
               
               
                 258 
                 1038 
                 1057 
                 GGCAGTTGAGCACGCGCAGG 
               
               
                   
               
               
                 29 
                 1040 
                 1059 
                 TTGGCAGTTGAGCACGCGCA 
               
               
                   
               
               
                 259 
                 1042 
                 1061 
                 CCTTGGCAGTTGAGCACGCG 
               
               
                   
               
               
                 30 
                 1045 
                 1064 
                 TTCCCTTGGCAGTTGAGCAC 
               
               
                   
               
               
                 260 
                 1047 
                 1066 
                 CCTTCCCTTGGCAGTTGAGC 
               
               
                   
               
               
                 261 
                 1051 
                 1070 
                 GTGCCCTTCCCTTGGCAGTT 
               
               
                   
               
               
                 262 
                 1053 
                 1072 
                 CCGTGCCCTTCCCTTGGCAG 
               
               
                   
               
               
                 263 
                 1064 
                 1083 
                 GGTGCCGCTAACCGTGCCCT 
               
               
                   
               
               
                 264 
                 1076 
                 1095 
                 CAGGCCTATGAGGGTGCCGC 
               
               
                   
               
               
                 31 
                 1077 
                 1096 
                 CCAGGCCTATGAGGGTGCCG 
               
               
                   
               
               
                 458 
                 1079 
                 1092 
                 GCCTATGAGGGTGC 
               
               
                   
               
               
                 459 
                 1084 
                 1097 
                 TCCAGGCCTATGAG 
               
               
                   
               
               
                 265 
                 1088 
                 1107 
                 CCGAATAAACTCCAGGCCTA 
               
               
                   
               
               
                 266 
                 1096 
                 1115 
                 TGGCTTTTCCGAATAAACTC 
               
               
                   
               
               
                 32 
                 1098 
                 1117 
                 GCTGGCTTTTCCGAATAAAC 
               
               
                   
               
               
                 267 
                 1100 
                 1119 
                 CAGCTGGCTTTTCCGAATAA 
               
               
                   
               
               
                 268 
                 1102 
                 1121 
                 ACCAGCTGGCTTTTCCGAAT 
               
               
                   
               
               
                 269 
                 1104 
                 1123 
                 GGACCAGCTGGCTTTTCCGA 
               
               
                   
               
               
                 270 
                 1108 
                 1127 
                 GGCTGGACCAGCTGGCTTTT 
               
               
                   
               
               
                 271 
                 1119 
                 1138 
                 GTGGCCCCACAGGCTGGACC 
               
               
                   
               
               
                 272 
                 1132 
                 1151 
                 AGCAGCACCACCAGTGGCCC 
               
               
                   
               
               
                 273 
                 1154 
                 1173 
                 GCTGTACCCACCCGCCAGGG 
               
               
                   
               
               
                 274 
                 1200 
                 1219 
                 CGACCCCAGCCCTCGCCAGG 
               
               
                   
               
               
                 33 
                 1210 
                 1229 
                 GTGACCAGCACGACCCCAGC 
               
               
                   
               
               
                 275 
                 1212 
                 1231 
                 CGGTGACCAGCACGACCCCA 
               
               
                   
               
               
                 276 
                 1214 
                 1233 
                 AGCGGTGACCAGCACGACCC 
               
               
                   
               
               
                 277 
                 1216 
                 1235 
                 GCAGCGGTGACCAGCACGAC 
               
               
                   
               
               
                 278 
                 1218 
                 1237 
                 CGGCAGCGGTGACCAGCACG 
               
               
                   
               
               
                 279 
                 1219 
                 1238 
                 CCGGCAGCGGTGACCAGCAC 
               
               
                   
               
               
                 280 
                 1222 
                 1241 
                 TTGCCGGCAGCGGTGACCAG 
               
               
                   
               
               
                 281 
                 1224 
                 1243 
                 AGTTGCCGGCAGCGGTGACC 
               
               
                   
               
               
                 282 
                 1226 
                 1245 
                 GAAGTTGCCGGCAGCGGTGA 
               
               
                   
               
               
                 283 
                 1228 
                 1247 
                 CGGAAGTTGCCGGCAGCGGT 
               
               
                   
               
               
                 284 
                 1230 
                 1249 
                 CCCGGAAGTTGCCGGCAGCG 
               
               
                   
               
               
                 285 
                 1232 
                 1251 
                 GTCCCGGAAGTTGCCGGCAG 
               
               
                   
               
               
                 286 
                 1273 
                 1292 
                 ATGACCTCGGGAGCTGAGGC 
               
               
                   
               
               
                 287 
                 1283 
                 1302 
                 CCCAACTGTGATGACCTCGG 
               
               
                   
               
               
                 288 
                 1295 
                 1314 
                 GGCATTGGTGGCCCCAACTG 
               
               
                   
               
               
                 149 
                 1297 
                 1316 
                 TGGGCATTGGTGGCCCCAAC 
               
               
                   
               
               
                 289 
                 1305 
                 1324 
                 GCTGGTCTTGGGCATTGGTG 
               
               
                   
               
               
                 290 
                 1318 
                 1337 
                 CCCAGGGTCACCGGCTGGTC 
               
               
                   
               
               
                 291 
                 1320 
                 1339 
                 TCCCCAGGGTCACCGGCTGG 
               
               
                   
               
               
                 292 
                 1322 
                 1341 
                 AGTCCCCAGGGTCACCGGCT 
               
               
                   
               
               
                 293 
                 1324 
                 1343 
                 AAAGTCCCCAGGGTCACCGG 
               
               
                   
               
               
                 34 
                 1326 
                 1345 
                 CCAAAGTCCCCAGGGTCACC 
               
               
                   
               
               
                 294 
                 1328 
                 1347 
                 CCCCAAAGTCCCCAGGGTCA 
               
               
                   
               
               
                 128 
                 1330 
                 1349 
                 GTCCCCAAAGTCCCCAGGGT 
               
               
                   
               
               
                 295 
                 1333 
                 1352 
                 TTGGTCCCCAAAGTCCCCAG 
               
               
                   
               
               
                 35 
                 1335 
                 1354 
                 AGTTGGTCCCCAAAGTCCCC 
               
               
                   
               
               
                 296 
                 1337 
                 1356 
                 AAAGTTGGTCCCCAAAGTCC 
               
               
                   
               
               
                 36 
                 1340 
                 1359 
                 GCCAAAGTTGGTCCCCAAAG 
               
               
                   
               
               
                 297 
                 1342 
                 1361 
                 CGGCCAAAGTTGGTCCCCAA 
               
               
                   
               
               
                 298 
                 1344 
                 1363 
                 AGCGGCCAAAGTTGGTCCCC 
               
               
                   
               
               
                 299 
                 1346 
                 1365 
                 ACAGCGGCCAAAGTTGGTCC 
               
               
                   
               
               
                 300 
                 1348 
                 1367 
                 ACACAGCGGCCAAAGTTGGT 
               
               
                   
               
               
                 301 
                 1350 
                 1369 
                 CCACACAGCGGCCAAAGTTG 
               
               
                   
               
               
                 37 
                 1352 
                 1371 
                 GTCCACACAGCGGCCAAAGT 
               
               
                   
               
               
                 302 
                 1354 
                 1373 
                 AGGTCCACACAGCGGCCAAA 
               
               
                   
               
               
                 303 
                 1356 
                 1375 
                 AGAGGTCCACACAGCGGCCA 
               
               
                   
               
               
                 304 
                 1358 
                 1377 
                 AAAGAGGTCCACACAGCGGC 
               
               
                   
               
               
                 38 
                 1361 
                 1380 
                 GGCAAAGAGGTCCACACAGC 
               
               
                   
               
               
                 305 
                 1380 
                 1399 
                 CAATGATGTCCTCCCCTGGG 
               
               
                   
               
               
                 306 
                 1387 
                 1406 
                 GAGGCACCAATGATGTCCTC 
               
               
                   
               
               
                 39 
                 1389 
                 1408 
                 TGGAGGCACCAATGATGTCC 
               
               
                   
               
               
                 307 
                 1391 
                 1410 
                 GCTGGAGGCACCAATGATGT 
               
               
                   
               
               
                 308 
                 1393 
                 1412 
                 TCGCTGGAGGCACCAATGAT 
               
               
                   
               
               
                 309 
                 1395 
                 1414 
                 AGTCGCTGGAGGCACCAATG 
               
               
                   
               
               
                 310 
                 1397 
                 1416 
                 GCAGTCGCTGGAGGCACCAA 
               
               
                   
               
               
                 40 
                 1400 
                 1419 
                 GCTGCAGTCGCTGGAGGCAC 
               
               
                   
               
               
                 311 
                 1402 
                 1421 
                 GTGCTGCAGTCGCTGGAGGC 
               
               
                   
               
               
                 312 
                 1404 
                 1423 
                 AGGTGCTGCAGTCGCTGGAG 
               
               
                   
               
               
                 313 
                 1406 
                 1425 
                 GCAGGTGCTGCAGTCGCTGG 
               
               
                   
               
               
                 314 
                 1407 
                 1426 
                 AGCAGGTGCTGCAGTCGCTG 
               
               
                   
               
               
                 315 
                 1409 
                 1428 
                 AAAGCAGGTGCTGCAGTCGC 
               
               
                   
               
               
                 41 
                 1411 
                 1430 
                 ACAAAGCAGGTGCTGCAGTC 
               
               
                   
               
               
                 316 
                 1413 
                 1432 
                 ACACAAAGCAGGTGCTGCAG 
               
               
                   
               
               
                 317 
                 1415 
                 1434 
                 TGACACAAAGCAGGTGCTGC 
               
               
                   
               
               
                 318 
                 1425 
                 1444 
                 TCCCACTCTGTGACACAAAG 
               
               
                   
               
               
                 101 
                 1465 
                 1484 
                 ATGGCTGCAATGCCAGCCAC 
               
               
                   
               
               
                 319 
                 1467 
                 1486 
                 TCATGGCTGCAATGCCAGCC 
               
               
                   
               
               
                 42 
                 1470 
                 1489 
                 GCATCATGGCTGCAATGCCA 
               
               
                   
               
               
                 320 
                 1472 
                 1491 
                 CAGCATCATGGCTGCAATGC 
               
               
                   
               
               
                 321 
                 1474 
                 1493 
                 GACAGCATCATGGCTGCAAT 
               
               
                   
               
               
                 322 
                 1476 
                 1495 
                 CAGACAGCATCATGGCTGCA 
               
               
                   
               
               
                 43 
                 1478 
                 1497 
                 GGCAGACAGCATCATGGCTG 
               
               
                   
               
               
                 323 
                 1480 
                 1499 
                 TCGGCAGACAGCATCATGGC 
               
               
                   
               
               
                 324 
                 1482 
                 1501 
                 GCTCGGCAGACAGCATCATG 
               
               
                   
               
               
                 325 
                 1484 
                 1503 
                 CGGCTCGGCAGACAGCATCA 
               
               
                   
               
               
                 326 
                 1486 
                 1505 
                 TCCGGCTCGGCAGACAGCAT 
               
               
                   
               
               
                 327 
                 1500 
                 1519 
                 CGGCCAGGGTGAGCTCCGGC 
               
               
                   
               
               
                 328 
                 1513 
                 1532 
                 CTCTGCCTCAACTCGGCCAG 
               
               
                   
               
               
                 329 
                 1515 
                 1534 
                 GTCTCTGCCTCAACTCGGCC 
               
               
                   
               
               
                 330 
                 1517 
                 1536 
                 CAGTCTCTGCCTCAACTCGG 
               
               
                   
               
               
                 331 
                 1519 
                 1538 
                 ATCAGTCTCTGCCTCAACTC 
               
               
                   
               
               
                 332 
                 1521 
                 1540 
                 GGATCAGTCTCTGCCTCAAC 
               
               
                   
               
               
                 333 
                 1523 
                 1542 
                 GTGGATCAGTCTCTGCCTCA 
               
               
                   
               
               
                 334 
                 1525 
                 1544 
                 AAGTGGATCAGTCTCTGCCT 
               
               
                   
               
               
                 44 
                 1526 
                 1545 
                 GAAGTGGATCAGTCTCTGCC 
               
               
                   
               
               
                 335 
                 1528 
                 1547 
                 GAGAAGTGGATCAGTCTCTG 
               
               
                   
               
               
                 336 
                 1530 
                 1549 
                 CAGAGAAGTGGATCAGTCTC 
               
               
                   
               
               
                 337 
                 1532 
                 1551 
                 GGCAGAGAAGTGGATCAGTC 
               
               
                   
               
               
                 45 
                 1534 
                 1553 
                 TTGGCAGAGAAGTGGATCAG 
               
               
                   
               
               
                 338 
                 1536 
                 1555 
                 CTTTGGCAGAGAAGTGGATC 
               
               
                   
               
               
                 46 
                 1539 
                 1558 
                 CATCTTTGGCAGAGAAGTGG 
               
               
                   
               
               
                 339 
                 1541 
                 1560 
                 GACATCTTTGGCAGAGAAGT 
               
               
                   
               
               
                 340 
                 1543 
                 1562 
                 ATGACATCTTTGGCAGAGAA 
               
               
                   
               
               
                 47 
                 1545 
                 1564 
                 TGATGACATCTTTGGCAGAG 
               
               
                   
               
               
                 341 
                 1547 
                 1566 
                 ATTGATGACATCTTTGGCAG 
               
               
                   
               
               
                 342 
                 1549 
                 1568 
                 TCATTGATGACATCTTTGGC 
               
               
                   
               
               
                 48 
                 1552 
                 1571 
                 GCCTCATTGATGACATCTTT 
               
               
                   
               
               
                 343 
                 1554 
                 1573 
                 AGGCCTCATTGATGACATCT 
               
               
                   
               
               
                 344 
                 1556 
                 1575 
                 CCAGGCCTCATTGATGACAT 
               
               
                   
               
               
                 345 
                 1558 
                 1577 
                 AACCAGGCCTCATTGATGAC 
               
               
                   
               
               
                 346 
                 1560 
                 1579 
                 GGAACCAGGCCTCATTGATG 
               
               
                   
               
               
                 347 
                 1561 
                 1580 
                 GGGAACCAGGCCTCATTGAT 
               
               
                   
               
               
                 348 
                 1562 
                 1581 
                 AGGGAACCAGGCCTCATTGA 
               
               
                   
               
               
                 349 
                 1563 
                 1582 
                 CAGGGAACCAGGCCTCATTG 
               
               
                   
               
               
                 49 
                 1564 
                 1583 
                 TCAGGGAACCAGGCCTCATT 
               
               
                   
               
               
                 49 
                 1564 
                 1583 
                 TCAGGGAACCAGGCCTCATT 
               
               
                   
               
               
                 350 
                 1565 
                 1584 
                 CTCAGGGAACCAGGCCTCAT 
               
               
                   
               
               
                 351 
                 1566 
                 1585 
                 CCTCAGGGAACCAGGCCTCA 
               
               
                   
               
               
                 352 
                 1567 
                 1586 
                 TCCTCAGGGAACCAGGCCTC 
               
               
                   
               
               
                 353 
                 1568 
                 1587 
                 GTCCTCAGGGAACCAGGCCT 
               
               
                   
               
               
                 50 
                 1569 
                 1588 
                 GGTCCTCAGGGAACCAGGCC 
               
               
                   
               
               
                 354 
                 1570 
                 1589 
                 TGGTCCTCAGGGAACCAGGC 
               
               
                   
               
               
                 355 
                 1571 
                 1590 
                 CTGGTCCTCAGGGAACCAGG 
               
               
                   
               
               
                 356 
                 1572 
                 1591 
                 GCTGGTCCTCAGGGAACCAG 
               
               
                   
               
               
                 357 
                 1573 
                 1592 
                 CGCTGGTCCTCAGGGAACCA 
               
               
                   
               
               
                 87 
                 1576 
                 1595 
                 ACCCGCTGGTCCTCAGGGAA 
               
               
                   
               
               
                 358 
                 1578 
                 1597 
                 GTACCCGCTGGTCCTCAGGG 
               
               
                   
               
               
                 359 
                 1580 
                 1599 
                 CAGTACCCGCTGGTCCTCAG 
               
               
                   
               
               
                 51 
                 1583 
                 1602 
                 GGTCAGTACCCGCTGGTCCT 
               
               
                   
               
               
                 119 
                 1605 
                 1624 
                 GCAGGGCGGCCACCAGGTTG 
               
               
                   
               
               
                 360 
                 1628 
                 1647 
                 ACCTGCCCCATGGGTGCTGG 
               
               
                   
               
               
                 52 
                 1640 
                 1659 
                 AAACAGCTGCCAACCTGCCC 
               
               
                   
               
               
                 361 
                 1642 
                 1661 
                 CAAAACAGCTGCCAACCTGC 
               
               
                   
               
               
                 53 
                 1645 
                 1664 
                 CTGCAAAACAGCTGCCAACC 
               
               
                   
               
               
                 362 
                 1647 
                 1666 
                 TCCTGCAAAACAGCTGCCAA 
               
               
                   
               
               
                 363 
                 1649 
                 1668 
                 AGTCCTGCAAAACAGCTGCC 
               
               
                   
               
               
                 364 
                 1660 
                 1679 
                 GCTGACCATACAGTCCTGCA 
               
               
                   
               
               
                 365 
                 1672 
                 1691 
                 GGCCCCGAGTGTGCTGACCA 
               
               
                   
               
               
                 54 
                 1675 
                 1694 
                 GTAGGCCCCGAGTGTGCTGA 
               
               
                   
               
               
                 366 
                 1677 
                 1696 
                 GTGTAGGCCCCGAGTGTGCT 
               
               
                   
               
               
                 367 
                 1679 
                 1698 
                 CCGTGTAGGCCCCGAGTGTG 
               
               
                   
               
               
                 368 
                 1681 
                 1700 
                 ATCCGTGTAGGCCCCGAGTG 
               
               
                   
               
               
                 369 
                 1683 
                 1702 
                 CCATCCGTGTAGGCCCCGAG 
               
               
                   
               
               
                 370 
                 1685 
                 1704 
                 GGCCATCCGTGTAGGCCCCG 
               
               
                   
               
               
                 371 
                 1687 
                 1706 
                 GTGGCCATCCGTGTAGGCCC 
               
               
                   
               
               
                 372 
                 1735 
                 1754 
                 CTGGAGCAGCTCAGCAGCTC 
               
               
                   
               
               
                 460 
                 1735 
                 1748 
                 CAGCTCAGCAGCTC 
               
               
                   
               
               
                 373 
                 1737 
                 1756 
                 AACTGGAGCAGCTCAGCAGC 
               
               
                   
               
               
                 55 
                 1740 
                 1759 
                 AGAAACTGGAGCAGCTCAGC 
               
               
                   
               
               
                 374 
                 1742 
                 1761 
                 GGAGAAACTGGAGCAGCTCA 
               
               
                   
               
               
                 375 
                 1744 
                 1763 
                 CTGGAGAAACTGGAGCAGCT 
               
               
                   
               
               
                 56 
                 1746 
                 1765 
                 TCCTGGAGAAACTGGAGCAG 
               
               
                   
               
               
                 57 
                 1812 
                 1831 
                 CGTTGTGGGCCCGGCAGACC 
               
               
                   
               
               
                 376 
                 1849 
                 1868 
                 CACCTGGCAATGGCGTAGAC 
               
               
                   
               
               
                 377 
                 1850 
                 1869 
                 GCACCTGGCAATGGCGTAGA 
               
               
                   
               
               
                 378 
                 1851 
                 1870 
                 AGCACCTGGCAATGGCGTAG 
               
               
                   
               
               
                 379 
                 1852 
                 1871 
                 CAGCACCTGGCAATGGCGTA 
               
               
                   
               
               
                 380 
                 1853 
                 1872 
                 GCAGCACCTGGCAATGGCGT 
               
               
                   
               
               
                 381 
                 1854 
                 1873 
                 GGCAGCACCTGGCAATGGCG 
               
               
                   
               
               
                 382 
                 1855 
                 1874 
                 AGGCAGCACCTGGCAATGGC 
               
               
                   
               
               
                 383 
                 1856 
                 1875 
                 CAGGCAGCACCTGGCAATGG 
               
               
                   
               
               
                 384 
                 1857 
                 1876 
                 GCAGGCAGCACCTGGCAATG 
               
               
                   
               
               
                 58 
                 1858 
                 1877 
                 AGCAGGCAGCACCTGGCAAT 
               
               
                   
               
               
                 385 
                 1859 
                 1878 
                 TAGCAGGCAGCACCTGGCAA 
               
               
                   
               
               
                 386 
                 1860 
                 1879 
                 GTAGCAGGCAGCACCTGGCA 
               
               
                   
               
               
                 387 
                 1905 
                 1924 
                 TGGCCTCAGCTGGTGGAGCT 
               
               
                   
               
               
                 388 
                 1915 
                 1934 
                 GTCCCCATGCTGGCCTCAGC 
               
               
                   
               
               
                 389 
                 1916 
                 1935 
                 GGTCCCCATGCTGGCCTCAG 
               
               
                   
               
               
                 390 
                 1917 
                 1936 
                 GGGTCCCCATGCTGGCCTCA 
               
               
                   
               
               
                 391 
                 1918 
                 1937 
                 CGGGTCCCCATGCTGGCCTC 
               
               
                   
               
               
                 392 
                 1919 
                 1938 
                 ACGGGTCCCCATGCTGGCCT 
               
               
                   
               
               
                 59 
                 1920 
                 1939 
                 CACGGGTCCCCATGCTGGCC 
               
               
                   
               
               
                 59 
                 1920 
                 1939 
                 CACGGGTCCCCATGCTGGCC 
               
               
                   
               
               
                 393 
                 1921 
                 1940 
                 ACACGGGTCCCCATGCTGGC 
               
               
                   
               
               
                 394 
                 1922 
                 1941 
                 GACACGGGTCCCCATGCTGG 
               
               
                   
               
               
                 395 
                 1923 
                 1942 
                 GGACACGGGTCCCCATGCTG 
               
               
                   
               
               
                 396 
                 1924 
                 1943 
                 TGGACACGGGTCCCCATGCT 
               
               
                   
               
               
                 397 
                 1925 
                 1944 
                 GTGGACACGGGTCCCCATGC 
               
               
                   
               
               
                 398 
                 1926 
                 1945 
                 AGTGGACACGGGTCCCCATG 
               
               
                   
               
               
                 399 
                 1927 
                 1946 
                 CAGTGGACACGGGTCCCCAT 
               
               
                   
               
               
                 400 
                 1928 
                 1947 
                 GCAGTGGACACGGGTCCCCA 
               
               
                   
               
               
                 401 
                 1929 
                 1948 
                 GGCAGTGGACACGGGTCCCC 
               
               
                   
               
               
                 402 
                 1930 
                 1949 
                 TGGCAGTGGACACGGGTCCC 
               
               
                   
               
               
                 403 
                 1931 
                 1950 
                 GTGGCAGTGGACACGGGTCC 
               
               
                   
               
               
                 404 
                 1932 
                 1951 
                 GGTGGCAGTGGACACGGGTC 
               
               
                   
               
               
                 405 
                 1933 
                 1952 
                 TGGTGGCAGTGGACACGGGT 
               
               
                   
               
               
                 406 
                 1936 
                 1955 
                 TGTTGGTGGCAGTGGACACG 
               
               
                   
               
               
                 407 
                 1962 
                 1981 
                 AGCTGCAGCCTGTGAGGACG 
               
               
                   
               
               
                 408 
                 1990 
                 2009 
                 GTGCCAAGGTCCTCCACCTC 
               
               
                   
               
               
                 409 
                 2010 
                 2029 
                 TCAGCACAGGCGGCTTGTGG 
               
               
                   
               
               
                 410 
                 2040 
                 2059 
                 CCACGCACTGGTTGGGCTGA 
               
               
                   
               
               
                 60 
                 2100 
                 2119 
                 CTTTGCATTCCAGACCTGGG 
               
               
                   
               
               
                 411 
                 2101 
                 2120 
                 ACTTTGCATTCCAGACCTGG 
               
               
                   
               
               
                 412 
                 2102 
                 2121 
                 GACTTTGCATTCCAGACCTG 
               
               
                   
               
               
                 413 
                 2103 
                 2122 
                 TGACTTTGCATTCCAGACCT 
               
               
                   
               
               
                 414 
                 2104 
                 2123 
                 TTGACTTTGCATTCCAGACC 
               
               
                   
               
               
                 61 
                 2105 
                 2124 
                 CTTGACTTTGCATTCCAGAC 
               
               
                   
               
               
                 415 
                 2107 
                 2126 
                 TCCTTGACTTTGCATTCCAG 
               
               
                   
               
               
                 416 
                 2120 
                 2139 
                 CGGGATTCCATGCTCCTTGA 
               
               
                   
               
               
                 417 
                 2150 
                 2169 
                 GCAGGCCACGGTCACCTGCT 
               
               
                   
               
               
                 418 
                 2187 
                 2206 
                 GGAGGGCACTGCAGCCAGTC 
               
               
                   
               
               
                 419 
                 2305 
                 2324 
                 CAGATGGCAACGGCTGTCAC 
               
               
                   
               
               
                 420 
                 2306 
                 2325 
                 GCAGATGGCAACGGCTGTCA 
               
               
                   
               
               
                 421 
                 2307 
                 2326 
                 AGCAGATGGCAACGGCTGTC 
               
               
                   
               
               
                 422 
                 2308 
                 2327 
                 CAGCAGATGGCAACGGCTGT 
               
               
                   
               
               
                 423 
                 2309 
                 2328 
                 GCAGCAGATGGCAACGGCTG 
               
               
                   
               
               
                 62 
                 2310 
                 2329 
                 GGCAGCAGATGGCAACGGCT 
               
               
                   
               
               
                 424 
                 2311 
                 2330 
                 CGGCAGCAGATGGCAACGGC 
               
               
                   
               
               
                 425 
                 2312 
                 2331 
                 CCGGCAGCAGATGGCAACGG 
               
               
                   
               
               
                 426 
                 2313 
                 2332 
                 TCCGGCAGCAGATGGCAACG 
               
               
                   
               
               
                 427 
                 2314 
                 2333 
                 CTCCGGCAGCAGATGGCAAC 
               
               
                   
               
               
                 428 
                 2315 
                 2334 
                 GCTCCGGCAGCAGATGGCAA 
               
               
                   
               
               
                 429 
                 2325 
                 2344 
                 CCAGGTGCCGGCTCCGGCAG 
               
               
                   
               
               
                 430 
                 2335 
                 2354 
                 GAGGCCTGCGCCAGGTGCCG 
               
               
                   
               
               
                 154 
                 2410 
                 2429 
                 TTTTAAAGCTCAGCCCCAGC 
               
               
                   
               
               
                 63 
                 2415 
                 2434 
                 AACCATTTTAAAGCTCAGCC 
               
               
                   
               
               
                 64 
                 2504 
                 2523 
                 TCAAGGGCCAGGCCAGCAGC 
               
               
                   
               
               
                 65 
                 2509 
                 2528 
                 CCCACTCAAGGGCCAGGCCA 
               
               
                   
               
               
                 122 
                 2582 
                 2601 
                 GGAGGGAGCTTCCTGGCACC 
               
               
                   
               
               
                 66 
                 2597 
                 2616 
                 ATGCCCCACAGTGAGGGAGG 
               
               
                   
               
               
                 67 
                 2606 
                 2625 
                 AATGGTGAAATGCCCCACAG 
               
               
                   
               
               
                 153 
                 2649 
                 2668 
                 TTGGGAGCAGCTGGCAGCAC 
               
               
                   
               
               
                 68 
                 2750 
                 2769 
                 CATGGGAAGAATCCTGCCTC 
               
               
                   
               
               
                 431 
                 2828 
                 2847 
                 ATGAGGGCCATCAGCACCTT 
               
               
                   
               
               
                 432 
                 2829 
                 2848 
                 GATGAGGGCCATCAGCACCT 
               
               
                   
               
               
                 433 
                 2830 
                 2849 
                 AGATGAGGGCCATCAGCACC 
               
               
                   
               
               
                 434 
                 2831 
                 2850 
                 GAGATGAGGGCCATCAGCAC 
               
               
                   
               
               
                 69 
                 2832 
                 2851 
                 GGAGATGAGGGCCATCAGCA 
               
               
                   
               
               
                 435 
                 2833 
                 2852 
                 TGGAGATGAGGGCCATCAGC 
               
               
                   
               
               
                 436 
                 2834 
                 2853 
                 CTGGAGATGAGGGCCATCAG 
               
               
                   
               
               
                 437 
                 2835 
                 2854 
                 GCTGGAGATGAGGGCCATCA 
               
               
                   
               
               
                 438 
                 2836 
                 2855 
                 AGCTGGAGATGAGGGCCATC 
               
               
                   
               
               
                 461 
                 2877 
                 2890 
                 TTAATCAGGGAGCC 
               
               
                   
               
               
                 70 
                 2900 
                 2919 
                 TAGATGCCATCCAGAAAGCT 
               
               
                   
               
               
                 439 
                 2902 
                 2921 
                 GCTAGATGCCATCCAGAAAG 
               
               
                   
               
               
                 440 
                 2903 
                 2922 
                 GGCTAGATGCCATCCAGAAA 
               
               
                   
               
               
                 441 
                 2904 
                 2923 
                 TGGCTAGATGCCATCCAGAA 
               
               
                   
               
               
                 442 
                 2905 
                 2924 
                 CTGGCTAGATGCCATCCAGA 
               
               
                   
               
               
                 71 
                 2906 
                 2925 
                 TCTGGCTAGATGCCATCCAG 
               
               
                   
               
               
                 443 
                 2907 
                 2926 
                 CTCTGGCTAGATGCCATCCA 
               
               
                   
               
               
                 444 
                 2908 
                 2927 
                 CCTCTGGCTAGATGCCATCC 
               
               
                   
               
               
                 445 
                 2909 
                 2928 
                 GCCTCTGGCTAGATGCCATC 
               
               
                   
               
               
                 446 
                 2910 
                 2929 
                 AGCCTCTGGCTAGATGCCAT 
               
               
                   
               
               
                 72 
                 2983 
                 3002 
                 GGCATAGAGCAGAGTAAAGG 
               
               
                   
               
               
                 73 
                 2988 
                 3007 
                 AGCCTGGCATAGAGCAGAGT 
               
               
                   
               
               
                 135 
                 2994 
                 3013 
                 TAGCACAGCCTGGCATAGAG 
               
               
                   
               
               
                 112 
                 3227 
                 3246 
                 GAAGAGGCTTGGCTTCAGAG 
               
               
                   
               
               
                 74 
                 3233 
                 3252 
                 AAGTAAGAAGAGGCTTGGCT 
               
               
                   
               
               
                 75 
                 3437 
                 3456 
                 GCTCAAGGAGGGACAGTTGT 
               
               
                   
               
               
                 76 
                 3472 
                 3491 
                 AAAGATAAATGTCTGCTTGC 
               
               
                   
               
               
                 77 
                 3477 
                 3496 
                 ACCCAAAAGATAAATGTCTG 
               
               
                   
               
               
                 78 
                 3543 
                 3562 
                 TCTTCAAGTTACAAAAGCAA 
               
               
                   
               
               
                 99 
                 3550 
                 3569 
                 ATAAATATCTTCAAGTTACA 
               
               
                   
               
            
           
         
       
     
     In certain embodiments, gapmer antisense compounds are targeted to a PCSK9 nucleic acid. In certain such embodiments, gapmer antisense compounds are targeted to SEQ ID NO: 1. In certain such embodiments, the nucleotide sequences illustrated in Table 2 have a 5-10-5 gapmer motif. Table 3 illustrates gapmer antisense compounds targeted to SEQ ID NO: 1, having a 5-10-5 motif, where the gap segment comprises 2′-deoxynucleotides and each wing segment comprises nucleotides comprising a 2′-O-methoxyethyl sugar modification. Internucleoside linkages are phosphorthioate, and cytidines are 5-methylcytidines. 
     
       
         
           
               
             
               
                 TABLE 3 
               
             
            
               
                   
               
               
                 Gapmer antisense compounds having a 5-10-5 motif targeted to SEQ ID NO: 1 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                   
                   
                 5′ 
                 3′ 
                   
                   
               
               
                   
                   
                   
                 Target 
                 Target 
                   
                   
               
               
                   
                   
                 SEQ 
                 Site on 
                 Site on 
                   
                   
               
               
                   
                   
                 ID 
                 SEQ ID 
                 SEQ ID 
                   
                   
               
               
                 Isis No 
                 Motif 
                 NO 
                 NO: 1 
                 NO: 1 
                 Mismatches 
                 Sequence (5′-3′) 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                 395149 
                 5-10-5 
                 4 
                 135 
                 154 
                 0 
                 GCGCGGAATCCTGGCTGGGA 
               
               
                   
               
               
                 395150 
                 5-10-5 
                 5 
                 242 
                 261 
                 0 
                 GAGGAGACCTAGAGGCCGTG 
               
               
                   
               
               
                 395151 
                 5-10-5 
                 6 
                 300 
                 319 
                 0 
                 AGGACCGCCTGGAGCTGACG 
               
               
                   
               
               
                 395152 
                 5-10-5 
                 7 
                 410 
                 429 
                 0 
                 ACGCAAGGCTAGCACCAGCT 
               
               
                   
               
               
                 399793 
                 5-10-5 
                 8 
                 417 
                 436 
                 0 
                 CCTCGGAACGCAAGGCTAGC 
               
               
                   
               
               
                 395153 
                 5-10-5 
                 9 
                 480 
                 499 
                 0 
                 CCTTGGCGCAGCGGTGGAAG 
               
               
                   
               
               
                 395154 
                 5-10-5 
                 10 
                 561 
                 580 
                 0 
                 GGCGGGCAGTGCGCTCTGAC 
               
               
                   
               
               
                 395155 
                 5-10-5 
                 11 
                 600 
                 619 
                 0 
                 TGGTGAGGTATCCCCGGCGG 
               
               
                   
               
               
                 399794 
                 5-10-5 
                 12 
                 606 
                 625 
                 0 
                 GGATCTTGGTGAGGTATCCC 
               
               
                   
               
               
                 399795 
                 5-10-5 
                 13 
                 615 
                 634 
                 0 
                 AGACATGCAGGATCTTGGTG 
               
               
                   
               
               
                 395156 
                 5-10-5 
                 14 
                 620 
                 639 
                 0 
                 ATGGAAGACATGCAGGATCT 
               
               
                   
               
               
                 395157 
                 5-10-5 
                 15 
                 646 
                 665 
                 0 
                 TTCACCAGGAAGCCAGGAAG 
               
               
                   
               
               
                 399796 
                 5-10-5 
                 16 
                 651 
                 670 
                 0 
                 TCATCTTCACCAGGAAGCCA 
               
               
                   
               
               
                 395158 
                 5-10-5 
                 17 
                 705 
                 724 
                 0 
                 CCTCGATGTAGTCGACATGG 
               
               
                   
               
               
                 395159 
                 5-10-5 
                 18 
                 785 
                 804 
                 0 
                 GTATTCATCCGCCCGGTACC 
               
               
                   
               
               
                 395160 
                 5-10-5 
                 19 
                 835 
                 854 
                 0 
                 CTGGTGTCTAGGAGATACAC 
               
               
                   
               
               
                 399797 
                 5-10-5 
                 20 
                 840 
                 859 
                 0 
                 GTATGCTGGTGTCTAGGAGA 
               
               
                   
               
               
                 395161 
                 5-10-5 
                 21 
                 860 
                 879 
                 0 
                 GATTTCCCGGTGGTCACTCT 
               
               
                   
               
               
                 399798 
                 5-10-5 
                 22 
                 866 
                 885 
                 0 
                 GCCCTCGATTTCCCGGTGGT 
               
               
                   
               
               
                 399799 
                 5-10-5 
                 23 
                 880 
                 899 
                 0 
                 GTGACCATGACCCTGCCCTC 
               
               
                   
               
               
                 395162 
                 5-10-5 
                 24 
                 890 
                 909 
                 0 
                 CTCGAAGTCGGTGACCATGA 
               
               
                   
               
               
                 395163 
                 5-10-5 
                 25 
                 923 
                 942 
                 0 
                 GTGGAAGCGGGTCCCGTCCT 
               
               
                   
               
               
                 395164 
                 5-10-5 
                 26 
                 970 
                 989 
                 0 
                 ACCCCTGCCAGGTGGGTGCC 
               
               
                   
               
               
                 399800 
                 5-10-5 
                 27 
                 975 
                 994 
                 0 
                 TGACCACCCCTGCCAGGTGG 
               
               
                   
               
               
                 395165 
                 5-10-5 
                 28 
                 1004 
                 1023 
                 0 
                 ACCCTTGGCCACGCCGGCAT 
               
               
                   
               
               
                 395166 
                 5-10-5 
                 29 
                 1040 
                 1059 
                 0 
                 TTGGCAGTTGAGCACGCGCA 
               
               
                   
               
               
                 399801 
                 5-10-5 
                 30 
                 1045 
                 1064 
                 0 
                 TTCCCTTGGCAGTTGAGCAC 
               
               
                   
               
               
                 395167 
                 5-10-5 
                 31 
                 1077 
                 1096 
                 0 
                 CCAGGCCTATGAGGGTGCCG 
               
               
                   
               
               
                 395168 
                 5-10-5 
                 32 
                 1098 
                 1117 
                 0 
                 GCTGGCTTTTCCGAATAAAC 
               
               
                   
               
               
                 395169 
                 5-10-5 
                 33 
                 1210 
                 1229 
                 0 
                 GTGACCAGCACGACCCCAGC 
               
               
                   
               
               
                 395170 
                 5-10-5 
                 149 
                 1297 
                 1316 
                 0 
                 TGGGCATTGGTGGCCCCAAC 
               
               
                   
               
               
                 395171 
                 5-10-5 
                 34 
                 1326 
                 1345 
                 0 
                 CCAAAGTCCCCAGGGTCACC 
               
               
                   
               
               
                 395172 
                 5-10-5 
                 128 
                 1330 
                 1349 
                 0 
                 GTCCCCAAAGTCCCCAGGGT 
               
               
                   
               
               
                 399802 
                 5-10-5 
                 35 
                 1335 
                 1354 
                 0 
                 AGTTGGTCCCCAAAGTCCCC 
               
               
                   
               
               
                 395173 
                 5-10-5 
                 36 
                 1340 
                 1359 
                 0 
                 GCCAAAGTTGGTCCCCAAAG 
               
               
                   
               
               
                 399803 
                 5-10-5 
                 37 
                 1352 
                 1371 
                 0 
                 GTCCACACAGCGGCCAAAGT 
               
               
                   
               
               
                 395174 
                 5-10-5 
                 38 
                 1361 
                 1380 
                 0 
                 GGCAAAGAGGTCCACACAGC 
               
               
                   
               
               
                 395175 
                 5-10-5 
                 39 
                 1389 
                 1408 
                 0 
                 TGGAGGCACCAATGATGTCC 
               
               
                   
               
               
                 399804 
                 5-10-5 
                 40 
                 1400 
                 1419 
                 0 
                 GCTGCAGTCGCTGGAGGCAC 
               
               
                   
               
               
                 399805 
                 5-10-5 
                 41 
                 1411 
                 1430 
                 0 
                 ACAAAGCAGGTGCTGCAGTC 
               
               
                   
               
               
                 395176 
                 5-10-5 
                 101 
                 1465 
                 1484 
                 0 
                 ATGGCTGCAATGCCAGCCAC 
               
               
                   
               
               
                 399806 
                 5-10-5 
                 42 
                 1470 
                 1489 
                 0 
                 GCATCATGGCTGCAATGCCA 
               
               
                   
               
               
                 399807 
                 5-10-5 
                 43 
                 1478 
                 1497 
                 0 
                 GGCAGACAGCATCATGGCTG 
               
               
                   
               
               
                 399808 
                 5-10-5 
                 44 
                 1526 
                 1545 
                 0 
                 GAAGTGGATCAGTCTCTGCC 
               
               
                   
               
               
                 395177 
                 5-10-5 
                 45 
                 1534 
                 1553 
                 0 
                 TTGGCAGAGAAGTGGATCAG 
               
               
                   
               
               
                 399809 
                 5-10-5 
                 46 
                 1539 
                 1558 
                 0 
                 CATCTTTGGCAGAGAAGTGG 
               
               
                   
               
               
                 399810 
                 5-10-5 
                 47 
                 1545 
                 1564 
                 0 
                 TGATGACATCTTTGGCAGAG 
               
               
                   
               
               
                 399811 
                 5-10-5 
                 48 
                 1552 
                 1571 
                 0 
                 GCCTCATTGATGACATCTTT 
               
               
                   
               
               
                 399812 
                 5-10-5 
                 49 
                 1564 
                 1583 
                 0 
                 TCAGGGAACCAGGCCTCATT 
               
               
                   
               
               
                 395178 
                 5-10-5 
                 50 
                 1569 
                 1588 
                 0 
                 GGTCCTCAGGGAACCAGGCC 
               
               
                   
               
               
                 395179 
                 5-10-5 
                 87 
                 1576 
                 1595 
                 0 
                 ACCCGCTGGTCCTCAGGGAA 
               
               
                   
               
               
                 399813 
                 5-10-5 
                 51 
                 1583 
                 1602 
                 0 
                 GGTCAGTACCCGCTGGTCCT 
               
               
                   
               
               
                 395180 
                 5-10-5 
                 119 
                 1605 
                 1624 
                 0 
                 GCAGGGCGGCCACCAGGTTG 
               
               
                   
               
               
                 395181 
                 5-10-5 
                 52 
                 1640 
                 1659 
                 0 
                 AAACAGCTGCCAACCTGCCC 
               
               
                   
               
               
                 399814 
                 5-10-5 
                 53 
                 1645 
                 1664 
                 0 
                 CTGCAAAACAGCTGCCAACC 
               
               
                   
               
               
                 395182 
                 5-10-5 
                 54 
                 1675 
                 1694 
                 0 
                 GTAGGCCCCGAGTGTGCTGA 
               
               
                   
               
               
                 399815 
                 5-10-5 
                 55 
                 1740 
                 1759 
                 0 
                 AGAAACTGGAGCAGCTCAGC 
               
               
                   
               
               
                 399816 
                 5-10-5 
                 56 
                 1746 
                 1765 
                 0 
                 TCCTGGAGAAACTGGAGCAG 
               
               
                   
               
               
                 395183 
                 5-10-5 
                 57 
                 1812 
                 1831 
                 0 
                 CGTTGTGGGCCCGGCAGACC 
               
               
                   
               
               
                 395184 
                 5-10-5 
                 58 
                 1858 
                 1877 
                 0 
                 AGCAGGCAGCACCTGGCAAT 
               
               
                   
               
               
                 395185 
                 5-10-5 
                 59 
                 1920 
                 1939 
                 0 
                 CACGGGTCCCCATGCTGGCC 
               
               
                   
               
               
                 395186 
                 5-10-5 
                 60 
                 2100 
                 2119 
                 0 
                 CTTTGCATTCCAGACCTGGG 
               
               
                   
               
               
                 399817 
                 5-10-5 
                 61 
                 2105 
                 2124 
                 0 
                 CTTGACTTTGCATTCCAGAC 
               
               
                   
               
               
                 395187 
                 5-10-5 
                 62 
                 2310 
                 2329 
                 0 
                 GGCAGCAGATGGCAACGGCT 
               
               
                   
               
               
                 395188 
                 5-10-5 
                 154 
                 2410 
                 2429 
                 0 
                 TTTTAAAGCTCAGCCCCAGC 
               
               
                   
               
               
                 399818 
                 5-10-5 
                 63 
                 2415 
                 2434 
                 0 
                 AACCATTTTAAAGCTCAGCC 
               
               
                   
               
               
                 395189 
                 5-10-5 
                 64 
                 2504 
                 2523 
                 0 
                 TCAAGGGCCAGGCCAGCAGC 
               
               
                   
               
               
                 399819 
                 5-10-5 
                 65 
                 2509 
                 2528 
                 0 
                 CCCACTCAAGGGCCAGGCCA 
               
               
                   
               
               
                 399820 
                 5-10-5 
                 122 
                 2582 
                 2601 
                 0 
                 GGAGGGAGCTTCCTGGCACC 
               
               
                   
               
               
                 395190 
                 5-10-5 
                 66 
                 2597 
                 2616 
                 0 
                 ATGCCCCACAGTGAGGGAGG 
               
               
                   
               
               
                 395191 
                 5-10-5 
                 67 
                 2606 
                 2625 
                 0 
                 AATGGTGAAATGCCCCACAG 
               
               
                   
               
               
                 395192 
                 5-10-5 
                 153 
                 2649 
                 2668 
                 0 
                 TTGGGAGCAGCTGGCAGCAC 
               
               
                   
               
               
                 395193 
                 5-10-5 
                 68 
                 2750 
                 2769 
                 0 
                 CATGGGAAGAATCCTGCCTC 
               
               
                   
               
               
                 395194 
                 5-10-5 
                 69 
                 2832 
                 2851 
                 0 
                 GGAGATGAGGGCCATCAGCA 
               
               
                   
               
               
                 395195 
                 5-10-5 
                 70 
                 2900 
                 2919 
                 0 
                 TAGATGCCATCCAGAAAGCT 
               
               
                   
               
               
                 399821 
                 5-10-5 
                 71 
                 2906 
                 2925 
                 0 
                 TCTGGCTAGATGCCATCCAG 
               
               
                   
               
               
                 395196 
                 5-10-5 
                 72 
                 2983 
                 3002 
                 0 
                 GGCATAGAGCAGAGTAAAGG 
               
               
                   
               
               
                 399822 
                 5-10-5 
                 73 
                 2988 
                 3007 
                 0 
                 AGCCTGGCATAGAGCAGAGT 
               
               
                   
               
               
                 399823 
                 5-10-5 
                 135 
                 2994 
                 3013 
                 0 
                 TAGCACAGCCTGGCATAGAG 
               
               
                   
               
               
                 395197 
                 5-10-5 
                 112 
                 3227 
                 3246 
                 0 
                 GAAGAGGCTTGGCTTCAGAG 
               
               
                   
               
               
                 399824 
                 5-10-5 
                 74 
                 3233 
                 3252 
                 0 
                 AAGTAAGAAGAGGCTTGGCT 
               
               
                   
               
               
                 395198 
                 5-10-5 
                 75 
                 3437 
                 3456 
                 0 
                 GCTCAAGGAGGGACAGTTGT 
               
               
                   
               
               
                 395199 
                 5-10-5 
                 76 
                 3472 
                 3491 
                 0 
                 AAAGATAAATGTCTGCTTGC 
               
               
                   
               
               
                 399825 
                 5-10-5 
                 77 
                 3477 
                 3496 
                 0 
                 ACCCAAAAGATAAATGTCTG 
               
               
                   
               
               
                 395200 
                 5-10-5 
                 78 
                 3543 
                 3562 
                 0 
                 TCTTCAAGTTACAAAAGCAA 
               
               
                   
               
               
                 399826 
                 5-10-5 
                 99 
                 3550 
                 3569 
                 0 
                 ATAAATATCTTCAAGTTACA 
               
               
                   
               
               
                 405861 
                 5-10-5 
                 162 
                 406 
                 425 
                 0 
                 AAGGCTAGCACCAGCTCCTC 
               
               
                   
               
               
                 405862 
                 5-10-5 
                 163 
                 407 
                 426 
                 0 
                 CAAGGCTAGCACCAGCTCCT 
               
               
                   
               
               
                 405863 
                 5-10-5 
                 164 
                 408 
                 427 
                 0 
                 GCAAGGCTAGCACCAGCTCC 
               
               
                   
               
               
                 405864 
                 5-10-5 
                 165 
                 409 
                 428 
                 0 
                 CGCAAGGCTAGCACCAGCTC 
               
               
                   
               
               
                 405865 
                 5-10-5 
                 166 
                 411 
                 430 
                 0 
                 AACGCAAGGCTAGCACCAGC 
               
               
                   
               
               
                 405866 
                 5-10-5 
                 167 
                 412 
                 431 
                 0 
                 GAACGCAAGGCTAGCACCAG 
               
               
                   
               
               
                 405867 
                 5-10-5 
                 168 
                 413 
                 432 
                 0 
                 GGAACGCAAGGCTAGCACCA 
               
               
                   
               
               
                 405868 
                 5-10-5 
                 169 
                 414 
                 433 
                 0 
                 CGGAACGCAAGGCTAGCACC 
               
               
                   
               
               
                 405869 
                 5-10-5 
                 218 
                 862 
                 881 
                 0 
                 TCGATTTCCCGGTGGTCACT 
               
               
                   
               
               
                 405870 
                 5-10-5 
                 219 
                 863 
                 882 
                 0 
                 CTCGATTTCCCGGTGGTCAC 
               
               
                   
               
               
                 405871 
                 5-10-5 
                 220 
                 864 
                 883 
                 0 
                 CCTCGATTTCCCGGTGGTCA 
               
               
                   
               
               
                 405872 
                 5-10-5 
                 221 
                 865 
                 884 
                 0 
                 CCCTCGATTTCCCGGTGGTC 
               
               
                   
               
               
                 405873 
                 5-10-5 
                 222 
                 867 
                 886 
                 0 
                 TGCCCTCGATTTCCCGGTGG 
               
               
                   
               
               
                 405874 
                 5-10-5 
                 223 
                 868 
                 887 
                 0 
                 CTGCCCTCGATTTCCCGGTG 
               
               
                   
               
               
                 405875 
                 5-10-5 
                 224 
                 869 
                 888 
                 0 
                 CCTGCCCTCGATTTCCCGGT 
               
               
                   
               
               
                 405876 
                 5-10-5 
                 225 
                 870 
                 889 
                 0 
                 CCCTGCCCTCGATTTCCCGG 
               
               
                   
               
               
                 405877 
                 5-10-5 
                 246 
                 1000 
                 1019 
                 0 
                 TTGGCCACGCCGGCATCCCG 
               
               
                   
               
               
                 405878 
                 5-10-5 
                 247 
                 1001 
                 1020 
                 0 
                 CTTGGCCACGCCGGCATCCC 
               
               
                   
               
               
                 405879 
                 5-10-5 
                 248 
                 1002 
                 1021 
                 0 
                 CCTTGGCCACGCCGGCATCC 
               
               
                   
               
               
                 405880 
                 5-10-5 
                 249 
                 1003 
                 1022 
                 0 
                 CCCTTGGCCACGCCGGCATC 
               
               
                   
               
               
                 405881 
                 5-10-5 
                 250 
                 1005 
                 1024 
                 0 
                 CACCCTTGGCCACGCCGGCA 
               
               
                   
               
               
                 405882 
                 5-10-5 
                 251 
                 1006 
                 1025 
                 0 
                 GCACCCTTGGCCACGCCGGC 
               
               
                   
               
               
                 405883 
                 5-10-5 
                 252 
                 1007 
                 1026 
                 0 
                 GGCACCCTTGGCCACGCCGG 
               
               
                   
               
               
                 405884 
                 5-10-5 
                 253 
                 1008 
                 1027 
                 0 
                 TGGCACCCTTGGCCACGCCG 
               
               
                   
               
               
                 405885 
                 5-10-5 
                 346 
                 1560 
                 1579 
                 0 
                 GGAACCAGGCCTCATTGATG 
               
               
                   
               
               
                 405886 
                 5-10-5 
                 347 
                 1561 
                 1580 
                 0 
                 GGGAACCAGGCCTCATTGAT 
               
               
                   
               
               
                 405887 
                 5-10-5 
                 348 
                 1562 
                 1581 
                 0 
                 AGGGAACCAGGCCTCATTGA 
               
               
                   
               
               
                 405888 
                 5-10-5 
                 349 
                 1563 
                 1582 
                 0 
                 CAGGGAACCAGGCCTCATTG 
               
               
                   
               
               
                 405889 
                 5-10-5 
                 350 
                 1565 
                 1584 
                 0 
                 CTCAGGGAACCAGGCCTCAT 
               
               
                   
               
               
                 405890 
                 5-10-5 
                 351 
                 1566 
                 1585 
                 0 
                 CCTCAGGGAACCAGGCCTCA 
               
               
                   
               
               
                 405891 
                 5-10-5 
                 352 
                 1567 
                 1586 
                 0 
                 TCCTCAGGGAACCAGGCCTC 
               
               
                   
               
               
                 405892 
                 5-10-5 
                 353 
                 1568 
                 1587 
                 0 
                 GTCCTCAGGGAACCAGGCCT 
               
               
                   
               
               
                 405893 
                 5-10-5 
                 431 
                 2828 
                 2847 
                 0 
                 ATGAGGGCCATCAGCACCTT 
               
               
                   
               
               
                 405894 
                 5-10-5 
                 432 
                 2829 
                 2848 
                 0 
                 GATGAGGGCCATCAGCACCT 
               
               
                   
               
               
                 405895 
                 5-10-5 
                 433 
                 2830 
                 2849 
                 0 
                 AGATGAGGGCCATCAGCACC 
               
               
                   
               
               
                 405896 
                 5-10-5 
                 434 
                 2831 
                 2850 
                 0 
                 GAGATGAGGGCCATCAGCAC 
               
               
                   
               
               
                 405897 
                 5-10-5 
                 435 
                 2833 
                 2852 
                 0 
                 TGGAGATGAGGGCCATCAGC 
               
               
                   
               
               
                 405898 
                 5-10-5 
                 436 
                 2834 
                 2853 
                 0 
                 CTGGAGATGAGGGCCATCAG 
               
               
                   
               
               
                 405899 
                 5-10-5 
                 437 
                 2835 
                 2854 
                 0 
                 GCTGGAGATGAGGGCCATCA 
               
               
                   
               
               
                 405900 
                 5-10-5 
                 438 
                 2836 
                 2855 
                 0 
                 AGCTGGAGATGAGGGCCATC 
               
               
                   
               
               
                 405901 
                 5-10-5 
                 439 
                 2902 
                 2921 
                 0 
                 GCTAGATGCCATCCAGAAAG 
               
               
                   
               
               
                 405902 
                 5-10-5 
                 440 
                 2903 
                 2922 
                 0 
                 GGCTAGATGCCATCCAGAAA 
               
               
                   
               
               
                 405903 
                 5-10-5 
                 441 
                 2904 
                 2923 
                 0 
                 TGGCTAGATGCCATCCAGAA 
               
               
                   
               
               
                 405904 
                 5-10-5 
                 442 
                 2905 
                 2924 
                 0 
                 CTGGCTAGATGCCATCCAGA 
               
               
                   
               
               
                 405905 
                 5-10-5 
                 443 
                 2907 
                 2926 
                 0 
                 CTCTGGCTAGATGCCATCCA 
               
               
                   
               
               
                 405906 
                 5-10-5 
                 444 
                 2908 
                 2927 
                 0 
                 CCTCTGGCTAGATGCCATCC 
               
               
                   
               
               
                 405907 
                 5-10-5 
                 445 
                 2909 
                 2928 
                 0 
                 GCCTCTGGCTAGATGCCATC 
               
               
                   
               
               
                 405908 
                 5-10-5 
                 446 
                 2910 
                 2929 
                 0 
                 AGCCTCTGGCTAGATGCCAT 
               
               
                   
               
               
                 405909 
                 5-10-5 
                 267 
                 1100 
                 1119 
                 0 
                 CAGCTGGCTTTTCCGAATAA 
               
               
                   
               
               
                 405910 
                 5-10-5 
                 268 
                 1102 
                 1121 
                 0 
                 ACCAGCTGGCTTTTCCGAAT 
               
               
                   
               
               
                 405911 
                 5-10-5 
                 269 
                 1104 
                 1123 
                 0 
                 GGACCAGCTGGCTTTTCCGA 
               
               
                   
               
               
                 405912 
                 5-10-5 
                 270 
                 1108 
                 1127 
                 0 
                 GGCTGGACCAGCTGGCTTTT 
               
               
                   
               
               
                 405913 
                 5-10-5 
                 275 
                 1212 
                 1231 
                 0 
                 CGGTGACCAGCACGACCCCA 
               
               
                   
               
               
                 405914 
                 5-10-5 
                 276 
                 1214 
                 1233 
                 0 
                 AGCGGTGACCAGCACGACCC 
               
               
                   
               
               
                 405915 
                 5-10-5 
                 277 
                 1216 
                 1235 
                 0 
                 GCAGCGGTGACCAGCACGAC 
               
               
                   
               
               
                 405916 
                 5-10-5 
                 278 
                 1218 
                 1237 
                 0 
                 CGGCAGCGGTGACCAGCACG 
               
               
                   
               
               
                 405917 
                 5-10-5 
                 280 
                 1222 
                 1241 
                 0 
                 TTGCCGGCAGCGGTGACCAG 
               
               
                   
               
               
                 405918 
                 5-10-5 
                 281 
                 1224 
                 1243 
                 0 
                 AGTTGCCGGCAGCGGTGACC 
               
               
                   
               
               
                 405919 
                 5-10-5 
                 282 
                 1226 
                 1245 
                 0 
                 GAAGTTGCCGGCAGCGGTGA 
               
               
                   
               
               
                 405920 
                 5-10-5 
                 283 
                 1228 
                 1247 
                 0 
                 CGGAAGTTGCCGGCAGCGGT 
               
               
                   
               
               
                 405921 
                 5-10-5 
                 284 
                 1230 
                 1249 
                 0 
                 CCCGGAAGTTGCCGGCAGCG 
               
               
                   
               
               
                 405922 
                 5-10-5 
                 285 
                 1232 
                 1251 
                 0 
                 GTCCCGGAAGTTGCCGGCAG 
               
               
                   
               
               
                 405923 
                 5-10-5 
                 288 
                 1295 
                 1314 
                 0 
                 GGCATTGGTGGCCCCAACTG 
               
               
                   
               
               
                 405924 
                 5-10-5 
                 290 
                 1318 
                 1337 
                 0 
                 CCCAGGGTCACCGGCTGGTC 
               
               
                   
               
               
                 405925 
                 5-10-5 
                 292 
                 1322 
                 1341 
                 0 
                 AGTCCCCAGGGTCACCGGCT 
               
               
                   
               
               
                 405926 
                 5-10-5 
                 293 
                 1324 
                 1343 
                 0 
                 AAAGTCCCCAGGGTCACCGG 
               
               
                   
               
               
                 405927 
                 5-10-5 
                 294 
                 1328 
                 1347 
                 0 
                 CCCCAAAGTCCCCAGGGTCA 
               
               
                   
               
               
                 405928 
                 5-10-5 
                 295 
                 1333 
                 1352 
                 0 
                 TTGGTCCCCAAAGTCCCCAG 
               
               
                   
               
               
                 405929 
                 5-10-5 
                 296 
                 1337 
                 1356 
                 0 
                 AAAGTTGGTCCCCAAAGTCC 
               
               
                   
               
               
                 405930 
                 5-10-5 
                 297 
                 1342 
                 1361 
                 0 
                 CGGCCAAAGTTGGTCCCCAA 
               
               
                   
               
               
                 405931 
                 5-10-5 
                 298 
                 1344 
                 1363 
                 0 
                 AGCGGCCAAAGTTGGTCCCC 
               
               
                   
               
               
                 405932 
                 5-10-5 
                 299 
                 1346 
                 1365 
                 0 
                 ACAGCGGCCAAAGTTGGTCC 
               
               
                   
               
               
                 405933 
                 5-10-5 
                 300 
                 1348 
                 1367 
                 0 
                 ACACAGCGGCCAAAGTTGGT 
               
               
                   
               
               
                 405934 
                 5-10-5 
                 301 
                 1350 
                 1369 
                 0 
                 CCACACAGCGGCCAAAGTTG 
               
               
                   
               
               
                 405935 
                 5-10-5 
                 302 
                 1354 
                 1373 
                 0 
                 AGGTCCACACAGCGGCCAAA 
               
               
                   
               
               
                 405936 
                 5-10-5 
                 304 
                 1358 
                 1377 
                 0 
                 AAAGAGGTCCACACAGCGGC 
               
               
                   
               
               
                 405937 
                 5-10-5 
                 306 
                 1387 
                 1406 
                 0 
                 GAGGCACCAATGATGTCCTC 
               
               
                   
               
               
                 405938 
                 5-10-5 
                 307 
                 1391 
                 1410 
                 0 
                 GCTGGAGGCACCAATGATGT 
               
               
                   
               
               
                 405939 
                 5-10-5 
                 308 
                 1393 
                 1412 
                 0 
                 TCGCTGGAGGCACCAATGAT 
               
               
                   
               
               
                 405940 
                 5-10-5 
                 309 
                 1395 
                 1414 
                 0 
                 AGTCGCTGGAGGCACCAATG 
               
               
                   
               
               
                 405941 
                 5-10-5 
                 310 
                 1397 
                 1416 
                 0 
                 GCAGTCGCTGGAGGCACCAA 
               
               
                   
               
               
                 405942 
                 5-10-5 
                 311 
                 1402 
                 1421 
                 0 
                 GTGCTGCAGTCGCTGGAGGC 
               
               
                   
               
               
                 405943 
                 5-10-5 
                 312 
                 1404 
                 1423 
                 0 
                 AGGTGCTGCAGTCGCTGGAG 
               
               
                   
               
               
                 405944 
                 5-10-5 
                 314 
                 1407 
                 1426 
                 0 
                 AGCAGGTGCTGCAGTCGCTG 
               
               
                   
               
               
                 405945 
                 5-10-5 
                 315 
                 1409 
                 1428 
                 0 
                 AAAGCAGGTGCTGCAGTCGC 
               
               
                   
               
               
                 405946 
                 5-10-5 
                 316 
                 1413 
                 1432 
                 0 
                 ACACAAAGCAGGTGCTGCAG 
               
               
                   
               
               
                 405947 
                 5-10-5 
                 317 
                 1415 
                 1434 
                 0 
                 TGACACAAAGCAGGTGCTGC 
               
               
                   
               
               
                 405948 
                 5-10-5 
                 319 
                 1467 
                 1486 
                 0 
                 TCATGGCTGCAATGCCAGCC 
               
               
                   
               
               
                 405949 
                 5-10-5 
                 320 
                 1472 
                 1491 
                 0 
                 CAGCATCATGGCTGCAATGC 
               
               
                   
               
               
                 405950 
                 5-10-5 
                 321 
                 1474 
                 1493 
                 0 
                 GACAGCATCATGGCTGCAAT 
               
               
                   
               
               
                 405951 
                 5-10-5 
                 322 
                 1476 
                 1495 
                 0 
                 CAGACAGCATCATGGCTGCA 
               
               
                   
               
               
                 405952 
                 5-10-5 
                 323 
                 1480 
                 1499 
                 0 
                 TCGGCAGACAGCATCATGGC 
               
               
                   
               
               
                 405953 
                 5-10-5 
                 325 
                 1484 
                 1503 
                 0 
                 CGGCTCGGCAGACAGCATCA 
               
               
                   
               
               
                 405954 
                 5-10-5 
                 326 
                 1486 
                 1505 
                 0 
                 TCCGGCTCGGCAGACAGCAT 
               
               
                   
               
               
                 405955 
                 5-10-5 
                 328 
                 1513 
                 1532 
                 0 
                 CTCTGCCTCAACTCGGCCAG 
               
               
                   
               
               
                 405956 
                 5-10-5 
                 329 
                 1515 
                 1534 
                 0 
                 GTCTCTGCCTCAACTCGGCC 
               
               
                   
               
               
                 405957 
                 5-10-5 
                 330 
                 1517 
                 1536 
                 0 
                 CAGTCTCTGCCTCAACTCGG 
               
               
                   
               
               
                 405958 
                 5-10-5 
                 331 
                 1519 
                 1538 
                 0 
                 ATCAGTCTCTGCCTCAACTC 
               
               
                   
               
               
                 405959 
                 5-10-5 
                 332 
                 1521 
                 1540 
                 0 
                 GGATCAGTCTCTGCCTCAAC 
               
               
                   
               
               
                 405960 
                 5-10-5 
                 333 
                 1523 
                 1542 
                 0 
                 GTGGATCAGTCTCTGCCTCA 
               
               
                   
               
               
                 405961 
                 5-10-5 
                 334 
                 1525 
                 1544 
                 0 
                 AAGTGGATCAGTCTCTGCCT 
               
               
                   
               
               
                 405962 
                 5-10-5 
                 335 
                 1528 
                 1547 
                 0 
                 GAGAAGTGGATCAGTCTCTG 
               
               
                   
               
               
                 405963 
                 5-10-5 
                 337 
                 1532 
                 1551 
                 0 
                 GGCAGAGAAGTGGATCAGTC 
               
               
                   
               
               
                 405964 
                 5-10-5 
                 338 
                 1536 
                 1555 
                 0 
                 CTTTGGCAGAGAAGTGGATC 
               
               
                   
               
               
                 405965 
                 5-10-5 
                 339 
                 1541 
                 1560 
                 0 
                 GACATCTTTGGCAGAGAAGT 
               
               
                   
               
               
                 405966 
                 5-10-5 
                 340 
                 1543 
                 1562 
                 0 
                 ATGACATCTTTGGCAGAGAA 
               
               
                   
               
               
                 405967 
                 5-10-5 
                 341 
                 1547 
                 1566 
                 0 
                 ATTGATGACATCTTTGGCAG 
               
               
                   
               
               
                 405968 
                 5-10-5 
                 342 
                 1549 
                 1568 
                 0 
                 TCATTGATGACATCTTTGGC 
               
               
                   
               
               
                 405969 
                 5-10-5 
                 343 
                 1554 
                 1573 
                 0 
                 AGGCCTCATTGATGACATCT 
               
               
                   
               
               
                 405970 
                 5-10-5 
                 344 
                 1556 
                 1575 
                 0 
                 CCAGGCCTCATTGATGACAT 
               
               
                   
               
               
                 405971 
                 5-10-5 
                 355 
                 1571 
                 1590 
                 0 
                 CTGGTCCTCAGGGAACCAGG 
               
               
                   
               
               
                 405972 
                 5-10-5 
                 357 
                 1573 
                 1592 
                 0 
                 CGCTGGTCCTCAGGGAACCA 
               
               
                   
               
               
                 405973 
                 5-10-5 
                 358 
                 1578 
                 1597 
                 0 
                 GTACCCGCTGGTCCTCAGGG 
               
               
                   
               
               
                 405974 
                 5-10-5 
                 359 
                 1580 
                 1599 
                 0 
                 CAGTACCCGCTGGTCCTCAG 
               
               
                   
               
               
                 405975 
                 5-10-5 
                 361 
                 1642 
                 1661 
                 0 
                 CAAAACAGCTGCCAACCTGC 
               
               
                   
               
               
                 405976 
                 5-10-5 
                 362 
                 1647 
                 1666 
                 0 
                 TCCTGCAAAACAGCTGCCAA 
               
               
                   
               
               
                 405977 
                 5-10-5 
                 363 
                 1649 
                 1668 
                 0 
                 AGTCCTGCAAAACAGCTGCC 
               
               
                   
               
               
                 405978 
                 5-10-5 
                 365 
                 1672 
                 1691 
                 0 
                 GGCCCCGAGTGTGCTGACCA 
               
               
                   
               
               
                 405979 
                 5-10-5 
                 366 
                 1677 
                 1696 
                 0 
                 GTGTAGGCCCCGAGTGTGCT 
               
               
                   
               
               
                 405980 
                 5-10-5 
                 367 
                 1679 
                 1698 
                 0 
                 CCGTGTAGGCCCCGAGTGTG 
               
               
                   
               
               
                 405981 
                 5-10-5 
                 368 
                 1681 
                 1700 
                 0 
                 ATCCGTGTAGGCCCCGAGTG 
               
               
                   
               
               
                 405982 
                 5-10-5 
                 370 
                 1685 
                 1704 
                 0 
                 GGCCATCCGTGTAGGCCCCG 
               
               
                   
               
               
                 405983 
                 5-10-5 
                 371 
                 1687 
                 1706 
                 0 
                 GTGGCCATCCGTGTAGGCCC 
               
               
                   
               
               
                 405984 
                 5-10-5 
                 372 
                 1735 
                 1754 
                 0 
                 CTGGAGCAGCTCAGCAGCTC 
               
               
                   
               
               
                 405985 
                 5-10-5 
                 373 
                 1737 
                 1756 
                 0 
                 AACTGGAGCAGCTCAGCAGC 
               
               
                   
               
               
                 405986 
                 5-10-5 
                 374 
                 1742 
                 1761 
                 0 
                 GGAGAAACTGGAGCAGCTCA 
               
               
                   
               
               
                 405987 
                 5-10-5 
                 375 
                 1744 
                 1763 
                 0 
                 CTGGAGAAACTGGAGCAGCT 
               
               
                   
               
               
                 405988 
                 5-10-5 
                 381 
                 1854 
                 1873 
                 0 
                 GGCAGCACCTGGCAATGGCG 
               
               
                   
               
               
                 405989 
                 5-10-5 
                 383 
                 1856 
                 1875 
                 0 
                 CAGGCAGCACCTGGCAATGG 
               
               
                   
               
               
                 405990 
                 5-10-5 
                 386 
                 1860 
                 1879 
                 0 
                 GTAGCAGGCAGCACCTGGCA 
               
               
                   
               
               
                 405991 
                 5-10-5 
                 394 
                 1922 
                 1941 
                 0 
                 GACACGGGTCCCCATGCTGG 
               
               
                   
               
               
                 405992 
                 5-10-5 
                 396 
                 1924 
                 1943 
                 0 
                 TGGACACGGGTCCCCATGCT 
               
               
                   
               
               
                 405993 
                 5-10-5 
                 398 
                 1926 
                 1945 
                 0 
                 AGTGGACACGGGTCCCCATG 
               
               
                   
               
               
                 405994 
                 5-10-5 
                 400 
                 1928 
                 1947 
                 0 
                 GCAGTGGACACGGGTCCCCA 
               
               
                   
               
               
                 405995 
                 5-10-5 
                 402 
                 1930 
                 1949 
                 0 
                 TGGCAGTGGACACGGGTCCC 
               
               
                   
               
               
                 405996 
                 5-10-5 
                 412 
                 2102 
                 2121 
                 0 
                 GACTTTGCATTCCAGACCTG 
               
               
                   
               
               
                 405997 
                 5-10-5 
                 415 
                 2107 
                 2126 
                 0 
                 TCCTTGACTTTGCATTCCAG 
               
               
                   
               
               
                 405998 
                 5-10-5 
                 426 
                 2313 
                 2332 
                 0 
                 TCCGGCAGCAGATGGCAACG 
               
               
                   
               
               
                 405999 
                 5-10-5 
                 160 
                 298 
                 317 
                 0 
                 GACCGCCTGGAGCTGACGGT 
               
               
                   
               
               
                 406000 
                 5-10-5 
                 173 
                 482 
                 501 
                 0 
                 ATCCTTGGCGCAGCGGTGGA 
               
               
                   
               
               
                 406001 
                 5-10-5 
                 174 
                 484 
                 503 
                 0 
                 GGATCCTTGGCGCAGCGGTG 
               
               
                   
               
               
                 406002 
                 5-10-5 
                 175 
                 488 
                 507 
                 0 
                 CCACGGATCCTTGGCGCAGC 
               
               
                   
               
               
                 406003 
                 5-10-5 
                 178 
                 555 
                 574 
                 0 
                 CAGTGCGCTCTGACTGCGAG 
               
               
                   
               
               
                 406004 
                 5-10-5 
                 179 
                 557 
                 576 
                 0 
                 GGCAGTGCGCTCTGACTGCG 
               
               
                   
               
               
                 406005 
                 5-10-5 
                 180 
                 559 
                 578 
                 0 
                 CGGGCAGTGCGCTCTGACTG 
               
               
                   
               
               
                 406006 
                 5-10-5 
                 181 
                 562 
                 581 
                 0 
                 CGGCGGGCAGTGCGCTCTGA 
               
               
                   
               
               
                 406007 
                 5-10-5 
                 183 
                 595 
                 614 
                 0 
                 AGGTATCCCCGGCGGGCAGC 
               
               
                   
               
               
                 406008 
                 5-10-5 
                 188 
                 602 
                 621 
                 0 
                 CTTGGTGAGGTATCCCCGGC 
               
               
                   
               
               
                 406009 
                 5-10-5 
                 190 
                 604 
                 623 
                 0 
                 ATCTTGGTGAGGTATCCCCG 
               
               
                   
               
               
                 406010 
                 5-10-5 
                 193 
                 609 
                 628 
                 0 
                 GCAGGATCTTGGTGAGGTAT 
               
               
                   
               
               
                 406011 
                 5-10-5 
                 194 
                 611 
                 630 
                 0 
                 ATGCAGGATCTTGGTGAGGT 
               
               
                   
               
               
                 406012 
                 5-10-5 
                 195 
                 613 
                 632 
                 0 
                 ACATGCAGGATCTTGGTGAG 
               
               
                   
               
               
                 406013 
                 5-10-5 
                 196 
                 617 
                 636 
                 0 
                 GAAGACATGCAGGATCTTGG 
               
               
                   
               
               
                 406014 
                 5-10-5 
                 199 
                 648 
                 667 
                 0 
                 TCTTCACCAGGAAGCCAGGA 
               
               
                   
               
               
                 406015 
                 5-10-5 
                 200 
                 653 
                 672 
                 0 
                 ACTCATCTTCACCAGGAAGC 
               
               
                   
               
               
                 406016 
                 5-10-5 
                 201 
                 655 
                 674 
                 0 
                 CCACTCATCTTCACCAGGAA 
               
               
                   
               
               
                 406017 
                 5-10-5 
                 203 
                 659 
                 678 
                 0 
                 GTCGCCACTCATCTTCACCA 
               
               
                   
               
               
                 406018 
                 5-10-5 
                 204 
                 661 
                 680 
                 0 
                 AGGTCGCCACTCATCTTCAC 
               
               
                   
               
               
                 406019 
                 5-10-5 
                 205 
                 663 
                 682 
                 0 
                 GCAGGTCGCCACTCATCTTC 
               
               
                   
               
               
                 406020 
                 5-10-5 
                 206 
                 665 
                 684 
                 0 
                 CAGCAGGTCGCCACTCATCT 
               
               
                   
               
               
                 406021 
                 5-10-5 
                 210 
                 782 
                 801 
                 0 
                 TTCATCCGCCCGGTACCGTG 
               
               
                   
               
               
                 406022 
                 5-10-5 
                 211 
                 784 
                 803 
                 0 
                 TATTCATCCGCCCGGTACCG 
               
               
                   
               
               
                 406023 
                 5-10-5 
                 212 
                 787 
                 806 
                 0 
                 TGGTATTCATCCGCCCGGTA 
               
               
                   
               
               
                 406024 
                 5-10-5 
                 213 
                 789 
                 808 
                 0 
                 GCTGGTATTCATCCGCCCGG 
               
               
                   
               
               
                 406025 
                 5-10-5 
                 216 
                 832 
                 851 
                 0 
                 GTGTCTAGGAGATACACCTC 
               
               
                   
               
               
                 406026 
                 5-10-5 
                 217 
                 837 
                 856 
                 0 
                 TGCTGGTGTCTAGGAGATAC 
               
               
                   
               
               
                 406027 
                 5-10-5 
                 226 
                 874 
                 893 
                 0 
                 ATGACCCTGCCCTCGATTTC 
               
               
                   
               
               
                 406028 
                 5-10-5 
                 227 
                 876 
                 895 
                 0 
                 CCATGACCCTGCCCTCGATT 
               
               
                   
               
               
                 406029 
                 5-10-5 
                 228 
                 878 
                 897 
                 0 
                 GACCATGACCCTGCCCTCGA 
               
               
                   
               
               
                 406030 
                 5-10-5 
                 229 
                 882 
                 901 
                 0 
                 CGGTGACCATGACCCTGCCC 
               
               
                   
               
               
                 406031 
                 5-10-5 
                 230 
                 884 
                 903 
                 0 
                 GTCGGTGACCATGACCCTGC 
               
               
                   
               
               
                 406032 
                 5-10-5 
                 232 
                 888 
                 907 
                 0 
                 CGAAGTCGGTGACCATGACC 
               
               
                   
               
               
                 406033 
                 5-10-5 
                 237 
                 967 
                 986 
                 0 
                 CCTGCCAGGTGGGTGCCATG 
               
               
                   
               
               
                 406034 
                 5-10-5 
                 238 
                 972 
                 991 
                 0 
                 CCACCCCTGCCAGGTGGGTG 
               
               
                   
               
               
                 406035 
                 5-10-5 
                 239 
                 977 
                 996 
                 0 
                 GCTGACCACCCCTGCCAGGT 
               
               
                   
               
               
                 406036 
                 5-10-5 
                 241 
                 989 
                 1008 
                 0 
                 GGCATCCCGGCCGCTGACCA 
               
               
                   
               
               
                 406037 
                 5-10-5 
                 242 
                 992 
                 1011 
                 0 
                 GCCGGCATCCCGGCCGCTGA 
               
               
                   
               
               
                 406038 
                 5-10-5 
                 245 
                 999 
                 1018 
                 0 
                 TGGCCACGCCGGCATCCCGG 
               
               
                   
               
               
                 406039 
                 5-10-5 
                 257 
                 1036 
                 1055 
                 0 
                 CAGTTGAGCACGCGCAGGCT 
               
               
                   
               
               
                 406040 
                 5-10-5 
                 258 
                 1038 
                 1057 
                 0 
                 GGCAGTTGAGCACGCGCAGG 
               
               
                   
               
               
                 406041 
                 5-10-5 
                 259 
                 1042 
                 1061 
                 0 
                 CCTTGGCAGTTGAGCACGCG 
               
               
                   
               
               
                 406042 
                 5-10-5 
                 260 
                 1047 
                 1066 
                 0 
                 CCTTCCCTTGGCAGTTGAGC 
               
               
                   
               
               
                 406043 
                 5-10-5 
                 261 
                 1051 
                 1070 
                 0 
                 GTGCCCTTCCCTTGGCAGTT 
               
               
                   
               
               
                 406044 
                 5-10-5 
                 262 
                 1053 
                 1072 
                 0 
                 CCGTGCCCTTCCCTTGGCAG 
               
               
                   
               
               
                 406045 
                 5-10-5 
                 266 
                 1096 
                 1115 
                 0 
                 TGGCTTTTCCGAATAAACTC 
               
               
                   
               
               
                 408642 
                 5-10-5 
                 264 
                 1076 
                 1095 
                 0 
                 CAGGCCTATGAGGGTGCCGC 
               
               
                   
               
               
                 408653 
                 5-10-5 
                 354 
                 1570 
                 1589 
                 0 
                 TGGTCCTCAGGGAACCAGGC 
               
               
                   
               
               
                 409126 
                 5-10-5 
                 447 
                 1004 
                 1023 
                 1 
                 ACCCTTGGTCACGCCGGCAT 
               
               
                   
               
               
                 410529 
                 5-10-5 
                 184 
                 597 
                 616 
                 0 
                 TGAGGTATCCCCGGCGGGCA 
               
               
                   
               
               
                 410530 
                 5-10-5 
                 185 
                 598 
                 617 
                 0 
                 GTGAGGTATCCCCGGCGGGC 
               
               
                   
               
               
                 410531 
                 5-10-5 
                 186 
                 599 
                 618 
                 0 
                 GGTGAGGTATCCCCGGCGGG 
               
               
                   
               
               
                 410532 
                 5-10-5 
                 187 
                 601 
                 620 
                 0 
                 TTGGTGAGGTATCCCCGGCG 
               
               
                   
               
               
                 410533 
                 5-10-5 
                 189 
                 603 
                 622 
                 0 
                 TCTTGGTGAGGTATCCCCGG 
               
               
                   
               
               
                 410534 
                 5-10-5 
                 191 
                 605 
                 624 
                 0 
                 GATCTTGGTGAGGTATCCCC 
               
               
                   
               
               
                 410535 
                 5-10-5 
                 192 
                 607 
                 626 
                 0 
                 AGGATCTTGGTGAGGTATCC 
               
               
                   
               
               
                 410536 
                 5-10-5 
                 243 
                 997 
                 1016 
                 0 
                 GCCACGCCGGCATCCCGGCC 
               
               
                   
               
               
                 410537 
                 5-10-5 
                 244 
                 998 
                 1017 
                 0 
                 GGCCACGCCGGCATCCCGGC 
               
               
                   
               
               
                 410538 
                 5-10-5 
                 254 
                 1009 
                 1028 
                 0 
                 CTGGCACCCTTGGCCACGCC 
               
               
                   
               
               
                 410539 
                 5-10-5 
                 255 
                 1010 
                 1029 
                 0 
                 GCTGGCACCCTTGGCCACGC 
               
               
                   
               
               
                 410540 
                 5-10-5 
                 356 
                 1572 
                 1591 
                 0 
                 GCTGGTCCTCAGGGAACCAG 
               
               
                   
               
               
                 410541 
                 5-10-5 
                 376 
                 1849 
                 1868 
                 0 
                 CACCTGGCAATGGCGTAGAC 
               
               
                   
               
               
                 410542 
                 5-10-5 
                 377 
                 1850 
                 1869 
                 0 
                 GCACCTGGCAATGGCGTAGA 
               
               
                   
               
               
                 410543 
                 5-10-5 
                 378 
                 1851 
                 1870 
                 0 
                 AGCACCTGGCAATGGCGTAG 
               
               
                   
               
               
                 410544 
                 5-10-5 
                 379 
                 1852 
                 1871 
                 0 
                 CAGCACCTGGCAATGGCGTA 
               
               
                   
               
               
                 410545 
                 5-10-5 
                 380 
                 1853 
                 1872 
                 0 
                 GCAGCACCTGGCAATGGCGT 
               
               
                   
               
               
                 410546 
                 5-10-5 
                 382 
                 1855 
                 1874 
                 0 
                 AGGCAGCACCTGGCAATGGC 
               
               
                   
               
               
                 410547 
                 5-10-5 
                 384 
                 1857 
                 1876 
                 0 
                 GCAGGCAGCACCTGGCAATG 
               
               
                   
               
               
                 410548 
                 5-10-5 
                 385 
                 1859 
                 1878 
                 0 
                 TAGCAGGCAGCACCTGGCAA 
               
               
                   
               
               
                 410549 
                 5-10-5 
                 388 
                 1915 
                 1934 
                 0 
                 GTCCCCATGCTGGCCTCAGC 
               
               
                   
               
               
                 410550 
                 5-10-5 
                 389 
                 1916 
                 1935 
                 0 
                 GGTCCCCATGCTGGCCTCAG 
               
               
                   
               
               
                 410551 
                 5-10-5 
                 390 
                 1917 
                 1936 
                 0 
                 GGGTCCCCATGCTGGCCTCA 
               
               
                   
               
               
                 410552 
                 5-10-5 
                 391 
                 1918 
                 1937 
                 0 
                 CGGGTCCCCATGCTGGCCTC 
               
               
                   
               
               
                 410553 
                 5-10-5 
                 392 
                 1919 
                 1938 
                 0 
                 ACGGGTCCCCATGCTGGCCT 
               
               
                   
               
               
                 410554 
                 5-10-5 
                 393 
                 1921 
                 1940 
                 0 
                 ACACGGGTCCCCATGCTGGC 
               
               
                   
               
               
                 410555 
                 5-10-5 
                 395 
                 1923 
                 1942 
                 0 
                 GGACACGGGTCCCCATGCTG 
               
               
                   
               
               
                 410556 
                 5-10-5 
                 397 
                 1925 
                 1944 
                 0 
                 GTGGACACGGGTCCCCATGC 
               
               
                   
               
               
                 410557 
                 5-10-5 
                 399 
                 1927 
                 1946 
                 0 
                 CAGTGGACACGGGTCCCCAT 
               
               
                   
               
               
                 410558 
                 5-10-5 
                 401 
                 1929 
                 1948 
                 0 
                 GGCAGTGGACACGGGTCCCC 
               
               
                   
               
               
                 410559 
                 5-10-5 
                 403 
                 1931 
                 1950 
                 0 
                 GTGGCAGTGGACACGGGTCC 
               
               
                   
               
               
                 410560 
                 5-10-5 
                 404 
                 1932 
                 1951 
                 0 
                 GGTGGCAGTGGACACGGGTC 
               
               
                   
               
               
                 410561 
                 5-10-5 
                 405 
                 1933 
                 1952 
                 0 
                 TGGTGGCAGTGGACACGGGT 
               
               
                   
               
               
                 410562 
                 5-10-5 
                 411 
                 2101 
                 2120 
                 0 
                 ACTTTGCATTCCAGACCTGG 
               
               
                   
               
               
                 410563 
                 5-10-5 
                 413 
                 2103 
                 2122 
                 0 
                 TGACTTTGCATTCCAGACCT 
               
               
                   
               
               
                 410564 
                 5-10-5 
                 414 
                 2104 
                 2123 
                 0 
                 TTGACTTTGCATTCCAGACC 
               
               
                   
               
               
                 410565 
                 5-10-5 
                 419 
                 2305 
                 2324 
                 0 
                 CAGATGGCAACGGCTGTCAC 
               
               
                   
               
               
                 410566 
                 5-10-5 
                 420 
                 2306 
                 2325 
                 0 
                 GCAGATGGCAACGGCTGTCA 
               
               
                   
               
               
                 410567 
                 5-10-5 
                 421 
                 2307 
                 2326 
                 0 
                 AGCAGATGGCAACGGCTGTC 
               
               
                   
               
               
                 410568 
                 5-10-5 
                 422 
                 2308 
                 2327 
                 0 
                 CAGCAGATGGCAACGGCTGT 
               
               
                   
               
               
                 410569 
                 5-10-5 
                 423 
                 2309 
                 2328 
                 0 
                 GCAGCAGATGGCAACGGCTG 
               
               
                   
               
               
                 410570 
                 5-10-5 
                 424 
                 2311 
                 2330 
                 0 
                 CGGCAGCAGATGGCAACGGC 
               
               
                   
               
               
                 410571 
                 5-10-5 
                 425 
                 2312 
                 2331 
                 0 
                 CCGGCAGCAGATGGCAACGG 
               
               
                   
               
               
                 410572 
                 5-10-5 
                 427 
                 2314 
                 2333 
                 0 
                 CTCCGGCAGCAGATGGCAAC 
               
               
                   
               
               
                 410573 
                 5-10-5 
                 428 
                 2315 
                 2334 
                 0 
                 GCTCCGGCAGCAGATGGCAA 
               
               
                   
               
               
                 410730 
                 5-10-5 
                 202 
                 657 
                 676 
                 0 
                 CGCCACTCATCTTCACCAGG 
               
               
                   
               
               
                 410731 
                 5-10-5 
                 207 
                 667 
                 686 
                 0 
                 TCCAGCAGGTCGCCACTCAT 
               
               
                   
               
               
                 410732 
                 5-10-5 
                 214 
                 791 
                 810 
                 0 
                 GGGCTGGTATTCATCCGCCC 
               
               
                   
               
               
                 410733 
                 5-10-5 
                 231 
                 886 
                 905 
                 0 
                 AAGTCGGTGACCATGACCCT 
               
               
                   
               
               
                 410734 
                 5-10-5 
                 279 
                 1219 
                 1238 
                 0 
                 CCGGCAGCGGTGACCAGCAC 
               
               
                   
               
               
                 410735 
                 5-10-5 
                 291 
                 1320 
                 1339 
                 0 
                 TCCCCAGGGTCACCGGCTGG 
               
               
                   
               
               
                 410736 
                 5-10-5 
                 303 
                 1356 
                 1375 
                 0 
                 AGAGGTCCACACAGCGGCCA 
               
               
                   
               
               
                 410737 
                 5-10-5 
                 313 
                 1406 
                 1425 
                 0 
                 GCAGGTGCTGCAGTCGCTGG 
               
               
                   
               
               
                 410738 
                 5-10-5 
                 324 
                 1482 
                 1501 
                 0 
                 GCTCGGCAGACAGCATCATG 
               
               
                   
               
               
                 410739 
                 5-10-5 
                 336 
                 1530 
                 1549 
                 0 
                 CAGAGAAGTGGATCAGTCTC 
               
               
                   
               
               
                 410740 
                 5-10-5 
                 345 
                 1558 
                 1577 
                 0 
                 AACCAGGCCTCATTGATGAC 
               
               
                   
               
               
                 410741 
                 5-10-5 
                 369 
                 1683 
                 1702 
                 0 
                 CCATCCGTGTAGGCCCCGAG 
               
               
                   
               
               
                 410742 
                 5-10-5 
                 159 
                 294 
                 313 
                 0 
                 GCCTGGAGCTGACGGTGCCC 
               
               
                   
               
               
                 410743 
                 5-10-5 
                 170 
                 421 
                 440 
                 0 
                 TCCTCCTCGGAACGCAAGGC 
               
               
                   
               
               
                 410744 
                 5-10-5 
                 171 
                 446 
                 465 
                 0 
                 GTGCTCGGGTGCTTCGGCCA 
               
               
                   
               
               
                 410745 
                 5-10-5 
                 172 
                 466 
                 485 
                 0 
                 TGGAAGGTGGCTGTGGTTCC 
               
               
                   
               
               
                 410746 
                 5-10-5 
                 176 
                 507 
                 526 
                 0 
                 CGTAGGTGCCAGGCAACCTC 
               
               
                   
               
               
                 410747 
                 5-10-5 
                 177 
                 545 
                 564 
                 0 
                 TGACTGCGAGAGGTGGGTCT 
               
               
                   
               
               
                 410748 
                 5-10-5 
                 182 
                 591 
                 610 
                 0 
                 ATCCCCGGCGGGCAGCCTGG 
               
               
                   
               
               
                 410749 
                 5-10-5 
                 197 
                 628 
                 647 
                 0 
                 AGAAGGCCATGGAAGACATG 
               
               
                   
               
               
                 410750 
                 5-10-5 
                 198 
                 638 
                 657 
                 0 
                 GAAGCCAGGAAGAAGGCCAT 
               
               
                   
               
               
                 410751 
                 5-10-5 
                 208 
                 685 
                 704 
                 0 
                 GGCAACTTCAAGGCCAGCTC 
               
               
                   
               
               
                 410752 
                 5-10-5 
                 209 
                 724 
                 743 
                 0 
                 GCAAAGACAGAGGAGTCCTC 
               
               
                   
               
               
                 410753 
                 5-10-5 
                 215 
                 821 
                 840 
                 0 
                 ATACACCTCCACCAGGCTGC 
               
               
                   
               
               
                 410754 
                 5-10-5 
                 233 
                 898 
                 917 
                 0 
                 GGCACATTCTCGAAGTCGGT 
               
               
                   
               
               
                 410755 
                 5-10-5 
                 234 
                 933 
                 952 
                 0 
                 TGGCCTGTCTGTGGAAGCGG 
               
               
                   
               
               
                 410756 
                 5-10-5 
                 235 
                 960 
                 979 
                 0 
                 GGTGGGTGCCATGACTGTCA 
               
               
                   
               
               
                 410757 
                 5-10-5 
                 240 
                 985 
                 1004 
                 0 
                 TCCCGGCCGCTGACCACCCC 
               
               
                   
               
               
                 410758 
                 5-10-5 
                 256 
                 1015 
                 1034 
                 0 
                 CGCATGCTGGCACCCTTGGC 
               
               
                   
               
               
                 410759 
                 5-10-5 
                 263 
                 1064 
                 1083 
                 0 
                 GGTGCCGCTAACCGTGCCCT 
               
               
                   
               
               
                 410760 
                 5-10-5 
                 265 
                 1088 
                 1107 
                 0 
                 CCGAATAAACTCCAGGCCTA 
               
               
                   
               
               
                 410761 
                 5-10-5 
                 271 
                 1119 
                 1138 
                 0 
                 GTGGCCCCACAGGCTGGACC 
               
               
                   
               
               
                 410762 
                 5-10-5 
                 272 
                 1132 
                 1151 
                 0 
                 AGCAGCACCACCAGTGGCCC 
               
               
                   
               
               
                 410763 
                 5-10-5 
                 273 
                 1154 
                 1173 
                 0 
                 GCTGTACCCACCCGCCAGGG 
               
               
                   
               
               
                 410764 
                 5-10-5 
                 274 
                 1200 
                 1219 
                 0 
                 CGACCCCAGCCCTCGCCAGG 
               
               
                   
               
               
                 410765 
                 5-10-5 
                 286 
                 1273 
                 1292 
                 0 
                 ATGACCTCGGGAGCTGAGGC 
               
               
                   
               
               
                 410766 
                 5-10-5 
                 287 
                 1283 
                 1302 
                 0 
                 CCCAACTGTGATGACCTCGG 
               
               
                   
               
               
                 410767 
                 5-10-5 
                 289 
                 1305 
                 1324 
                 0 
                 GCTGGTCTTGGGCATTGGTG 
               
               
                   
               
               
                 410768 
                 5-10-5 
                 305 
                 1380 
                 1399 
                 0 
                 CAATGATGTCCTCCCCTGGG 
               
               
                   
               
               
                 410769 
                 5-10-5 
                 318 
                 1425 
                 1444 
                 0 
                 TCCCACTCTGTGACACAAAG 
               
               
                   
               
               
                 410770 
                 5-10-5 
                 327 
                 1500 
                 1519 
                 0 
                 CGGCCAGGGTGAGCTCCGGC 
               
               
                   
               
               
                 410771 
                 5-10-5 
                 360 
                 1628 
                 1647 
                 0 
                 ACCTGCCCCATGGGTGCTGG 
               
               
                   
               
               
                 410772 
                 5-10-5 
                 364 
                 1660 
                 1679 
                 0 
                 GCTGACCATACAGTCCTGCA 
               
               
                   
               
               
                 410773 
                 5-10-5 
                 387 
                 1905 
                 1924 
                 0 
                 TGGCCTCAGCTGGTGGAGCT 
               
               
                   
               
               
                 410774 
                 5-10-5 
                 406 
                 1936 
                 1955 
                 0 
                 TGTTGGTGGCAGTGGACACG 
               
               
                   
               
               
                 410775 
                 5-10-5 
                 407 
                 1962 
                 1981 
                 0 
                 AGCTGCAGCCTGTGAGGACG 
               
               
                   
               
               
                 410776 
                 5-10-5 
                 408 
                 1990 
                 2009 
                 0 
                 GTGCCAAGGTCCTCCACCTC 
               
               
                   
               
               
                 410777 
                 5-10-5 
                 409 
                 2010 
                 2029 
                 0 
                 TCAGCACAGGCGGCTTGTGG 
               
               
                   
               
               
                 410778 
                 5-10-5 
                 410 
                 2040 
                 2059 
                 0 
                 CCACGCACTGGTTGGGCTGA 
               
               
                   
               
               
                 410779 
                 5-10-5 
                 416 
                 2120 
                 2139 
                 0 
                 CGGGATTCCATGCTCCTTGA 
               
               
                   
               
               
                 410780 
                 5-10-5 
                 417 
                 2150 
                 2169 
                 0 
                 GCAGGCCACGGTCACCTGCT 
               
               
                   
               
               
                 410781 
                 5-10-5 
                 418 
                 2187 
                 2206 
                 0 
                 GGAGGGCACTGCAGCCAGTC 
               
               
                   
               
               
                 410782 
                 5-10-5 
                 429 
                 2325 
                 2344 
                 0 
                 CCAGGTGCCGGCTCCGGCAG 
               
               
                   
               
               
                 410783 
                 5-10-5 
                 430 
                 2335 
                 2354 
                 0 
                 GAGGCCTGCGCCAGGTGCCG 
               
               
                   
               
            
           
         
       
     
     In certain embodiments, gap-widened antisense compounds are targeted to a PCSK9 nucleic acid. In certain such embodiments, gap-widened antisense compounds are targeted to SEQ ID NO: 1. In certain such embodiments, the nucleotide sequences illustrated in Table 2 have a 3-14-3 gap-widened motif. Table 4 illustrates gap-widened antisense compounds targeted to SEQ ID NO: 1, having a 3-14-3 motif, where the gap segment comprises 2′-deoxynucleotides and each wing segment comprises nucleotides comprising a 2′-O-methoxyethyl sugar modification. Internucleoside linkages are phosphorthioate, and cytidines are 5-methylcytidines. 
     
       
         
           
               
             
               
                 TABLE 4 
               
             
            
               
                   
               
               
                 Gapmer antisense compounds having a 3-14-3 motif targeted to SEQ ID NO: 1 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                   
                   
                 5′ Target 
                 3′ Target 
                   
                   
               
               
                   
                   
                 SEQ 
                 Site on 
                 Site on 
                   
                   
               
               
                   
                   
                 ID 
                 SEQ ID 
                 SEQ ID 
                   
                   
               
               
                 Isis No 
                 Motif 
                 NO 
                 NO: 1 
                 NO: 1 
                 Mismatches 
                 Sequence (5′-3′) 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                 399871 
                 3-14-3 
                 4 
                 135 
                 154 
                 0 
                 GCGCGGAATCCTGGCTGGGA 
               
               
                   
               
               
                 399872 
                 3-14-3 
                 5 
                 242 
                 261 
                 0 
                 GAGGAGACCTAGAGGCCGTG 
               
               
                   
               
               
                 399873 
                 3-14-3 
                 6 
                 300 
                 319 
                 0 
                 AGGACCGCCTGGAGCTGACG 
               
               
                   
               
               
                 399874 
                 3-14-3 
                 7 
                 410 
                 429 
                 0 
                 ACGCAAGGCTAGCACCAGCT 
               
               
                   
               
               
                 399949 
                 3-14-3 
                 8 
                 417 
                 436 
                 0 
                 CCTCGGAACGCAAGGCTAGC 
               
               
                   
               
               
                 399875 
                 3-14-3 
                 9 
                 480 
                 499 
                 0 
                 CCTTGGCGCAGCGGTGGAAG 
               
               
                   
               
               
                 399876 
                 3-14-3 
                 10 
                 561 
                 580 
                 0 
                 GGCGGGCAGTGCGCTCTGAC 
               
               
                   
               
               
                 399877 
                 3-14-3 
                 11 
                 600 
                 619 
                 0 
                 TGGTGAGGTATCCCCGGCGG 
               
               
                   
               
               
                 399950 
                 3-14-3 
                 12 
                 606 
                 625 
                 0 
                 GGATCTTGGTGAGGTATCCC 
               
               
                   
               
               
                 399951 
                 3-14-3 
                 13 
                 615 
                 634 
                 0 
                 AGACATGCAGGATCTTGGTG 
               
               
                   
               
               
                 399878 
                 3-14-3 
                 14 
                 620 
                 639 
                 0 
                 ATGGAAGACATGCAGGATCT 
               
               
                   
               
               
                 399879 
                 3-14-3 
                 15 
                 646 
                 665 
                 0 
                 TTCACCAGGAAGCCAGGAAG 
               
               
                   
               
               
                 399952 
                 3-14-3 
                 16 
                 651 
                 670 
                 0 
                 TCATCTTCACCAGGAAGCCA 
               
               
                   
               
               
                 399880 
                 3-14-3 
                 17 
                 705 
                 724 
                 0 
                 CCTCGATGTAGTCGACATGG 
               
               
                   
               
               
                 399881 
                 3-14-3 
                 18 
                 785 
                 804 
                 0 
                 GTATTCATCCGCCCGGTACC 
               
               
                   
               
               
                 399882 
                 3-14-3 
                 19 
                 835 
                 854 
                 0 
                 CTGGTGTCTAGGAGATACAC 
               
               
                   
               
               
                 399953 
                 3-14-3 
                 20 
                 840 
                 859 
                 0 
                 GTATGCTGGTGTCTAGGAGA 
               
               
                   
               
               
                 399883 
                 3-14-3 
                 21 
                 860 
                 879 
                 0 
                 GATTTCCCGGTGGTCACTCT 
               
               
                   
               
               
                 399954 
                 3-14-3 
                 22 
                 866 
                 885 
                 0 
                 GCCCTCGATTTCCCGGTGGT 
               
               
                   
               
               
                 399955 
                 3-14-3 
                 23 
                 880 
                 899 
                 0 
                 GTGACCATGACCCTGCCCTC 
               
               
                   
               
               
                 399884 
                 3-14-3 
                 24 
                 890 
                 909 
                 0 
                 CTCGAAGTCGGTGACCATGA 
               
               
                   
               
               
                 399885 
                 3-14-3 
                 25 
                 923 
                 942 
                 0 
                 GTGGAAGCGGGTCCCGTCCT 
               
               
                   
               
               
                 399886 
                 3-14-3 
                 26 
                 970 
                 989 
                 0 
                 ACCCCTGCCAGGTGGGTGCC 
               
               
                   
               
               
                 399956 
                 3-14-3 
                 27 
                 975 
                 994 
                 0 
                 TGACCACCCCTGCCAGGTGG 
               
               
                   
               
               
                 399887 
                 3-14-3 
                 28 
                 1004 
                 1023 
                 0 
                 ACCCTTGGCCACGCCGGCAT 
               
               
                   
               
               
                 399888 
                 3-14-3 
                 29 
                 1040 
                 1059 
                 0 
                 TTGGCAGTTGAGCACGCGCA 
               
               
                   
               
               
                 399957 
                 3-14-3 
                 30 
                 1045 
                 1064 
                 0 
                 TTCCCTTGGCAGTTGAGCAC 
               
               
                   
               
               
                 399889 
                 3-14-3 
                 31 
                 1077 
                 1096 
                 0 
                 CCAGGCCTATGAGGGTGCCG 
               
               
                   
               
               
                 399890 
                 3-14-3 
                 32 
                 1098 
                 1117 
                 0 
                 GCTGGCTTTTCCGAATAAAC 
               
               
                   
               
               
                 399891 
                 3-14-3 
                 33 
                 1210 
                 1229 
                 0 
                 GTGACCAGCACGACCCCAGC 
               
               
                   
               
               
                 399892 
                 3-14-3 
                 149 
                 1297 
                 1316 
                 0 
                 TGGGCATTGGTGGCCCCAAC 
               
               
                   
               
               
                 399893 
                 3-14-3 
                 34 
                 1326 
                 1345 
                 0 
                 CCAAAGTCCCCAGGGTCACC 
               
               
                   
               
               
                 399894 
                 3-14-3 
                 128 
                 1330 
                 1349 
                 0 
                 GTCCCCAAAGTCCCCAGGGT 
               
               
                   
               
               
                 399958 
                 3-14-3 
                 35 
                 1335 
                 1354 
                 0 
                 AGTTGGTCCCCAAAGTCCCC 
               
               
                   
               
               
                 399895 
                 3-14-3 
                 36 
                 1340 
                 1359 
                 0 
                 GCCAAAGTTGGTCCCCAAAG 
               
               
                   
               
               
                 399959 
                 3-14-3 
                 37 
                 1352 
                 1371 
                 0 
                 GTCCACACAGCGGCCAAAGT 
               
               
                   
               
               
                 399896 
                 3-14-3 
                 38 
                 1361 
                 1380 
                 0 
                 GGCAAAGAGGTCCACACAGC 
               
               
                   
               
               
                 399897 
                 3-14-3 
                 39 
                 1389 
                 1408 
                 0 
                 TGGAGGCACCAATGATGTCC 
               
               
                   
               
               
                 399960 
                 3-14-3 
                 40 
                 1400 
                 1419 
                 0 
                 GCTGCAGTCGCTGGAGGCAC 
               
               
                   
               
               
                 399961 
                 3-14-3 
                 41 
                 1411 
                 1430 
                 0 
                 ACAAAGCAGGTGCTGCAGTC 
               
               
                   
               
               
                 399898 
                 3-14-3 
                 101 
                 1465 
                 1484 
                 0 
                 ATGGCTGCAATGCCAGCCAC 
               
               
                   
               
               
                 399962 
                 3-14-3 
                 42 
                 1470 
                 1489 
                 0 
                 GCATCATGGCTGCAATGCCA 
               
               
                   
               
               
                 399963 
                 3-14-3 
                 43 
                 1478 
                 1497 
                 0 
                 GGCAGACAGCATCATGGCTG 
               
               
                   
               
               
                 399964 
                 3-14-3 
                 44 
                 1526 
                 1545 
                 0 
                 GAAGTGGATCAGTCTCTGCC 
               
               
                   
               
               
                 399899 
                 3-14-3 
                 45 
                 1534 
                 1553 
                 0 
                 TTGGCAGAGAAGTGGATCAG 
               
               
                   
               
               
                 399965 
                 3-14-3 
                 46 
                 1539 
                 1558 
                 0 
                 CATCTTTGGCAGAGAAGTGG 
               
               
                   
               
               
                 399966 
                 3-14-3 
                 47 
                 1545 
                 1564 
                 0 
                 TGATGACATCTTTGGCAGAG 
               
               
                   
               
               
                 399967 
                 3-14-3 
                 48 
                 1552 
                 1571 
                 0 
                 GCCTCATTGATGACATCTTT 
               
               
                   
               
               
                 399968 
                 3-14-3 
                 49 
                 1564 
                 1583 
                 0 
                 TCAGGGAACCAGGCCTCATT 
               
               
                   
               
               
                 399900 
                 3-14-3 
                 50 
                 1569 
                 1588 
                 0 
                 GGTCCTCAGGGAACCAGGCC 
               
               
                   
               
               
                 399901 
                 3-14-3 
                 87 
                 1576 
                 1595 
                 0 
                 ACCCGCTGGTCCTCAGGGAA 
               
               
                   
               
               
                 399969 
                 3-14-3 
                 51 
                 1583 
                 1602 
                 0 
                 GGTCAGTACCCGCTGGTCCT 
               
               
                   
               
               
                 399902 
                 3-14-3 
                 119 
                 1605 
                 1624 
                 0 
                 GCAGGGCGGCCACCAGGTTG 
               
               
                   
               
               
                 399903 
                 3-14-3 
                 52 
                 1640 
                 1659 
                 0 
                 AAACAGCTGCCAACCTGCCC 
               
               
                   
               
               
                 399970 
                 3-14-3 
                 53 
                 1645 
                 1664 
                 0 
                 CTGCAAAACAGCTGCCAACC 
               
               
                   
               
               
                 399904 
                 3-14-3 
                 54 
                 1675 
                 1694 
                 0 
                 GTAGGCCCCGAGTGTGCTGA 
               
               
                   
               
               
                 399971 
                 3-14-3 
                 55 
                 1740 
                 1759 
                 0 
                 AGAAACTGGAGCAGCTCAGC 
               
               
                   
               
               
                 399972 
                 3-14-3 
                 56 
                 1746 
                 1765 
                 0 
                 TCCTGGAGAAACTGGAGCAG 
               
               
                   
               
               
                 399905 
                 3-14-3 
                 57 
                 1812 
                 1831 
                 0 
                 CGTTGTGGGCCCGGCAGACC 
               
               
                   
               
               
                 399906 
                 3-14-3 
                 58 
                 1858 
                 1877 
                 0 
                 AGCAGGCAGCACCTGGCAAT 
               
               
                   
               
               
                 399907 
                 3-14-3 
                 59 
                 1920 
                 1939 
                 0 
                 CACGGGTCCCCATGCTGGCC 
               
               
                   
               
               
                 399908 
                 3-14-3 
                 60 
                 2100 
                 2119 
                 0 
                 CTTTGCATTCCAGACCTGGG 
               
               
                   
               
               
                 399973 
                 3-14-3 
                 61 
                 2105 
                 2124 
                 0 
                 CTTGACTTTGCATTCCAGAC 
               
               
                   
               
               
                 399909 
                 3-14-3 
                 62 
                 2310 
                 2329 
                 0 
                 GGCAGCAGATGGCAACGGCT 
               
               
                   
               
               
                 399910 
                 3-14-3 
                 154 
                 2410 
                 2429 
                 0 
                 TTTTAAAGCTCAGCCCCAGC 
               
               
                   
               
               
                 399974 
                 3-14-3 
                 63 
                 2415 
                 2434 
                 0 
                 AACCATTTTAAAGCTCAGCC 
               
               
                   
               
               
                 399911 
                 3-14-3 
                 64 
                 2504 
                 2523 
                 0 
                 TCAAGGGCCAGGCCAGCAGC 
               
               
                   
               
               
                 399975 
                 3-14-3 
                 65 
                 2509 
                 2528 
                 0 
                 CCCACTCAAGGGCCAGGCCA 
               
               
                   
               
               
                 399976 
                 3-14-3 
                 122 
                 2582 
                 2601 
                 0 
                 GGAGGGAGCTTCCTGGCACC 
               
               
                   
               
               
                 399912 
                 3-14-3 
                 66 
                 2597 
                 2616 
                 0 
                 ATGCCCCACAGTGAGGGAGG 
               
               
                   
               
               
                 399913 
                 3-14-3 
                 67 
                 2606 
                 2625 
                 0 
                 AATGGTGAAATGCCCCACAG 
               
               
                   
               
               
                 399914 
                 3-14-3 
                 153 
                 2649 
                 2668 
                 0 
                 TTGGGAGCAGCTGGCAGCAC 
               
               
                   
               
               
                 399915 
                 3-14-3 
                 68 
                 2750 
                 2769 
                 0 
                 CATGGGAAGAATCCTGCCTC 
               
               
                   
               
               
                 399916 
                 3-14-3 
                 69 
                 2832 
                 2851 
                 0 
                 GGAGATGAGGGCCATCAGCA 
               
               
                   
               
               
                 399917 
                 3-14-3 
                 70 
                 2900 
                 2919 
                 0 
                 TAGATGCCATCCAGAAAGCT 
               
               
                   
               
               
                 399977 
                 3-14-3 
                 71 
                 2906 
                 2925 
                 0 
                 TCTGGCTAGATGCCATCCAG 
               
               
                   
               
               
                 399918 
                 3-14-3 
                 72 
                 2983 
                 3002 
                 0 
                 GGCATAGAGCAGAGTAAAGG 
               
               
                   
               
               
                 399978 
                 3-14-3 
                 73 
                 2988 
                 3007 
                 0 
                 AGCCTGGCATAGAGCAGAGT 
               
               
                   
               
               
                 399979 
                 3-14-3 
                 135 
                 2994 
                 3013 
                 0 
                 TAGCACAGCCTGGCATAGAG 
               
               
                   
               
               
                 399919 
                 3-14-3 
                 112 
                 3227 
                 3246 
                 0 
                 GAAGAGGCTTGGCTTCAGAG 
               
               
                   
               
               
                 399980 
                 3-14-3 
                 74 
                 3233 
                 3252 
                 0 
                 AAGTAAGAAGAGGCTTGGCT 
               
               
                   
               
               
                 399920 
                 3-14-3 
                 75 
                 3437 
                 3456 
                 0 
                 GCTCAAGGAGGGACAGTTGT 
               
               
                   
               
               
                 399921 
                 3-14-3 
                 76 
                 3472 
                 3491 
                 0 
                 AAAGATAAATGTCTGCTTGC 
               
               
                   
               
               
                 399981 
                 3-14-3 
                 77 
                 3477 
                 3496 
                 0 
                 ACCCAAAAGATAAATGTCTG 
               
               
                   
               
               
                 399922 
                 3-14-3 
                 78 
                 3543 
                 3562 
                 0 
                 TCTTCAAGTTACAAAAGCAA 
               
               
                   
               
               
                 399982 
                 3-14-3 
                 99 
                 3550 
                 3569 
                 0 
                 ATAAATATCTTCAAGTTACA 
               
               
                   
               
               
                 410574 
                 3-14-3 
                 184 
                 597 
                 616 
                 0 
                 TGAGGTATCCCCGGCGGGCA 
               
               
                   
               
               
                 410575 
                 3-14-3 
                 185 
                 598 
                 617 
                 0 
                 GTGAGGTATCCCCGGCGGGC 
               
               
                   
               
               
                 410576 
                 3-14-3 
                 186 
                 599 
                 618 
                 0 
                 GGTGAGGTATCCCCGGCGGG 
               
               
                   
               
               
                 410577 
                 3-14-3 
                 187 
                 601 
                 620 
                 0 
                 TTGGTGAGGTATCCCCGGCG 
               
               
                   
               
               
                 410578 
                 3-14-3 
                 188 
                 602 
                 621 
                 0 
                 CTTGGTGAGGTATCCCCGGC 
               
               
                   
               
               
                 410579 
                 3-14-3 
                 189 
                 603 
                 622 
                 0 
                 TCTTGGTGAGGTATCCCCGG 
               
               
                   
               
               
                 410580 
                 3-14-3 
                 190 
                 604 
                 623 
                 0 
                 ATCTTGGTGAGGTATCCCCG 
               
               
                   
               
               
                 410581 
                 3-14-3 
                 191 
                 605 
                 624 
                 0 
                 GATCTTGGTGAGGTATCCCC 
               
               
                   
               
               
                 410582 
                 3-14-3 
                 192 
                 607 
                 626 
                 0 
                 AGGATCTTGGTGAGGTATCC 
               
               
                   
               
               
                 405604 
                 3-14-3 
                 236 
                 963 
                 982 
                 0 
                 CCAGGTGGGTGCCATGACTG 
               
               
                   
               
               
                 410583 
                 3-14-3 
                 243 
                 997 
                 1016 
                 0 
                 GCCACGCCGGCATCCCGGCC 
               
               
                   
               
               
                 410584 
                 3-14-3 
                 244 
                 998 
                 1017 
                 0 
                 GGCCACGCCGGCATCCCGGC 
               
               
                   
               
               
                 410585 
                 3-14-3 
                 245 
                 999 
                 1018 
                 0 
                 TGGCCACGCCGGCATCCCGG 
               
               
                   
               
               
                 410586 
                 3-14-3 
                 246 
                 1000 
                 1019 
                 0 
                 TTGGCCACGCCGGCATCCCG 
               
               
                   
               
               
                 410587 
                 3-14-3 
                 247 
                 1001 
                 1020 
                 0 
                 CTTGGCCACGCCGGCATCCC 
               
               
                   
               
               
                 410588 
                 3-14-3 
                 248 
                 1002 
                 1021 
                 0 
                 CCTTGGCCACGCCGGCATCC 
               
               
                   
               
               
                 410589 
                 3-14-3 
                 249 
                 1003 
                 1022 
                 0 
                 CCCTTGGCCACGCCGGCATC 
               
               
                   
               
               
                 410590 
                 3-14-3 
                 250 
                 1005 
                 1024 
                 0 
                 CACCCTTGGCCACGCCGGCA 
               
               
                   
               
               
                 410591 
                 3-14-3 
                 251 
                 1006 
                 1025 
                 0 
                 GCACCCTTGGCCACGCCGGC 
               
               
                   
               
               
                 410592 
                 3-14-3 
                 252 
                 1007 
                 1026 
                 0 
                 GGCACCCTTGGCCACGCCGG 
               
               
                   
               
               
                 410593 
                 3-14-3 
                 253 
                 1008 
                 1027 
                 0 
                 TGGCACCCTTGGCCACGCCG 
               
               
                   
               
               
                 410594 
                 3-14-3 
                 254 
                 1009 
                 1028 
                 0 
                 CTGGCACCCTTGGCCACGCC 
               
               
                   
               
               
                 410595 
                 3-14-3 
                 255 
                 1010 
                 1029 
                 0 
                 GCTGGCACCCTTGGCCACGC 
               
               
                   
               
               
                 410596 
                 3-14-3 
                 348 
                 1562 
                 1581 
                 0 
                 AGGGAACCAGGCCTCATTGA 
               
               
                   
               
               
                 410597 
                 3-14-3 
                 349 
                 1563 
                 1582 
                 0 
                 CAGGGAACCAGGCCTCATTG 
               
               
                   
               
               
                 410598 
                 3-14-3 
                 350 
                 1565 
                 1584 
                 0 
                 CTCAGGGAACCAGGCCTCAT 
               
               
                   
               
               
                 410599 
                 3-14-3 
                 351 
                 1566 
                 1585 
                 0 
                 CCTCAGGGAACCAGGCCTCA 
               
               
                   
               
               
                 410600 
                 3-14-3 
                 352 
                 1567 
                 1586 
                 0 
                 TCCTCAGGGAACCAGGCCTC 
               
               
                   
               
               
                 410601 
                 3-14-3 
                 353 
                 1568 
                 1587 
                 0 
                 GTCCTCAGGGAACCAGGCCT 
               
               
                   
               
               
                 410602 
                 3-14-3 
                 354 
                 1570 
                 1589 
                 0 
                 TGGTCCTCAGGGAACCAGGC 
               
               
                   
               
               
                 410603 
                 3-14-3 
                 355 
                 1571 
                 1590 
                 0 
                 CTGGTCCTCAGGGAACCAGG 
               
               
                   
               
               
                 410604 
                 3-14-3 
                 356 
                 1572 
                 1591 
                 0 
                 GCTGGTCCTCAGGGAACCAG 
               
               
                   
               
               
                 405641 
                 3-14-3 
                 373 
                 1737 
                 1756 
                 0 
                 AACTGGAGCAGCTCAGCAGC 
               
               
                   
               
               
                 410605 
                 3-14-3 
                 376 
                 1849 
                 1868 
                 0 
                 CACCTGGCAATGGCGTAGAC 
               
               
                   
               
               
                 410606 
                 3-14-3 
                 377 
                 1850 
                 1869 
                 0 
                 GCACCTGGCAATGGCGTAGA 
               
               
                   
               
               
                 410607 
                 3-14-3 
                 378 
                 1851 
                 1870 
                 0 
                 AGCACCTGGCAATGGCGTAG 
               
               
                   
               
               
                 410608 
                 3-14-3 
                 379 
                 1852 
                 1871 
                 0 
                 CAGCACCTGGCAATGGCGTA 
               
               
                   
               
               
                 410609 
                 3-14-3 
                 380 
                 1853 
                 1872 
                 0 
                 GCAGCACCTGGCAATGGCGT 
               
               
                   
               
               
                 410610 
                 3-14-3 
                 381 
                 1854 
                 1873 
                 0 
                 GGCAGCACCTGGCAATGGCG 
               
               
                   
               
               
                 410611 
                 3-14-3 
                 382 
                 1855 
                 1874 
                 0 
                 AGGCAGCACCTGGCAATGGC 
               
               
                   
               
               
                 410612 
                 3-14-3 
                 383 
                 1856 
                 1875 
                 0 
                 CAGGCAGCACCTGGCAATGG 
               
               
                   
               
               
                 410613 
                 3-14-3 
                 384 
                 1857 
                 1876 
                 0 
                 GCAGGCAGCACCTGGCAATG 
               
               
                   
               
               
                 410614 
                 3-14-3 
                 385 
                 1859 
                 1878 
                 0 
                 TAGCAGGCAGCACCTGGCAA 
               
               
                   
               
               
                 410615 
                 3-14-3 
                 388 
                 1915 
                 1934 
                 0 
                 GTCCCCATGCTGGCCTCAGC 
               
               
                   
               
               
                 410616 
                 3-14-3 
                 389 
                 1916 
                 1935 
                 0 
                 GGTCCCCATGCTGGCCTCAG 
               
               
                   
               
               
                 410617 
                 3-14-3 
                 390 
                 1917 
                 1936 
                 0 
                 GGGTCCCCATGCTGGCCTCA 
               
               
                   
               
               
                 410618 
                 3-14-3 
                 391 
                 1918 
                 1937 
                 0 
                 CGGGTCCCCATGCTGGCCTC 
               
               
                   
               
               
                 410619 
                 3-14-3 
                 392 
                 1919 
                 1938 
                 0 
                 ACGGGTCCCCATGCTGGCCT 
               
               
                   
               
               
                 410620 
                 3-14-3 
                 393 
                 1921 
                 1940 
                 0 
                 ACACGGGTCCCCATGCTGGC 
               
               
                   
               
               
                 410621 
                 3-14-3 
                 394 
                 1922 
                 1941 
                 0 
                 GACACGGGTCCCCATGCTGG 
               
               
                   
               
               
                 410622 
                 3-14-3 
                 395 
                 1923 
                 1942 
                 0 
                 GGACACGGGTCCCCATGCTG 
               
               
                   
               
               
                 410623 
                 3-14-3 
                 396 
                 1924 
                 1943 
                 0 
                 TGGACACGGGTCCCCATGCT 
               
               
                   
               
               
                 410624 
                 3-14-3 
                 397 
                 1925 
                 1944 
                 0 
                 GTGGACACGGGTCCCCATGC 
               
               
                   
               
               
                 410625 
                 3-14-3 
                 398 
                 1926 
                 1945 
                 0 
                 AGTGGACACGGGTCCCCATG 
               
               
                   
               
               
                 410626 
                 3-14-3 
                 399 
                 1927 
                 1946 
                 0 
                 CAGTGGACACGGGTCCCCAT 
               
               
                   
               
               
                 410627 
                 3-14-3 
                 400 
                 1928 
                 1947 
                 0 
                 GCAGTGGACACGGGTCCCCA 
               
               
                   
               
               
                 410628 
                 3-14-3 
                 401 
                 1929 
                 1948 
                 0 
                 GGCAGTGGACACGGGTCCCC 
               
               
                   
               
               
                 410629 
                 3-14-3 
                 402 
                 1930 
                 1949 
                 0 
                 TGGCAGTGGACACGGGTCCC 
               
               
                   
               
               
                 410630 
                 3-14-3 
                 403 
                 1931 
                 1950 
                 0 
                 GTGGCAGTGGACACGGGTCC 
               
               
                   
               
               
                 410631 
                 3-14-3 
                 404 
                 1932 
                 1951 
                 0 
                 GGTGGCAGTGGACACGGGTC 
               
               
                   
               
               
                 410632 
                 3-14-3 
                 405 
                 1933 
                 1952 
                 0 
                 TGGTGGCAGTGGACACGGGT 
               
               
                   
               
               
                 410633 
                 3-14-3 
                 411 
                 2101 
                 2120 
                 0 
                 ACTTTGCATTCCAGACCTGG 
               
               
                   
               
               
                 410634 
                 3-14-3 
                 412 
                 2102 
                 2121 
                 0 
                 GACTTTGCATTCCAGACCTG 
               
               
                   
               
               
                 410635 
                 3-14-3 
                 413 
                 2103 
                 2122 
                 0 
                 TGACTTTGCATTCCAGACCT 
               
               
                   
               
               
                 410636 
                 3-14-3 
                 414 
                 2104 
                 2123 
                 0 
                 TTGACTTTGCATTCCAGACC 
               
               
                   
               
               
                 410637 
                 3-14-3 
                 419 
                 2305 
                 2324 
                 0 
                 CAGATGGCAACGGCTGTCAC 
               
               
                   
               
               
                 410638 
                 3-14-3 
                 420 
                 2306 
                 2325 
                 0 
                 GCAGATGGCAACGGCTGTCA 
               
               
                   
               
               
                 410639 
                 3-14-3 
                 421 
                 2307 
                 2326 
                 0 
                 AGCAGATGGCAACGGCTGTC 
               
               
                   
               
               
                 410640 
                 3-14-3 
                 422 
                 2308 
                 2327 
                 0 
                 CAGCAGATGGCAACGGCTGT 
               
               
                   
               
               
                 410641 
                 3-14-3 
                 423 
                 2309 
                 2328 
                 0 
                 GCAGCAGATGGCAACGGCTG 
               
               
                   
               
               
                 410642 
                 3-14-3 
                 424 
                 2311 
                 2330 
                 0 
                 CGGCAGCAGATGGCAACGGC 
               
               
                   
               
               
                 410643 
                 3-14-3 
                 425 
                 2312 
                 2331 
                 0 
                 CCGGCAGCAGATGGCAACGG 
               
               
                   
               
               
                 410644 
                 3-14-3 
                 426 
                 2313 
                 2332 
                 0 
                 TCCGGCAGCAGATGGCAACG 
               
               
                   
               
               
                 410645 
                 3-14-3 
                 427 
                 2314 
                 2333 
                 0 
                 CTCCGGCAGCAGATGGCAAC 
               
               
                   
               
               
                 410646 
                 3-14-3 
                 428 
                 2315 
                 2334 
                 0 
                 GCTCCGGCAGCAGATGGCAA 
               
               
                   
               
            
           
         
       
     
     In certain embodiments, gap-widened antisense compounds are targeted to a PCSK9 nucleic acid. In certain such embodiments, gap-widened antisense compounds are targeted to SEQ ID NO: 1. In certain such embodiments, the nucleotide sequences illustrated in Table 2 have a 2-13-5 gap-widened motif. Table 5 illustrates gap-widened antisense compounds targeted to SEQ ID NO: 1, having a 2-13-5 motif, where the gap segment comprises 2′-deoxynucleotides and each wing segment comprises nucleotides comprising a 2′-O-methoxyethyl sugar modification. Internucleoside linkages are phosphorthioate, and cytidines are 5-methylcytidines. 
     
       
         
           
               
             
               
                 TABLE 5 
               
             
            
               
                   
               
               
                 Gapmer antisense compounds having a 2-13-5 motif targeted to SEQ ID NO: 1 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                   
                   
                 5′ Target 
                 3′ Target 
                   
                   
               
               
                   
                   
                 SEQ 
                 Site on 
                 Site on 
                   
                   
               
               
                   
                   
                 ID 
                 SEQ ID 
                 SEQ ID 
                   
                   
               
               
                 Isis No 
                 Motif 
                 NO 
                 NO: 1 
                 NO: 1 
                 Mismatches 
                 Sequence (5′-3′) 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                 410647 
                 2-13-5 
                 184 
                 597 
                 616 
                 0 
                 TGAGGTATCCCCGGCGGGCA 
               
               
                   
               
               
                 410648 
                 2-13-5 
                 185 
                 598 
                 617 
                 0 
                 GTGAGGTATCCCCGGCGGGC 
               
               
                   
               
               
                 410649 
                 2-13-5 
                 186 
                 599 
                 618 
                 0 
                 GGTGAGGTATCCCCGGCGGG 
               
               
                   
               
               
                 410650 
                 2-13-5 
                 11 
                 600 
                 619 
                 0 
                 TGGTGAGGTATCCCCGGCGG 
               
               
                   
               
               
                 410651 
                 2-13-5 
                 187 
                 601 
                 620 
                 0 
                 TTGGTGAGGTATCCCCGGCG 
               
               
                   
               
               
                 410652 
                 2-13-5 
                 188 
                 602 
                 621 
                 0 
                 CTTGGTGAGGTATCCCCGGC 
               
               
                   
               
               
                 410653 
                 2-13-5 
                 189 
                 603 
                 622 
                 0 
                 TCTTGGTGAGGTATCCCCGG 
               
               
                   
               
               
                 410654 
                 2-13-5 
                 190 
                 604 
                 623 
                 0 
                 ATCTTGGTGAGGTATCCCCG 
               
               
                   
               
               
                 410655 
                 2-13-5 
                 191 
                 605 
                 624 
                 0 
                 GATCTTGGTGAGGTATCCCC 
               
               
                   
               
               
                 410656 
                 2-13-5 
                 12 
                 606 
                 625 
                 0 
                 GGATCTTGGTGAGGTATCCC 
               
               
                   
               
               
                 410657 
                 2-13-5 
                 192 
                 607 
                 626 
                 0 
                 AGGATCTTGGTGAGGTATCC 
               
               
                   
               
               
                 410658 
                 2-13-5 
                 243 
                 997 
                 1016 
                 0 
                 GCCACGCCGGCATCCCGGCC 
               
               
                   
               
               
                 410659 
                 2-13-5 
                 244 
                 998 
                 1017 
                 0 
                 GGCCACGCCGGCATCCCGGC 
               
               
                   
               
               
                 410660 
                 2-13-5 
                 245 
                 999 
                 1018 
                 0 
                 TGGCCACGCCGGCATCCCGG 
               
               
                   
               
               
                 410661 
                 2-13-5 
                 246 
                 1000 
                 1019 
                 0 
                 TTGGCCACGCCGGCATCCCG 
               
               
                   
               
               
                 410662 
                 2-13-5 
                 247 
                 1001 
                 1020 
                 0 
                 CTTGGCCACGCCGGCATCCC 
               
               
                   
               
               
                 410663 
                 2-13-5 
                 248 
                 1002 
                 1021 
                 0 
                 CCTTGGCCACGCCGGCATCC 
               
               
                   
               
               
                 410664 
                 2-13-5 
                 249 
                 1003 
                 1022 
                 0 
                 CCCTTGGCCACGCCGGCATC 
               
               
                   
               
               
                 410665 
                 2-13-5 
                 28 
                 1004 
                 1023 
                 0 
                 ACCCTTGGCCACGCCGGCAT 
               
               
                   
               
               
                 410666 
                 2-13-5 
                 250 
                 1005 
                 1024 
                 0 
                 CACCCTTGGCCACGCCGGCA 
               
               
                   
               
               
                 410667 
                 2-13-5 
                 251 
                 1006 
                 1025 
                 0 
                 GCACCCTTGGCCACGCCGGC 
               
               
                   
               
               
                 410668 
                 2-13-5 
                 252 
                 1007 
                 1026 
                 0 
                 GGCACCCTTGGCCACGCCGG 
               
               
                   
               
               
                 410669 
                 2-13-5 
                 253 
                 1008 
                 1027 
                 0 
                 TGGCACCCTTGGCCACGCCG 
               
               
                   
               
               
                 410670 
                 2-13-5 
                 254 
                 1009 
                 1028 
                 0 
                 CTGGCACCCTTGGCCACGCC 
               
               
                   
               
               
                 410671 
                 2-13-5 
                 255 
                 1010 
                 1029 
                 0 
                 GCTGGCACCCTTGGCCACGC 
               
               
                   
               
               
                 410672 
                 2-13-5 
                 348 
                 1562 
                 1581 
                 0 
                 AGGGAACCAGGCCTCATTGA 
               
               
                   
               
               
                 410673 
                 2-13-5 
                 349 
                 1563 
                 1582 
                 0 
                 CAGGGAACCAGGCCTCATTG 
               
               
                   
               
               
                 410674 
                 2-13-5 
                 49 
                 1564 
                 1583 
                 0 
                 TCAGGGAACCAGGCCTCATT 
               
               
                   
               
               
                 410675 
                 2-13-5 
                 350 
                 1565 
                 1584 
                 0 
                 CTCAGGGAACCAGGCCTCAT 
               
               
                   
               
               
                 410676 
                 2-13-5 
                 351 
                 1566 
                 1585 
                 0 
                 CCTCAGGGAACCAGGCCTCA 
               
               
                   
               
               
                 410677 
                 2-13-5 
                 352 
                 1567 
                 1586 
                 0 
                 TCCTCAGGGAACCAGGCCTC 
               
               
                   
               
               
                 410678 
                 2-13-5 
                 353 
                 1568 
                 1587 
                 0 
                 GTCCTCAGGGAACCAGGCCT 
               
               
                   
               
               
                 410679 
                 2-13-5 
                 50 
                 1569 
                 1588 
                 0 
                 GGTCCTCAGGGAACCAGGCC 
               
               
                   
               
               
                 410680 
                 2-13-5 
                 354 
                 1570 
                 1589 
                 0 
                 TGGTCCTCAGGGAACCAGGC 
               
               
                   
               
               
                 410681 
                 2-13-5 
                 355 
                 1571 
                 1590 
                 0 
                 CTGGTCCTCAGGGAACCAGG 
               
               
                   
               
               
                 410682 
                 2-13-5 
                 356 
                 1572 
                 1591 
                 0 
                 GCTGGTCCTCAGGGAACCAG 
               
               
                   
               
               
                 410683 
                 2-13-5 
                 376 
                 1849 
                 1868 
                 0 
                 CACCTGGCAATGGCGTAGAC 
               
               
                   
               
               
                 410684 
                 2-13-5 
                 377 
                 1850 
                 1869 
                 0 
                 GCACCTGGCAATGGCGTAGA 
               
               
                   
               
               
                 410685 
                 2-13-5 
                 378 
                 1851 
                 1870 
                 0 
                 AGCACCTGGCAATGGCGTAG 
               
               
                   
               
               
                 410686 
                 2-13-5 
                 379 
                 1852 
                 1871 
                 0 
                 CAGCACCTGGCAATGGCGTA 
               
               
                   
               
               
                 410687 
                 2-13-5 
                 380 
                 1853 
                 1872 
                 0 
                 GCAGCACCTGGCAATGGCGT 
               
               
                   
               
               
                 410688 
                 2-13-5 
                 381 
                 1854 
                 1873 
                 0 
                 GGCAGCACCTGGCAATGGCG 
               
               
                   
               
               
                 410689 
                 2-13-5 
                 382 
                 1855 
                 1874 
                 0 
                 AGGCAGCACCTGGCAATGGC 
               
               
                   
               
               
                 410690 
                 2-13-5 
                 383 
                 1856 
                 1875 
                 0 
                 CAGGCAGCACCTGGCAATGG 
               
               
                   
               
               
                 410691 
                 2-13-5 
                 384 
                 1857 
                 1876 
                 0 
                 GCAGGCAGCACCTGGCAATG 
               
               
                   
               
               
                 410692 
                 2-13-5 
                 58 
                 1858 
                 1877 
                 0 
                 AGCAGGCAGCACCTGGCAAT 
               
               
                   
               
               
                 410693 
                 2-13-5 
                 385 
                 1859 
                 1878 
                 0 
                 TAGCAGGCAGCACCTGGCAA 
               
               
                   
               
               
                 410694 
                 2-13-5 
                 388 
                 1915 
                 1934 
                 0 
                 GTCCCCATGCTGGCCTCAGC 
               
               
                   
               
               
                 410695 
                 2-13-5 
                 389 
                 1916 
                 1935 
                 0 
                 GGTCCCCATGCTGGCCTCAG 
               
               
                   
               
               
                 410696 
                 2-13-5 
                 390 
                 1917 
                 1936 
                 0 
                 GGGTCCCCATGCTGGCCTCA 
               
               
                   
               
               
                 410697 
                 2-13-5 
                 391 
                 1918 
                 1937 
                 0 
                 CGGGTCCCCATGCTGGCCTC 
               
               
                   
               
               
                 410698 
                 2-13-5 
                 392 
                 1919 
                 1938 
                 0 
                 ACGGGTCCCCATGCTGGCCT 
               
               
                   
               
               
                 410699 
                 2-13-5 
                 59 
                 1920 
                 1939 
                 0 
                 CACGGGTCCCCATGCTGGCC 
               
               
                   
               
               
                 410700 
                 2-13-5 
                 393 
                 1921 
                 1940 
                 0 
                 ACACGGGTCCCCATGCTGGC 
               
               
                   
               
               
                 410701 
                 2-13-5 
                 394 
                 1922 
                 1941 
                 0 
                 GACACGGGTCCCCATGCTGG 
               
               
                   
               
               
                 410702 
                 2-13-5 
                 395 
                 1923 
                 1942 
                 0 
                 GGACACGGGTCCCCATGCTG 
               
               
                   
               
               
                 410703 
                 2-13-5 
                 396 
                 1924 
                 1943 
                 0 
                 TGGACACGGGTCCCCATGCT 
               
               
                   
               
               
                 410704 
                 2-13-5 
                 397 
                 1925 
                 1944 
                 0 
                 GTGGACACGGGTCCCCATGC 
               
               
                   
               
               
                 410705 
                 2-13-5 
                 398 
                 1926 
                 1945 
                 0 
                 AGTGGACACGGGTCCCCATG 
               
               
                   
               
               
                 410706 
                 2-13-5 
                 399 
                 1927 
                 1946 
                 0 
                 CAGTGGACACGGGTCCCCAT 
               
               
                   
               
               
                 410707 
                 2-13-5 
                 400 
                 1928 
                 1947 
                 0 
                 GCAGTGGACACGGGTCCCCA 
               
               
                   
               
               
                 410708 
                 2-13-5 
                 401 
                 1929 
                 1948 
                 0 
                 GGCAGTGGACACGGGTCCCC 
               
               
                   
               
               
                 410709 
                 2-13-5 
                 402 
                 1930 
                 1949 
                 0 
                 TGGCAGTGGACACGGGTCCC 
               
               
                   
               
               
                 410710 
                 2-13-5 
                 403 
                 1931 
                 1950 
                 0 
                 GTGGCAGTGGACACGGGTCC 
               
               
                   
               
               
                 410711 
                 2-13-5 
                 404 
                 1932 
                 1951 
                 0 
                 GGTGGCAGTGGACACGGGTC 
               
               
                   
               
               
                 410712 
                 2-13-5 
                 405 
                 1933 
                 1952 
                 0 
                 TGGTGGCAGTGGACACGGGT 
               
               
                   
               
               
                 410713 
                 2-13-5 
                 60 
                 2100 
                 2119 
                 0 
                 CTTTGCATTCCAGACCTGGG 
               
               
                   
               
               
                 410714 
                 2-13-5 
                 411 
                 2101 
                 2120 
                 0 
                 ACTTTGCATTCCAGACCTGG 
               
               
                   
               
               
                 410715 
                 2-13-5 
                 412 
                 2102 
                 2121 
                 0 
                 GACTTTGCATTCCAGACCTG 
               
               
                   
               
               
                 410716 
                 2-13-5 
                 413 
                 2103 
                 2122 
                 0 
                 TGACTTTGCATTCCAGACCT 
               
               
                   
               
               
                 410717 
                 2-13-5 
                 414 
                 2104 
                 2123 
                 0 
                 TTGACTTTGCATTCCAGACC 
               
               
                   
               
               
                 410718 
                 2-13-5 
                 61 
                 2105 
                 2124 
                 0 
                 CTTGACTTTGCATTCCAGAC 
               
               
                   
               
               
                 410719 
                 2-13-5 
                 419 
                 2305 
                 2324 
                 0 
                 CAGATGGCAACGGCTGTCAC 
               
               
                   
               
               
                 410720 
                 2-13-5 
                 420 
                 2306 
                 2325 
                 0 
                 GCAGATGGCAACGGCTGTCA 
               
               
                   
               
               
                 410721 
                 2-13-5 
                 421 
                 2307 
                 2326 
                 0 
                 AGCAGATGGCAACGGCTGTC 
               
               
                   
               
               
                 410722 
                 2-13-5 
                 422 
                 2308 
                 2327 
                 0 
                 CAGCAGATGGCAACGGCTGT 
               
               
                   
               
               
                 410723 
                 2-13-5 
                 423 
                 2309 
                 2328 
                 0 
                 GCAGCAGATGGCAACGGCTG 
               
               
                   
               
               
                 410724 
                 2-13-5 
                 62 
                 2310 
                 2329 
                 0 
                 GGCAGCAGATGGCAACGGCT 
               
               
                   
               
               
                 410725 
                 2-13-5 
                 424 
                 2311 
                 2330 
                 0 
                 CGGCAGCAGATGGCAACGGC 
               
               
                   
               
               
                 410726 
                 2-13-5 
                 425 
                 2312 
                 2331 
                 0 
                 CCGGCAGCAGATGGCAACGG 
               
               
                   
               
               
                 410727 
                 2-13-5 
                 426 
                 2313 
                 2332 
                 0 
                 TCCGGCAGCAGATGGCAACG 
               
               
                   
               
               
                 410728 
                 2-13-5 
                 427 
                 2314 
                 2333 
                 0 
                 CTCCGGCAGCAGATGGCAAC 
               
               
                   
               
               
                 410729 
                 2-13-5 
                 428 
                 2315 
                 2334 
                 0 
                 GCTCCGGCAGCAGATGGCAA 
               
               
                   
               
            
           
         
       
     
     In certain embodiments, gap-widened antisense compounds are targeted to a PCSK9 nucleic acid. In certain such embodiments, gap-widened antisense compounds are targeted to SEQ ID NO: 1. In certain such embodiments, the nucleotide sequences illustrated in Table 2 have a 3-13-4 gap-widened motif. Table 6 illustrates gap-widened antisense compounds targeted to SEQ ID NO: 1, having a 3-13-4 motif, where the gap segment comprises 2′-deoxynucleotides and each wing segment comprises nucleotides comprising a 2′-O-methoxyethyl sugar modification. Internucleoside linkages are phosphorthioate, and cytidines are 5-methylcytidines. 
     
       
         
           
               
             
               
                 TABLE 6 
               
             
            
               
                   
               
               
                 Gapmer antisense compounds having a 3-13-4 
               
               
                 motif targeted to SEQ ID NO: 1 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                   
                 SEQ 
                 5′ 
                 3′ 
                   
                   
               
               
                   
                   
                 ID 
                 start 
                 Start 
                 Mis- 
                   
               
               
                 Oligo 
                 Motif 
                 NO: 
                 site 
                 Site 
                 matches 
                 OligoSeq 
               
               
                   
               
               
                 405526 
                 3-13-4 
                 236 
                  963 
                  982 
                 0 
                 CCAGGTGGGT 
               
               
                   
                   
                   
                   
                   
                   
                 GCCATGACTG 
               
               
                   
               
               
                 405557 
                 3-13-4 
                  50 
                 1569 
                 1588 
                 0 
                 GGTCCTCAGG 
               
               
                   
                   
                   
                   
                   
                   
                 GAACCAGGCC 
               
               
                   
               
               
                 405564 
                 3-13-4 
                 373 
                 1737 
                 1756 
                 0 
                 AACTGGAGCA 
               
               
                   
                   
                   
                   
                   
                   
                 GCTCAGCAGC 
               
               
                   
               
            
           
         
       
     
     The following embodiments set forth target regions of PCSK9 nucleic acids. Also illustrated are examples of antisense compounds targeted to the target regions. It is understood that the sequence set forth in each SEQ ID NO is independent of any modification to a sugar moiety, an internucleoside linkage, or a nucleobase. As such, antisense compounds defined by a SEQ ID NO may comprise, independently, one or more modifications to a sugar moiety, an internucleoside linkage, or a nucleobase. Antisense compounds described by Isis Number (Isis No) indicate a combination of nucleobase sequence and motif. 
     In certain embodiments, antisense compounds target a range of a PCSK9 nucleic acid. In certain embodiment, such compounds contain at least an 8 nucleotide core sequence in common. In certain embodiments, such compounds sharing at least an 8 nucleotide core sequence targets the following nucleotide regions of SEQ ID NO: 1: 294-317, 406-440, 406-526, 410-436, 410-499, 446-526, 545-581, 591-619, 591-704, 591-743, 595-622, 600-626, 600-639, 600-670, 601-628, 602-628, 603-630, 611-636, 620-647, 638-665, 648-674, 657-684, 705-743, 782-810, 821-859, 835-859, 835-917, 835-942, 860-887, 860-899, 860-909, 860-917, 869-895, 878-905, 888-909, 923-952, 960-1034, 960-1173, 960-986, 967-991, 970-1023, 970-1064, 970-1117, 970-996, 977-1004, 985-1011, 989-1016, 992-1019, 997-1024, 997-1024, 998-1025, 999-1026, 1000-1027, 1001-1028, 1002-1021, 1002-1029, 1003-1029, 1004-1029, 1005-1029, 1006-1029, 1007-1034, 1036-1061, 1045-1072, 1076-1096, 1088-1115, 1098-1123, 1200-1251, 1210-1237, 1219-1245, 1228-1251, 1273-1444, 1295-1316, 1318-1345, 1328-1354, 1337-1361, 1344-1371, 1354-1377, 1380-1406, 1389-1416, 1400-1426, 1409-1434, 1465-1491, 1465-1602, 1474-1499, 1482-1519, 1513-1540, 1523-1549, 1526-1602, 1526-1624, 1532-1558, 1541-1568, 1552-1579, 1560-1587, 1561-1589, 1564-1591, 1565-1592, 1566-1592, 1567-1592, 1570-1597, 1571-1599, 1605-1706, 1628-1706, 1640-1666, 1672-1698, 1681-1706, 1735-1761, 1735-1765, 1740-1765, 1849-1876, 1849-1879, 1850-1877, 1851-1877, 1852-1878, 1852-1879, 1853-1879, 1854-1879, 1905-1955, 1915-1942, 1916-1943, 1917-1944, 1918-1945, 1919-1946, 1920-1939, 1920-1947, 1921-1948, 1922-1949, 1923-1950, 1924-1951, 1925-1952, 1926-1952, 1927-1952, 1928-1955, 1962-2059, 2040-2126, 2100-2126, 2100-2139, 2100-2206, 2101-2126, 2305-2332, 2305-2354, 2306-2333, 2307-2334, 2308-2334, 2309-2334, 2310-2334, 2410-2434, 2504-2528, 2509-2528, 2582-2625, 2606-2668, 2828-2855, 2832-2851, 2900-2927, 2900-2929, 2902-2927, 2983-3007, 2983-3013, 3227-3252, 3227-3456, 3472-3496, or 3543-3569. 
     In certain embodiments, a target region is nucleotides 294-317 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 294-317 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 159 or 160. In certain such embodiments, an antisense compound targeted to nucleotides 294-317 of SEQ ID NO: 1 is selected from ISIS NOs: 410742 or 405999. 
     In certain embodiments, a target region is nucleotides 406-440 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 406-440 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 7, 8, 162, 163, 164, 165, 166, 167, 168, 169 or 170. In certain such embodiments, an antisense compound targeted to nucleotides 406-440 of SEQ ID NO: 1 is selected from ISIS NOs: 405861, 405862, 405863, 405864, 395152, 399874, 405865, 405866, 405867, 405868, 399793, 399949, or 410743. 
     In certain embodiments, a target region is nucleotides 406-526 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 406-526 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 7, 8, 9, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, or 176. In certain such embodiments, an antisense compound targeted to nucleotides 406-526 of SEQ ID NO: 1 is selected from ISIS NOs: 405861, 405862, 405863, 405864, 395152, 399874, 405865, 405866, 405867, 405868, 399793, 399950, 410743, 410744, 410745, 395153, 399875, 406000, 406001, 406002 or 410746. 
     In certain embodiments, a target region is nucleotides 410-436 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 410-436 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 7, 8, 166, 167, 168, 169 or 169. In certain such embodiments, an antisense compound targeted to nucleotides 410-436 of SEQ ID NO: 1 is selected from ISIS NOs: 395152, 399874, 405865, 405866, 405867, 405868, or 399793. 
     In certain embodiments, a target region is nucleotides 410-499 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 410-499 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a 5 nucleotide sequence selected from SEQ ID NOs: 7, 8, 9, 166, 167, 169, 170, 171 or 172. In certain such embodiments, an antisense compound targeted to nucleotides 410-499 of SEQ ID NO: 1 is selected from ISIS NOs: 395152, 399874, 405865, 405866, 405867, 405868, 399793, 399949, 410743, 410744, 410745, 395153, or 399875. 
     In certain embodiments, a target region is nucleotides 446-526 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 446-526 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 9, 171, 172, 173, 174, 175 or 176. In certain such embodiments, an antisense compound targeted to nucleotides 446-526 of SEQ ID NO: 1 is selected from ISIS NOs: 410744, 410745, 395153, 399875, 406000, 406001, 406002, or 410746. 
     In certain embodiments, a target region is nucleotides 545-581 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 545-581 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 10, 177, 178, 179, 180 or 181. In certain such embodiments, an antisense compound targeted to nucleotides 545-581 of SEQ ID NO: 1 is selected from ISIS NOs: 410747, 406003, 406004, 406005, 395154, 399876, or 406006. 
     In certain embodiments, a target region is nucleotides 591-619 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 591-619 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 11, 182, 183, 184, 185 or 186. In certain such embodiments, an antisense compound targeted to nucleotides 591-619 of SEQ ID NO: 1 is selected from ISIS NOs: 410748, 406007, 410529, 410574, 410647, 410530, 410575, 410648, 410531, 410576, 410649, 395155, 399877, or 410650. 
     In certain embodiments, a target region is nucleotides 591-704 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 591-704 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 11, 12, 13, 14, 15, 16, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, or 208. In certain such embodiments, an antisense compound targeted to nucleotides 591-704 of SEQ ID NO: 1 is selected from ISIS NOs: 410748, 406007, 410529, 410574, 410647, 410530, 410575, 410648, 410531, 410576, 410649, 395155, 399877, 410650, 410532, 410577, 410651, 406008, 410578, 410652, 410533, 410579, 410653, 406009, 410580, 410654, 410534, 410581, 410655, 399794, 399950, 410656, or 410751. 
     In certain embodiments, a target region is nucleotides 591-743 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 591-743 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 11, 12, 13, 14, 15, 16, 17, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, or 209. In certain such embodiments, an antisense compound targeted to nucleotides 591-743 of SEQ ID NO: 1 is selected from ISIS NOs: 410748, 406007, 410529, 410574, 410647, 410530, 410575, 410648, 410531, 410576, 410649, 395155, 399877, 410650, 410532, 410577, 410651, 406008, 410578, 410652, 410533, 410579, 410653, 406009, 410580, 410654, 410534, 410581, 410655, 399794, 399950, 410656, or 410752. 
     In certain embodiments, a target region is nucleotides 595-622 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 595-622 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 11, 183, 184, 185, 186, 187, 188, or 189. In certain such embodiments, an antisense compound targeted to nucleotides 595-622 of SEQ ID NO: 1 is selected from ISIS NOs: 406007, 410529, 410574, 410647, 410530, 410575, 410648, 410531, 410576, 410649, 395155, 399877, 410650, 410532, 410577, 410651, 406008, 410578, 410652, 410533, 410579, or 410653. 
     In certain embodiments, a target region is nucleotides 600-626 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 600-626 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 11, 12, 87, 188, 189, 190, 191, or 192. In certain such embodiments, an antisense compound targeted to nucleotides 600-626 of SEQ ID NO: 1 is selected from ISIS NOs: 395155, 399877, 410650, 410532, 410577, 410651, 406008, 410578, 410652, 410533, 410579, 410653, 406009, 410580, 410654, 410534, 410581, 410655, 399794, 399950, 410656, 410535, 410582, or 410657. 
     In certain embodiments, a target region is nucleotides 600-639 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 600-639 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 11, 12, 13, 14, 187, 188, 189, 190, 191, 192, 193, 194, 195, or 196. In certain such embodiments, an antisense compound targeted to nucleotides 600-639 of SEQ ID NO: 1 is selected from ISIS NOs: 395155, 399877, 410650, 410532, 410577, 410651, 406008, 410578, 410652, 410533, 410579, 410653, 406009, 410580, 410654, 410534, 410581, 410655, 399794, 399950, 410656, 410535, 410582, 410657, 406010, 406011, 406012, 399795, 399951, 406013, 395156, or 399878. 
     In certain embodiments, a target region is nucleotides 600-670 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 600-670 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 11, 12, 13, 14, 15, 16, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, or 199. In certain such embodiments, an antisense compound targeted to nucleotides 600-670 of SEQ ID NO: 1 is selected from ISIS NOs: 395155, 399877, 410650, 410532, 410577, 410651, 406008, 410578, 410652, 410533, 410579, 410653, 406009, 410580, 410654, 410534, 410581, 410655, 399794, 399950, 410656, 410535, 410582, 410657, 406010, 406011, 406012, 399795, 399951, 406013, 395156, 399878, or 399952. 
     In certain embodiments, a target region is nucleotides 601-628 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 601-628 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 12, 187, 188, 189, 190, 191, 192 or 193. In certain such embodiments, an antisense compound targeted to nucleotides 601-628 of SEQ ID NO: 1 is selected from ISIS NOs: 410532, 410577, 410651, 406008, 410578, 410652, 410533, 410579, 410653, 406009, 410580, 410654, 410534, 410581, 410655, 399794, 399950, 410656, 410535, 410582, 410657, or 406010. 
     In certain embodiments, a target region is nucleotides 602-628 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 602-628 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 12, 188, 189, 190, 191, 192 or 193. In certain such embodiments, an antisense compound targeted to nucleotides 602-628 of SEQ ID NO: 1 is selected from ISIS NOs: 406008, 410578, 410652, 410533, 410579, 410653, 406009, 410580, 410654, 410534, 410581, 410655, 399794, 399950, 410656, 410535, 410582, 410657, or 406010. 
     In certain embodiments, a target region is nucleotides 603-630 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 603-630 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 12, 189, 190, 191, 192, 193 or 194. In certain such embodiments, an antisense compound targeted to nucleotides 603-630 of SEQ ID NO: 1 is selected from ISIS NOs: 410533, 410579, 410653, 406009, 410580, 410654, 410534, 410581, 410655, 399794, 399950, 410656, 410535, 410582, 410657, 406010, or 406011. 
     In certain embodiments, a target region is nucleotides 611-636 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 611-636 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 13, 194, 195 or 196. In certain such embodiments, an antisense compound targeted to nucleotides 611-636 of SEQ ID NO: 1 is selected from ISIS NOs: 406011, 406012, 399795, 399951, or 406013. 
     In certain embodiments, a target region is nucleotides 620-647 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 620-647 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 14 or 197. In certain such embodiments, an antisense compound targeted to nucleotides 620-647 of SEQ ID NO: 1 is selected from ISIS NOs: 395156, 399878, or 410749. 
     In certain embodiments, a target region is nucleotides 638-665 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 638-665 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 15 or 198. In certain such embodiments, an antisense compound targeted to nucleotides 638-665 of SEQ ID NO: 1 is selected from ISIS NOs: 410750, 395157, or 399879. 
     In certain embodiments, a target region is nucleotides 648-674 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 648-674 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 16, 199, 200, or 201. In certain such embodiments, an antisense compound targeted to nucleotides 648-674 of SEQ ID NO: 1 is selected from ISIS NOs: 406014, 399796, 399952, 406015, or 406016. 
     In certain embodiments, a target region is nucleotides 657-684 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 657-684 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 202, 203, 204, 205, or 206. In certain such embodiments, an antisense compound targeted to nucleotides 657-684 of SEQ ID NO: 1 is selected from ISIS NOs: 410730, 406017, 406018, 406019, or 406020. 
     In certain embodiments, a target region is nucleotides 705-743 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 705-743 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 17 or 209. In certain such embodiments, an antisense compound targeted to nucleotides 705-743 of SEQ ID NO: 1 is selected from ISIS NOs: 395158, 399880, or 410752. 
     In certain embodiments, a target region is nucleotides 782-810 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 782-810 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 18, 210, 211, 212, 213, or 214. In certain such embodiments, an antisense compound targeted to nucleotides 782-810 of SEQ ID NO: 1 is selected from ISIS NOs: 406021, 406022, 395159, 399881, 406023, 406024, or 410732. 
     In certain embodiments, a target region is nucleotides 821-859 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 821-859 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 19, 20, 215, 216 or 217. In certain such embodiments, an antisense compound targeted to nucleotides 821-859 of SEQ ID NO: 1 is selected from ISIS NOs: 410753, 406025, 395160, 399882, 406026, 399797, or 399953. 
     In certain embodiments, a target region is nucleotides 835-859 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 835-859 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 19, 20 or 217. In certain such embodiments, an antisense compound targeted to nucleotides 835-859 of SEQ ID NO: 1 is selected from ISIS NOs: 395160, 399882, 406026, 399797, or 399953. 
     In certain embodiments, a target region is nucleotides 835-917 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 835-917 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 19, 20, 21, 22, 23, 24, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232 or 233. In certain such embodiments, an antisense compound targeted to nucleotides 835-917 of SEQ ID NO: 1 is selected from ISIS NOs: 395160, 399882, 406026, 399797, 399953, 395161, 399883, 405869, 405870, 405871, 405872, 399798, 399954, 405873, 405874, 405875, 405876, 406027, 406028, 406029, 399799, 399955, 406030, 406031, 410733, 406032, 395162, 399884, or 410754. 
     In certain embodiments, a target region is nucleotides 835-942 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 835-942 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 19, 20, 21, 22, 23, 24, 25, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, or 233. In certain such embodiments, an antisense compound targeted to nucleotides 835-942 of SEQ ID NO: 1 is selected from ISIS NOs: 395160, 399882, 406026, 399797, 399953, 395161, 399883, 405869, 405870, 405871, 405872, 399798, 399954, 405873, 405874, 405875, 405876, 406027, 406028, 406029, 399799, 399955, 406030, 406031, 410733, 406032, 395162, 399884, 410754, 395163, or 399885. 
     In certain embodiments, a target region is nucleotides 860-887 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 860-887 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 21, 22, 218, 219, 220, 221, 222 or 223. In certain such embodiments, an antisense compound targeted to nucleotides 860-887 of SEQ ID NO: 1 is selected from ISIS NOs: 395161, 399883, 405869, 405870, 405871, 405872, 399798, 399954, 405873, or 405874. 
     In certain embodiments, a target region is nucleotides 860-899 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 860-899 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 21, 22, 23, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227 or 228. In certain such embodiments, an antisense compound targeted to nucleotides 860-899 of SEQ ID NO: 1 is selected from ISIS NOs: 395161, 399883, 405869, 405870, 405871, 405872, 399798, 399954, 405873, 405874, 405875, 405876, 406027, 406028, 406029, 399799, or 399955. 
     In certain embodiments, a target region is nucleotides 860-909 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 860-909 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 21, 22, 23, 24, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231 or 232. In certain such embodiments, an antisense compound targeted to nucleotides 860-909 of SEQ ID NO: 1 is selected from ISIS NOs: 395161, 399883, 405869, 405870, 405871, 405872, 399798, 399954, 405873, 405874, 405875, 405876, 406027, 406028, 406029, 399799, 399955, 406030, 406031, 410733, 406032, 395162, or 399884. 
     In certain embodiments, a target region is nucleotides 860-917 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 860-917 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 21, 22, 23, 24, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, or 233. In certain such embodiments, an antisense compound targeted to nucleotides 860-917 of SEQ ID NO: 1 is selected from ISIS NOs: 395161, 399883, 405869, 405870, 405871, 405872, 399798, 399954, 405873, 405874, 405875, 405876, 406027, 406028, 406029, 399799, 399955, 406030, 406031, 410733, 406032, 395162, 399884, or 410754. 
     In certain embodiments, a target region is nucleotides 869-895 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 869-895 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 224, 225, 226, or 227. In certain such embodiments, an antisense compound targeted to nucleotides 869-895 of SEQ ID NO: 1 is selected from ISIS NOs: 405875, 405876, 406027, or 406028. 
     In certain embodiments, a target region is nucleotides 878-905 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 878-905 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 23, 228, 229, 230, or 231. In certain such embodiments, an antisense compound targeted to nucleotides 878-905 of SEQ ID NO: 1 is selected from ISIS NOs: 406029, 399799, 399955, 406030, 406031, or 410733. 
     In certain embodiments, a target region is nucleotides 888-909 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 888-909 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 24 or 232. In certain such embodiments, an antisense compound targeted to nucleotides 888-909 of SEQ ID NO: 1 is selected from ISIS NOs: 406032, 395162, or 399884. 
     In certain embodiments, a target region is nucleotides 923-952 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 923-952 of SEQ ID NO: 1. In 5 certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 25 or 234. In certain such embodiments, an antisense compound targeted to nucleotides 923-952 of SEQ ID NO: 1 is selected from ISIS NOs: 395163, 399885, or 410755. 
     In certain embodiments, a target region is nucleotides 960-1034 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 960-1034 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 26, 27, 28, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, or 256. In certain such embodiments, an antisense compound targeted to nucleotides 960-1034 of SEQ ID NO: 1 is selected from ISIS NOs: 410756, 405526, 405604, 406033, 395164, 399886, 406034, 399800, 399956, 406035, 410757, 406036, 406037, 410536, 410583, 410658, 410537, 410584, 410659, 406038, 410585, 410660, 405877, 410586, 410661, 405878, 410587, 410662, 405879, 410588, 410663, 405880, or 410758. 
     In certain embodiments, a target region is nucleotides 960-1173 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 960-1173 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 26, 27, 28, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, or 273. In certain such embodiments, an antisense compound targeted to nucleotides 960-1173 of SEQ ID NO: 1 is selected from ISIS NOs: 410756, 405526, 405604, 406033, 395164, 399886, 406034, 399800, 399956, 406035, 410757, 406036, 406037, 410536, 410583, 410658, 410537, 410584, 410659, 406038, 410585, 410660, 405877, 410586, 410661, 405878, 410587, 410662, 405879, 410588, 410663, 405880, or 410763. 
     In certain embodiments, a target region is nucleotides 960-986 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 960-986 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 235, 236, or 237. In certain such embodiments, an antisense compound targeted to nucleotides 960-986 of SEQ ID NO: 1 is selected from ISIS NOs: 410756, 405526, 405604, or 406033. 
     In certain embodiments, a target region is nucleotides 967-991 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 967-991 of SEQ ID NO: 1. In 5 certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 237 or 238. In certain such embodiments, an antisense compound targeted to nucleotides 967-991 of SEQ ID NO: 1 is selected from ISIS NOs: 406033 or 406034. 
     In certain embodiments, a target region is nucleotides 970-1023 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 970-1023 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 26, 27, 28, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, or 249. In certain such embodiments, an antisense compound targeted to nucleotides 970-1023 of SEQ ID NO: 1 is selected from ISIS NOs: 395164, 399886, 406034, 399800, 399956, 406035, 410757, 406036, 406037, 410536, 410583, 410658, 410537, 410584, 410659, 406038, 410585, 410660, 405877, 410586, 410661, 405878, 410587, 410662, 405879, 410588, 410663, 405880, 410589, 410664, 395165, 399887, or 410665. 
     In certain embodiments, a target region is nucleotides 970-1064 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 970-1064 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 26, 27, 28, 29, 30, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 149, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, or 263. In certain such embodiments, an antisense compound targeted to nucleotides 970-1064 of SEQ ID NO: 1 is selected from ISIS NOs: 395164, 399886, 406034, 399800, 399956, 406035, 410757, 406036, 406037, 410536, 410583, 410658, 410537, 410584, 410659, 406038, 410585, 410660, 405877, 410586, 410661, 405878, 410587, 410662, 405879, 410588, 410663, 405880, 410589, 410664, 395165, 399887, or 399957. 
     In certain embodiments, a target region is nucleotides 970-1117 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 970-1117 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 26, 27, 28, 29, 30, 31, 32, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 149, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, or 266. In certain such embodiments, an antisense compound targeted to nucleotides 970-1117 of SEQ ID NO: 1 is selected from ISIS NOs: 395164, 399886, 406034, 399800, 399956, 406035, 410757, 406036, 406037, 410536, 410583, 410658, 410537, 410584, 410659, 406038, 410585, 410660, 405877, 410586, 410661, 405878, 410587, 410662, 405879, 410588, 410663, 405880, 410589, 410664, 395165, 399887, or 399890. 
     In certain embodiments, a target region is nucleotides 970-996 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 970-996 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 26, 27, or 238. In certain such embodiments, an antisense compound targeted to nucleotides 970-996 of SEQ ID NO: 1 is selected from ISIS NOs: 395164, 399886, 406034, 399800, 399956, or 406035. 
     In certain embodiments, a target region is nucleotides 977-1004 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 977-1004 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 239 or 240. In certain such embodiments, an antisense compound targeted to nucleotides 977-1004 of SEQ ID NO: 1 is selected from ISIS NOs: 406035 or 410757. 
     In certain embodiments, a target region is nucleotides 985-1011 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 985-1011 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 240, 241, or 242. In certain such embodiments, an antisense compound targeted to nucleotides 985-1011 of SEQ ID NO: 1 is selected from ISIS NOs: 410757, 406036, or 406037. 
     In certain embodiments, a target region is nucleotides 989-1016 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 989-1016 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 241, 242, or 243. In certain such embodiments, an antisense compound targeted to nucleotides 989-1016 of SEQ ID NO: 1 is selected from ISIS NOs: 406036, 406037, 410536, 410583, or 410658. 
     In certain embodiments, a target region is nucleotides 992-1019 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 992-1019 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 242, 243, 244, 245, or 246. In certain such embodiments, an antisense compound targeted to nucleotides 992-1019 of SEQ ID NO: 1 is selected from ISIS NOs: 406037, 410536, 410583, 410658, 410537, 410584, 410659, 406038, 410585, 410660, 405877, 410586, or 410661. 
     In certain embodiments, a target region is nucleotides 997-1024 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 997-1024 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 243, 244, 245, 246, 247, 248, 249, or 250. In certain such embodiments, an antisense compound targeted to nucleotides 997-1024 of SEQ ID NO: 1 is selected from ISIS NOs: 410536, 410583, 410658, 410537, 410584, 410659, 406038, 410585, 410660, 405877, 410586, 410661, 405878, 410587, 410662, 405879, 410588, 410663, 405880, 410589, 410664, 395165, 399887, 409126, 410665, 405881, 410590, or 410666. 
     In certain embodiments, a target region is nucleotides 997-1024 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 997-1024 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 243, 244, 245, 246, 247, 248, 249, or 250. In certain such embodiments, an antisense compound targeted to nucleotides 997-1024 of SEQ ID NO: 1 is selected from ISIS NOs: 410536, 410583, 410658, 410537, 410584, 410659, 406038, 410585, 410660, 405877, 410586, 410661, 405878, 410587, 410662, 405879, 410588, 410663, 405880, 410589, 410664, 395165, 399887, 409126, 410665, 405881, 410590, or 410666. 
     In certain embodiments, a target region is nucleotides 998-1025 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 998-1025 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 28, 244, 245, 246, 247, 248, 249, 250, or 251. In certain such embodiments, an antisense compound targeted to nucleotides 998-1025 of SEQ ID NO: 1 is selected from ISIS NOs: 410537, 410584, 410659, 406038, 410585, 410660, 405877, 410586, 410661, 405878, 410587, 410662, 405879, 410588, 410663, 405880, 410589, 410664, 395165, 399887, 410665, 405881, 410590, 410666, 405882, 410591, or 410667. 
     In certain embodiments, a target region is nucleotides 999-1026 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 999-1026 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 28, 245, 246, 247, 248, 249, 250, 251, or 252. In certain such embodiments, an antisense compound targeted to nucleotides 999-1026 of SEQ ID NO: 1 is selected from ISIS NOs: 406038, 410585, 410660, 405877, 410586, 410661, 405878, 410587, 410662, 405879, 410588, 410663, 405880, 410589, 410664, 395165, 399887, 410665, 405881, 410590, 410666, 405882, 410591, 410667, 405833, 410592, or 410668. 
     In certain embodiments, a target region is nucleotides 1000-1027 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 1000-1027 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 28, 246, 247, 248, 249, 250, 251, 252, or 253. In certain such embodiments, an antisense compound targeted to nucleotides 1000-1027 of SEQ ID NO: 1 is selected from ISIS NOs: 405877, 410586, 410661, 405878, 410587, 410662, 405879, 410588, 410663, 405880, 410589, 410664, 395165, 399887, 410665, 405881, 410590, 410666, 405882, 410591, 410667, 405833, 410592, 410668, 405884, 410593, or 410669. 
     In certain embodiments, a target region is nucleotides 1001-1028 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 1001-1028 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 28, 247, 248, 249, 250, 251, 252, 253, or 254. In certain such embodiments, an antisense compound targeted to nucleotides 1001-1028 of SEQ ID NO: 1 is selected from ISIS NOs: 405878, 410587, 410662, 405879, 410588, 410663, 405880, 410589, 410664, 395165, 399887, 410665, 405881, 410590, 410666, 405882, 410591, 410667, 405833, 410592, 410668, 405884, 410593, 410669, 410538, 410594, or 410670. 
     In certain embodiments, a target region is nucleotides 1002-1021 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 1002-1021 of SEQ ID NO: 1. In one such embodiment, an antisense compound targeted to nucleotides 1002-1021 of SEQ ID NO: 1 is ISIS NO: 405879. 
     In certain embodiments, a target region is nucleotides 1002-1029 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 1002-1029 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 28, 248, 249, 250, 251, 252, 253, 254, or 255. In certain such embodiments, an antisense compound targeted to nucleotides 1002-1029 of SEQ ID NO: 1 is selected from ISIS NOs: 405879, 410588, 410663, 405880, 410589, 410664, 395165, 399887, 410665, 405881, 410590, 410666, 405882, 410591, 410667, 405833, 410592, 410668, 405884, 410593, 410669, 410538, 410594, 410670, 410539, 410595, or 410671. 
     In certain embodiments, a target region is nucleotides 1003-1029 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 1003-1029 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 28, 249, 250, 251,252, 253, 254, or 255. In certain such embodiments, an antisense compound targeted to nucleotides 1003-1029 of SEQ ID NO: 1 is selected from ISIS NOs: 405880, 410589, 410664, 395165, 399887, 409126, 410665, 405881, 410590, 410666, 405882, 410591, 410667, 405883, 410592, 410668, 405884, 410593, 410669, 410538, 410594, 410670, 410539, 410595, or 410671. 
     In certain embodiments, a target region is nucleotides 1004-1029 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 1004-1029 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 28, 250, 251,252, 253, 254, or 255. In certain such embodiments, an antisense compound targeted to nucleotides 1004-1029 of SEQ ID NO: 1 is selected from ISIS NOs: 395165, 399887, 409126, 410665, 405881, 410590, 410666, 405882, 410591, 410667, 405883, 410592, 410668, 405884, 410593, 410669, 410538, 410594, 410670, 410539, 410595, or 410671. 
     In certain embodiments, a target region is nucleotides 1005-1029 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 1005-1029 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 250, 251,252, 253, 254, or 255. In certain such embodiments, an antisense compound targeted to nucleotides 1005-1029 of SEQ ID NO: 1 is selected from ISIS NOs: 410665, 405881, 410590, 410666, 405882, 410591, 410667, 405883, 410592, 410668, 405884, 410593, 410669, 410538, 410594, 410670, 410539, 410595, or 410671. 
     In certain embodiments, a target region is nucleotides 1006-1029 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 1006-1029 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 251, 252, 253, 254, or 255. In certain such embodiments, an antisense compound targeted to nucleotides 1006-1029 of SEQ ID NO: 1 is selected from ISIS NOs: 405882, 410591, 410667, 405883, 410592, 410668, 405884, 410593, 410669, 410538, 410594, 410670, 410539, 410595, or 410671. 
     In certain embodiments, a target region is nucleotides 1007-1034 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 1007-1034 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 252, 253, 254, 255, or 256. In certain such embodiments, an antisense compound targeted to nucleotides 1007-1034 of SEQ ID NO: 1 is selected from ISIS NOs: 405883, 410592, 410668, 405884, 410593, 410669, 410538, 410594, 410670, 410539, 410595, 410671, or 410758. 
     In certain embodiments, a target region is nucleotides 1036-1061 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 1036-1061 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 29, 257, 258, or 259. In certain such embodiments, an antisense compound targeted to nucleotides 1036-1061 of SEQ ID NO: 1 is selected from ISIS NOs: 406039, 406040, 395166, 399888, or 406041. 
     In certain embodiments, a target region is nucleotides 1045-1072 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 1045-1072 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 30, 260, 261, or 262. In certain such embodiments, an antisense compound targeted to nucleotides 1045-1072 of SEQ ID NO: 1 is selected from ISIS NOs: 399801, 399957, 406042, 406043, or 406044. 
     In certain embodiments, a target region is nucleotides 1076-1096 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 1076-1096 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 31 or 264. In certain such embodiments, an antisense compound targeted to nucleotides 1076-1096 of SEQ ID NO: 1 is selected from ISIS NOs: 408642, 395167, or 399889. 
     In certain embodiments, a target region is nucleotides 1088-1115 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 1088-1115 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 265 or 266. In certain such embodiments, an antisense compound targeted to nucleotides 1088-1115 of SEQ ID NO: 1 is selected from ISIS NOs: 410760 or 406045. 
     In certain embodiments, a target region is nucleotides 1098-1123 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 1098-1123 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 32, 267, 268, or 269. In certain such embodiments, an antisense compound targeted to nucleotides 1098-1123 of SEQ ID NO: 1 is selected from ISIS NOs: 395168, 399890, 405909, 405910, or 405911. 
     In certain embodiments, a target region is nucleotides 1200-1251 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 1200-1251 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 33, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, or 285. In certain such embodiments, an antisense compound targeted to nucleotides 1200-1251 of SEQ ID NO: 1 is selected from ISIS NOs: 410764, 395169, 399891, 405913, 405914, 405915, 405916, 410734, 405917, 405918, 405919, 405920, 405921, or 405922. 
     In certain embodiments, a target region is nucleotides 1210-1237 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 1210-1237 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 33, 275, 276, 277, or 278. In certain such embodiments, an antisense compound targeted to nucleotides 1210-1237 of SEQ ID NO: 1 is selected from ISIS NOs: 395169, 399891, 405913, 405914, 405915, or 405916. 
     In certain embodiments, a target region is nucleotides 1219-1245 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 1219-1245 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 279, 280, 281 or 282. In certain such embodiments, an antisense compound targeted to nucleotides 1219-1245 of SEQ ID NO: 1 is selected from ISIS NOs: 410734, 405917, 405918, or 405919. 
     In certain embodiments, a target region is nucleotides 1228-1251 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 1228-1251 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 283, 284, or 285. In certain such embodiments, an antisense compound targeted to nucleotides 1228-1251 of SEQ ID NO: 1 is selected from ISIS NOs: 405920, 405921, or 405922. 
     In certain embodiments, a target region is nucleotides 1273-1444 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 1273-1444 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 34, 35, 36, 37, 38, 39, 40, 41, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307,308, 309, 310, 311, 312, 313, 314, 315, 316, 316, and 318. In certain such embodiments, an antisense compound targeted to nucleotides 1273-1444 of SEQ ID NO: 1 is selected from ISIS NOs: 410765, 410766, 405923, 395170, 399892, 410767, 405924, 410735, 405925, 405926, 395171, 399893, 405927, 395172, 399894, 405928, 399802, 399958, 405929, 395173, 399895, 405930, 405931, 405932, 405933, 405934, 399803, 399959, 405935, 410736, 405936, 395174, or 410769. 
     In certain embodiments, a target region is nucleotides 1295-1316 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 1295-1316 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 149 or 288. In certain such embodiments, an antisense compound targeted to nucleotides 1295-1316 of SEQ ID NO: 1 is selected from ISIS NOs: 405923, 395170, or 399892. 
     In certain embodiments, a target region is nucleotides 1318-1345 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 1318-1345 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 34, 290, 291, 292 or 293. In certain such embodiments, an antisense compound targeted to nucleotides 1318-1345 of SEQ ID NO: 1 is selected from ISIS NOs: 405924, 410735, 405925, 405926, 395171, or 399893. 
     In certain embodiments, a target region is nucleotides 1328-1354 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 1328-1354 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 35, 128, 294 or 295. In certain such embodiments, an antisense compound targeted to nucleotides 1328-1354 of SEQ ID NO: 1 is selected from ISIS NOs: 405927, 395172, 399894, 405928, 399802, or 399958. 
     In certain embodiments, a target region is nucleotides 1337-1361 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 1337-1361 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 36, 296, or 297. In certain such embodiments, an antisense compound targeted to nucleotides 1337-1361 of SEQ ID NO: 1 is selected from ISIS NOs: 405929, 395173, 399895, or 405930. 
     In certain embodiments, a target region is nucleotides 1344-1371 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 1344-1371 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 37, 298, 299, 300, or 301. In certain such embodiments, an antisense compound targeted to nucleotides 1344-1371 of SEQ ID NO: 1 is selected from ISIS NOs: 405931, 405932, 405933, 405934, 399803, or 399959. 
     In certain embodiments, a target region is nucleotides 1354-1377 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 1354-1377 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 302, 303, or 304. In certain such embodiments, an antisense compound targeted to nucleotides 1354-1377 of SEQ ID NO: 1 is selected from ISIS NOs: 405935, 410736, or 405936. 
     In certain embodiments, a target region is nucleotides 1380-1406 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 1380-1406 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 305 or 306. In certain such embodiments, an antisense compound targeted to nucleotides 1380-1406 of SEQ ID NO: 1 is selected from ISIS NOs: 410768 or 405937. 
     In certain embodiments, a target region is nucleotides 1389-1416 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 1389-1416 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 39, 307, 308, 309 or 310. In certain such embodiments, an antisense compound targeted to nucleotides 1389-1416 of SEQ ID NO: 1 is selected from ISIS NOs: 395175, 399897, 405938, 405939, 405940, or 405941. 
     In certain embodiments, a target region is nucleotides 1400-1426 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 1400-1426 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 40, 311, 312, 313, or 314. In certain such embodiments, an antisense compound targeted to nucleotides 1400-1426 of SEQ ID NO: 1 is selected from ISIS NOs: 399804, 399960, 405942, 405943, 410737, or 405944. 
     In certain embodiments, a target region is nucleotides 1409-1434 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 1409-1434 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 41, 315, 316, or 317. In certain such embodiments, an antisense compound targeted to nucleotides 1409-1434 of SEQ ID NO: 1 is selected from ISIS NOs: 405945, 399805, 399961, 405946, or 405947. 
     In certain embodiments, a target region is nucleotides 1465-1491 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 1465-1491 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 42, 101, 319, or 320. In certain such embodiments, an antisense compound targeted to nucleotides 1465-1491 of SEQ ID NO: 1 is selected from ISIS NOs: 395176, 399898, 405948, 399806, 399962, or 405949. 
     In certain embodiments, a target region is nucleotides 1465-1602 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 1465-1602 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 87, 101, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, or 359. In certain such embodiments, an antisense compound targeted to nucleotides 1465-1602 of SEQ ID NO: 1 is selected from ISIS NOs: 395176, 399898, 405948, 399806, 399962, 405949, 405950, 405951, 399807, 399963, 405952, 410738, 405953, 405954, 410770, 405955, 405956, 405957, 405958, 405959, 405960, 405961, 399808, 399964, 405962, 410739, 405963, 395177, 399899, 405964, 399809, 399965, or 399969. 
     In certain embodiments, a target region is nucleotides 1474-1499 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 1474-1499 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 43, 321, 322, or 323. In certain such embodiments, an antisense compound targeted to nucleotides 1474-1499 of SEQ ID NO: 1 is selected from ISIS NOs: 405950, 405951, 399807, 399963, or 405952. 
     In certain embodiments, a target region is nucleotides 1482-1519 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 1482-1519 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 324, 325, 326, or 327. In certain such embodiments, an antisense compound targeted to nucleotides 1482-1519 of SEQ ID NO: 1 is selected from ISIS NOs: 410738, 405953, 405954, or 410770. 
     In certain embodiments, a target region is nucleotides 1513-1540 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 1513-1540 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 328, 329, 330, 331, or 332. In certain such embodiments, an antisense compound targeted to nucleotides 1513-1540 of SEQ ID NO: 1 is selected from ISIS NOs: 405955, 405956, 405957, 405958, or 405959. 
     In certain embodiments, a target region is nucleotides 1523-1549 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 1523-1549 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 44, 333, 334, 335, or 336. In certain such embodiments, an antisense compound targeted to nucleotides 1523-1549 of SEQ ID NO: 1 is selected from ISIS NOs: 405960, 405961, 399808, 399964, 405962, or 410739. 
     In certain embodiments, a target region is nucleotides 1526-1602 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 1526-1602 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 44, 45, 46, 47, 48, 49, 50, 51, 87, 335, 336, 337, 338, 339, 340, 341, 342, 343, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, or 359. In certain such embodiments, an antisense compound targeted to nucleotides 1526-1602 of SEQ ID NO: 1 is selected from ISIS NOs: 399808, 399964, 405962, 410739, 405963, 395177, 399899, 405964, 399809, 399965, 405965, 405966, 399810, 399966, 405967, 405968, 399811, 399967, 405969, 405970, 410740, 405885, 405886, 405887, 410596, 410672, 405888, 410597, 410673, 399812, 399968, 410674, or 399969. 
     In certain embodiments, a target region is nucleotides 1526-1624 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 1526-1624 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 44, 45, 46, 47, 48, 49, 50, 51, 87, 119, 335, 336, 337, 338, 339, 340, 341, 342, 343, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, or 359. In certain such embodiments, an antisense compound targeted to nucleotides 1526-1624 of SEQ ID NO: 1 is selected from ISIS NOs: 399808, 399964, 405962, 410739, 405963, 395177, 399899, 405964, 399809, 399965, 405965, 405966, 399810, 399966, 405967, 405968, 399811, 399967, 405969, 405970, 410740, 405885, 405886, 405887, 410596, 410672, 405888, 410597, 410673, 399812, 399968, 410674, or 399902. 
     In certain embodiments, a target region is nucleotides 1532-1558 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 1532-1558 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 45, 46, 337, or 338. In certain such embodiments, an antisense compound targeted to nucleotides 1532-1558 of SEQ ID NO: 1 is selected from ISIS NOs: 405963, 395177, 399899, 405964, 399809, or 399965. 
     In certain embodiments, a target region is nucleotides 1541-1568 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 1541-1568 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 47, 340, 341, or 342. In certain such embodiments, an antisense compound targeted to nucleotides 1541-1568 of SEQ ID NO: 1 is selected from ISIS NOs: 405965, 405966, 399810, 399966, 405967, or 405968. 
     In certain embodiments, a target region is nucleotides 1552-1579 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 1552-1579 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 48, 343, 344, 345, or 346. In certain such embodiments, an antisense compound targeted to nucleotides 1552-1579 of SEQ ID NO: 1 is selected from ISIS NOs: 399811, 399967, 405969, 405970, 410740, or 405885. 
     In certain embodiments, a target region is nucleotides 1560-1587 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 1560-1587 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 49, 346, 347, 348, 349, 350, 351, 352, or 353. In certain such embodiments, an antisense compound targeted to nucleotides 1560-1587 of SEQ ID NO: 1 is selected from ISIS NOs: 405885, 405886, 405887, 410596, 410672, 405888, 410597, 410673, 399812, 399968, 410674, 405889, 410598, 410675, 405890, 410599, 410676, 405891, 410600, 410677, 405892, 410601, or 410678. 
     In certain embodiments, a target region is nucleotides 1561-1589 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 1561-1589 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 49, 50, 346, 347, 348, 349, 350, 351, 352, 353, or 354. In certain such embodiments, an antisense compound targeted to nucleotides 1561-1589 of SEQ ID NO: 1 is selected from ISIS NOs: 405886, 405887, 410596, 410672, 405888, 410597, 410673, 399812, 399968, 410674, 405889, 410598, 410675, 405890, 410599, 410676, 405891, 410600, 410677, 405892, 410601, 410678, 395178, 399900, 405557, 410679, 408653, 410602, or 410680. 
     In certain embodiments, a target region is nucleotides 1564-1591 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 1564-1591 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 49, 50, 350, 351, 352, 353, 354, 355, or 356. In certain such embodiments, an antisense compound targeted to nucleotides 1564-1591 of SEQ ID NO: 1 is selected from ISIS NOs: 399812, 399968, 410674, 405889, 410598, 410675, 405890, 410599, 410676, 405891, 410600, 410677, 405892, 410601, 410678, 395178, 399900, 405557, 410679, 408653, 410602, 410680, 405971, 410603, 410681, 410540, 410604, or 410682. 
     In certain embodiments, a target region is nucleotides 1565-1592 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 1565-1592 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 50, 350, 351, 352, 353, 354, 355, 356, or 357. In certain such embodiments, an antisense compound targeted to nucleotides 1565-1592 of SEQ ID NO: 1 is selected from ISIS NOs: 405889, 410598, 410675, 405890, 410599, 410676, 405891, 410600, 410677, 405892, 410601, 410678, 395178, 399900, 405557, 410679, 408653, 410602, 410680, 405971, 410603, 410681, 410540, 410604, 410682, or 405972. 
     In certain embodiments, a target region is nucleotides 1566-1592 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 1566-1592 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 50, 351, 352, 353, 354, 355, 356, or 357. In certain such embodiments, an antisense compound targeted to nucleotides 1566-1592 of SEQ ID NO: 1 is selected from ISIS NOs: 405890, 410599, 410676, 405891, 410600, 410677, 405892, 410601, 410678, 395178, 399900, 405557, 410679, 408653, 410602, 410680, 405971, 410603, 410681, 410540, 410604, 410682, or 405972. 
     In certain embodiments, a target region is nucleotides 1567-1592 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 1567-1592 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 50, 352, 353, 354, 355, 356, or 357. In certain such embodiments, an antisense compound targeted to nucleotides 1567-1592 of SEQ ID NO: 1 is selected from ISIS NOs: 405891, 410600, 410677, 405892, 410601, 410678, 395178, 399900, 405557, 410679, 408653, 410602, 410680, 405971, 410603, 410681, 410540, 410604, 410682, or 405972. 
     In certain embodiments, a target region is nucleotides 1570-1597 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 1570-1597 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 354, 355, 356, 357 or 358. In certain such embodiments, an antisense compound targeted to nucleotides 1570-1597 of SEQ ID NO: 1 is selected from ISIS NOs: 408653, 410602, 410680, 405971, 410603, 410681, 410540, 410604, 410682, 405972 or 405973. 
     In certain embodiments, a target region is nucleotides 1571-1599 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 1571-1599 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 87, 356, 357, 358, or 359. In certain such embodiments, an antisense compound targeted to nucleotides 1571-1599 of SEQ ID NO: 1 is selected from ISIS NOs: 405971, 410603, 410681, 410540, 410604, 410682, 405972, 395179, 399901, 405973, or 405974. 
     In certain embodiments, a target region is nucleotides 1605-1706 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 1605-1706 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 52, 53, 54, 119, 360, 361, 362, 363, 364, 365, 366, 367, 368, 369, 370, or 371. In certain such embodiments, an antisense compound targeted to nucleotides 1605-1706 of SEQ ID NO: 1 is selected from ISIS NOs: 395180, 399902, 410771, 395181, 399903, 405975, 399814, 399970, 405976, 405977, 410772, 405978, 395182, 399904, 405979, 405980, 405981, 410741, 405982, or 405983. 
     In certain embodiments, a target region is nucleotides 1628-1706 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 1628-1706 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 52, 53, 54, 360, 361, 362, 363, 364, 365, 366, 367, 368, 369, 370, or 371. In certain such embodiments, an antisense compound targeted to nucleotides 1628-1706 of SEQ ID NO: 1 is selected from ISIS NOs: 410771, 395181, 399903, 405975, 399814, 399970, 405976, 405977, 410772, 405978, 395182, 399904, 405979, 405980, 405981, 410741, 405982, or 405983. 
     In certain embodiments, a target region is nucleotides 1640-1666 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 1640-1666 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 52, 53, 361, or 362. In certain such embodiments, an antisense compound targeted to nucleotides 1640-1666 of SEQ ID NO: 1 is selected from ISIS NOs: 395181, 399903, 405975, 399814, 399970, or 405976. 
     In certain embodiments, a target region is nucleotides 1672-1698 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 1672-1698 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 54, 365, 366, or 367. In certain such embodiments, an antisense compound targeted to nucleotides 1672-1698 of SEQ ID NO: 1 is selected from ISIS NOs: 405978, 395182, 399904, 405979, or 405980. 
     In certain embodiments, a target region is nucleotides 1681-1706 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 1681-1706 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 368, 369, 370, or 371. In certain such embodiments, an antisense compound targeted to nucleotides 1681-1706 of SEQ ID NO: 1 is selected from ISIS NOs: 405981, 410741, 405982, or 405983. 
     In certain embodiments, a target region is nucleotides 1735-1761 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 1735-1761 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 55, 372, 373, or 374. In certain such embodiments, an antisense compound targeted to nucleotides 1735-1761 of SEQ ID NO: 1 is selected from ISIS NOs: 405984, 405564, 405641, 405985, 399815, 399971, or 405986. 
     In certain embodiments, a target region is nucleotides 1735-1765 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 1735-1765 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 55, 56, 372, 373, 374, or 375. In certain such embodiments, an antisense compound targeted to nucleotides 1735-1765 of SEQ ID NO: 1 is selected from ISIS NOs: 405984, 405564, 405641, 405985, 399815, 399971, 405986, 405987, 399816 or 399972. 
     In certain embodiments, a target region is nucleotides 1740-1765 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 1740-1765 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 55, 56, 374, or 375. In certain such embodiments, an antisense compound targeted to nucleotides 1740-1765 of SEQ ID NO: 1 is selected from ISIS NOs: 399815, 399971, 405986, 405987, 399816, or 399972. 
     In certain embodiments, a target region is nucleotides 1849-1876 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 1849-1876 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 376, 377, 378, 379, 380, 381, 382, 383, or 384. In certain such embodiments, an antisense compound targeted to nucleotides 1849-1876 of SEQ ID NO: 1 is selected from ISIS NOs: 410541, 410605, 410683, 410542, 410606, 410684, 410543, 410607, 410685, 410544, 410608, 410686, 410545, 410609, 410687, 405988, 410610, 410688, 410546, 410611, 410689, 405989, 410612, 410690, 410547, 410613, or 410691. 
     In certain embodiments, a target region is nucleotides 1849-1879 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 1849-1879 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 58, 376, 377, 378, 379, 380, 381, 382, 383, 384, 385, or 386. In certain such embodiments, an antisense compound targeted to nucleotides 1849-1879 of SEQ ID NO: 1 is selected from ISIS NOs: 410541, 410605, 410683, 410542, 410606, 410684, 410543, 410607, 410685, 410544, 410608, 410686, 410545, 410609, 410687, 405988, 410610, 410688, 410546, 410611, 410689, 405989, 410612, 410690, 410547, 410613, 395184, 410691, 399906, 410692, 410548, 410614, or 405990. 
     In certain embodiments, a target region is nucleotides 1850-1877 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 1850-1877 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 58, 377, 378, 379, 380, 381, 382, 383 or 384. In certain such embodiments, an antisense compound targeted to nucleotides 1850-1877 of SEQ ID NO: 1 is selected from ISIS NOs: 410542, 410606, 410684, 410543, 410607, 410685, 410544, 410608, 410686, 410545, 410609, 410687, 405988, 410610, 410688, 410546, 410611, 410689, 405989, 410612, 410690, 410547, 410613, 395184, 410691, 399906, or 410692. 
     In certain embodiments, a target region is nucleotides 1851-1877 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 1851-1877 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 58, 378, 379, 380, 381, 382, 383, or 384. In certain such embodiments, an antisense compound targeted to nucleotides 1851-1877 of SEQ ID NO: 1 is selected from ISIS NOs: 410543, 410607, 410685, 410544, 410608, 410686, 410545, 410609, 410687, 405988, 410610, 410688, 410546, 410611, 410689, 405989, 410612, 410690, 410547, 410613, 395184, 410691, 399906, or 410692. 
     In certain embodiments, a target region is nucleotides 1852-1878 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 1852-1878 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 58, 379, 380, 381, 382, 383, 384, or 385. In certain such embodiments, an antisense compound targeted to nucleotides 1852-1878 of SEQ ID NO: 1 is selected from ISIS NOs: 410544, 410608, 410686, 410545, 410609, 410687, 405988, 410610, 410688, 410546, 410611, 410689, 405989, 410612, 410690, 410547, 410613, 395184, 410691, 399906, 410692, 410548, 410614, or 410693. 
     In certain embodiments, a target region is nucleotides 1852-1879 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 1852-1879 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 58, 379, 380, 381, 382, 383, 384, 385, or 386. In certain such embodiments, an antisense compound targeted to nucleotides 1852-1879 of SEQ ID NO: 1 is selected from ISIS NOs: 410544, 410608, 410686, 410545, 410609, 410687, 405988, 410610, 410688, 410546, 410611, 410689, 405989, 410612, 410690, 410547, 410613, 395184, 410691, 399906, 410692, 410548, 410614, 410693, or 405990. 
     In certain embodiments, a target region is nucleotides 1853-1879 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 1853-1879 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 58, 380, 381, 382, 383, 384, 385 or 386. In certain such embodiments, an antisense compound targeted to nucleotides 1853-1879 of SEQ ID NO: 1 is selected from ISIS NOs: 410545, 410609, 410687, 405988, 410610, 410688, 410546, 410611, 410689, 405989, 410612, 410690, 410547, 410613, 395184, 410691, 399906, 410692, 410548, 410614, 410693, or 405990. 
     In certain embodiments, a target region is nucleotides 1854-1879 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 1854-1879 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 58, 381, 382, 383, 384, 385, or 386. In certain such embodiments, an antisense compound targeted to nucleotides 1854-1879 of SEQ ID NO: 1 is selected from ISIS NOs: 405988, 410610, 410688, 410546, 410611, 410689, 405989, 410612, 410690, 410547, 410613, 395184, 410691, 399906, 410692, 410548, 410614, 410693, or 405990. 
     In certain embodiments, a target region is nucleotides 1905-1955 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 1905-1955 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 59, 387, 388, 389, 390, 391, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, or 406. In certain such embodiments, an antisense compound targeted to nucleotides 1905-1955 of SEQ ID NO: 1 is selected from ISIS NOs: 410773, 410549, 410615, 410694, 410550, 410616, 410695, 410551, 410617, 410696, 410552, 410618, 410697, 410553, 410619, 410698, 395185, 399907, 410699, 410554, 410620, 410700, 405991, 410621, 410701, 410555, 410622, 410702, 405992, 410623, 410703, 410556, or 410774. 
     In certain embodiments, a target region is nucleotides 1915-1942 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 1915-1942 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 59, 388, 389, 390, 391, 392, 393, 394, or 395. In certain such embodiments, an antisense compound targeted to nucleotides 1915-1942 of SEQ ID NO: 1 is selected from ISIS NOs: 410549, 410615, 410694, 410550, 410616, 410695, 410551, 410617, 410696, 410552, 410618, 410697, 410553, 410619, 410698, 395185, 399907, 410699, 410554, 410620, 410700, 405991, 410621, 410701, 410555, 410622, or 410702. 
     In certain embodiments, a target region is nucleotides 1916-1943 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 1916-1943 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 59, 389, 390, 391, 392, 393, 394, 395, or 396. In certain such embodiments, an antisense compound targeted to nucleotides 1916-1943 of SEQ ID NO: 1 is selected from ISIS NOs: 410550, 410616, 410695, 410551, 410617, 410696, 410552, 410618, 410697, 410553, 410619, 410698, 395185, 399907, 410699, 410554, 410620, 410700, 405991, 410621, 410701, 410555, 410622, 410702, 405992, 410623, or 410703. 
     In certain embodiments, a target region is nucleotides 1917-1944 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 1917-1944 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 59, 390, 391, 392, 393, 394, 395, 396, or 397. In certain such embodiments, an antisense compound targeted to nucleotides 1917-1944 of SEQ ID NO: 1 is selected from ISIS NOs: 410551, 410617, 410696, 410552, 410618, 410697, 410553, 410619, 410698, 395185, 399907, 410699, 410554, 410620, 410700, 405991, 410621, 410701, 410555, 410622, 410702, 405992, 410623, 410703, 410556, 410624, or 410704. 
     In certain embodiments, a target region is nucleotides 1918-1945 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 1918-1945 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 59, 391, 392, 393, 394, 395, 396, 397, or 398. In certain such embodiments, an antisense compound targeted to nucleotides 1918-1945 of SEQ ID NO: 1 is selected from ISIS NOs: 410552, 410618, 410697, 410553, 410619, 410698, 395185, 399907, 410699, 410554, 410620, 410700, 405991, 410621, 410701, 410555, 410622, 410702, 405992, 410623, 410703, 410556, 410624, 410704, 405993, 410625, or 410705. 
     In certain embodiments, a target region is nucleotides 1919-1946 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 1919-1946 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 59, 392, 393, 394, 395, 396, 397, or 399. In certain such embodiments, an antisense compound targeted to nucleotides 1919-1946 of SEQ ID NO: 1 is selected from ISIS NOs: 410553, 410619, 410698, 395185, 399907, 410699, 410554, 410620, 410700, 405991, 410621, 410701, 410555, 410622, 410702, 405992, 410623, 410703, 410556, 410624, 410704, 405993, 410625, 410705, 410557, 410626, or 410706. 
     In certain embodiments, a target region is nucleotides 1920-1939 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 1920-1939 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 59. In certain such embodiments, an antisense compound targeted to nucleotides 1920-1939 of SEQ ID NO: 1 is selected from ISIS NOs: 395185, 399907, or 410699. 
     In certain embodiments, a target region is nucleotides 1920-1947 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 1920-1947 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 59, 393, 394, 395, 396, 397, 398, 399, or 400. In certain such embodiments, an antisense compound targeted to nucleotides 1920-1947 of SEQ ID NO: 1 is selected from ISIS NOs: 395185, 399907, 410699, 410554, 410620, 410700, 405991, 410621, 410701, 410555, 410622, 410702, 405992, 410623, 410703, 410556, 410624, 410704, 405993, 410625, 410705, 410557, 410626, 410706, 405944, 410627, or 410707. 
     In certain embodiments, a target region is nucleotides 1921-1948 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 1921-1948 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 393, 394, 395, 396, 397, 398, 399, 400, or 401. In certain such embodiments, an antisense compound targeted to nucleotides 1921-1948 of SEQ ID NO: 1 is selected from ISIS NOs: 410554, 410620, 410700, 405991, 410621, 410701, 410555, 410622, 410702, 405992, 410623, 410703, 410556, 410624, 410704, 405993, 410625, 410705, 410557, 410626, 410706, 405944, 410627, 410707, 410558, 410628, or 410708. 
     In certain embodiments, a target region is nucleotides 1922-1949 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 1922-1949 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 394, 395, 396, 397, 398, 399, 400, 401, or 402. In certain such embodiments, an antisense compound targeted to nucleotides 1922-1949 of SEQ ID NO: 1 is selected from ISIS NOs: 405991, 410621, 410701, 410555, 410622, 410702, 405992, 410623, 410703, 410556, 410624, 410704, 405993, 410625, 410705, 410557, 410626, 410706, 405944, 410627, 410707, 410558, 410628, 410708, 405995, 410629, or 410709. 
     In certain embodiments, a target region is nucleotides 1923-1950 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 1923-1950 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 395, 396, 397, 398, 399, 400, 401, 402, or 403. In certain such embodiments, an antisense compound targeted to nucleotides 1923-1950 of SEQ ID NO: 1 is selected from ISIS NOs: 410555, 410622, 410702, 405992, 410623, 410703, 410556, 410624, 410704, 405993, 410625, 410705, 410557, 410626, 410706, 405944, 410627, 410707, 410558, 410628, 410708, 405995, 410629, 410709, 410559, 410630, or 410710. 
     In certain embodiments, a target region is nucleotides 1924-1951 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 1924-1951 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 396, 397, 398, 399, 400, 401, 402, 403, or 404. In certain such embodiments, an antisense compound targeted to nucleotides 1924-1951 of SEQ ID NO: 1 is selected from ISIS NOs: 405992, 410623, 410703, 410556, 410624, 410704, 405993, 410625, 410705, 410557, 410626, 410706, 405994, 410627, 410707, 410558, 410628, 410708, 405995, 410629, 410709, 410559, 410630, 410710, 410560, 410631, or 410711. 
     In certain embodiments, a target region is nucleotides 1925-1952 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 1925-1952 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 397, 398, 399, 400, 401, 402, 403, 404, or 405. In certain such embodiments, an antisense compound targeted to nucleotides 1925-1952 of SEQ ID NO: 1 is selected from ISIS NOs: 410556, 410624, 410704, 405993, 410625, 410705, 410557, 410626, 410706, 405994, 410627, 410707, 410558, 410628, 410708, 405995, 410629, 410709, 410559, 410630, 410710, 410560, 410631, 410711, 410561, 410632, or 410712. 
     In certain embodiments, a target region is nucleotides 1926-1952 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 1926-1952 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 398, 399, 400, 401, 402, 403, 404, or 405. In certain such embodiments, an antisense compound targeted to nucleotides 1926-1952 of SEQ ID NO: 1 is selected from ISIS NOs: 405993, 410625, 410705, 410557, 410626, 410706, 405994, 410627, 410707, 410558, 410628, 410708, 405995, 410629, 410709, 410559, 410630, 410710, 410560, 410631, 410711, 410561, 410632, or 410712. 
     In certain embodiments, a target region is nucleotides 1927-1952 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 1927-1952 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 399, 400, 401, 402, 403, 404, or 405. In certain such embodiments, an antisense compound targeted to nucleotides 1927-1952 of SEQ ID NO: 1 is selected from ISIS NOs: 410557, 410626, 410706, 405994, 410627, 410707, 410558, 410628, 410708, 405995, 410629, 410709, 410559, 410630, 410710, 410560, 410631, 410711, 410561, 410632, or 410712. 
     In certain embodiments, a target region is nucleotides 1928-1955 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 1928-1955 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 400, 401, 402, 403, 404, 405, or 406. In certain such embodiments, an antisense compound targeted to nucleotides 1928-1955 of SEQ ID NO: 1 is selected from ISIS NOs: 405994, 410627, 410707, 410558, 410628, 410708, 405995, 410629, 410709, 410559, 410630, 410710, 410560, 410631, 410711, 410561, 410632, 410712, or 410774. 
     In certain embodiments, a target region is nucleotides 1962-2059 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 1962-2059 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 407, 408, 409, or 410. In certain such embodiments, an antisense compound targeted to nucleotides 1962-2059 of SEQ ID NO: 1 is selected from ISIS NOs: 410775, 410776, 410777, or 410778. 
     In certain embodiments, a target region is nucleotides 2040-2126 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 2040-2126 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 60, 61, 410, 411, 412, 413, 414, or 415. In certain such embodiments, an antisense compound targeted to nucleotides 2040-2126 of SEQ ID NO: 1 is selected from ISIS NOs: 410778, 395186, 399908, 410713, 410562, 410633, 410714, 405996, 410634, 410715, 410563, 410635, 410716, 410564, 410636, 410717, 399817, 399973, 410718, or 405997. 
     In certain embodiments, a target region is nucleotides 2100-2126 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 2100-2126 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 60, 61, 411, 412, 413, 414, or 415. In certain such embodiments, an antisense compound targeted to nucleotides 2100-2126 of SEQ ID NO: 1 is selected from ISIS NOs: 395186, 399908, 410713, 410562, 410633, 410714, 405996, 410634, 410715, 410563, 410635, 410716, 410564, 410636, 410717, 399817, 399973, 410718 or 405997. 
     In certain embodiments, a target region is nucleotides 2100-2139 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 2100-2139 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 60, 61, 411, 412, 413, 414, 415, or 416. In certain such embodiments, an antisense compound targeted to nucleotides 2100-2139 of SEQ ID NO: 1 is selected from ISIS NOs: 395186, 399908, 410713, 410562, 410633, 410714, 405996, 410634, 410715, 410563, 410635, 410716, 410564, 410636, 410717, 399817, 399973, 410718, 405997 or 410779. 
     In certain embodiments, a target region is nucleotides 2100-2206 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 2100-2206 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 60, 61, 411, 412, 413, 414, 415, 416, 417, or 418. In certain such embodiments, an antisense compound targeted to nucleotides 2100-2206 of SEQ ID NO: 1 is selected from ISIS NOs: 395186, 399908, 410713, 410562, 410633, 410714, 405996, 410634, 410715, 410563, 410635, 410716, 410564, 410636, 410717, 399817, 399973, 410718, 405997, 405997, 410780, or 410781. 
     In certain embodiments, a target region is nucleotides 2101-2126 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 2101-2126 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 61, 411, 412, 413, 414, or 415. In certain such embodiments, an antisense compound targeted to nucleotides 2101-2126 of SEQ ID NO: 1 is selected from ISIS NOs: 410562, 410633, 410714, 405996, 410634, 410715, 410563, 410635, 410716, 410564, 410636, 410717, 399817, 399973, 410718, or 405997. 
     In certain embodiments, a target region is nucleotides 2305-2332 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 2305-2332 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 62, 419, 420, 421, 422, 423, 424, 425, or 426. In certain such embodiments, an antisense compound targeted to nucleotides 2305-2332 of SEQ ID NO: 1 is selected from ISIS NOs: 410565, 410637, 410719, 410566, 410638, 410720, 410567, 410639, 410721, 410568, 410640, 410722, 410569, 410641, 410723, 395187, 399909, 410724, 410570, 410642, 410725, 410571, 410643, 410726, 405998, 410644, or 410727. 
     In certain embodiments, a target region is nucleotides 2305-2354 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 2305-2354 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 62, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, or 430. In certain such embodiments, an antisense compound targeted to nucleotides 2305-2354 of SEQ ID NO: 1 is selected from ISIS NOs: 410565, 410637, 410719, 410566, 410638, 410720, 410567, 410639, 410721, 410568, 410640, 410722, 410569, 410641, 410723, 395187, 399909, 410724, 410570, 410642, 410725, 410571, 410643, 410726, 405998, 410644, 410727, 410572, 410645, 410728, 410573, 410646, or 410783. 
     In certain embodiments, a target region is nucleotides 2306-2333 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 2306-2333 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 62, 420, 421, 422, 423, 424, 425, 426, or 427. In certain such embodiments, an antisense compound targeted to nucleotides 2306-2333 of SEQ ID NO: 1 is selected from ISIS NOs: 410566, 410638, 410720, 410567, 410639, 410721, 410568, 410640, 410722, 410569, 410641, 410723, 395187, 399909, 410724, 410570, 410642, 410725, 410571, 410643, 410726, 405998, 410644, 410727, 410572, 410645, or 410728. 
     In certain embodiments, a target region is nucleotides 2307-2334 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 2307-2334 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 62, 421, 422, 423, 424, 425, 426, 427, or 428. In certain such embodiments, an antisense compound targeted to nucleotides 2307-2334 of SEQ ID NO: 1 is selected from ISIS NOs: 410567, 410639, 410721, 410568, 410640, 410722, 410569, 410641, 410723, 395187, 399909, 410724, 410570, 410642, 410725, 410571, 410643, 410726, 405998, 410644, 410727, 410572, 410645, 410728, 410573, 410646, or 410729. 
     In certain embodiments, a target region is nucleotides 2308-2334 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 2308-2334 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 62, 422, 423, 424, 425, 426, 427, or 428. In certain such embodiments, an antisense compound targeted to nucleotides 2308-2334 of SEQ ID NO: 1 is selected from ISIS NOs: 410568, 410640, 410722, 410569, 410641, 410723, 395187, 399909, 410724, 410570, 410642, 410725, 410571, 410643, 410726, 405998, 410644, 410727, 410572, 410645, 410728, 410573, 410646, or 410729. 
     In certain embodiments, a target region is nucleotides 2309-2334 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 2309-2334 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 62, 423, 424, 425, 426, 427, or 428. In certain such embodiments, an antisense compound targeted to nucleotides 2309-2334 of SEQ ID NO: 1 is selected from ISIS NOs: 410569, 410641, 410723, 395187, 399909, 410724, 410570, 410642, 410725, 410571, 410643, 410726, 405998, 410644, 410727, 410572, 410645, 410728, 410573, 410646, or 410729. 
     In certain embodiments, a target region is nucleotides 2310-2334 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 2310-2334 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 62, 424, 425, 426, 427, or 428. In certain such embodiments, an antisense compound targeted to nucleotides 2310-2334 of SEQ ID NO: 1 is selected from ISIS NOs: 395187, 399909, 410724, 410570, 410642, 410725, 410571, 410643, 410726, 405998, 410644, 410727, 410572, 410645, 410728, 410573, 410646, or 410729. 
     In certain embodiments, a target region is nucleotides 2410-2434 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 2410-2434 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 63 or 154. In certain such embodiments, an antisense compound targeted to nucleotides 2410-2434 of SEQ ID NO: 1 is selected from ISIS NOs: 395188, 399910, 399818, or 399974. 
     In certain embodiments, a target region is nucleotides 2504-2528 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 2504-2528 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 64 or 65. In certain such embodiments, an antisense compound targeted to nucleotides 2504-2528 of SEQ ID NO: 1 is selected from ISIS NOs: 395189, 399911, 399819, or 399975. 
     In certain embodiments, a target region is nucleotides 2509-2528 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 2509-2528 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 65. In certain such embodiments, an antisense compound targeted to nucleotides 2509-2528 of SEQ ID NO: 1 is selected from ISIS NOs: 399819 or 399975. 
     In certain embodiments, a target region is nucleotides 2582-2625 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 2582-2625 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 66, 67 or 122. In certain such embodiments, an antisense compound targeted to nucleotides 2582-2625 of SEQ ID NO: 1 is selected from ISIS NOs: 399820, 399976, 395190, 399912, 395191, or 399913. 
     In certain embodiments, a target region is nucleotides 2606-2668 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 2606-2668 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 67 or 153. In certain such embodiments, an antisense compound targeted to nucleotides 2606-2668 of SEQ ID NO: 1 is selected from ISIS NOs: 395191, 399913, 395192, or 399914. 
     In certain embodiments, a target region is nucleotides 2828-2855 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 2828-2855 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 69, 431, 432, 433, 434, 435, 436, 437 or 438. In certain such embodiments, an antisense compound targeted to nucleotides 2828-2855 of SEQ ID NO: 1 is selected from ISIS NOs: 405893, 405894, 405895, 405896, 395194, 399916, 405897, 405898, 405899, or 405900. 
     In certain embodiments, a target region is nucleotides 2832-2851 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 2832-2851 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 69. In certain such embodiments, an antisense compound targeted to nucleotides 2832-2851 of SEQ ID NO: 1 is selected from ISIS NOs: 395194, or 399916. 
     In certain embodiments, a target region is nucleotides 2900-2927 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 2900-2927 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 70, 71, 439, 440, 441, 442, 443 or 444. In certain such embodiments, an antisense compound targeted to nucleotides 2900-2927 of SEQ ID NO: 1 is selected from ISIS NOs: 395195, 399917, 405901, 405902, 405903, 405904, 399821, 399977, 405905, or 405906. 
     In certain embodiments, a target region is nucleotides 2900-2929 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 2900-2929 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 70, 71, 439, 440, 441, 442, 443, 444, 446 or 446. In certain such embodiments, an antisense compound targeted to nucleotides 2900-2929 of SEQ ID NO: 1 is selected from ISIS NOs: 395195, 399917, 405901, 405902, 405903, 405904, 399821, 399977, 405905, 405906, 405907, or 405908. 
     In certain embodiments, a target region is nucleotides 2902-2927 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 2902-2927 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 71, 439, 440, 441, 442, 443 or 444. In certain such embodiments, an antisense compound targeted to nucleotides 2902-2927 of SEQ ID NO: 1 is selected from ISIS NOs: 405901, 405902, 405903, 405904, 399821, 399977, 405905, or 405906. 
     In certain embodiments, a target region is nucleotides 2983-3007 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 2983-3007 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 72 or 73. In certain such embodiments, an antisense compound targeted to nucleotides 2983-3007 of SEQ ID NO: 1 is selected from ISIS NOs: 395196, 399918, 399822, or 399978. 
     In certain embodiments, a target region is nucleotides 2983-3013 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 2983-3013 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 72, 73 or 135. In certain such embodiments, an antisense compound targeted to nucleotides 2983-3013 of SEQ ID NO: 1 is selected from ISIS NOs: 395196, 399918, 399822, 399978, 399823, or 399979. 
     In certain embodiments, a target region is nucleotides 3227-3252 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 3227-3252 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 74 or 112. In certain such embodiments, an 5 antisense compound targeted to nucleotides 3227-3252 of SEQ ID NO: 1 is selected from ISIS NOs: 395197, 399919, 399824, or 399980. 
     In certain embodiments, a target region is nucleotides 3227-3456 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 3227-3456 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 74, 75 or 112. In certain such embodiments, an antisense compound targeted to nucleotides 3227-3456 of SEQ ID NO: 1 is selected from ISIS NOs: 395197, 399919, 399824, 399980, 395198, or 399920. 
     In certain embodiments, a target region is nucleotides 3472-3496 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 3472-3496 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 76 or 77. In certain such embodiments, an antisense compound targeted to nucleotides 3472-3496 of SEQ ID NO: 1 is selected from ISIS NOs: 395199, 399921, 399825 or 399981. 
     In certain embodiments, a target region is nucleotides 3543-3569 of SEQ ID NO: 1. In certain embodiments, an antisense compound is targeted to nucleotides 3543-3569 of SEQ ID NO: 1. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 78 or 99. In certain such embodiments, an antisense compound targeted to nucleotides 3543-3569 of SEQ ID NO: 1 is selected from ISIS NOs: 395200, 399922, 399826 or 399982. 
     In certain embodiments, antisense compound target a PCSK9 nucleic acid having the sequence of nucleotides 25475000 to 25504000 of GENBANK® Accession No. NT_032977.8, first deposited with GENBANK® on Feb. 26, 2006, and incorporated herein as SEQ ID NO: 2. In certain such embodiments, an antisense oligonucleotide is targeted to SEQ ID NO: 2. In certain such embodiments, an antisense oligonucleotide that is targeted to SEQ ID NO: 2 is at least 90% complementary to SEQ ID NO: 2. In certain such embodiments, an antisense oligonucleotide that is targeted to SEQ ID NO: 2 is at least 95% complementary to SEQ ID NO: 2. In certain such embodiments, an antisense oligonucleotide that is targeted to SEQ ID NO: 1 is 100% complementary to SEQ ID NO: 1. In certain such embodiments, an antisense oligonucleotide comprises a nucleotide sequence selected from a nucleotide sequence set forth in Table 7. 
     
       
         
           
               
             
               
                 TABLE 7 
               
             
            
               
                   
               
               
                 Antisense sequences targeted to 
               
               
                 NT_032977.8 (SEQ ID NO: 2) 
               
            
           
           
               
               
               
               
            
               
                   
                 5′ 
                 3′ 
                   
               
               
                   
                 Start 
                 Start 
                   
               
               
                   
                 Site to 
                 Site to 
                   
               
               
                 SEQ ID 
                 SEQ ID 
                 SEQ ID 
                   
               
               
                 NO 
                 NO: 2 
                 NO: 2 
                 Sequence (5′ to 3′) 
               
               
                   
               
            
           
           
               
               
               
               
            
               
                 4 
                 2274 
                 2293 
                 GCGCGGAATCCTGGCTGGGA 
               
               
                   
               
               
                 5 
                 2381 
                 2400 
                 GAGGAGACCTAGAGGCCGTG 
               
               
                   
               
               
                 159 
                 2433 
                 2452 
                 GCCTGGAGCTGACGGTGCCC 
               
               
                   
               
               
                 160 
                 2437 
                 2456 
                 GACCGCCTGGAGCTGACGGT 
               
               
                   
               
               
                 6 
                 2439 
                 2458 
                 AGGACCGCCTGGAGCTGACG 
               
               
                   
               
               
                 162 
                 2545 
                 2564 
                 AAGGCTAGCACCAGCTCCTC 
               
               
                   
               
               
                 163 
                 2546 
                 2565 
                 CAAGGCTAGCACCAGCTCCT 
               
               
                   
               
               
                 164 
                 2547 
                 2566 
                 GCAAGGCTAGCACCAGCTCC 
               
               
                   
               
               
                 165 
                 2548 
                 2567 
                 CGCAAGGCTAGCACCAGCTC 
               
               
                   
               
               
                 7 
                 2549 
                 2568 
                 ACGCAAGGCTAGCACCAGCT 
               
               
                   
               
               
                 166 
                 2550 
                 2569 
                 AACGCAAGGCTAGCACCAGC 
               
               
                   
               
               
                 167 
                 2551 
                 2570 
                 GAACGCAAGGCTAGCACCAG 
               
               
                   
               
               
                 168 
                 2552 
                 2571 
                 GGAACGCAAGGCTAGCACCA 
               
               
                   
               
               
                 169 
                 2553 
                 2572 
                 CGGAACGCAAGGCTAGCACC 
               
               
                   
               
               
                 8 
                 2556 
                 2575 
                 CCTCGGAACGCAAGGCTAGC 
               
               
                   
               
               
                 170 
                 2560 
                 2579 
                 TCCTCCTCGGAACGCAAGGC 
               
               
                   
               
               
                 171 
                 2585 
                 2604 
                 GTGCTCGGGTGCTTCGGCCA 
               
               
                   
               
               
                 172 
                 2605 
                 2624 
                 TGGAAGGTGGCTGTGGTTCC 
               
               
                   
               
               
                 9 
                 2619 
                 2638 
                 CCTTGGCGCAGCGGTGGAAG 
               
               
                   
               
               
                 107 
                 3056 
                 3075 
                 CCCACTATAATGGCAAGCCC 
               
               
                   
               
               
                 80 
                 4306 
                 4325 
                 AACCCAGTTCTAATGCACCT 
               
               
                   
               
               
                 106 
                 5140 
                 5159 
                 CCAGTCAGAGTAGAACAGAG 
               
               
                   
               
               
                 102 
                 5590 
                 5609 
                 ATGTGCAGAGATCAATCACA 
               
               
                   
               
               
                 121 
                 5599 
                 5618 
                 GGAGCCTACATGTGCAGAGA 
               
               
                   
               
               
                 94 
                 5667 
                 5686 
                 AGCATGGCACCAGCATCTGC 
               
               
                   
               
               
                 176 
                 6444 
                 6463 
                 CGTAGGTGCCAGGCAACCTC 
               
               
                   
               
               
                 177 
                 6482 
                 6501 
                 TGACTGCGAGAGGTGGGTCT 
               
               
                   
               
               
                 178 
                 6492 
                 6511 
                 CAGTGCGCTCTGACTGCGAG 
               
               
                   
               
               
                 179 
                 6494 
                 6513 
                 GGCAGTGCGCTCTGACTGCG 
               
               
                   
               
               
                 180 
                 6496 
                 6515 
                 CGGGCAGTGCGCTCTGACTG 
               
               
                   
               
               
                 10 
                 6498 
                 6517 
                 GGCGGGCAGTGCGCTCTGAC 
               
               
                   
               
               
                 181 
                 6499 
                 6518 
                 CGGCGGGCAGTGCGCTCTGA 
               
               
                   
               
               
                 182 
                 6528 
                 6547 
                 ATCCCCGGCGGGCAGCCTGG 
               
               
                   
               
               
                 183 
                 6532 
                 6551 
                 AGGTATCCCCGGCGGGCAGC 
               
               
                   
               
               
                 184 
                 6534 
                 6553 
                 TGAGGTATCCCCGGCGGGCA 
               
               
                   
               
               
                 185 
                 6535 
                 6554 
                 GTGAGGTATCCCCGGCGGGC 
               
               
                   
               
               
                 186 
                 6536 
                 6555 
                 GGTGAGGTATCCCCGGCGGG 
               
               
                   
               
               
                 11 
                 6537 
                 6556 
                 TGGTGAGGTATCCCCGGCGG 
               
               
                   
               
               
                 187 
                 6538 
                 6557 
                 TTGGTGAGGTATCCCCGGCG 
               
               
                   
               
               
                 188 
                 6539 
                 6558 
                 CTTGGTGAGGTATCCCCGGC 
               
               
                   
               
               
                 189 
                 6540 
                 6559 
                 TCTTGGTGAGGTATCCCCGG 
               
               
                   
               
               
                 190 
                 6541 
                 6560 
                 ATCTTGGTGAGGTATCCCCG 
               
               
                   
               
               
                 191 
                 6542 
                 6561 
                 GATCTTGGTGAGGTATCCCC 
               
               
                   
               
               
                 12 
                 6543 
                 6562 
                 GGATCTTGGTGAGGTATCCC 
               
               
                   
               
               
                 192 
                 6544 
                 6563 
                 AGGATCTTGGTGAGGTATCC 
               
               
                   
               
               
                 193 
                 6546 
                 6565 
                 GCAGGATCTTGGTGAGGTAT 
               
               
                   
               
               
                 194 
                 6548 
                 6567 
                 ATGCAGGATCTTGGTGAGGT 
               
               
                   
               
               
                 195 
                 6550 
                 6569 
                 ACATGCAGGATCTTGGTGAG 
               
               
                   
               
               
                 13 
                 6552 
                 6571 
                 AGACATGCAGGATCTTGGTG 
               
               
                   
               
               
                 196 
                 6554 
                 6573 
                 GAAGACATGCAGGATCTTGG 
               
               
                   
               
               
                 14 
                 6557 
                 6576 
                 ATGGAAGACATGCAGGATCT 
               
               
                   
               
               
                 197 
                 6565 
                 6584 
                 AGAAGGCCATGGAAGACATG 
               
               
                   
               
               
                 198 
                 6575 
                 6594 
                 GAAGCCAGGAAGAAGGCCAT 
               
               
                   
               
               
                 15 
                 6583 
                 6602 
                 TTCACCAGGAAGCCAGGAAG 
               
               
                   
               
               
                 199 
                 6585 
                 6604 
                 TCTTCACCAGGAAGCCAGGA 
               
               
                   
               
               
                 16 
                 6588 
                 6607 
                 TCATCTTCACCAGGAAGCCA 
               
               
                   
               
               
                 200 
                 6590 
                 6609 
                 ACTCATCTTCACCAGGAAGC 
               
               
                   
               
               
                 201 
                 6592 
                 6611 
                 CCACTCATCTTCACCAGGAA 
               
               
                   
               
               
                 202 
                 6594 
                 6613 
                 CGCCACTCATCTTCACCAGG 
               
               
                   
               
               
                 203 
                 6596 
                 6615 
                 GTCGCCACTCATCTTCACCA 
               
               
                   
               
               
                 204 
                 6598 
                 6617 
                 AGGTCGCCACTCATCTTCAC 
               
               
                   
               
               
                 205 
                 6600 
                 6619 
                 GCAGGTCGCCACTCATCTTC 
               
               
                   
               
               
                 206 
                 6602 
                 6621 
                 CAGCAGGTCGCCACTCATCT 
               
               
                   
               
               
                 207 
                 6604 
                 6623 
                 TCCAGCAGGTCGCCACTCAT 
               
               
                   
               
               
                 108 
                 6652 
                 6671 
                 CCCAGCCCTATCAGGAAGTG 
               
               
                   
               
               
                 144 
                 7099 
                 7118 
                 TGACATCCAGGAGGGAGGAG 
               
               
                   
               
               
                 91 
                 7556 
                 7575 
                 AGACTGATGGAAGGCATTGA 
               
               
                   
               
               
                 131 
                 7565 
                 7584 
                 GTGTTGAGCAGACTGATGGA 
               
               
                   
               
               
                 145 
                 8836 
                 8855 
                 TGACATCTTGTCTGGGAGCC 
               
               
                   
               
               
                 90 
                 8948 
                 8967 
                 AGACTAGGAGCCTGAGTTTT 
               
               
                   
               
               
                 125 
                 9099 
                 9118 
                 GGCCTGCAGAAGCCAGAGAG 
               
               
                   
               
               
                 17 
                 9130 
                 9149 
                 CCTCGATGTAGTCGACATGG 
               
               
                   
               
               
                 209 
                 9149 
                 9168 
                 GCAAAGACAGAGGAGTCCTC 
               
               
                   
               
               
                 210 
                 9207 
                 9226 
                 TTCATCCGCCCGGTACCGTG 
               
               
                   
               
               
                 211 
                 9209 
                 9228 
                 TATTCATCCGCCCGGTACCG 
               
               
                   
               
               
                 18 
                 9210 
                 9229 
                 GTATTCATCCGCCCGGTACC 
               
               
                   
               
               
                 212 
                 9212 
                 9231 
                 TGGTATTCATCCGCCCGGTA 
               
               
                   
               
               
                 213 
                 9214 
                 9233 
                 GCTGGTATTCATCCGCCCGG 
               
               
                   
               
               
                 214 
                 9216 
                 9235 
                 GGGCTGGTATTCATCCGCCC 
               
               
                   
               
               
                 148 
                 10252 
                 10271 
                 TGGCAGCAACTCAGACATAT 
               
               
                   
               
               
                 127 
                 10633 
                 10652 
                 GGTGGTAATTTGTCACAGCA 
               
               
                   
               
               
                 84 
                 11308 
                 11327 
                 AAGGTCACACAGTTAAGAGT 
               
               
                   
               
               
                 79 
                 11472 
                 11491 
                 AAATGCAGGGCTAAAATCAC 
               
               
                   
               
               
                 88 
                 12715 
                 12734 
                 ACTGGATACATTGGCAGACA 
               
               
                   
               
               
                 111 
                 12928 
                 12947 
                 CTAGAGGAACCACTAGATAT 
               
               
                   
               
               
                 85 
                 13681 
                 13700 
                 ACAAATTCCCAGACTCAGCA 
               
               
                   
               
               
                 100 
                 13746 
                 13765 
                 ATCTCAGGACAGGTGAGCAA 
               
               
                   
               
               
                 116 
                 13760 
                 13779 
                 GAGTAGAGATTCTCATCTCA 
               
               
                   
               
               
                 129 
                 13816 
                 13835 
                 GTGCCATCTGAACAGCACCT 
               
               
                   
               
               
                 117 
                 13828 
                 13847 
                 GAGTCTTCTGAAGTGCCATC 
               
               
                   
               
               
                 81 
                 13903 
                 13922 
                 AAGCAGGGCCTCAGGTGGAA 
               
               
                   
               
               
                 110 
                 13926 
                 13945 
                 CCTGGAACCCCTGCAGCCAG 
               
               
                   
               
               
                 152 
                 13977 
                 13996 
                 TTCAGGCAGGTTGCTGCTAG 
               
               
                   
               
               
                 83 
                 13986 
                 14005 
                 AAGGAAGACTTCAGGCAGGT 
               
               
                   
               
               
                 140 
                 13998 
                 14017 
                 TCAGCCAGGCCAAAGGAAGA 
               
               
                   
               
               
                 137 
                 14112 
                 14131 
                 TAGGGAGAGCTCACAGATGC 
               
               
                   
               
               
                 136 
                 14122 
                 14141 
                 TAGGAGAAAGTAGGGAGAGC 
               
               
                   
               
               
                 132 
                 14179 
                 14198 
                 TAAAAGCTGCAAGAGACTCA 
               
               
                   
               
               
                 139 
                 14267 
                 14286 
                 TCAGAGAAAACAGTCACCGA 
               
               
                   
               
               
                 92 
                 14397 
                 14416 
                 AGAGACAGGAAGCTGCAGCT 
               
               
                   
               
               
                 142 
                 14404 
                 14423 
                 TCATTTTAGAGACAGGAAGC 
               
               
                   
               
               
                 113 
                 14441 
                 14460 
                 GAATAACAGTGATGTCTGGC 
               
               
                   
               
               
                 138 
                 14494 
                 14513 
                 TCACAGCTCACCGAGTCTGC 
               
               
                   
               
               
                 98 
                 14524 
                 14543 
                 AGTGTAAAATAAAGCCCCTA 
               
               
                   
               
               
                 96 
                 14601 
                 14620 
                 AGGACCCAAGTCATCCTGCT 
               
               
                   
               
               
                 124 
                 14631 
                 14650 
                 GGCCATCAGCTGGCAATGCT 
               
               
                   
               
               
                 82 
                 14670 
                 14689 
                 AAGGAAAGGGAGGCCTAGAG 
               
               
                   
               
               
                 133 
                 14675 
                 14694 
                 TAGACAAGGAAAGGGAGGCC 
               
               
                   
               
               
                 103 
                 14681 
                 14700 
                 ATTTCATAGACAAGGAAAGG 
               
               
                   
               
               
                 155 
                 14801 
                 14820 
                 CTTATAGTTAACACACAGAA 
               
               
                   
               
               
                 156 
                 14809 
                 14828 
                 AAGTCAACCTTATAGTTAAC 
               
               
                   
               
               
                 215 
                 14877 
                 14896 
                 ATACACCTCCACCAGGCTGC 
               
               
                   
               
               
                 216 
                 14888 
                 14907 
                 GTGTCTAGGAGATACACCTC 
               
               
                   
               
               
                 19 
                 14891 
                 14910 
                 CTGGTGTCTAGGAGATACAC 
               
               
                   
               
               
                 217 
                 14893 
                 14912 
                 TGCTGGTGTCTAGGAGATAC 
               
               
                   
               
               
                 20 
                 14896 
                 14915 
                 GTATGCTGGTGTCTAGGAGA 
               
               
                   
               
               
                 21 
                 14916 
                 14935 
                 GATTTCCCGGTGGTCACTCT 
               
               
                   
               
               
                 218 
                 14918 
                 14937 
                 TCGATTTCCCGGTGGTCACT 
               
               
                   
               
               
                 219 
                 14919 
                 14938 
                 CTCGATTTCCCGGTGGTCAC 
               
               
                   
               
               
                 220 
                 14920 
                 14939 
                 CCTCGATTTCCCGGTGGTCA 
               
               
                   
               
               
                 221 
                 14921 
                 14940 
                 CCCTCGATTTCCCGGTGGTC 
               
               
                   
               
               
                 22 
                 14922 
                 14941 
                 GCCCTCGATTTCCCGGTGGT 
               
               
                   
               
               
                 222 
                 14923 
                 14942 
                 TGCCCTCGATTTCCCGGTGG 
               
               
                   
               
               
                 223 
                 14924 
                 14943 
                 CTGCCCTCGATTTCCCGGTG 
               
               
                   
               
               
                 224 
                 14925 
                 14944 
                 CCTGCCCTCGATTTCCCGGT 
               
               
                   
               
               
                 225 
                 14926 
                 14945 
                 CCCTGCCCTCGATTTCCCGG 
               
               
                   
               
               
                 226 
                 14930 
                 14949 
                 ATGACCCTGCCCTCGATTTC 
               
               
                   
               
               
                 227 
                 14932 
                 14951 
                 CCATGACCCTGCCCTCGATT 
               
               
                   
               
               
                 228 
                 14934 
                 14953 
                 GACCATGACCCTGCCCTCGA 
               
               
                   
               
               
                 23 
                 14936 
                 14955 
                 GTGACCATGACCCTGCCCTC 
               
               
                   
               
               
                 229 
                 14938 
                 14957 
                 CGGTGACCATGACCCTGCCC 
               
               
                   
               
               
                 230 
                 14940 
                 14959 
                 GTCGGTGACCATGACCCTGC 
               
               
                   
               
               
                 231 
                 14942 
                 14961 
                 AAGTCGGTGACCATGACCCT 
               
               
                   
               
               
                 232 
                 14944 
                 14963 
                 CGAAGTCGGTGACCATGACC 
               
               
                   
               
               
                 24 
                 14946 
                 14965 
                 CTCGAAGTCGGTGACCATGA 
               
               
                   
               
               
                 233 
                 14954 
                 14973 
                 GGCACATTCTCGAAGTCGGT 
               
               
                   
               
               
                 25 
                 14979 
                 14998 
                 GTGGAAGCGGGTCCCGTCCT 
               
               
                   
               
               
                 235 
                 15254 
                 15273 
                 GGTGGGTGCCATGACTGTCA 
               
               
                   
               
               
                 236 
                 15257 
                 15276 
                 CCAGGTGGGTGCCATGACTG 
               
               
                   
               
               
                 237 
                 15261 
                 15280 
                 CCTGCCAGGTGGGTGCCATG 
               
               
                   
               
               
                 26 
                 15264 
                 15283 
                 ACCCCTGCCAGGTGGGTGCC 
               
               
                   
               
               
                 238 
                 15266 
                 15285 
                 CCACCCCTGCCAGGTGGGTG 
               
               
                   
               
               
                 27 
                 15269 
                 15288 
                 TGACCACCCCTGCCAGGTGG 
               
               
                   
               
               
                 239 
                 15271 
                 15290 
                 GCTGACCACCCCTGCCAGGT 
               
               
                   
               
               
                 240 
                 15279 
                 15298 
                 TCCCGGCCGCTGACCACCCC 
               
               
                   
               
               
                 241 
                 15283 
                 15302 
                 GGCATCCCGGCCGCTGACCA 
               
               
                   
               
               
                 242 
                 15286 
                 15305 
                 GCCGGCATCCCGGCCGCTGA 
               
               
                   
               
               
                 243 
                 15291 
                 15310 
                 GCCACGCCGGCATCCCGGCC 
               
               
                   
               
               
                 244 
                 15292 
                 15311 
                 GGCCACGCCGGCATCCCGGC 
               
               
                   
               
               
                 245 
                 15293 
                 15312 
                 TGGCCACGCCGGCATCCCGG 
               
               
                   
               
               
                 246 
                 15294 
                 15313 
                 TTGGCCACGCCGGCATCCCG 
               
               
                   
               
               
                 247 
                 15295 
                 15314 
                 CTTGGCCACGCCGGCATCCC 
               
               
                   
               
               
                 248 
                 15296 
                 15315 
                 CCTTGGCCACGCCGGCATCC 
               
               
                   
               
               
                 249 
                 15297 
                 15316 
                 CCCTTGGCCACGCCGGCATC 
               
               
                   
               
               
                 28 
                 15298 
                 15317 
                 ACCCTTGGCCACGCCGGCAT 
               
               
                   
               
               
                 447 
                 15298 
                 15317 
                 ACCCTTGGTCACGCCGGCAT 
               
               
                   
               
               
                 250 
                 15299 
                 15318 
                 CACCCTTGGCCACGCCGGCA 
               
               
                   
               
               
                 251 
                 15300 
                 15319 
                 GCACCCTTGGCCACGCCGGC 
               
               
                   
               
               
                 252 
                 15301 
                 15320 
                 GGCACCCTTGGCCACGCCGG 
               
               
                   
               
               
                 253 
                 15302 
                 15321 
                 TGGCACCCTTGGCCACGCCG 
               
               
                   
               
               
                 254 
                 15303 
                 15322 
                 CTGGCACCCTTGGCCACGCC 
               
               
                   
               
               
                 255 
                 15304 
                 15323 
                 GCTGGCACCCTTGGCCACGC 
               
               
                   
               
               
                 256 
                 15309 
                 15328 
                 CGCATGCTGGCACCCTTGGC 
               
               
                   
               
               
                 257 
                 15330 
                 15349 
                 CAGTTGAGCACGCGCAGGCT 
               
               
                   
               
               
                 258 
                 15332 
                 15351 
                 GGCAGTTGAGCACGCGCAGG 
               
               
                   
               
               
                 29 
                 15334 
                 15353 
                 TTGGCAGTTGAGCACGCGCA 
               
               
                   
               
               
                 259 
                 15336 
                 15355 
                 CCTTGGCAGTTGAGCACGCG 
               
               
                   
               
               
                 30 
                 15339 
                 15358 
                 TTCCCTTGGCAGTTGAGCAC 
               
               
                   
               
               
                 260 
                 15341 
                 15360 
                 CCTTCCCTTGGCAGTTGAGC 
               
               
                   
               
               
                 261 
                 15345 
                 15364 
                 GTGCCCTTCCCTTGGCAGTT 
               
               
                   
               
               
                 262 
                 15347 
                 15366 
                 CCGTGCCCTTCCCTTGGCAG 
               
               
                   
               
               
                 263 
                 15358 
                 15377 
                 GGTGCCGCTAACCGTGCCCT 
               
               
                   
               
               
                 86 
                 15471 
                 15490 
                 ACAGCATTCTTGGTTAGGAG 
               
               
                   
               
               
                 97 
                 16134 
                 16153 
                 AGTCAAGCTGCTGCCCAGAG 
               
               
                   
               
               
                 120 
                 16668 
                 16687 
                 GCTAGTTATTAAGCACCTGC 
               
               
                   
               
               
                 150 
                 17267 
                 17286 
                 TGTGAGCTCTGGCCCAGTGG 
               
               
                   
               
               
                 115 
                 18377 
                 18396 
                 GAGTAAGGCAGGTTACTCTC 
               
               
                   
               
               
                 134 
                 18408 
                 18427 
                 TAGATGTGACTAACATTTAA 
               
               
                   
               
               
                 157 
                 18561 
                 18580 
                 AGGAACAAAGCCAAGGTCAC 
               
               
                   
               
               
                 266 
                 18591 
                 18610 
                 TGGCTTTTCCGAATAAACTC 
               
               
                   
               
               
                 32 
                 18593 
                 18612 
                 GCTGGCTTTTCCGAATAAAC 
               
               
                   
               
               
                 267 
                 18595 
                 18614 
                 CAGCTGGCTTTTCCGAATAA 
               
               
                   
               
               
                 268 
                 18597 
                 18616 
                 ACCAGCTGGCTTTTCCGAAT 
               
               
                   
               
               
                 269 
                 18599 
                 18618 
                 GGACCAGCTGGCTTTTCCGA 
               
               
                   
               
               
                 270 
                 18603 
                 18622 
                 GGCTGGACCAGCTGGCTTTT 
               
               
                   
               
               
                 271 
                 18614 
                 18633 
                 GTGGCCCCACAGGCTGGACC 
               
               
                   
               
               
                 272 
                 18627 
                 18646 
                 AGCAGCACCACCAGTGGCCC 
               
               
                   
               
               
                 273 
                 18649 
                 18668 
                 GCTGTACCCACCCGCCAGGG 
               
               
                   
               
               
                 274 
                 18695 
                 18714 
                 CGACCCCAGCCCTCGCCAGG 
               
               
                   
               
               
                 33 
                 18705 
                 18724 
                 GTGACCAGCACGACCCCAGC 
               
               
                   
               
               
                 275 
                 18707 
                 18726 
                 CGGTGACCAGCACGACCCCA 
               
               
                   
               
               
                 276 
                 18709 
                 18728 
                 AGCGGTGACCAGCACGACCC 
               
               
                   
               
               
                 277 
                 18711 
                 18730 
                 GCAGCGGTGACCAGCACGAC 
               
               
                   
               
               
                 278 
                 18713 
                 18732 
                 CGGCAGCGGTGACCAGCACG 
               
               
                   
               
               
                 279 
                 18714 
                 18733 
                 CCGGCAGCGGTGACCAGCAC 
               
               
                   
               
               
                 280 
                 18717 
                 18736 
                 TTGCCGGCAGCGGTGACCAG 
               
               
                   
               
               
                 281 
                 18719 
                 18738 
                 AGTTGCCGGCAGCGGTGACC 
               
               
                   
               
               
                 282 
                 18721 
                 18740 
                 GAAGTTGCCGGCAGCGGTGA 
               
               
                   
               
               
                 283 
                 18723 
                 18742 
                 CGGAAGTTGCCGGCAGCGGT 
               
               
                   
               
               
                 284 
                 18725 
                 18744 
                 CCCGGAAGTTGCCGGCAGCG 
               
               
                   
               
               
                 285 
                 18727 
                 18746 
                 GTCCCGGAAGTTGCCGGCAG 
               
               
                   
               
               
                 105 
                 19203 
                 19222 
                 CACATTAGCCTTGCTCAAGT 
               
               
                   
               
               
                 151 
                 19913 
                 19932 
                 TGTGATGACCTGGAAAGGTG 
               
               
                   
               
               
                 288 
                 19931 
                 19950 
                 GGCATTGGTGGCCCCAACTG 
               
               
                   
               
               
                 149 
                 19933 
                 19952 
                 TGGGCATTGGTGGCCCCAAC 
               
               
                   
               
               
                 289 
                 19941 
                 19960 
                 GCTGGTCTTGGGCATTGGTG 
               
               
                   
               
               
                 290 
                 19954 
                 19973 
                 CCCAGGGTCACCGGCTGGTC 
               
               
                   
               
               
                 291 
                 19956 
                 19975 
                 TCCCCAGGGTCACCGGCTGG 
               
               
                   
               
               
                 292 
                 19958 
                 19977 
                 AGTCCCCAGGGTCACCGGCT 
               
               
                   
               
               
                 293 
                 19960 
                 19979 
                 AAAGTCCCCAGGGTCACCGG 
               
               
                   
               
               
                 34 
                 19962 
                 19981 
                 CCAAAGTCCCCAGGGTCACC 
               
               
                   
               
               
                 294 
                 19964 
                 19983 
                 CCCCAAAGTCCCCAGGGTCA 
               
               
                   
               
               
                 128 
                 19966 
                 19985 
                 GTCCCCAAAGTCCCCAGGGT 
               
               
                   
               
               
                 295 
                 19969 
                 19988 
                 TTGGTCCCCAAAGTCCCCAG 
               
               
                   
               
               
                 35 
                 19971 
                 19990 
                 AGTTGGTCCCCAAAGTCCCC 
               
               
                   
               
               
                 296 
                 19973 
                 19992 
                 AAAGTTGGTCCCCAAAGTCC 
               
               
                   
               
               
                 36 
                 19976 
                 19995 
                 GCCAAAGTTGGTCCCCAAAG 
               
               
                   
               
               
                 297 
                 19978 
                 19997 
                 CGGCCAAAGTTGGTCCCCAA 
               
               
                   
               
               
                 298 
                 19980 
                 19999 
                 AGCGGCCAAAGTTGGTCCCC 
               
               
                   
               
               
                 299 
                 19982 
                 20001 
                 ACAGCGGCCAAAGTTGGTCC 
               
               
                   
               
               
                 300 
                 19984 
                 20003 
                 ACACAGCGGCCAAAGTTGGT 
               
               
                   
               
               
                 301 
                 19986 
                 20005 
                 CCACACAGCGGCCAAAGTTG 
               
               
                   
               
               
                 37 
                 19988 
                 20007 
                 GTCCACACAGCGGCCAAAGT 
               
               
                   
               
               
                 302 
                 19990 
                 20009 
                 AGGTCCACACAGCGGCCAAA 
               
               
                   
               
               
                 303 
                 19992 
                 20011 
                 AGAGGTCCACACAGCGGCCA 
               
               
                   
               
               
                 304 
                 19994 
                 20013 
                 AAAGAGGTCCACACAGCGGC 
               
               
                   
               
               
                 38 
                 19997 
                 20016 
                 GGCAAAGAGGTCCACACAGC 
               
               
                   
               
               
                 305 
                 20016 
                 20035 
                 CAATGATGTCCTCCCCTGGG 
               
               
                   
               
               
                 306 
                 20023 
                 20042 
                 GAGGCACCAATGATGTCCTC 
               
               
                   
               
               
                 39 
                 20025 
                 20044 
                 TGGAGGCACCAATGATGTCC 
               
               
                   
               
               
                 307 
                 20027 
                 20046 
                 GCTGGAGGCACCAATGATGT 
               
               
                   
               
               
                 308 
                 20029 
                 20048 
                 TCGCTGGAGGCACCAATGAT 
               
               
                   
               
               
                 309 
                 20031 
                 20050 
                 AGTCGCTGGAGGCACCAATG 
               
               
                   
               
               
                 310 
                 20033 
                 20052 
                 GCAGTCGCTGGAGGCACCAA 
               
               
                   
               
               
                 40 
                 20036 
                 20055 
                 GCTGCAGTCGCTGGAGGCAC 
               
               
                   
               
               
                 311 
                 20038 
                 20057 
                 GTGCTGCAGTCGCTGGAGGC 
               
               
                   
               
               
                 312 
                 20040 
                 20059 
                 AGGTGCTGCAGTCGCTGGAG 
               
               
                   
               
               
                 313 
                 20042 
                 20061 
                 GCAGGTGCTGCAGTCGCTGG 
               
               
                   
               
               
                 314 
                 20043 
                 20062 
                 AGCAGGTGCTGCAGTCGCTG 
               
               
                   
               
               
                 315 
                 20045 
                 20064 
                 AAAGCAGGTGCTGCAGTCGC 
               
               
                   
               
               
                 41 
                 20047 
                 20066 
                 ACAAAGCAGGTGCTGCAGTC 
               
               
                   
               
               
                 316 
                 20049 
                 20068 
                 ACACAAAGCAGGTGCTGCAG 
               
               
                   
               
               
                 317 
                 20051 
                 20070 
                 TGACACAAAGCAGGTGCTGC 
               
               
                   
               
               
                 318 
                 20061 
                 20080 
                 TCCCACTCTGTGACACAAAG 
               
               
                   
               
               
                 158 
                 20100 
                 20119 
                 GTGGTGACTTACCAGCCACG 
               
               
                   
               
               
                 109 
                 20188 
                 20207 
                 CCCCTGCACAGAGCCTGGCA 
               
               
                   
               
               
                 141 
                 20624 
                 20643 
                 TCATGGCTGCAATGCCTGGT 
               
               
                   
               
               
                 320 
                 20629 
                 20648 
                 CAGCATCATGGCTGCAATGC 
               
               
                   
               
               
                 321 
                 20631 
                 20650 
                 GACAGCATCATGGCTGCAAT 
               
               
                   
               
               
                 322 
                 20633 
                 20652 
                 CAGACAGCATCATGGCTGCA 
               
               
                   
               
               
                 43 
                 20635 
                 20654 
                 GGCAGACAGCATCATGGCTG 
               
               
                   
               
               
                 323 
                 20637 
                 20656 
                 TCGGCAGACAGCATCATGGC 
               
               
                   
               
               
                 324 
                 20639 
                 20658 
                 GCTCGGCAGACAGCATCATG 
               
               
                   
               
               
                 325 
                 20641 
                 20660 
                 CGGCTCGGCAGACAGCATCA 
               
               
                   
               
               
                 326 
                 20643 
                 20662 
                 TCCGGCTCGGCAGACAGCAT 
               
               
                   
               
               
                 327 
                 20657 
                 20676 
                 CGGCCAGGGTGAGCTCCGGC 
               
               
                   
               
               
                 328 
                 20670 
                 20689 
                 CTCTGCCTCAACTCGGCCAG 
               
               
                   
               
               
                 329 
                 20672 
                 20691 
                 GTCTCTGCCTCAACTCGGCC 
               
               
                   
               
               
                 330 
                 20674 
                 20693 
                 CAGTCTCTGCCTCAACTCGG 
               
               
                   
               
               
                 331 
                 20676 
                 20695 
                 ATCAGTCTCTGCCTCAACTC 
               
               
                   
               
               
                 332 
                 20678 
                 20697 
                 GGATCAGTCTCTGCCTCAAC 
               
               
                   
               
               
                 333 
                 20680 
                 20699 
                 GTGGATCAGTCTCTGCCTCA 
               
               
                   
               
               
                 334 
                 20682 
                 20701 
                 AAGTGGATCAGTCTCTGCCT 
               
               
                   
               
               
                 44 
                 20683 
                 20702 
                 GAAGTGGATCAGTCTCTGCC 
               
               
                   
               
               
                 335 
                 20685 
                 20704 
                 GAGAAGTGGATCAGTCTCTG 
               
               
                   
               
               
                 336 
                 20687 
                 20706 
                 CAGAGAAGTGGATCAGTCTC 
               
               
                   
               
               
                 337 
                 20689 
                 20708 
                 GGCAGAGAAGTGGATCAGTC 
               
               
                   
               
               
                 45 
                 20691 
                 20710 
                 TTGGCAGAGAAGTGGATCAG 
               
               
                   
               
               
                 338 
                 20693 
                 20712 
                 CTTTGGCAGAGAAGTGGATC 
               
               
                   
               
               
                 46 
                 20696 
                 20715 
                 CATCTTTGGCAGAGAAGTGG 
               
               
                   
               
               
                 339 
                 20698 
                 20717 
                 GACATCTTTGGCAGAGAAGT 
               
               
                   
               
               
                 340 
                 20700 
                 20719 
                 ATGACATCTTTGGCAGAGAA 
               
               
                   
               
               
                 47 
                 20702 
                 20721 
                 TGATGACATCTTTGGCAGAG 
               
               
                   
               
               
                 341 
                 20704 
                 20723 
                 ATTGATGACATCTTTGGCAG 
               
               
                   
               
               
                 342 
                 20706 
                 20725 
                 TCATTGATGACATCTTTGGC 
               
               
                   
               
               
                 48 
                 20709 
                 20728 
                 GCCTCATTGATGACATCTTT 
               
               
                   
               
               
                 343 
                 20711 
                 20730 
                 AGGCCTCATTGATGACATCT 
               
               
                   
               
               
                 344 
                 20713 
                 20732 
                 CCAGGCCTCATTGATGACAT 
               
               
                   
               
               
                 345 
                 20715 
                 20734 
                 AACCAGGCCTCATTGATGAC 
               
               
                   
               
               
                 346 
                 20717 
                 20736 
                 GGAACCAGGCCTCATTGATG 
               
               
                   
               
               
                 347 
                 20718 
                 20737 
                 GGGAACCAGGCCTCATTGAT 
               
               
                   
               
               
                 348 
                 20719 
                 20738 
                 AGGGAACCAGGCCTCATTGA 
               
               
                   
               
               
                 349 
                 20720 
                 20739 
                 CAGGGAACCAGGCCTCATTG 
               
               
                   
               
               
                 49 
                 20721 
                 20740 
                 TCAGGGAACCAGGCCTCATT 
               
               
                   
               
               
                 350 
                 20722 
                 20741 
                 CTCAGGGAACCAGGCCTCAT 
               
               
                   
               
               
                 351 
                 20723 
                 20742 
                 CCTCAGGGAACCAGGCCTCA 
               
               
                   
               
               
                 352 
                 20724 
                 20743 
                 TCCTCAGGGAACCAGGCCTC 
               
               
                   
               
               
                 353 
                 20725 
                 20744 
                 GTCCTCAGGGAACCAGGCCT 
               
               
                   
               
               
                 50 
                 20726 
                 20745 
                 GGTCCTCAGGGAACCAGGCC 
               
               
                   
               
               
                 354 
                 20727 
                 20746 
                 TGGTCCTCAGGGAACCAGGC 
               
               
                   
               
               
                 355 
                 20728 
                 20747 
                 CTGGTCCTCAGGGAACCAGG 
               
               
                   
               
               
                 356 
                 20729 
                 20748 
                 GCTGGTCCTCAGGGAACCAG 
               
               
                   
               
               
                 357 
                 20730 
                 20749 
                 CGCTGGTCCTCAGGGAACCA 
               
               
                   
               
               
                 87 
                 20733 
                 20752 
                 ACCCGCTGGTCCTCAGGGAA 
               
               
                   
               
               
                 358 
                 20735 
                 20754 
                 GTACCCGCTGGTCCTCAGGG 
               
               
                   
               
               
                 359 
                 20737 
                 20756 
                 CAGTACCCGCTGGTCCTCAG 
               
               
                   
               
               
                 51 
                 20740 
                 20759 
                 GGTCAGTACCCGCTGGTCCT 
               
               
                   
               
               
                 119 
                 20762 
                 20781 
                 GCAGGGCGGCCACCAGGTTG 
               
               
                   
               
               
                 360 
                 20785 
                 20804 
                 ACCTGCCCCATGGGTGCTGG 
               
               
                   
               
               
                 93 
                 20995 
                 21014 
                 AGAGAGGAGGGCTTAAAGAA 
               
               
                   
               
               
                 95 
                 21082 
                 21101 
                 AGCTGCCAACCTGCAAAAAG 
               
               
                   
               
               
                 361 
                 21088 
                 21107 
                 CAAAACAGCTGCCAACCTGC 
               
               
                   
               
               
                 53 
                 21091 
                 21110 
                 CTGCAAAACAGCTGCCAACC 
               
               
                   
               
               
                 362 
                 21093 
                 21112 
                 TCCTGCAAAACAGCTGCCAA 
               
               
                   
               
               
                 363 
                 21095 
                 21114 
                 AGTCCTGCAAAACAGCTGCC 
               
               
                   
               
               
                 364 
                 21106 
                 21125 
                 GCTGACCATACAGTCCTGCA 
               
               
                   
               
               
                 365 
                 21118 
                 21137 
                 GGCCCCGAGTGTGCTGACCA 
               
               
                   
               
               
                 54 
                 21121 
                 21140 
                 GTAGGCCCCGAGTGTGCTGA 
               
               
                   
               
               
                 366 
                 21123 
                 21142 
                 GTGTAGGCCCCGAGTGTGCT 
               
               
                   
               
               
                 367 
                 21125 
                 21144 
                 CCGTGTAGGCCCCGAGTGTG 
               
               
                   
               
               
                 368 
                 21127 
                 21146 
                 ATCCGTGTAGGCCCCGAGTG 
               
               
                   
               
               
                 369 
                 21129 
                 21148 
                 CCATCCGTGTAGGCCCCGAG 
               
               
                   
               
               
                 370 
                 21131 
                 21150 
                 GGCCATCCGTGTAGGCCCCG 
               
               
                   
               
               
                 371 
                 21133 
                 21152 
                 GTGGCCATCCGTGTAGGCCC 
               
               
                   
               
               
                 372 
                 21181 
                 21200 
                 CTGGAGCAGCTCAGCAGCTC 
               
               
                   
               
               
                 460 
                 21181 
                 21194 
                 CAGCTCAGCAGCTC 
               
               
                   
               
               
                 373 
                 21183 
                 21202 
                 AACTGGAGCAGCTCAGCAGC 
               
               
                   
               
               
                 55 
                 21186 
                 21205 
                 AGAAACTGGAGCAGCTCAGC 
               
               
                   
               
               
                 374 
                 21188 
                 21207 
                 GGAGAAACTGGAGCAGCTCA 
               
               
                   
               
               
                 375 
                 21190 
                 21209 
                 CTGGAGAAACTGGAGCAGCT 
               
               
                   
               
               
                 56 
                 21192 
                 21211 
                 TCCTGGAGAAACTGGAGCAG 
               
               
                   
               
               
                 143 
                 21481 
                 21500 
                 TGAAAATCCATCCAGCACTG 
               
               
                   
               
               
                 89 
                 21589 
                 21608 
                 AGAACCATGGAGCACCTGAG 
               
               
                   
               
               
                 448 
                 21692 
                 21711 
                 CTGCCCTTCCACCAAAATGC 
               
               
                   
               
               
                 449 
                 21693 
                 21712 
                 ACTGCCCTTCCACCAAAATG 
               
               
                   
               
               
                 450 
                 21694 
                 21713 
                 CACTGCCCTTCCACCAAAAT 
               
               
                   
               
               
                 451 
                 21695 
                 21714 
                 GCACTGCCCTTCCACCAAAA 
               
               
                   
               
               
                 123 
                 21696 
                 21715 
                 GGCACTGCCCTTCCACCAAA 
               
               
                   
               
               
                 452 
                 21697 
                 21716 
                 GGGCACTGCCCTTCCACCAA 
               
               
                   
               
               
                 453 
                 21698 
                 21717 
                 TGGGCACTGCCCTTCCACCA 
               
               
                   
               
               
                 454 
                 21699 
                 21718 
                 CTGGGCACTGCCCTTCCACC 
               
               
                   
               
               
                 455 
                 21700 
                 21719 
                 GCTGGGCACTGCCCTTCCAC 
               
               
                   
               
               
                 57 
                 22096 
                 22115 
                 CGTTGTGGGCCCGGCAGACC 
               
               
                   
               
               
                 376 
                 22133 
                 22152 
                 CACCTGGCAATGGCGTAGAC 
               
               
                   
               
               
                 377 
                 22134 
                 22153 
                 GCACCTGGCAATGGCGTAGA 
               
               
                   
               
               
                 378 
                 22135 
                 22154 
                 AGCACCTGGCAATGGCGTAG 
               
               
                   
               
               
                 379 
                 22136 
                 22155 
                 CAGCACCTGGCAATGGCGTA 
               
               
                   
               
               
                 380 
                 22137 
                 22156 
                 GCAGCACCTGGCAATGGCGT 
               
               
                   
               
               
                 381 
                 22138 
                 22157 
                 GGCAGCACCTGGCAATGGCG 
               
               
                   
               
               
                 382 
                 22139 
                 22158 
                 AGGCAGCACCTGGCAATGGC 
               
               
                   
               
               
                 383 
                 22140 
                 22159 
                 CAGGCAGCACCTGGCAATGG 
               
               
                   
               
               
                 384 
                 22141 
                 22160 
                 GCAGGCAGCACCTGGCAATG 
               
               
                   
               
               
                 58 
                 22142 
                 22161 
                 AGCAGGCAGCACCTGGCAAT 
               
               
                   
               
               
                 385 
                 22143 
                 22162 
                 TAGCAGGCAGCACCTGGCAA 
               
               
                   
               
               
                 386 
                 22144 
                 22163 
                 GTAGCAGGCAGCACCTGGCA 
               
               
                   
               
               
                 387 
                 22189 
                 22208 
                 TGGCCTCAGCTGGTGGAGCT 
               
               
                   
               
               
                 388 
                 22199 
                 22218 
                 GTCCCCATGCTGGCCTCAGC 
               
               
                   
               
               
                 389 
                 22200 
                 22219 
                 GGTCCCCATGCTGGCCTCAG 
               
               
                   
               
               
                 390 
                 22201 
                 22220 
                 GGGTCCCCATGCTGGCCTCA 
               
               
                   
               
               
                 391 
                 22202 
                 22221 
                 CGGGTCCCCATGCTGGCCTC 
               
               
                   
               
               
                 392 
                 22203 
                 22222 
                 ACGGGTCCCCATGCTGGCCT 
               
               
                   
               
               
                 59 
                 22204 
                 22223 
                 CACGGGTCCCCATGCTGGCC 
               
               
                   
               
               
                 393 
                 22205 
                 22224 
                 ACACGGGTCCCCATGCTGGC 
               
               
                   
               
               
                 394 
                 22206 
                 22225 
                 GACACGGGTCCCCATGCTGG 
               
               
                   
               
               
                 395 
                 22207 
                 22226 
                 GGACACGGGTCCCCATGCTG 
               
               
                   
               
               
                 396 
                 22208 
                 22227 
                 TGGACACGGGTCCCCATGCT 
               
               
                   
               
               
                 397 
                 22209 
                 22228 
                 GTGGACACGGGTCCCCATGC 
               
               
                   
               
               
                 398 
                 22210 
                 22229 
                 AGTGGACACGGGTCCCCATG 
               
               
                   
               
               
                 399 
                 22211 
                 22230 
                 CAGTGGACACGGGTCCCCAT 
               
               
                   
               
               
                 400 
                 22212 
                 22231 
                 GCAGTGGACACGGGTCCCCA 
               
               
                   
               
               
                 401 
                 22213 
                 22232 
                 GGCAGTGGACACGGGTCCCC 
               
               
                   
               
               
                 402 
                 22214 
                 22233 
                 TGGCAGTGGACACGGGTCCC 
               
               
                   
               
               
                 403 
                 22215 
                 22234 
                 GTGGCAGTGGACACGGGTCC 
               
               
                   
               
               
                 404 
                 22216 
                 22235 
                 GGTGGCAGTGGACACGGGTC 
               
               
                   
               
               
                 405 
                 22217 
                 22236 
                 TGGTGGCAGTGGACACGGGT 
               
               
                   
               
               
                 406 
                 22220 
                 22239 
                 TGTTGGTGGCAGTGGACACG 
               
               
                   
               
               
                 126 
                 22292 
                 22311 
                 GGTGCATAAGGAGAAAGAGA 
               
               
                   
               
               
                 408 
                 23985 
                 24004 
                 GTGCCAAGGTCCTCCACCTC 
               
               
                   
               
               
                 409 
                 24005 
                 24024 
                 TCAGCACAGGCGGCTTGTGG 
               
               
                   
               
               
                 410 
                 24035 
                 24054 
                 CCACGCACTGGTTGGGCTGA 
               
               
                   
               
               
                 60 
                 24095 
                 24114 
                 CTTTGCATTCCAGACCTGGG 
               
               
                   
               
               
                 411 
                 24096 
                 24115 
                 ACTTTGCATTCCAGACCTGG 
               
               
                   
               
               
                 412 
                 24097 
                 24116 
                 GACTTTGCATTCCAGACCTG 
               
               
                   
               
               
                 413 
                 24098 
                 24117 
                 TGACTTTGCATTCCAGACCT 
               
               
                   
               
               
                 414 
                 24099 
                 24118 
                 TTGACTTTGCATTCCAGACC 
               
               
                   
               
               
                 61 
                 24100 
                 24119 
                 CTTGACTTTGCATTCCAGAC 
               
               
                   
               
               
                 415 
                 24102 
                 24121 
                 TCCTTGACTTTGCATTCCAG 
               
               
                   
               
               
                 416 
                 24115 
                 24134 
                 CGGGATTCCATGCTCCTTGA 
               
               
                   
               
               
                 147 
                 24858 
                 24877 
                 TGAGTTCATTTAAGAGTGGA 
               
               
                   
               
               
                 118 
                 24907 
                 24926 
                 GCACCATCCAGACCAGAATC 
               
               
                   
               
               
                 114 
                 25413 
                 25432 
                 GAGAGGTTCAGATCCAGGCC 
               
               
                   
               
               
                 418 
                 25994 
                 26013 
                 GGAGGGCACTGCAGCCAGTC 
               
               
                   
               
               
                 419 
                 26112 
                 26131 
                 CAGATGGCAACGGCTGTCAC 
               
               
                   
               
               
                 420 
                 26113 
                 26132 
                 GCAGATGGCAACGGCTGTCA 
               
               
                   
               
               
                 421 
                 26114 
                 26133 
                 AGCAGATGGCAACGGCTGTC 
               
               
                   
               
               
                 422 
                 26115 
                 26134 
                 CAGCAGATGGCAACGGCTGT 
               
               
                   
               
               
                 423 
                 26116 
                 26135 
                 GCAGCAGATGGCAACGGCTG 
               
               
                   
               
               
                 62 
                 26117 
                 26136 
                 GGCAGCAGATGGCAACGGCT 
               
               
                   
               
               
                 424 
                 26118 
                 26137 
                 CGGCAGCAGATGGCAACGGC 
               
               
                   
               
               
                 425 
                 26119 
                 26138 
                 CCGGCAGCAGATGGCAACGG 
               
               
                   
               
               
                 426 
                 26120 
                 26139 
                 TCCGGCAGCAGATGGCAACG 
               
               
                   
               
               
                 427 
                 26121 
                 26140 
                 CTCCGGCAGCAGATGGCAAC 
               
               
                   
               
               
                 428 
                 26122 
                 26141 
                 GCTCCGGCAGCAGATGGCAA 
               
               
                   
               
               
                 429 
                 26132 
                 26151 
                 CCAGGTGCCGGCTCCGGCAG 
               
               
                   
               
               
                 430 
                 26142 
                 26161 
                 GAGGCCTGCGCCAGGTGCCG 
               
               
                   
               
               
                 154 
                 26217 
                 26236 
                 TTTTAAAGCTCAGCCCCAGC 
               
               
                   
               
               
                 63 
                 26222 
                 26241 
                 AACCATTTTAAAGCTCAGCC 
               
               
                   
               
               
                 64 
                 26311 
                 26330 
                 TCAAGGGCCAGGCCAGCAGC 
               
               
                   
               
               
                 65 
                 26316 
                 26335 
                 CCCACTCAAGGGCCAGGCCA 
               
               
                   
               
               
                 122 
                 26389 
                 26408 
                 GGAGGGAGCTTCCTGGCACC 
               
               
                   
               
               
                 66 
                 26404 
                 26423 
                 ATGCCCCACAGTGAGGGAGG 
               
               
                   
               
               
                 67 
                 26413 
                 26432 
                 AATGGTGAAATGCCCCACAG 
               
               
                   
               
               
                 153 
                 26456 
                 26475 
                 TTGGGAGCAGCTGGCAGCAC 
               
               
                   
               
               
                 68 
                 26557 
                 26576 
                 CATGGGAAGAATCCTGCCTC 
               
               
                   
               
               
                 431 
                 26635 
                 26654 
                 ATGAGGGCCATCAGCACCTT 
               
               
                   
               
               
                 432 
                 26636 
                 26655 
                 GATGAGGGCCATCAGCACCT 
               
               
                   
               
               
                 433 
                 26637 
                 26656 
                 AGATGAGGGCCATCAGCACC 
               
               
                   
               
               
                 434 
                 26638 
                 26657 
                 GAGATGAGGGCCATCAGCAC 
               
               
                   
               
               
                 69 
                 26639 
                 26658 
                 GGAGATGAGGGCCATCAGCA 
               
               
                   
               
               
                 435 
                 26640 
                 26659 
                 TGGAGATGAGGGCCATCAGC 
               
               
                   
               
               
                 436 
                 26641 
                 26660 
                 CTGGAGATGAGGGCCATCAG 
               
               
                   
               
               
                 437 
                 26642 
                 26661 
                 GCTGGAGATGAGGGCCATCA 
               
               
                   
               
               
                 438 
                 26643 
                 26662 
                 AGCTGGAGATGAGGGCCATC 
               
               
                   
               
               
                 461 
                 26684 
                 26697 
                 TTAATCAGGGAGCC 
               
               
                   
               
               
                 70 
                 26707 
                 26726 
                 TAGATGCCATCCAGAAAGCT 
               
               
                   
               
               
                 439 
                 26709 
                 26728 
                 GCTAGATGCCATCCAGAAAG 
               
               
                   
               
               
                 440 
                 26710 
                 26729 
                 GGCTAGATGCCATCCAGAAA 
               
               
                   
               
               
                 441 
                 26711 
                 26730 
                 TGGCTAGATGCCATCCAGAA 
               
               
                   
               
               
                 442 
                 26712 
                 26731 
                 CTGGCTAGATGCCATCCAGA 
               
               
                   
               
               
                 71 
                 26713 
                 26732 
                 TCTGGCTAGATGCCATCCAG 
               
               
                   
               
               
                 443 
                 26714 
                 26733 
                 CTCTGGCTAGATGCCATCCA 
               
               
                   
               
               
                 444 
                 26715 
                 26734 
                 CCTCTGGCTAGATGCCATCC 
               
               
                   
               
               
                 445 
                 26716 
                 26735 
                 GCCTCTGGCTAGATGCCATC 
               
               
                   
               
               
                 446 
                 26717 
                 26736 
                 AGCCTCTGGCTAGATGCCAT 
               
               
                   
               
               
                 72 
                 26790 
                 26809 
                 GGCATAGAGCAGAGTAAAGG 
               
               
                   
               
               
                 73 
                 26795 
                 26814 
                 AGCCTGGCATAGAGCAGAGT 
               
               
                   
               
               
                 135 
                 26801 
                 26820 
                 TAGCACAGCCTGGCATAGAG 
               
               
                   
               
               
                 112 
                 27034 
                 27053 
                 GAAGAGGCTTGGCTTCAGAG 
               
               
                   
               
               
                 74 
                 27040 
                 27059 
                 AAGTAAGAAGAGGCTTGGCT 
               
               
                   
               
               
                 75 
                 27244 
                 27263 
                 GCTCAAGGAGGGACAGTTGT 
               
               
                   
               
               
                 76 
                 27279 
                 27298 
                 AAAGATAAATGTCTGCTTGC 
               
               
                   
               
               
                 77 
                 27284 
                 27303 
                 ACCCAAAAGATAAATGTCTG 
               
               
                   
               
               
                 78 
                 27350 
                 27369 
                 TCTTCAAGTTACAAAAGCAA 
               
               
                   
               
               
                 99 
                 27357 
                 27376 
                 ATAAATATCTTCAAGTTACA 
               
               
                   
               
            
           
         
       
     
     In certain embodiments, gapmer antisense compounds are targeted to a PCSK9 nucleic acid. In certain such embodiments, gapmer antisense compounds are targeted to SEQ ID NO: 2. In certain such embodiments, the nucleotide sequences illustrated in Table 7 have a 5-10-5 gapmer motif. Table 8 illustrates gapmer antisense compounds targeted to SEQ ID NO: 2, having a 5-10-5 motif, where the gap segment comprises 2′-deoxynucleotides and each wing segment comprises nucleotides comprising a 2′-O-methoxyethyl sugar modification. Internucleoside linkages are phosphorthioate, and cytidines are 5-methylcytidines. 
     
       
         
           
               
             
               
                 TABLE 8 
               
             
            
               
                   
               
               
                 Gapmer antisense compounds having a 5-10-5 motif targeted to SEQ ID NO: 2 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                   
                   
                 5′ Target 
                 3′ Target 
                   
                   
               
               
                   
                   
                   
                 Site on 
                 Site on 
                   
                   
               
               
                   
                   
                 SEQ ID 
                 SEQ ID 
                 SEQ ID 
                   
                   
               
               
                 Isis No 
                 Motif 
                 NO 
                 NO:2 
                 NO: 2 
                 Mismatches 
                 Sequence (5′-3′) 
               
               
                   
               
               
                 395149 
                 5-10-5 
                   4 
                  2274 
                  2293 
                 0 
                 GCGCGGAATCCTGGCTGGGA 
               
               
                   
               
               
                 395150 
                 5-10-5 
                   5 
                  2381 
                  2400 
                 0 
                 GAGGAGACCTAGAGGCCGTG 
               
               
                   
               
               
                 395151 
                 5-10-5 
                   6 
                  2439 
                  2458 
                 0 
                 AGGACCGCCTGGAGCTGACG 
               
               
                   
               
               
                 395152 
                 5-10-5 
                   7 
                  2549 
                  2568 
                 0 
                 ACGCAAGGCTAGCACCAGCT 
               
               
                   
               
               
                 399793 
                 5-10-5 
                   8 
                  2556 
                  2575 
                 0 
                 CCTCGGAACGCAAGGCTAGC 
               
               
                   
               
               
                 395153 
                 5-10-5 
                   9 
                  2619 
                  2638 
                 0 
                 CCTTGGCGCAGCGGTGGAAG 
               
               
                   
               
               
                 399837 
                 5-10-5 
                 107 
                  3056 
                  3075 
                 0 
                 CCCACTATAATGGCAAGCCC 
               
               
                   
               
               
                 399838 
                 5-10-5 
                  80 
                  4306 
                  4325 
                 0 
                 AACCCAGTTCTAATGCACCT 
               
               
                   
               
               
                 399839 
                 5-10-5 
                 106 
                  5140 
                  5159 
                 0 
                 CCAGTCAGAGTAGAACAGAG 
               
               
                   
               
               
                 395221 
                 5-10-5 
                 102 
                  5590 
                  5609 
                 0 
                 ATGTGCAGAGATCAATCACA 
               
               
                   
               
               
                 399840 
                 5-10-5 
                 121 
                  5599 
                  5618 
                 0 
                 GGAGCCTACATGTGCAGAGA 
               
               
                   
               
               
                 399841 
                 5-10-5 
                  94 
                  5667 
                  5686 
                 0 
                 AGCATGGCACCAGCATCTGC 
               
               
                   
               
               
                 395154 
                 5-10-5 
                  10 
                  6498 
                  6517 
                 0 
                 GGCGGGCAGTGCGCTCTGAC 
               
               
                   
               
               
                 395155 
                 5-10-5 
                  11 
                  6537 
                  6556 
                 0 
                 TGGTGAGGTATCCCCGGCGG 
               
               
                   
               
               
                 399794 
                 5-10-5 
                  12 
                  6543 
                  6562 
                 0 
                 GGATCTTGGTGAGGTATCCC 
               
               
                   
               
               
                 399795 
                 5-10-5 
                  13 
                  6552 
                  6571 
                 0 
                 AGACATGCAGGATCTTGGTG 
               
               
                   
               
               
                 395156 
                 5-10-5 
                  14 
                  6557 
                  6576 
                 0 
                 ATGGAAGACATGCAGGATCT 
               
               
                   
               
               
                 395157 
                 5-10-5 
                  15 
                  6583 
                  6602 
                 0 
                 TTCACCAGGAAGCCAGGAAG 
               
               
                   
               
               
                 399796 
                 5-10-5 
                  16 
                  6588 
                  6607 
                 0 
                 TCATCTTCACCAGGAAGCCA 
               
               
                   
               
               
                 399842 
                 5-10-5 
                 108 
                  6652 
                  6671 
                 0 
                 CCCAGCCCTATCAGGAAGTG 
               
               
                   
               
               
                 399843 
                 5-10-5 
                 144 
                  7099 
                  7118 
                 0 
                 TGACATCCAGGAGGGAGGAG 
               
               
                   
               
               
                 399844 
                 5-10-5 
                  91 
                  7556 
                  7575 
                 0 
                 AGACTGATGGAAGGCATTGA 
               
               
                   
               
               
                 399845 
                 5-10-5 
                 131 
                  7565 
                  7584 
                 0 
                 GTGTTGAGCAGACTGATGGA 
               
               
                   
               
               
                 399846 
                 5-10-5 
                 145 
                  8836 
                  8855 
                 0 
                 TGACATCTTGTCTGGGAGCC 
               
               
                   
               
               
                 399847 
                 5-10-5 
                  90 
                  8948 
                  8967 
                 0 
                 AGACTAGGAGCCTGAGTTTT 
               
               
                   
               
               
                 399848 
                 5-10-5 
                 125 
                  9099 
                  9118 
                 0 
                 GGCCTGCAGAAGCCAGAGAG 
               
               
                   
               
               
                 395158 
                 5-10-5 
                  17 
                  9130 
                  9149 
                 0 
                 CCTCGATGTAGTCGACATGG 
               
               
                   
               
               
                 395159 
                 5-10-5 
                  18 
                  9210 
                  9229 
                 0 
                 GTATTCATCCGCCCGGTACC 
               
               
                   
               
               
                 399849 
                 5-10-5 
                 148 
                 10252 
                 10271 
                 0 
                 TGGCAGCAACTCAGACATAT 
               
               
                   
               
               
                 395222 
                 5-10-5 
                 127 
                 10633 
                 10652 
                 0 
                 GGTGGTAATTTGTCACAGCA 
               
               
                   
               
               
                 395223 
                 5-10-5 
                  84 
                 11308 
                 11327 
                 0 
                 AAGGTCACACAGTTAAGAGT 
               
               
                   
               
               
                 399850 
                 5-10-5 
                  79 
                 11472 
                 11491 
                 0 
                 AAATGCAGGGCTAAAATCAC 
               
               
                   
               
               
                 399851 
                 5-10-5 
                  88 
                 12715 
                 12734 
                 0 
                 ACTGGATACATTGGCAGACA 
               
               
                   
               
               
                 399852 
                 5-10-5 
                 111 
                 12928 
                 12947 
                 0 
                 CTAGAGGAACCACTAGATAT 
               
               
                   
               
               
                 395201 
                 5-10-5 
                  85 
                 13681 
                 13700 
                 0 
                 ACAAATTCCCAGACTCAGCA 
               
               
                   
               
               
                 399827 
                 5-10-5 
                 100 
                 13746 
                 13765 
                 0 
                 ATCTCAGGACAGGTGAGCAA 
               
               
                   
               
               
                 399828 
                 5-10-5 
                 116 
                 13760 
                 13779 
                 0 
                 GAGTAGAGATTCTCATCTCA 
               
               
                   
               
               
                 395202 
                 5-10-5 
                 129 
                 13816 
                 13835 
                 0 
                 GTGCCATCTGAACAGCACCT 
               
               
                   
               
               
                 399829 
                 5-10-5 
                 117 
                 13828 
                 13847 
                 0 
                 GAGTCTTCTGAAGTGCCATC 
               
               
                   
               
               
                 399830 
                 5-10-5 
                  81 
                 13903 
                 13922 
                 0 
                 AAGCAGGGCCTCAGGTGGAA 
               
               
                   
               
               
                 395203 
                 5-10-5 
                 110 
                 13926 
                 13945 
                 0 
                 CCTGGAACCCCTGCAGCCAG 
               
               
                   
               
               
                 395204 
                 5-10-5 
                 152 
                 13977 
                 13996 
                 0 
                 TTCAGGCAGGTTGCTGCTAG 
               
               
                   
               
               
                 399831 
                 5-10-5 
                  83 
                 13986 
                 14005 
                 0 
                 AAGGAAGACTTCAGGCAGGT 
               
               
                   
               
               
                 395205 
                 5-10-5 
                 140 
                 13998 
                 14017 
                 0 
                 TCAGCCAGGCCAAAGGAAGA 
               
               
                   
               
               
                 399832 
                 5-10-5 
                 137 
                 14112 
                 14131 
                 0 
                 TAGGGAGAGCTCACAGATGC 
               
               
                   
               
               
                 395206 
                 5-10-5 
                 136 
                 14122 
                 14141 
                 0 
                 TAGGAGAAAGTAGGGAGAGC 
               
               
                   
               
               
                 395207 
                 5-10-5 
                 132 
                 14179 
                 14198 
                 0 
                 TAAAAGCTGCAAGAGACTCA 
               
               
                   
               
               
                 395208 
                 5-10-5 
                 139 
                 14267 
                 14286 
                 0 
                 TCAGAGAAAACAGTCACCGA 
               
               
                   
               
               
                 399833 
                 5-10-5 
                  92 
                 14397 
                 14416 
                 0 
                 AGAGACAGGAAGCTGCAGCT 
               
               
                   
               
               
                 395209 
                 5-10-5 
                 142 
                 14404 
                 14423 
                 0 
                 TCATTTTAGAGACAGGAAGC 
               
               
                   
               
               
                 395210 
                 5-10-5 
                 113 
                 14441 
                 14460 
                 0 
                 GAATAACAGTGATGTCTGGC 
               
               
                   
               
               
                 395211 
                 5-10-5 
                 138 
                 14494 
                 14513 
                 0 
                 TCACAGCTCACCGAGTCTGC 
               
               
                   
               
               
                 395212 
                 5-10-5 
                  98 
                 14524 
                 14543 
                 0 
                 AGTGTAAAATAAAGCCCCTA 
               
               
                   
               
               
                 395213 
                 5-10-5 
                  96 
                 14601 
                 14620 
                 0 
                 AGGACCCAAGTCATCCTGCT 
               
               
                   
               
               
                 395214 
                 5-10-5 
                 124 
                 14631 
                 14650 
                 0 
                 GGCCATCAGCTGGCAATGCT 
               
               
                   
               
               
                 399834 
                 5-10-5 
                  82 
                 14670 
                 14689 
                 0 
                 AAGGAAAGGGAGGCCTAGAG 
               
               
                   
               
               
                 395215 
                 5-10-5 
                 133 
                 14675 
                 14694 
                 0 
                 TAGACAAGGAAAGGGAGGCC 
               
               
                   
               
               
                 395216 
                 5-10-5 
                 103 
                 14681 
                 14700 
                 0 
                 ATTTCATAGACAAGGAAAGG 
               
               
                   
               
               
                 395217 
                 5-10-5 
                 155 
                 14801 
                 14820 
                 0 
                 CTTATAGTTAACACACAGAA 
               
               
                   
               
               
                 399835 
                 5-10-5 
                 156 
                 14809 
                 14828 
                 0 
                 AAGTCAACCTTATAGTTAAC 
               
               
                   
               
               
                 395160 
                 5-10-5 
                  19 
                 14891 
                 14910 
                 0 
                 CTGGTGTCTAGGAGATACAC 
               
               
                   
               
               
                 399797 
                 5-10-5 
                  20 
                 14896 
                 14915 
                 0 
                 GTATGCTGGTGTCTAGGAGA 
               
               
                   
               
               
                 395161 
                 5-10-5 
                  21 
                 14916 
                 14935 
                 0 
                 GATTTCCCGGTGGTCACTCT 
               
               
                   
               
               
                 399798 
                 5-10-5 
                  22 
                 14922 
                 14941 
                 0 
                 GCCCTCGATTTCCCGGTGGT 
               
               
                   
               
               
                 399799 
                 5-10-5 
                  23 
                 14936 
                 14955 
                 0 
                 GTGACCATGACCCTGCCCTC 
               
               
                   
               
               
                 395162 
                 5-10-5 
                  24 
                 14946 
                 14965 
                 0 
                 CTCGAAGTCGGTGACCATGA 
               
               
                   
               
               
                 395163 
                 5-10-5 
                  25 
                 14979 
                 14998 
                 0 
                 GTGGAAGCGGGTCCCGTCCT 
               
               
                   
               
               
                 395164 
                 5-10-5 
                  26 
                 15264 
                 15283 
                 0 
                 ACCCCTGCCAGGTGGGTGCC 
               
               
                   
               
               
                 399800 
                 5-10-5 
                  27 
                 15269 
                 15288 
                 0 
                 TGACCACCCCTGCCAGGTGG 
               
               
                   
               
               
                 395165 
                 5-10-5 
                  28 
                 15298 
                 15317 
                 0 
                 ACCCTTGGCCACGCCGGCAT 
               
               
                   
               
               
                 395166 
                 5-10-5 
                  29 
                 15334 
                 15353 
                 0 
                 TTGGCAGTTGAGCACGCGCA 
               
               
                   
               
               
                 399801 
                 5-10-5 
                  30 
                 15339 
                 15358 
                 0 
                 TTCCCTTGGCAGTTGAGCAC 
               
               
                   
               
               
                 399853 
                 5-10-5 
                  86 
                 15471 
                 15490 
                 0 
                 ACAGCATTCTTGGTTAGGAG 
               
               
                   
               
               
                 399854 
                 5-10-5 
                  97 
                 16134 
                 16153 
                 0 
                 AGTCAAGCTGCTGCCCAGAG 
               
               
                   
               
               
                 399855 
                 5-10-5 
                 120 
                 16668 
                 16687 
                 0 
                 GCTAGTTATTAAGCACCTGC 
               
               
                   
               
               
                 399856 
                 5-10-5 
                 150 
                 17267 
                 17286 
                 0 
                 TGTGAGCTCTGGCCCAGTGG 
               
               
                   
               
               
                 399857 
                 5-10-5 
                 115 
                 18377 
                 18396 
                 0 
                 GAGTAAGGCAGGTTACTCTC 
               
               
                   
               
               
                 399858 
                 5-10-5 
                 134 
                 18408 
                 18427 
                 0 
                 TAGATGTGACTAACATTTAA 
               
               
                   
               
               
                 395224 
                 5-10-5 
                 157 
                 18561 
                 18580 
                 0 
                 AGGAACAAAGCCAAGGTCAC 
               
               
                   
               
               
                 395168 
                 5-10-5 
                  32 
                 18593 
                 18612 
                 0 
                 GCTGGCTTTTCCGAATAAAC 
               
               
                   
               
               
                 395169 
                 5-10-5 
                  33 
                 18705 
                 18724 
                 0 
                 GTGACCAGCACGACCCCAGC 
               
               
                   
               
               
                 399859 
                 5-10-5 
                 105 
                 19203 
                 19222 
                 0 
                 CACATTAGCCTTGCTCAAGT 
               
               
                   
               
               
                 399860 
                 5-10-5 
                 151 
                 19913 
                 19932 
                 0 
                 TGTGATGACCTGGAAAGGTG 
               
               
                   
               
               
                 395170 
                 5-10-5 
                 149 
                 19933 
                 19952 
                 0 
                 TGGGCATTGGTGGCCCCAAC 
               
               
                   
               
               
                 395171 
                 5-10-5 
                  34 
                 19962 
                 19981 
                 0 
                 CCAAAGTCCCCAGGGTCACC 
               
               
                   
               
               
                 395172 
                 5-10-5 
                 128 
                 19966 
                 19985 
                 0 
                 GTCCCCAAAGTCCCCAGGGT 
               
               
                   
               
               
                 399802 
                 5-10-5 
                  35 
                 19971 
                 19990 
                 0 
                 AGTTGGTCCCCAAAGTCCCC 
               
               
                   
               
               
                 395173 
                 5-10-5 
                  36 
                 19976 
                 19995 
                 0 
                 GCCAAAGTTGGTCCCCAAAG 
               
               
                   
               
               
                 399803 
                 5-10-5 
                  37 
                 19988 
                 20007 
                 0 
                 GTCCACACAGCGGCCAAAGT 
               
               
                   
               
               
                 395174 
                 5-10-5 
                  38 
                 19997 
                 20016 
                 0 
                 GGCAAAGAGGTCCACACAGC 
               
               
                   
               
               
                 395175 
                 5-10-5 
                  39 
                 20025 
                 20044 
                 0 
                 TGGAGGCACCAATGATGTCC 
               
               
                   
               
               
                 399804 
                 5-10-5 
                  40 
                 20036 
                 20055 
                 0 
                 GCTGCAGTCGCTGGAGGCAC 
               
               
                   
               
               
                 399805 
                 5-10-5 
                  41 
                 20047 
                 20066 
                 0 
                 ACAAAGCAGGTGCTGCAGTC 
               
               
                   
               
               
                 399861 
                 5-10-5 
                 158 
                 20100 
                 20119 
                 0 
                 GTGGTGACTTACCAGCCACG 
               
               
                   
               
               
                 399862 
                 5-10-5 
                 109 
                 20188 
                 20207 
                 0 
                 CCCCTGCACAGAGCCTGGCA 
               
               
                   
               
               
                 399863 
                 5-10-5 
                 141 
                 20624 
                 20643 
                 0 
                 TCATGGCTGCAATGCCTGGT 
               
               
                   
               
               
                 399807 
                 5-10-5 
                  43 
                 20635 
                 20654 
                 0 
                 GGCAGACAGCATCATGGCTG 
               
               
                   
               
               
                 399808 
                 5-10-5 
                  44 
                 20683 
                 20702 
                 0 
                 GAAGTGGATCAGTCTCTGCC 
               
               
                   
               
               
                 395177 
                 5-10-5 
                  45 
                 20691 
                 20710 
                 0 
                 TTGGCAGAGAAGTGGATCAG 
               
               
                   
               
               
                 399809 
                 5-10-5 
                  46 
                 20696 
                 20715 
                 0 
                 CATCTTTGGCAGAGAAGTGG 
               
               
                   
               
               
                 399810 
                 5-10-5 
                  47 
                 20702 
                 20721 
                 0 
                 TGATGACATCTTTGGCAGAG 
               
               
                   
               
               
                 399811 
                 5-10-5 
                  48 
                 20709 
                 20728 
                 0 
                 GCCTCATTGATGACATCTTT 
               
               
                   
               
               
                 399812 
                 5-10-5 
                  49 
                 20721 
                 20740 
                 0 
                 TCAGGGAACCAGGCCTCATT 
               
               
                   
               
               
                 395178 
                 5-10-5 
                  50 
                 20726 
                 20745 
                 0 
                 GGTCCTCAGGGAACCAGGCC 
               
               
                   
               
               
                 395179 
                 5-10-5 
                  87 
                 20733 
                 20752 
                 0 
                 ACCCGCTGGTCCTCAGGGAA 
               
               
                   
               
               
                 399813 
                 5-10-5 
                  51 
                 20740 
                 20759 
                 0 
                 GGTCAGTACCCGCTGGTCCT 
               
               
                   
               
               
                 395180 
                 5-10-5 
                 119 
                 20762 
                 20781 
                 0 
                 GCAGGGCGGCCACCAGGTTG 
               
               
                   
               
               
                 399864 
                 5-10-5 
                  93 
                 20995 
                 21014 
                 0 
                 AGAGAGGAGGGCTTAAAGAA 
               
               
                   
               
               
                 399865 
                 5-10-5 
                  95 
                 21082 
                 21101 
                 0 
                 AGCTGCCAACCTGCAAAAAG 
               
               
                   
               
               
                 399814 
                 5-10-5 
                  53 
                 21091 
                 21110 
                 0 
                 CTGCAAAACAGCTGCCAACC 
               
               
                   
               
               
                 395182 
                 5-10-5 
                  54 
                 21121 
                 21140 
                 0 
                 GTAGGCCCCGAGTGTGCTGA 
               
               
                   
               
               
                 399815 
                 5-10-5 
                  55 
                 21186 
                 21205 
                 0 
                 AGAAACTGGAGCAGCTCAGC 
               
               
                   
               
               
                 399816 
                 5-10-5 
                  56 
                 21192 
                 21211 
                 0 
                 TCCTGGAGAAACTGGAGCAG 
               
               
                   
               
               
                 399866 
                 5-10-5 
                 143 
                 21481 
                 21500 
                 0 
                 TGAAAATCCATCCAGCACTG 
               
               
                   
               
               
                 399867 
                 5-10-5 
                  89 
                 21589 
                 21608 
                 0 
                 AGAACCATGGAGCACCTGAG 
               
               
                   
               
               
                 399868 
                 5-10-5 
                 123 
                 21696 
                 21715 
                 0 
                 GGCACTGCCCTTCCACCAAA 
               
               
                   
               
               
                 395183 
                 5-10-5 
                  57 
                 22096 
                 22115 
                 0 
                 CGTTGTGGGCCCGGCAGACC 
               
               
                   
               
               
                 395184 
                 5-10-5 
                  58 
                 22142 
                 22161 
                 0 
                 AGCAGGCAGCACCTGGCAAT 
               
               
                   
               
               
                 395185 
                 5-10-5 
                  59 
                 22204 
                 22223 
                 0 
                 CACGGGTCCCCATGCTGGCC 
               
               
                   
               
               
                 395225 
                 5-10-5 
                 126 
                 22292 
                 22311 
                 0 
                 GGTGCATAAGGAGAAAGAGA 
               
               
                   
               
               
                 395186 
                 5-10-5 
                  60 
                 24095 
                 24114 
                 0 
                 CTTTGCATTCCAGACCTGGG 
               
               
                   
               
               
                 399817 
                 5-10-5 
                  61 
                 24100 
                 24119 
                 0 
                 CTTGACTTTGCATTCCAGAC 
               
               
                   
               
               
                 395226 
                 5-10-5 
                 147 
                 24858 
                 24877 
                 0 
                 TGAGTTCATTTAAGAGTGGA 
               
               
                   
               
               
                 399869 
                 5-10-5 
                 118 
                 24907 
                 24926 
                 0 
                 GCACCATCCAGACCAGAATC 
               
               
                   
               
               
                 399870 
                 5-10-5 
                 114 
                 25413 
                 25432 
                 0 
                 GAGAGGTTCAGATCCAGGCC 
               
               
                   
               
               
                 395187 
                 5-10-5 
                  62 
                 26117 
                 26136 
                 0 
                 GGCAGCAGATGGCAACGGCT 
               
               
                   
               
               
                 395188 
                 5-10-5 
                 154 
                 26217 
                 26236 
                 0 
                 TTTTAAAGCTCAGCCCCAGC 
               
               
                   
               
               
                 399818 
                 5-10-5 
                  63 
                 26222 
                 26241 
                 0 
                 AACCATTTTAAAGCTCAGCC 
               
               
                   
               
               
                 395189 
                 5-10-5 
                  64 
                 26311 
                 26330 
                 0 
                 TCAAGGGCCAGGCCAGCAGC 
               
               
                   
               
               
                 399819 
                 5-10-5 
                  65 
                 26316 
                 26335 
                 0 
                 CCCACTCAAGGGCCAGGCCA 
               
               
                   
               
               
                 399820 
                 5-10-5 
                 122 
                 26389 
                 26408 
                 0 
                 GGAGGGAGCTTCCTGGCACC 
               
               
                   
               
               
                 395190 
                 5-10-5 
                  66 
                 26404 
                 26423 
                 0 
                 ATGCCCCACAGTGAGGGAGG 
               
               
                   
               
               
                 395191 
                 5-10-5 
                  67 
                 26413 
                 26432 
                 0 
                 AATGGTGAAATGCCCCACAG 
               
               
                   
               
               
                 395192 
                 5-10-5 
                 153 
                 26456 
                 26475 
                 0 
                 TTGGGAGCAGCTGGCAGCAC 
               
               
                   
               
               
                 395193 
                 5-10-5 
                  68 
                 26557 
                 26576 
                 0 
                 CATGGGAAGAATCCTGCCTC 
               
               
                   
               
               
                 395194 
                 5-10-5 
                  69 
                 26639 
                 26658 
                 0 
                 GGAGATGAGGGCCATCAGCA 
               
               
                   
               
               
                 395195 
                 5-10-5 
                  70 
                 26707 
                 26726 
                 0 
                 TAGATGCCATCCAGAAAGCT 
               
               
                   
               
               
                 399821 
                 5-10-5 
                  71 
                 26713 
                 26732 
                 0 
                 TCTGGCTAGATGCCATCCAG 
               
               
                   
               
               
                 395196 
                 5-10-5 
                  72 
                 26790 
                 26809 
                 0 
                 GGCATAGAGCAGAGTAAAGG 
               
               
                   
               
               
                 399822 
                 5-10-5 
                  73 
                 26795 
                 26814 
                 0 
                 AGCCTGGCATAGAGCAGAGT 
               
               
                   
               
               
                 399823 
                 5-10-5 
                 135 
                 26801 
                 26820 
                 0 
                 TAGCACAGCCTGGCATAGAG 
               
               
                   
               
               
                 395197 
                 5-10-5 
                 112 
                 27034 
                 27053 
                 0 
                 GAAGAGGCTTGGCTTCAGAG 
               
               
                   
               
               
                 399824 
                 5-10-5 
                  74 
                 27040 
                 27059 
                 0 
                 AAGTAAGAAGAGGCTTGGCT 
               
               
                   
               
               
                 395198 
                 5-10-5 
                  75 
                 27244 
                 27263 
                 0 
                 GCTCAAGGAGGGACAGTTGT 
               
               
                   
               
               
                 395199 
                 5-10-5 
                  76 
                 27279 
                 27298 
                 0 
                 AAAGATAAATGTCTGCTTGC 
               
               
                   
               
               
                 399825 
                 5-10-5 
                  77 
                 27284 
                 27303 
                 0 
                 ACCCAAAAGATAAATGTCTG 
               
               
                   
               
               
                 395200 
                 5-10-5 
                  78 
                 27350 
                 27369 
                 0 
                 TCTTCAAGTTACAAAAGCAA 
               
               
                   
               
               
                 399826 
                 5-10-5 
                  99 
                 27357 
                 27376 
                 0 
                 ATAAATATCTTCAAGTTACA 
               
               
                   
               
               
                 405861 
                 5-10-5 
                 162 
                  2545 
                  2564 
                 0 
                 AAGGCTAGCACCAGCTCCTC 
               
               
                   
               
               
                 405862 
                 5-10-5 
                 163 
                  2546 
                  2565 
                 0 
                 CAAGGCTAGCACCAGCTCCT 
               
               
                   
               
               
                 405863 
                 5-10-5 
                 164 
                  2547 
                  2566 
                 0 
                 GCAAGGCTAGCACCAGCTCC 
               
               
                   
               
               
                 405864 
                 5-10-5 
                 165 
                  2548 
                  2567 
                 0 
                 CGCAAGGCTAGCACCAGCTC 
               
               
                   
               
               
                 405865 
                 5-10-5 
                 166 
                  2550 
                  2569 
                 0 
                 AACGCAAGGCTAGCACCAGC 
               
               
                   
               
               
                 405866 
                 5-10-5 
                 167 
                  2551 
                  2570 
                 0 
                 GAACGCAAGGCTAGCACCAG 
               
               
                   
               
               
                 405867 
                 5-10-5 
                 168 
                  2552 
                  2571 
                 0 
                 GGAACGCAAGGCTAGCACCA 
               
               
                   
               
               
                 405868 
                 5-10-5 
                 169 
                  2553 
                  2572 
                 0 
                 CGGAACGCAAGGCTAGCACC 
               
               
                   
               
               
                 405869 
                 5-10-5 
                 218 
                 14918 
                 14937 
                 0 
                 TCGATTTCCCGGTGGTCACT 
               
               
                   
               
               
                 405870 
                 5-10-5 
                 219 
                 14919 
                 14938 
                 0 
                 CTCGATTTCCCGGTGGTCAC 
               
               
                   
               
               
                 405871 
                 5-10-5 
                 220 
                 14920 
                 14939 
                 0 
                 CCTCGATTTCCCGGTGGTCA 
               
               
                   
               
               
                 405872 
                 5-10-5 
                 221 
                 14921 
                 14940 
                 0 
                 CCCTCGATTTCCCGGTGGTC 
               
               
                   
               
               
                 405873 
                 5-10-5 
                 222 
                 14923 
                 14942 
                 0 
                 TGCCCTCGATTTCCCGGTGG 
               
               
                   
               
               
                 405874 
                 5-10-5 
                 223 
                 14924 
                 14943 
                 0 
                 CTGCCCTCGATTTCCCGGTG 
               
               
                   
               
               
                 405875 
                 5-10-5 
                 224 
                 14925 
                 14944 
                 0 
                 CCTGCCCTCGATTTCCCGGT 
               
               
                   
               
               
                 405876 
                 5-10-5 
                 225 
                 14926 
                 14945 
                 0 
                 CCCTGCCCTCGATTTCCCGG 
               
               
                   
               
               
                 405877 
                 5-10-5 
                 246 
                 15294 
                 15313 
                 0 
                 TTGGCCACGCCGGCATCCCG 
               
               
                   
               
               
                 405878 
                 5-10-5 
                 247 
                 15295 
                 15314 
                 0 
                 CTTGGCCACGCCGGCATCCC 
               
               
                   
               
               
                 405879 
                 5-10-5 
                 248 
                 15296 
                 15315 
                 0 
                 CCTTGGCCACGCCGGCATCC 
               
               
                   
               
               
                 405880 
                 5-10-5 
                 249 
                 15297 
                 15316 
                 0 
                 CCCTTGGCCACGCCGGCATC 
               
               
                   
               
               
                 405881 
                 5-10-5 
                 250 
                 15299 
                 15318 
                 0 
                 CACCCTTGGCCACGCCGGCA 
               
               
                   
               
               
                 405882 
                 5-10-5 
                 251 
                 15300 
                 15319 
                 0 
                 GCACCCTTGGCCACGCCGGC 
               
               
                   
               
               
                 405883 
                 5-10-5 
                 252 
                 15301 
                 15320 
                 0 
                 GGCACCCTTGGCCACGCCGG 
               
               
                   
               
               
                 405884 
                 5-10-5 
                 253 
                 15302 
                 15321 
                 0 
                 TGGCACCCTTGGCCACGCCG 
               
               
                   
               
               
                 405885 
                 5-10-5 
                 346 
                 20717 
                 20736 
                 0 
                 GGAACCAGGCCTCATTGATG 
               
               
                   
               
               
                 405886 
                 5-10-5 
                 347 
                 20718 
                 20737 
                 0 
                 GGGAACCAGGCCTCATTGAT 
               
               
                   
               
               
                 405887 
                 5-10-5 
                 348 
                 20719 
                 20738 
                 0 
                 AGGGAACCAGGCCTCATTGA 
               
               
                   
               
               
                 405888 
                 5-10-5 
                 349 
                 20720 
                 20739 
                 0 
                 CAGGGAACCAGGCCTCATTG 
               
               
                   
               
               
                 405889 
                 5-10-5 
                 350 
                 20722 
                 20741 
                 0 
                 CTCAGGGAACCAGGCCTCAT 
               
               
                   
               
               
                 405890 
                 5-10-5 
                 351 
                 20723 
                 20742 
                 0 
                 CCTCAGGGAACCAGGCCTCA 
               
               
                   
               
               
                 405891 
                 5-10-5 
                 352 
                 20724 
                 20743 
                 0 
                 TCCTCAGGGAACCAGGCCTC 
               
               
                   
               
               
                 405892 
                 5-10-5 
                 353 
                 20725 
                 20744 
                 0 
                 GTCCTCAGGGAACCAGGCCT 
               
               
                   
               
               
                 405893 
                 5-10-5 
                 431 
                 26635 
                 26654 
                 0 
                 ATGAGGGCCATCAGCACCTT 
               
               
                   
               
               
                 405894 
                 5-10-5 
                 432 
                 26636 
                 26655 
                 0 
                 GATGAGGGCCATCAGCACCT 
               
               
                   
               
               
                 405895 
                 5-10-5 
                 433 
                 26637 
                 26656 
                 0 
                 AGATGAGGGCCATCAGCACC 
               
               
                   
               
               
                 405896 
                 5-10-5 
                 434 
                 26638 
                 26657 
                 0 
                 GAGATGAGGGCCATCAGCAC 
               
               
                   
               
               
                 405897 
                 5-10-5 
                 435 
                 26640 
                 26659 
                 0 
                 TGGAGATGAGGGCCATCAGC 
               
               
                   
               
               
                 405898 
                 5-10-5 
                 436 
                 26641 
                 26660 
                 0 
                 CTGGAGATGAGGGCCATCAG 
               
               
                   
               
               
                 405899 
                 5-10-5 
                 437 
                 26642 
                 26661 
                 0 
                 GCTGGAGATGAGGGCCATCA 
               
               
                   
               
               
                 405900 
                 5-10-5 
                 438 
                 26643 
                 26662 
                 0 
                 AGCTGGAGATGAGGGCCATC 
               
               
                   
               
               
                 405901 
                 5-10-5 
                 439 
                 26709 
                 26728 
                 0 
                 GCTAGATGCCATCCAGAAAG 
               
               
                   
               
               
                 405902 
                 5-10-5 
                 440 
                 26710 
                 26729 
                 0 
                 GGCTAGATGCCATCCAGAAA 
               
               
                   
               
               
                 405903 
                 5-10-5 
                 441 
                 26711 
                 26730 
                 0 
                 TGGCTAGATGCCATCCAGAA 
               
               
                   
               
               
                 405904 
                 5-10-5 
                 442 
                 26712 
                 26731 
                 0 
                 CTGGCTAGATGCCATCCAGA 
               
               
                   
               
               
                 405905 
                 5-10-5 
                 443 
                 26714 
                 26733 
                 0 
                 CTCTGGCTAGATGCCATCCA 
               
               
                   
               
               
                 405906 
                 5-10-5 
                 444 
                 26715 
                 26734 
                 0 
                 CCTCTGGCTAGATGCCATCC 
               
               
                   
               
               
                 405907 
                 5-10-5 
                 445 
                 26716 
                 26735 
                 0 
                 GCCTCTGGCTAGATGCCATC 
               
               
                   
               
               
                 405908 
                 5-10-5 
                 446 
                 26717 
                 26736 
                 0 
                 AGCCTCTGGCTAGATGCCAT 
               
               
                   
               
               
                 405909 
                 5-10-5 
                 267 
                 18595 
                 18614 
                 0 
                 CAGCTGGCTTTTCCGAATAA 
               
               
                   
               
               
                 405910 
                 5-10-5 
                 268 
                 18597 
                 18616 
                 0 
                 ACCAGCTGGCTTTTCCGAAT 
               
               
                   
               
               
                 405911 
                 5-10-5 
                 269 
                 18599 
                 18618 
                 0 
                 GGACCAGCTGGCTTTTCCGA 
               
               
                   
               
               
                 405912 
                 5-10-5 
                 270 
                 18603 
                 18622 
                 0 
                 GGCTGGACCAGCTGGCTTTT 
               
               
                   
               
               
                 405913 
                 5-10-5 
                 275 
                 18707 
                 18726 
                 0 
                 CGGTGACCAGCACGACCCCA 
               
               
                   
               
               
                 405914 
                 5-10-5 
                 276 
                 18709 
                 18728 
                 0 
                 AGCGGTGACCAGCACGACCC 
               
               
                   
               
               
                 405915 
                 5-10-5 
                 277 
                 18711 
                 18730 
                 0 
                 GCAGCGGTGACCAGCACGAC 
               
               
                   
               
               
                 405916 
                 5-10-5 
                 278 
                 18713 
                 18732 
                 0 
                 CGGCAGCGGTGACCAGCACG 
               
               
                   
               
               
                 405917 
                 5-10-5 
                 280 
                 18717 
                 18736 
                 0 
                 TTGCCGGCAGCGGTGACCAG 
               
               
                   
               
               
                 405918 
                 5-10-5 
                 281 
                 18719 
                 18738 
                 0 
                 AGTTGCCGGCAGCGGTGACC 
               
               
                   
               
               
                 405919 
                 5-10-5 
                 282 
                 18721 
                 18740 
                 0 
                 GAAGTTGCCGGCAGCGGTGA 
               
               
                   
               
               
                 405920 
                 5-10-5 
                 283 
                 18723 
                 18742 
                 0 
                 CGGAAGTTGCCGGCAGCGGT 
               
               
                   
               
               
                 405921 
                 5-10-5 
                 284 
                 18725 
                 18744 
                 0 
                 CCCGGAAGTTGCCGGCAGCG 
               
               
                   
               
               
                 405922 
                 5-10-5 
                 285 
                 18727 
                 18746 
                 0 
                 GTCCCGGAAGTTGCCGGCAG 
               
               
                   
               
               
                 405923 
                 5-10-5 
                 288 
                 19931 
                 19950 
                 0 
                 GGCATTGGTGGCCCCAACTG 
               
               
                   
               
               
                 405924 
                 5-10-5 
                 290 
                 19954 
                 19973 
                 0 
                 CCCAGGGTCACCGGCTGGTC 
               
               
                   
               
               
                 405925 
                 5-10-5 
                 292 
                 19958 
                 19977 
                 0 
                 AGTCCCCAGGGTCACCGGCT 
               
               
                   
               
               
                 405926 
                 5-10-5 
                 293 
                 19960 
                 19979 
                 0 
                 AAAGTCCCCAGGGTCACCGG 
               
               
                   
               
               
                 405927 
                 5-10-5 
                 294 
                 19964 
                 19983 
                 0 
                 CCCCAAAGTCCCCAGGGTCA 
               
               
                   
               
               
                 405928 
                 5-10-5 
                 295 
                 19969 
                 19988 
                 0 
                 TTGGTCCCCAAAGTCCCCAG 
               
               
                   
               
               
                 405929 
                 5-10-5 
                 296 
                 19973 
                 19992 
                 0 
                 AAAGTTGGTCCCCAAAGTCC 
               
               
                   
               
               
                 405930 
                 5-10-5 
                 297 
                 19978 
                 19997 
                 0 
                 CGGCCAAAGTTGGTCCCCAA 
               
               
                   
               
               
                 405931 
                 5-10-5 
                 298 
                 19980 
                 19999 
                 0 
                 AGCGGCCAAAGTTGGTCCCC 
               
               
                   
               
               
                 405932 
                 5-10-5 
                 299 
                 19982 
                 20001 
                 0 
                 ACAGCGGCCAAAGTTGGTCC 
               
               
                   
               
               
                 405933 
                 5-10-5 
                 300 
                 19984 
                 20003 
                 0 
                 ACACAGCGGCCAAAGTTGGT 
               
               
                   
               
               
                 405934 
                 5-10-5 
                 301 
                 19986 
                 20005 
                 0 
                 CCACACAGCGGCCAAAGTTG 
               
               
                   
               
               
                 405935 
                 5-10-5 
                 302 
                 19990 
                 20009 
                 0 
                 AGGTCCACACAGCGGCCAAA 
               
               
                   
               
               
                 405936 
                 5-10-5 
                 304 
                 19994 
                 20013 
                 0 
                 AAAGAGGTCCACACAGCGGC 
               
               
                   
               
               
                 405937 
                 5-10-5 
                 306 
                 20023 
                 20042 
                 0 
                 GAGGCACCAATGATGTCCTC 
               
               
                   
               
               
                 405938 
                 5-10-5 
                 307 
                 20027 
                 20046 
                 0 
                 GCTGGAGGCACCAATGATGT 
               
               
                   
               
               
                 405939 
                 5-10-5 
                 308 
                 20029 
                 20048 
                 0 
                 TCGCTGGAGGCACCAATGAT 
               
               
                   
               
               
                 405940 
                 5-10-5 
                 309 
                 20031 
                 20050 
                 0 
                 AGTCGCTGGAGGCACCAATG 
               
               
                   
               
               
                 405941 
                 5-10-5 
                 310 
                 20033 
                 20052 
                 0 
                 GCAGTCGCTGGAGGCACCAA 
               
               
                   
               
               
                 405942 
                 5-10-5 
                 311 
                 20038 
                 20057 
                 0 
                 GTGCTGCAGTCGCTGGAGGC 
               
               
                   
               
               
                 405943 
                 5-10-5 
                 312 
                 20040 
                 20059 
                 0 
                 AGGTGCTGCAGTCGCTGGAG 
               
               
                   
               
               
                 405944 
                 5-10-5 
                 314 
                 20043 
                 20062 
                 0 
                 AGCAGGTGCTGCAGTCGCTG 
               
               
                   
               
               
                 405945 
                 5-10-5 
                 315 
                 20045 
                 20064 
                 0 
                 AAAGCAGGTGCTGCAGTCGC 
               
               
                   
               
               
                 405946 
                 5-10-5 
                 316 
                 20049 
                 20068 
                 0 
                 ACACAAAGCAGGTGCTGCAG 
               
               
                   
               
               
                 405947 
                 5-10-5 
                 317 
                 20051 
                 20070 
                 0 
                 TGACACAAAGCAGGTGCTGC 
               
               
                   
               
               
                 405949 
                 5-10-5 
                 320 
                 20629 
                 20648 
                 0 
                 CAGCATCATGGCTGCAATGC 
               
               
                   
               
               
                 405950 
                 5-10-5 
                 321 
                 20631 
                 20650 
                 0 
                 GACAGCATCATGGCTGCAAT 
               
               
                   
               
               
                 405951 
                 5-10-5 
                 322 
                 20633 
                 20652 
                 0 
                 CAGACAGCATCATGGCTGCA 
               
               
                   
               
               
                 405952 
                 5-10-5 
                 323 
                 20637 
                 20656 
                 0 
                 TCGGCAGACAGCATCATGGC 
               
               
                   
               
               
                 405953 
                 5-10-5 
                 325 
                 20641 
                 20660 
                 0 
                 CGGCTCGGCAGACAGCATCA 
               
               
                   
               
               
                 405954 
                 5-10-5 
                 326 
                 20643 
                 20662 
                 0 
                 TCCGGCTCGGCAGACAGCAT 
               
               
                   
               
               
                 405955 
                 5-10-5 
                 328 
                 20670 
                 20689 
                 0 
                 CTCTGCCTCAACTCGGCCAG 
               
               
                   
               
               
                 405956 
                 5-10-5 
                 329 
                 20672 
                 20691 
                 0 
                 GTCTCTGCCTCAACTCGGCC 
               
               
                   
               
               
                 405957 
                 5-10-5 
                 330 
                 20674 
                 20693 
                 0 
                 CAGTCTCTGCCTCAACTCGG 
               
               
                   
               
               
                 405958 
                 5-10-5 
                 331 
                 20676 
                 20695 
                 0 
                 ATCAGTCTCTGCCTCAACTC 
               
               
                   
               
               
                 405959 
                 5-10-5 
                 332 
                 20678 
                 20697 
                 0 
                 GGATCAGTCTCTGCCTCAAC 
               
               
                   
               
               
                 405960 
                 5-10-5 
                 333 
                 20680 
                 20699 
                 0 
                 GTGGATCAGTCTCTGCCTCA 
               
               
                   
               
               
                 405961 
                 5-10-5 
                 334 
                 20682 
                 20701 
                 0 
                 AAGTGGATCAGTCTCTGCCT 
               
               
                   
               
               
                 405962 
                 5-10-5 
                 335 
                 20685 
                 20704 
                 0 
                 GAGAAGTGGATCAGTCTCTG 
               
               
                   
               
               
                 405963 
                 5-10-5 
                 337 
                 20689 
                 20708 
                 0 
                 GGCAGAGAAGTGGATCAGTC 
               
               
                   
               
               
                 405964 
                 5-10-5 
                 338 
                 20693 
                 20712 
                 0 
                 CTTTGGCAGAGAAGTGGATC 
               
               
                   
               
               
                 405965 
                 5-10-5 
                 339 
                 20698 
                 20717 
                 0 
                 GACATCTTTGGCAGAGAAGT 
               
               
                   
               
               
                 405966 
                 5-10-5 
                 340 
                 20700 
                 20719 
                 0 
                 ATGACATCTTTGGCAGAGAA 
               
               
                   
               
               
                 405967 
                 5-10-5 
                 341 
                 20704 
                 20723 
                 0 
                 ATTGATGACATCTTTGGCAG 
               
               
                   
               
               
                 405968 
                 5-10-5 
                 342 
                 20706 
                 20725 
                 0 
                 TCATTGATGACATCTTTGGC 
               
               
                   
               
               
                 405969 
                 5-10-5 
                 343 
                 20711 
                 20730 
                 0 
                 AGGCCTCATTGATGACATCT 
               
               
                   
               
               
                 405970 
                 5-10-5 
                 344 
                 20713 
                 20732 
                 0 
                 CCAGGCCTCATTGATGACAT 
               
               
                   
               
               
                 405971 
                 5-10-5 
                 355 
                 20728 
                 20747 
                 0 
                 CTGGTCCTCAGGGAACCAGG 
               
               
                   
               
               
                 405972 
                 5-10-5 
                 357 
                 20730 
                 20749 
                 0 
                 CGCTGGTCCTCAGGGAACCA 
               
               
                   
               
               
                 405973 
                 5-10-5 
                 358 
                 20735 
                 20754 
                 0 
                 GTACCCGCTGGTCCTCAGGG 
               
               
                   
               
               
                 405974 
                 5-10-5 
                 359 
                 20737 
                 20756 
                 0 
                 CAGTACCCGCTGGTCCTCAG 
               
               
                   
               
               
                 405975 
                 5-10-5 
                 361 
                 21088 
                 21107 
                 0 
                 CAAAACAGCTGCCAACCTGC 
               
               
                   
               
               
                 405976 
                 5-10-5 
                 362 
                 21093 
                 21112 
                 0 
                 TCCTGCAAAACAGCTGCCAA 
               
               
                   
               
               
                 405977 
                 5-10-5 
                 363 
                 21095 
                 21114 
                 0 
                 AGTCCTGCAAAACAGCTGCC 
               
               
                   
               
               
                 405978 
                 5-10-5 
                 365 
                 21118 
                 21137 
                 0 
                 GGCCCCGAGTGTGCTGACCA 
               
               
                   
               
               
                 405979 
                 5-10-5 
                 366 
                 21123 
                 21142 
                 0 
                 GTGTAGGCCCCGAGTGTGCT 
               
               
                   
               
               
                 405980 
                 5-10-5 
                 367 
                 21125 
                 21144 
                 0 
                 CCGTGTAGGCCCCGAGTGTG 
               
               
                   
               
               
                 405981 
                 5-10-5 
                 368 
                 21127 
                 21146 
                 0 
                 ATCCGTGTAGGCCCCGAGTG 
               
               
                   
               
               
                 405982 
                 5-10-5 
                 370 
                 21131 
                 21150 
                 0 
                 GGCCATCCGTGTAGGCCCCG 
               
               
                   
               
               
                 405983 
                 5-10-5 
                 371 
                 21133 
                 21152 
                 0 
                 GTGGCCATCCGTGTAGGCCC 
               
               
                   
               
               
                 405984 
                 5-10-5 
                 372 
                 21181 
                 21200 
                 0 
                 CTGGAGCAGCTCAGCAGCTC 
               
               
                   
               
               
                 405985 
                 5-10-5 
                 373 
                 21183 
                 21202 
                 0 
                 AACTGGAGCAGCTCAGCAGC 
               
               
                   
               
               
                 405986 
                 5-10-5 
                 374 
                 21188 
                 21207 
                 0 
                 GGAGAAACTGGAGCAGCTCA 
               
               
                   
               
               
                 405987 
                 5-10-5 
                 375 
                 21190 
                 21209 
                 0 
                 CTGGAGAAACTGGAGCAGCT 
               
               
                   
               
               
                 405988 
                 5-10-5 
                 381 
                 22138 
                 22157 
                 0 
                 GGCAGCACCTGGCAATGGCG 
               
               
                   
               
               
                 405989 
                 5-10-5 
                 383 
                 22140 
                 22159 
                 0 
                 CAGGCAGCACCTGGCAATGG 
               
               
                   
               
               
                 405990 
                 5-10-5 
                 386 
                 22144 
                 22163 
                 0 
                 GTAGCAGGCAGCACCTGGCA 
               
               
                   
               
               
                 405991 
                 5-10-5 
                 394 
                 22206 
                 22225 
                 0 
                 GACACGGGTCCCCATGCTGG 
               
               
                   
               
               
                 405992 
                 5-10-5 
                 396 
                 22208 
                 22227 
                 0 
                 TGGACACGGGTCCCCATGCT 
               
               
                   
               
               
                 405993 
                 5-10-5 
                 398 
                 22210 
                 22229 
                 0 
                 AGTGGACACGGGTCCCCATG 
               
               
                   
               
               
                 405994 
                 5-10-5 
                 400 
                 22212 
                 22231 
                 0 
                 GCAGTGGACACGGGTCCCCA 
               
               
                   
               
               
                 405995 
                 5-10-5 
                 402 
                 22214 
                 22233 
                 0 
                 TGGCAGTGGACACGGGTCCC 
               
               
                   
               
               
                 405996 
                 5-10-5 
                 412 
                 24097 
                 24116 
                 0 
                 GACTTTGCATTCCAGACCTG 
               
               
                   
               
               
                 405997 
                 5-10-5 
                 415 
                 24102 
                 24121 
                 0 
                 TCCTTGACTTTGCATTCCAG 
               
               
                   
               
               
                 405998 
                 5-10-5 
                 426 
                 26120 
                 26139 
                 0 
                 TCCGGCAGCAGATGGCAACG 
               
               
                   
               
               
                 405999 
                 5-10-5 
                 160 
                  2437 
                 2456 
                 0 
                 GACCGCCTGGAGCTGACGGT 
               
               
                   
               
               
                 406003 
                 5-10-5 
                 178 
                  6492 
                  6511 
                 0 
                 CAGTGCGCTCTGACTGCGAG 
               
               
                   
               
               
                 406004 
                 5-10-5 
                 179 
                  6494 
                  6513 
                 0 
                 GGCAGTGCGCTCTGACTGCG 
               
               
                   
               
               
                 406005 
                 5-10-5 
                 180 
                  6496 
                  6515 
                 0 
                 CGGGCAGTGCGCTCTGACTG 
               
               
                   
               
               
                 406006 
                 5-10-5 
                 181 
                  6499 
                  6518 
                 0 
                 CGGCGGGCAGTGCGCTCTGA 
               
               
                   
               
               
                 406007 
                 5-10-5 
                 183 
                  6532 
                  6551 
                 0 
                 AGGTATCCCCGGCGGGCAGC 
               
               
                   
               
               
                 406008 
                 5-10-5 
                 188 
                  6539 
                  6558 
                 0 
                 CTTGGTGAGGTATCCCCGGC 
               
               
                   
               
               
                 406009 
                 5-10-5 
                 190 
                  6541 
                  6560 
                 0 
                 ATCTTGGTGAGGTATCCCCG 
               
               
                   
               
               
                 406010 
                 5-10-5 
                 193 
                  6546 
                  6565 
                 0 
                 GCAGGATCTTGGTGAGGTAT 
               
               
                   
               
               
                 406011 
                 5-10-5 
                 194 
                  6548 
                  6567 
                 0 
                 ATGCAGGATCTTGGTGAGGT 
               
               
                   
               
               
                 406012 
                 5-10-5 
                 195 
                  6550 
                  6569 
                 0 
                 ACATGCAGGATCTTGGTGAG 
               
               
                   
               
               
                 406013 
                 5-10-5 
                 196 
                  6554 
                  6573 
                 0 
                 GAAGACATGCAGGATCTTGG 
               
               
                   
               
               
                 406014 
                 5-10-5 
                 199 
                  6585 
                  6604 
                 0 
                 TCTTCACCAGGAAGCCAGGA 
               
               
                   
               
               
                 406015 
                 5-10-5 
                 200 
                  6590 
                  6609 
                 0 
                 ACTCATCTTCACCAGGAAGC 
               
               
                   
               
               
                 406016 
                 5-10-5 
                 201 
                  6592 
                  6611 
                 0 
                 CCACTCATCTTCACCAGGAA 
               
               
                   
               
               
                 406017 
                 5-10-5 
                 203 
                  6596 
                  6615 
                 0 
                 GTCGCCACTCATCTTCACCA 
               
               
                   
               
               
                 406018 
                 5-10-5 
                 204 
                  6598 
                  6617 
                 0 
                 AGGTCGCCACTCATCTTCAC 
               
               
                   
               
               
                 406019 
                 5-10-5 
                 205 
                  6600 
                  6619 
                 0 
                 GCAGGTCGCCACTCATCTTC 
               
               
                   
               
               
                 406020 
                 5-10-5 
                 206 
                  6602 
                  6621 
                 0 
                 CAGCAGGTCGCCACTCATCT 
               
               
                   
               
               
                 406021 
                 5-10-5 
                 210 
                  9207 
                  9226 
                 0 
                 TTCATCCGCCCGGTACCGTG 
               
               
                   
               
               
                 406022 
                 5-10-5 
                 211 
                  9209 
                  9228 
                 0 
                 TATTCATCCGCCCGGTACCG 
               
               
                   
               
               
                 406023 
                 5-10-5 
                 212 
                  9212 
                  9231 
                 0 
                 TGGTATTCATCCGCCCGGTA 
               
               
                   
               
               
                 406024 
                 5-10-5 
                 213 
                  9214 
                  9233 
                 0 
                 GCTGGTATTCATCCGCCCGG 
               
               
                   
               
               
                 406025 
                 5-10-5 
                 216 
                 14888 
                 14907 
                 0 
                 GTGTCTAGGAGATACACCTC 
               
               
                   
               
               
                 406026 
                 5-10-5 
                 217 
                 14893 
                 14912 
                 0 
                 TGCTGGTGTCTAGGAGATAC 
               
               
                   
               
               
                 406027 
                 5-10-5 
                 226 
                 14930 
                 14949 
                 0 
                 ATGACCCTGCCCTCGATTTC 
               
               
                   
               
               
                 406028 
                 5-10-5 
                 227 
                 14932 
                 14951 
                 0 
                 CCATGACCCTGCCCTCGATT 
               
               
                   
               
               
                 406029 
                 5-10-5 
                 228 
                 14934 
                 14953 
                 0 
                 GACCATGACCCTGCCCTCGA 
               
               
                   
               
               
                 406030 
                 5-10-5 
                 229 
                 14938 
                 14957 
                 0 
                 CGGTGACCATGACCCTGCCC 
               
               
                   
               
               
                 406031 
                 5-10-5 
                 230 
                 14940 
                 14959 
                 0 
                 GTCGGTGACCATGACCCTGC 
               
               
                   
               
               
                 406032 
                 5-10-5 
                 232 
                 14944 
                 14963 
                 0 
                 CGAAGTCGGTGACCATGACC 
               
               
                   
               
               
                 406033 
                 5-10-5 
                 237 
                 15261 
                 15280 
                 0 
                 CCTGCCAGGTGGGTGCCATG 
               
               
                   
               
               
                 406034 
                 5-10-5 
                 238 
                 15266 
                 15285 
                 0 
                 CCACCCCTGCCAGGTGGGTG 
               
               
                   
               
               
                 406035 
                 5-10-5 
                 239 
                 15271 
                 15290 
                 0 
                 GCTGACCACCCCTGCCAGGT 
               
               
                   
               
               
                 406036 
                 5-10-5 
                 241 
                 15283 
                 15302 
                 0 
                 GGCATCCCGGCCGCTGACCA 
               
               
                   
               
               
                 406037 
                 5-10-5 
                 242 
                 15286 
                 15305 
                 0 
                 GCCGGCATCCCGGCCGCTGA 
               
               
                   
               
               
                 406038 
                 5-10-5 
                 245 
                 15293 
                 15312 
                 0 
                 TGGCCACGCCGGCATCCCGG 
               
               
                   
               
               
                 406039 
                 5-10-5 
                 257 
                 15330 
                 15349 
                 0 
                 CAGTTGAGCACGCGCAGGCT 
               
               
                   
               
               
                 406040 
                 5-10-5 
                 258 
                 15332 
                 15351 
                 0 
                 GGCAGTTGAGCACGCGCAGG 
               
               
                   
               
               
                 406041 
                 5-10-5 
                 259 
                 15336 
                 15355 
                 0 
                 CCTTGGCAGTTGAGCACGCG 
               
               
                   
               
               
                 406042 
                 5-10-5 
                 260 
                 15341 
                 15360 
                 0 
                 CCTTCCCTTGGCAGTTGAGC 
               
               
                   
               
               
                 406043 
                 5-10-5 
                 261 
                 15345 
                 15364 
                 0 
                 GTGCCCTTCCCTTGGCAGTT 
               
               
                   
               
               
                 406044 
                 5-10-5 
                 262 
                 15347 
                 15366 
                 0 
                 CCGTGCCCTTCCCTTGGCAG 
               
               
                   
               
               
                 406045 
                 5-10-5 
                 266 
                 18591 
                 18610 
                 0 
                 TGGCTTTTCCGAATAAACTC 
               
               
                   
               
               
                 406478 
                 5-10-5 
                 448 
                 21692 
                 21711 
                 0 
                 CTGCCCTTCCACCAAAATGC 
               
               
                   
               
               
                 406479 
                 5-10-5 
                 449 
                 21693 
                 21712 
                 0 
                 ACTGCCCTTCCACCAAAATG 
               
               
                   
               
               
                 406480 
                 5-10-5 
                 450 
                 21694 
                 21713 
                 0 
                 CACTGCCCTTCCACCAAAAT 
               
               
                   
               
               
                 406481 
                 5-10-5 
                 451 
                 21695 
                 21714 
                 0 
                 GCACTGCCCTTCCACCAAAA 
               
               
                   
               
               
                 406482 
                 5-10-5 
                 452 
                 21697 
                 21716 
                 0 
                 GGGCACTGCCCTTCCACCAA 
               
               
                   
               
               
                 406483 
                 5-10-5 
                 453 
                 21698 
                 21717 
                 0 
                 TGGGCACTGCCCTTCCACCA 
               
               
                   
               
               
                 406484 
                 5-10-5 
                 454 
                 21699 
                 21718 
                 0 
                 CTGGGCACTGCCCTTCCACC 
               
               
                   
               
               
                 406485 
                 5-10-5 
                 455 
                 21700 
                 21719 
                 0 
                 GCTGGGCACTGCCCTTCCAC 
               
               
                   
               
               
                 408653 
                 5-10-5 
                 354 
                 20727 
                 20746 
                 0 
                 TGGTCCTCAGGGAACCAGGC 
               
               
                   
               
               
                 409126 
                 5-10-5 
                 447 
                 15298 
                 15317 
                 1 
                 ACCCTTGGTCACGCCGGCAT 
               
               
                   
               
               
                 410529 
                 5-10-5 
                 184 
                  6534 
                  6553 
                 0 
                 TGAGGTATCCCCGGCGGGCA 
               
               
                   
               
               
                 410530 
                 5-10-5 
                 185 
                  6535 
                  6554 
                 0 
                 GTGAGGTATCCCCGGCGGGC 
               
               
                   
               
               
                 410531 
                 5-10-5 
                 186 
                  6536 
                  6555 
                 0 
                 GGTGAGGTATCCCCGGCGGG 
               
               
                   
               
               
                 410532 
                 5-10-5 
                 187 
                  6538 
                  6557 
                 0 
                 TTGGTGAGGTATCCCCGGCG 
               
               
                   
               
               
                 410533 
                 5-10-5 
                 189 
                  6540 
                  6559 
                 0 
                 TCTTGGTGAGGTATCCCCGG 
               
               
                   
               
               
                 410534 
                 5-10-5 
                 191 
                  6542 
                  6561 
                 0 
                 GATCTTGGTGAGGTATCCCC 
               
               
                   
               
               
                 410535 
                 5-10-5 
                 192 
                  6544 
                  6563 
                 0 
                 AGGATCTTGGTGAGGTATCC 
               
               
                   
               
               
                 410536 
                 5-10-5 
                 243 
                 15291 
                 15310 
                 0 
                 GCCACGCCGGCATCCCGGCC 
               
               
                   
               
               
                 410537 
                 5-10-5 
                 244 
                 15292 
                 15311 
                 0 
                 GGCCACGCCGGCATCCCGGC 
               
               
                   
               
               
                 410538 
                 5-10-5 
                 254 
                 15303 
                 15322 
                 0 
                 CTGGCACCCTTGGCCACGCC 
               
               
                   
               
               
                 410539 
                 5-10-5 
                 255 
                 15304 
                 15323 
                 0 
                 GCTGGCACCCTTGGCCACGC 
               
               
                   
               
               
                 410540 
                 5-10-5 
                 356 
                 20729 
                 20748 
                 0 
                 GCTGGTCCTCAGGGAACCAG 
               
               
                   
               
               
                 410541 
                 5-10-5 
                 376 
                 22133 
                 22152 
                 0 
                 CACCTGGCAATGGCGTAGAC 
               
               
                   
               
               
                 410542 
                 5-10-5 
                 377 
                 22134 
                 22153 
                 0 
                 GCACCTGGCAATGGCGTAGA 
               
               
                   
               
               
                 410543 
                 5-10-5 
                 378 
                 22135 
                 22154 
                 0 
                 AGCACCTGGCAATGGCGTAG 
               
               
                   
               
               
                 410544 
                 5-10-5 
                 379 
                 22136 
                 22155 
                 0 
                 CAGCACCTGGCAATGGCGTA 
               
               
                   
               
               
                 410545 
                 5-10-5 
                 380 
                 22137 
                 22156 
                 0 
                 GCAGCACCTGGCAATGGCGT 
               
               
                   
               
               
                 410546 
                 5-10-5 
                 382 
                 22139 
                 22158 
                 0 
                 AGGCAGCACCTGGCAATGGC 
               
               
                   
               
               
                 410547 
                 5-10-5 
                 384 
                 22141 
                 22160 
                 0 
                 GCAGGCAGCACCTGGCAATG 
               
               
                   
               
               
                 410548 
                 5-10-5 
                 385 
                 22143 
                 22162 
                 0 
                 TAGCAGGCAGCACCTGGCAA 
               
               
                   
               
               
                 410549 
                 5-10-5 
                 388 
                 22199 
                 22218 
                 0 
                 GTCCCCATGCTGGCCTCAGC 
               
               
                   
               
               
                 410550 
                 5-10-5 
                 389 
                 22200 
                 22219 
                 0 
                 GGTCCCCATGCTGGCCTCAG 
               
               
                   
               
               
                 410551 
                 5-10-5 
                 390 
                 22201 
                 22220 
                 0 
                 GGGTCCCCATGCTGGCCTCA 
               
               
                   
               
               
                 410552 
                 5-10-5 
                 391 
                 22202 
                 22221 
                 0 
                 CGGGTCCCCATGCTGGCCTC 
               
               
                   
               
               
                 410553 
                 5-10-5 
                 392 
                 22203 
                 22222 
                 0 
                 ACGGGTCCCCATGCTGGCCT 
               
               
                   
               
               
                 410554 
                 5-10-5 
                 393 
                 22205 
                 22224 
                 0 
                 ACACGGGTCCCCATGCTGGC 
               
               
                   
               
               
                 410555 
                 5-10-5 
                 395 
                 22207 
                 22226 
                 0 
                 GGACACGGGTCCCCATGCTG 
               
               
                   
               
               
                 410556 
                 5-10-5 
                 397 
                 22209 
                 22228 
                 0 
                 GTGGACACGGGTCCCCATGC 
               
               
                   
               
               
                 410557 
                 5-10-5 
                 399 
                 22211 
                 22230 
                 0 
                 CAGTGGACACGGGTCCCCAT 
               
               
                   
               
               
                 410558 
                 5-10-5 
                 401 
                 22213 
                 22232 
                 0 
                 GGCAGTGGACACGGGTCCCC 
               
               
                   
               
               
                 410559 
                 5-10-5 
                 403 
                 22215 
                 22234 
                 0 
                 GTGGCAGTGGACACGGGTCC 
               
               
                   
               
               
                 410560 
                 5-10-5 
                 404 
                 22216 
                 22235 
                 0 
                 GGTGGCAGTGGACACGGGTC 
               
               
                   
               
               
                 410561 
                 5-10-5 
                 405 
                 22217 
                 22236 
                 0 
                 TGGTGGCAGTGGACACGGGT 
               
               
                   
               
               
                 410562 
                 5-10-5 
                 411 
                 24096 
                 24115 
                 0 
                 ACTTTGCATTCCAGACCTGG 
               
               
                   
               
               
                 410563 
                 5-10-5 
                 413 
                 24098 
                 24117 
                 0 
                 TGACTTTGCATTCCAGACCT 
               
               
                   
               
               
                 410564 
                 5-10-5 
                 414 
                 24099 
                 24118 
                 0 
                 TTGACTTTGCATTCCAGACC 
               
               
                   
               
               
                 410565 
                 5-10-5 
                 419 
                 26112 
                 26131 
                 0 
                 CAGATGGCAACGGCTGTCAC 
               
               
                   
               
               
                 410566 
                 5-10-5 
                 420 
                 26113 
                 26132 
                 0 
                 GCAGATGGCAACGGCTGTCA 
               
               
                   
               
               
                 410567 
                 5-10-5 
                 421 
                 26114 
                 26133 
                 0 
                 AGCAGATGGCAACGGCTGTC 
               
               
                   
               
               
                 410568 
                 5-10-5 
                 422 
                 26115 
                 26134 
                 0 
                 CAGCAGATGGCAACGGCTGT 
               
               
                   
               
               
                 410569 
                 5-10-5 
                 423 
                 26116 
                 26135 
                 0 
                 GCAGCAGATGGCAACGGCTG 
               
               
                   
               
               
                 410570 
                 5-10-5 
                 424 
                 26118 
                 26137 
                 0 
                 CGGCAGCAGATGGCAACGGC 
               
               
                   
               
               
                 410571 
                 5-10-5 
                 425 
                 26119 
                 26138 
                 0 
                 CCGGCAGCAGATGGCAACGG 
               
               
                   
               
               
                 410572 
                 5-10-5 
                 427 
                 26121 
                 26140 
                 0 
                 CTCCGGCAGCAGATGGCAAC 
               
               
                   
               
               
                 410573 
                 5-10-5 
                 428 
                 26122 
                 26141 
                 0 
                 GCTCCGGCAGCAGATGGCAA 
               
               
                   
               
               
                 410730 
                 5-10-5 
                 202 
                  6594 
                  6613 
                 0 
                 CGCCACTCATCTTCACCAGG 
               
               
                   
               
               
                 410731 
                 5-10-5 
                 207 
                  6604 
                  6623 
                 0 
                 TCCAGCAGGTCGCCACTCAT 
               
               
                   
               
               
                 410732 
                 5-10-5 
                 214 
                  9216 
                  9235 
                 0 
                 GGGCTGGTATTCATCCGCCC 
               
               
                   
               
               
                 410733 
                 5-10-5 
                 231 
                 14942 
                 14961 
                 0 
                 AAGTCGGTGACCATGACCCT 
               
               
                   
               
               
                 410734 
                 5-10-5 
                 279 
                 18714 
                 18733 
                 0 
                 CCGGCAGCGGTGACCAGCAC 
               
               
                   
               
               
                 410735 
                 5-10-5 
                 291 
                 19956 
                 19975 
                 0 
                 TCCCCAGGGTCACCGGCTGG 
               
               
                   
               
               
                 410736 
                 5-10-5 
                 303 
                 19992 
                 20011 
                 0 
                 AGAGGTCCACACAGCGGCCA 
               
               
                   
               
               
                 410737 
                 5-10-5 
                 313 
                 20042 
                 20061 
                 0 
                 GCAGGTGCTGCAGTCGCTGG 
               
               
                   
               
               
                 410738 
                 5-10-5 
                 324 
                 20639 
                 20658 
                 0 
                 GCTCGGCAGACAGCATCATG 
               
               
                   
               
               
                 410739 
                 5-10-5 
                 336 
                 20687 
                 20706 
                 0 
                 CAGAGAAGTGGATCAGTCTC 
               
               
                   
               
               
                 410740 
                 5-10-5 
                 345 
                 20715 
                 20734 
                 0 
                 AACCAGGCCTCATTGATGAC 
               
               
                   
               
               
                 410741 
                 5-10-5 
                 369 
                 21129 
                 21148 
                 0 
                 CCATCCGTGTAGGCCCCGAG 
               
               
                   
               
               
                 410742 
                 5-10-5 
                 159 
                  2433 
                  2452 
                 0 
                 GCCTGGAGCTGACGGTGCCC 
               
               
                   
               
               
                 410743 
                 5-10-5 
                 170 
                  2560 
                  2579 
                 0 
                 TCCTCCTCGGAACGCAAGGC 
               
               
                   
               
               
                 410744 
                 5-10-5 
                 171 
                  2585 
                  2604 
                 0 
                 GTGCTCGGGTGCTTCGGCCA 
               
               
                   
               
               
                 410745 
                 5-10-5 
                 172 
                  2605 
                  2624 
                 0 
                 TGGAAGGTGGCTGTGGTTCC 
               
               
                   
               
               
                 410746 
                 5-10-5 
                 176 
                  6444 
                  6463 
                 0 
                 CGTAGGTGCCAGGCAACCTC 
               
               
                   
               
               
                 410747 
                 5-10-5 
                 177 
                  6482 
                  6501 
                 0 
                 TGACTGCGAGAGGTGGGTCT 
               
               
                   
               
               
                 410748 
                 5-10-5 
                 182 
                  6528 
                  6547 
                 0 
                 ATCCCCGGCGGGCAGCCTGG 
               
               
                   
               
               
                 410749 
                 5-10-5 
                 197 
                  6565 
                  6584 
                 0 
                 AGAAGGCCATGGAAGACATG 
               
               
                   
               
               
                 410750 
                 5-10-5 
                 198 
                  6575 
                  6594 
                 0 
                 GAAGCCAGGAAGAAGGCCAT 
               
               
                   
               
               
                 410752 
                 5-10-5 
                 209 
                  9149 
                  9168 
                 0 
                 GCAAAGACAGAGGAGTCCTC 
               
               
                   
               
               
                 410753 
                 5-10-5 
                 215 
                 14877 
                 14896 
                 0 
                 ATACACCTCCACCAGGCTGC 
               
               
                   
               
               
                 410754 
                 5-10-5 
                 233 
                 14954 
                 14973 
                 0 
                 GGCACATTCTCGAAGTCGGT 
               
               
                   
               
               
                 410756 
                 5-10-5 
                 235 
                 15254 
                 15273 
                 0 
                 GGTGGGTGCCATGACTGTCA 
               
               
                   
               
               
                 410757 
                 5-10-5 
                 240 
                 15279 
                 15298 
                 0 
                 TCCCGGCCGCTGACCACCCC 
               
               
                   
               
               
                 410758 
                 5-10-5 
                 256 
                 15309 
                 15328 
                 0 
                 CGCATGCTGGCACCCTTGGC 
               
               
                   
               
               
                 410759 
                 5-10-5 
                 263 
                 15358 
                 15377 
                 0 
                 GGTGCCGCTAACCGTGCCCT 
               
               
                   
               
               
                 410761 
                 5-10-5 
                 271 
                 18614 
                 18633 
                 0 
                 GTGGCCCCACAGGCTGGACC 
               
               
                   
               
               
                 410762 
                 5-10-5 
                 272 
                 18627 
                 18646 
                 0 
                 AGCAGCACCACCAGTGGCCC 
               
               
                   
               
               
                 410763 
                 5-10-5 
                 273 
                 18649 
                 18668 
                 0 
                 GCTGTACCCACCCGCCAGGG 
               
               
                   
               
               
                 410764 
                 5-10-5 
                 274 
                 18695 
                 18714 
                 0 
                 CGACCCCAGCCCTCGCCAGG 
               
               
                   
               
               
                 410767 
                 5-10-5 
                 289 
                 19941 
                 19960 
                 0 
                 GCTGGTCTTGGGCATTGGTG 
               
               
                   
               
               
                 410768 
                 5-10-5 
                 305 
                 20016 
                 20035 
                 0 
                 CAATGATGTCCTCCCCTGGG 
               
               
                   
               
               
                 410769 
                 5-10-5 
                 318 
                 20061 
                 20080 
                 0 
                 TCCCACTCTGTGACACAAAG 
               
               
                   
               
               
                 410770 
                 5-10-5 
                 327 
                 20657 
                 20676 
                 0 
                 CGGCCAGGGTGAGCTCCGGC 
               
               
                   
               
               
                 410771 
                 5-10-5 
                 360 
                 20785 
                 20804 
                 0 
                 ACCTGCCCCATGGGTGCTGG 
               
               
                   
               
               
                 410772 
                 5-10-5 
                 364 
                 21106 
                 21125 
                 0 
                 GCTGACCATACAGTCCTGCA 
               
               
                   
               
               
                 410773 
                 5-10-5 
                 387 
                 22189 
                 22208 
                 0 
                 TGGCCTCAGCTGGTGGAGCT 
               
               
                   
               
               
                 410774 
                 5-10-5 
                 406 
                 22220 
                 22239 
                 0 
                 TGTTGGTGGCAGTGGACACG 
               
               
                   
               
               
                 410776 
                 5-10-5 
                 408 
                 23985 
                 24004 
                 0 
                 GTGCCAAGGTCCTCCACCTC 
               
               
                   
               
               
                 410777 
                 5-10-5 
                 409 
                 24005 
                 24024 
                 0 
                 TCAGCACAGGCGGCTTGTGG 
               
               
                   
               
               
                 410778 
                 5-10-5 
                 410 
                 24035 
                 24054 
                 0 
                 CCACGCACTGGTTGGGCTGA 
               
               
                   
               
               
                 410779 
                 5-10-5 
                 416 
                 24115 
                 24134 
                 0 
                 CGGGATTCCATGCTCCTTGA 
               
               
                   
               
               
                 410781 
                 5-10-5 
                 418 
                 25994 
                 26013 
                 0 
                 GGAGGGCACTGCAGCCAGTC 
               
               
                   
               
               
                 410782 
                 5-10-5 
                 429 
                 26132 
                 26151 
                 0 
                 CCAGGTGCCGGCTCCGGCAG 
               
               
                   
               
               
                 410783 
                 5-10-5 
                 430 
                 26142 
                 26161 
                 0 
                 GAGGCCTGCGCCAGGTGCCG 
               
               
                   
               
            
           
         
       
     
     In certain embodiments, gap-widened antisense compounds are targeted to a PCSK9 nucleic acid. In certain such embodiments, gap-widened antisense compounds are targeted to SEQ ID NO: 2. In certain such embodiments, the nucleotide sequences illustrated in Table 7 have a 3-14-3 gap-widened motif. Table 9 illustrates gap-widened antisense compounds targeted to SEQ ID NO: 2, having a 3-14-3 motif, where the gap segment comprises 2′-deoxynucleotides and each wing segment comprises nucleotides comprising a 2′-O-methoxyethyl sugar modification. Internucleoside linkages are phosphorthioate, and cytidines are 5-methylcytidines. 
     
       
         
           
               
             
               
                 TABLE 9 
               
             
            
               
                   
               
               
                 Gapmer antisense compounds having a 3-14-3 motif targeted to SEQ ID NO: 2 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                   
                   
                 5′ Target 
                 3′ Target 
                   
                   
               
               
                   
                   
                   
                 Site on 
                 Site on 
                   
                   
               
               
                   
                   
                 SEQ ID 
                 SEQ ID 
                 SEQ ID 
                   
                   
               
               
                 Isis No 
                 Motif 
                 NO 
                 NO: 2 
                 NO: 2 
                 Mismatches 
                 Sequence (5′-3′) 
               
               
                   
               
               
                 399871 
                 3-14-3 
                   4 
                  2274 
                  2293 
                 0 
                 GCGCGGAATCCTGGCTGGGA 
               
               
                   
               
               
                 399872 
                 3-14-3 
                   5 
                  2381 
                  2400 
                 0 
                 GAGGAGACCTAGAGGCCGTG 
               
               
                   
               
               
                 399873 
                 3-14-3 
                   6 
                  2439 
                  2458 
                 0 
                 AGGACCGCCTGGAGCTGACG 
               
               
                   
               
               
                 399874 
                 3-14-3 
                   7 
                  2549 
                  2568 
                 0 
                 ACGCAAGGCTAGCACCAGCT 
               
               
                   
               
               
                 399875 
                 3-14-3 
                   9 
                  2619 
                  2638 
                 0 
                 CCTTGGCGCAGCGGTGGAAG 
               
               
                   
               
               
                 399876 
                 3-14-3 
                  10 
                  6498 
                  6517 
                 0 
                 GGCGGGCAGTGCGCTCTGAC 
               
               
                   
               
               
                 399877 
                 3-14-3 
                  11 
                  6537 
                  6556 
                 0 
                 TGGTGAGGTATCCCCGGCGG 
               
               
                   
               
               
                 399878 
                 3-14-3 
                  14 
                  6557 
                  6576 
                 0 
                 ATGGAAGACATGCAGGATCT 
               
               
                   
               
               
                 399879 
                 3-14-3 
                  15 
                  6583 
                  6602 
                 0 
                 TTCACCAGGAAGCCAGGAAG 
               
               
                   
               
               
                 399880 
                 3-14-3 
                  17 
                  9130 
                  9149 
                 0 
                 CCTCGATGTAGTCGACATGG 
               
               
                   
               
               
                 399881 
                 3-14-3 
                  18 
                  9210 
                  9229 
                 0 
                 GTATTCATCCGCCCGGTACC 
               
               
                   
               
               
                 399882 
                 3-14-3 
                  19 
                 14891 
                 14910 
                 0 
                 CTGGTGTCTAGGAGATACAC 
               
               
                   
               
               
                 399883 
                 3-14-3 
                  21 
                 14916 
                 14935 
                 0 
                 GATTTCCCGGTGGTCACTCT 
               
               
                   
               
               
                 399884 
                 3-14-3 
                  24 
                 14946 
                 14965 
                 0 
                 CTCGAAGTCGGTGACCATGA 
               
               
                   
               
               
                 399885 
                 3-14-3 
                  25 
                 14979 
                 14998 
                 0 
                 GTGGAAGCGGGTCCCGTCCT 
               
               
                   
               
               
                 399886 
                 3-14-3 
                  26 
                 15264 
                 15283 
                 0 
                 ACCCCTGCCAGGTGGGTGCC 
               
               
                   
               
               
                 399887 
                 3-14-3 
                  28 
                 15298 
                 15317 
                 0 
                 ACCCTTGGCCACGCCGGCAT 
               
               
                   
               
               
                 399888 
                 3-14-3 
                  29 
                 15334 
                 15353 
                 0 
                 TTGGCAGTTGAGCACGCGCA 
               
               
                   
               
               
                 399890 
                 3-14-3 
                  32 
                 18593 
                 18612 
                 0 
                 GCTGGCTTTTCCGAATAAAC 
               
               
                   
               
               
                 399891 
                 3-14-3 
                  33 
                 18705 
                 18724 
                 0 
                 GTGACCAGCACGACCCCAGC 
               
               
                   
               
               
                 399892 
                 3-14-3 
                 149 
                 19933 
                 19952 
                 0 
                 TGGGCATTGGTGGCCCCAAC 
               
               
                   
               
               
                 399893 
                 3-14-3 
                  34 
                 19962 
                 19981 
                 0 
                 CCAAAGTCCCCAGGGTCACC 
               
               
                   
               
               
                 399894 
                 3-14-3 
                 128 
                 19966 
                 19985 
                 0 
                 GTCCCCAAAGTCCCCAGGGT 
               
               
                   
               
               
                 399895 
                 3-14-3 
                  36 
                 19976 
                 19995 
                 0 
                 GCCAAAGTTGGTCCCCAAAG 
               
               
                   
               
               
                 399896 
                 3-14-3 
                  38 
                 19997 
                 20016 
                 0 
                 GGCAAAGAGGTCCACACAGC 
               
               
                   
               
               
                 399897 
                 3-14-3 
                  39 
                 20025 
                 20044 
                 0 
                 TGGAGGCACCAATGATGTCC 
               
               
                   
               
               
                 399899 
                 3-14-3 
                  45 
                 20691 
                 20710 
                 0 
                 TTGGCAGAGAAGTGGATCAG 
               
               
                   
               
               
                 399900 
                 3-14-3 
                  50 
                 20726 
                 20745 
                 0 
                 GGTCCTCAGGGAACCAGGCC 
               
               
                   
               
               
                 399901 
                 3-14-3 
                  87 
                 20733 
                 20752 
                 0 
                 ACCCGCTGGTCCTCAGGGAA 
               
               
                   
               
               
                 399902 
                 3-14-3 
                 119 
                 20762 
                 20781 
                 0 
                 GCAGGGCGGCCACCAGGTTG 
               
               
                   
               
               
                 399904 
                 3-14-3 
                  54 
                 21121 
                 21140 
                 0 
                 GTAGGCCCCGAGTGTGCTGA 
               
               
                   
               
               
                 399905 
                 3-14-3 
                  57 
                 22096 
                 22115 
                 0 
                 CGTTGTGGGCCCGGCAGACC 
               
               
                   
               
               
                 399906 
                 3-14-3 
                  58 
                 22142 
                 22161 
                 0 
                 AGCAGGCAGCACCTGGCAAT 
               
               
                   
               
               
                 399907 
                 3-14-3 
                  59 
                 22204 
                 22223 
                 0 
                 CACGGGTCCCCATGCTGGCC 
               
               
                   
               
               
                 399908 
                 3-14-3 
                  60 
                 24095 
                 24114 
                 0 
                 CTTTGCATTCCAGACCTGGG 
               
               
                   
               
               
                 399909 
                 3-14-3 
                  62 
                 26117 
                 26136 
                 0 
                 GGCAGCAGATGGCAACGGCT 
               
               
                   
               
               
                 399910 
                 3-14-3 
                 154 
                 26217 
                 26236 
                 0 
                 TTTTAAAGCTCAGCCCCAGC 
               
               
                   
               
               
                 399911 
                 3-14-3 
                  64 
                 26311 
                 26330 
                 0 
                 TCAAGGGCCAGGCCAGCAGC 
               
               
                   
               
               
                 399912 
                 3-14-3 
                  66 
                 26404 
                 26423 
                 0 
                 ATGCCCCACAGTGAGGGAGG 
               
               
                   
               
               
                 399913 
                 3-14-3 
                  67 
                 26413 
                 26432 
                 0 
                 AATGGTGAAATGCCCCACAG 
               
               
                   
               
               
                 399914 
                 3-14-3 
                 153 
                 26456 
                 26475 
                 0 
                 TTGGGAGCAGCTGGCAGCAC 
               
               
                   
               
               
                 399915 
                 3-14-3 
                  68 
                 26557 
                 26576 
                 0 
                 CATGGGAAGAATCCTGCCTC 
               
               
                   
               
               
                 399916 
                 3-14-3 
                  69 
                 26639 
                 26658 
                 0 
                 GGAGATGAGGGCCATCAGCA 
               
               
                   
               
               
                 399917 
                 3-14-3 
                  70 
                 26707 
                 26726 
                 0 
                 TAGATGCCATCCAGAAAGCT 
               
               
                   
               
               
                 399918 
                 3-14-3 
                  72 
                 26790 
                 26809 
                 0 
                 GGCATAGAGCAGAGTAAAGG 
               
               
                   
               
               
                 399919 
                 3-14-3 
                 112 
                 27034 
                 27053 
                 0 
                 GAAGAGGCTTGGCTTCAGAG 
               
               
                   
               
               
                 399920 
                 3-14-3 
                  75 
                 27244 
                 27263 
                 0 
                 GCTCAAGGAGGGACAGTTGT 
               
               
                   
               
               
                 399921 
                 3-14-3 
                  76 
                 27279 
                 27298 
                 0 
                 AAAGATAAATGTCTGCTTGC 
               
               
                   
               
               
                 399922 
                 3-14-3 
                  78 
                 27350 
                 27369 
                 0 
                 TCTTCAAGTTACAAAAGCAA 
               
               
                   
               
               
                 399923 
                 3-14-3 
                  85 
                 13681 
                 13700 
                 0 
                 ACAAATTCCCAGACTCAGCA 
               
               
                   
               
               
                 399924 
                 3-14-3 
                 129 
                 13816 
                 13835 
                 0 
                 GTGCCATCTGAACAGCACCT 
               
               
                   
               
               
                 399925 
                 3-14-3 
                 110 
                 13926 
                 13945 
                 0 
                 CCTGGAACCCCTGCAGCCAG 
               
               
                   
               
               
                 399926 
                 3-14-3 
                 152 
                 13977 
                 13996 
                 0 
                 TTCAGGCAGGTTGCTGCTAG 
               
               
                   
               
               
                 399927 
                 3-14-3 
                 140 
                 13998 
                 14017 
                 0 
                 TCAGCCAGGCCAAAGGAAGA 
               
               
                   
               
               
                 399928 
                 3-14-3 
                 136 
                 14122 
                 14141 
                 0 
                 TAGGAGAAAGTAGGGAGAGC 
               
               
                   
               
               
                 399929 
                 3-14-3 
                 132 
                 14179 
                 14198 
                 0 
                 TAAAAGCTGCAAGAGACTCA 
               
               
                   
               
               
                 399930 
                 3-14-3 
                 139 
                 14267 
                 14286 
                 0 
                 TCAGAGAAAACAGTCACCGA 
               
               
                   
               
               
                 399931 
                 3-14-3 
                 142 
                 14404 
                 14423 
                 0 
                 TCATTTTAGAGACAGGAAGC 
               
               
                   
               
               
                 399932 
                 3-14-3 
                 113 
                 14441 
                 14460 
                 0 
                 GAATAACAGTGATGTCTGGC 
               
               
                   
               
               
                 399933 
                 3-14-3 
                 138 
                 14494 
                 14513 
                 0 
                 TCACAGCTCACCGAGTCTGC 
               
               
                   
               
               
                 399934 
                 3-14-3 
                  98 
                 14524 
                 14543 
                 0 
                 AGTGTAAAATAAAGCCCCTA 
               
               
                   
               
               
                 399935 
                 3-14-3 
                  96 
                 14601 
                 14620 
                 0 
                 AGGACCCAAGTCATCCTGCT 
               
               
                   
               
               
                 399936 
                 3-14-3 
                 124 
                 14631 
                 14650 
                 0 
                 GGCCATCAGCTGGCAATGCT 
               
               
                   
               
               
                 399937 
                 3-14-3 
                 133 
                 14675 
                 14694 
                 0 
                 TAGACAAGGAAAGGGAGGCC 
               
               
                   
               
               
                 399938 
                 3-14-3 
                 103 
                 14681 
                 14700 
                 0 
                 ATTTCATAGACAAGGAAAGG 
               
               
                   
               
               
                 399939 
                 3-14-3 
                 155 
                 14801 
                 14820 
                 0 
                 CTTATAGTTAACACACAGAA 
               
               
                   
               
               
                 399943 
                 3-14-3 
                 102 
                  5590 
                  5609 
                 0 
                 ATGTGCAGAGATCAATCACA 
               
               
                   
               
               
                 399944 
                 3-14-3 
                 127 
                 10633 
                 10652 
                 0 
                 GGTGGTAATTTGTCACAGCA 
               
               
                   
               
               
                 399945 
                 3-14-3 
                  84 
                 11308 
                 11327 
                 0 
                 AAGGTCACACAGTTAAGAGT 
               
               
                   
               
               
                 399946 
                 3-14-3 
                 157 
                 18561 
                 18580 
                 0 
                 AGGAACAAAGCCAAGGTCAC 
               
               
                   
               
               
                 399947 
                 3-14-3 
                 126 
                 22292 
                 22311 
                 0 
                 GGTGCATAAGGAGAAAGAGA 
               
               
                   
               
               
                 399948 
                 3-14-3 
                 147 
                 24858 
                 24877 
                 0 
                 TGAGTTCATTTAAGAGTGGA 
               
               
                   
               
               
                 399949 
                 3-14-3 
                   8 
                  2556 
                  2575 
                 0 
                 CCTCGGAACGCAAGGCTAGC 
               
               
                   
               
               
                 399950 
                 3-14-3 
                  12 
                  6543 
                  6562 
                 0 
                 GGATCTTGGTGAGGTATCCC 
               
               
                   
               
               
                 399951 
                 3-14-3 
                  13 
                  6552 
                  6571 
                 0 
                 AGACATGCAGGATCTTGGTG 
               
               
                   
               
               
                 399952 
                 3-14-3 
                  16 
                  6588 
                  6607 
                 0 
                 TCATCTTCACCAGGAAGCCA 
               
               
                   
               
               
                 399953 
                 3-14-3 
                  20 
                 14896 
                 14915 
                 0 
                 GTATGCTGGTGTCTAGGAGA 
               
               
                   
               
               
                 399954 
                 3-14-3 
                  22 
                 14922 
                 14941 
                 0 
                 GCCCTCGATTTCCCGGTGGT 
               
               
                   
               
               
                 399955 
                 3-14-3 
                  23 
                 14936 
                 14955 
                 0 
                 GTGACCATGACCCTGCCCTC 
               
               
                   
               
               
                 399956 
                 3-14-3 
                  27 
                 15269 
                 15288 
                 0 
                 TGACCACCCCTGCCAGGTGG 
               
               
                   
               
               
                 399957 
                 3-14-3 
                  30 
                 15339 
                 15358 
                 0 
                 TTCCCTTGGCAGTTGAGCAC 
               
               
                   
               
               
                 399958 
                 3-14-3 
                  35 
                 19971 
                 19990 
                 0 
                 AGTTGGTCCCCAAAGTCCCC 
               
               
                   
               
               
                 399959 
                 3-14-3 
                  37 
                 19988 
                 20007 
                 0 
                 GTCCACACAGCGGCCAAAGT 
               
               
                   
               
               
                 399960 
                 3-14-3 
                  40 
                 20036 
                 20055 
                 0 
                 GCTGCAGTCGCTGGAGGCAC 
               
               
                   
               
               
                 399961 
                 3-14-3 
                  41 
                 20047 
                 20066 
                 0 
                 ACAAAGCAGGTGCTGCAGTC 
               
               
                   
               
               
                 399963 
                 3-14-3 
                  43 
                 20635 
                 20654 
                 0 
                 GGCAGACAGCATCATGGCTG 
               
               
                   
               
               
                 399964 
                 3-14-3 
                  44 
                 20683 
                 20702 
                 0 
                 GAAGTGGATCAGTCTCTGCC 
               
               
                   
               
               
                 399965 
                 3-14-3 
                  46 
                 20696 
                 20715 
                 0 
                 CATCTTTGGCAGAGAAGTGG 
               
               
                   
               
               
                 399966 
                 3-14-3 
                  47 
                 20702 
                 20721 
                 0 
                 TGATGACATCTTTGGCAGAG 
               
               
                   
               
               
                 399967 
                 3-14-3 
                  48 
                 20709 
                 20728 
                 0 
                 GCCTCATTGATGACATCTTT 
               
               
                   
               
               
                 399968 
                 3-14-3 
                  49 
                 20721 
                 20740 
                 0 
                 TCAGGGAACCAGGCCTCATT 
               
               
                   
               
               
                 399969 
                 3-14-3 
                  51 
                 20740 
                 20759 
                 0 
                 GGTCAGTACCCGCTGGTCCT 
               
               
                   
               
               
                 399970 
                 3-14-3 
                  53 
                 21091 
                 21110 
                 0 
                 CTGCAAAACAGCTGCCAACC 
               
               
                   
               
               
                 399971 
                 3-14-3 
                  55 
                 21186 
                 21205 
                 0 
                 AGAAACTGGAGCAGCTCAGC 
               
               
                   
               
               
                 399972 
                 3-14-3 
                  56 
                 21192 
                 21211 
                 0 
                 TCCTGGAGAAACTGGAGCAG 
               
               
                   
               
               
                 399973 
                 3-14-3 
                  61 
                 24100 
                 24119 
                 0 
                 CTTGACTTTGCATTCCAGAC 
               
               
                   
               
               
                 399974 
                 3-14-3 
                  63 
                 26222 
                 26241 
                 0 
                 AACCATTTTAAAGCTCAGCC 
               
               
                   
               
               
                 399975 
                 3-14-3 
                  65 
                 26316 
                 26335 
                 0 
                 CCCACTCAAGGGCCAGGCCA 
               
               
                   
               
               
                 399976 
                 3-14-3 
                 122 
                 26389 
                 26408 
                 0 
                 GGAGGGAGCTTCCTGGCACC 
               
               
                   
               
               
                 399977 
                 3-14-3 
                  71 
                 26713 
                 26732 
                 0 
                 TCTGGCTAGATGCCATCCAG 
               
               
                   
               
               
                 399978 
                 3-14-3 
                  73 
                 26795 
                 26814 
                 0 
                 AGCCTGGCATAGAGCAGAGT 
               
               
                   
               
               
                 399979 
                 3-14-3 
                 135 
                 26801 
                 26820 
                 0 
                 TAGCACAGCCTGGCATAGAG 
               
               
                   
               
               
                 399980 
                 3-14-3 
                  74 
                 27040 
                 27059 
                 0 
                 AAGTAAGAAGAGGCTTGGCT 
               
               
                   
               
               
                 399981 
                 3-14-3 
                  77 
                 27284 
                 27303 
                 0 
                 ACCCAAAAGATAAATGTCTG 
               
               
                   
               
               
                 399982 
                 3-14-3 
                  99 
                 27357 
                 27376 
                 0 
                 ATAAATATCTTCAAGTTACA 
               
               
                   
               
               
                 399983 
                 3-14-3 
                 100 
                 13746 
                 13765 
                 0 
                 ATCTCAGGACAGGTGAGCAA 
               
               
                   
               
               
                 399984 
                 3-14-3 
                 116 
                 13760 
                 13779 
                 0 
                 GAGTAGAGATTCTCATCTCA 
               
               
                   
               
               
                 399985 
                 3-14-3 
                 117 
                 13828 
                 13847 
                 0 
                 GAGTCTTCTGAAGTGCCATC 
               
               
                   
               
               
                 399986 
                 3-14-3 
                  81 
                 13903 
                 13922 
                 0 
                 AAGCAGGGCCTCAGGTGGAA 
               
               
                   
               
               
                 399987 
                 3-14-3 
                  83 
                 13986 
                 14005 
                 0 
                 AAGGAAGACTTCAGGCAGGT 
               
               
                   
               
               
                 399988 
                 3-14-3 
                 137 
                 14112 
                 14131 
                 0 
                 TAGGGAGAGCTCACAGATGC 
               
               
                   
               
               
                 399989 
                 3-14-3 
                  92 
                 14397 
                 14416 
                 0 
                 AGAGACAGGAAGCTGCAGCT 
               
               
                   
               
               
                 399990 
                 3-14-3 
                  82 
                 14670 
                 14689 
                 0 
                 AAGGAAAGGGAGGCCTAGAG 
               
               
                   
               
               
                 399991 
                 3-14-3 
                 156 
                 14809 
                 14828 
                 0 
                 AAGTCAACCTTATAGTTAAC 
               
               
                   
               
               
                 399993 
                 3-14-3 
                 107 
                  3056 
                  3075 
                 0 
                 CCCACTATAATGGCAAGCCC 
               
               
                   
               
               
                 399994 
                 3-14-3 
                  80 
                  4306 
                  4325 
                 0 
                 AACCCAGTTCTAATGCACCT 
               
               
                   
               
               
                 399995 
                 3-14-3 
                 106 
                  5140 
                  5159 
                 0 
                 CCAGTCAGAGTAGAACAGAG 
               
               
                   
               
               
                 399996 
                 3-14-3 
                 121 
                  5599 
                  5618 
                 0 
                 GGAGCCTACATGTGCAGAGA 
               
               
                   
               
               
                 399997 
                 3-14-3 
                  94 
                  5667 
                  5686 
                 0 
                 AGCATGGCACCAGCATCTGC 
               
               
                   
               
               
                 399998 
                 3-14-3 
                 108 
                  6652 
                  6671 
                 0 
                 CCCAGCCCTATCAGGAAGTG 
               
               
                   
               
               
                 399999 
                 3-14-3 
                 144 
                  7099 
                  7118 
                 0 
                 TGACATCCAGGAGGGAGGAG 
               
               
                   
               
               
                 400000 
                 3-14-3 
                  91 
                  7556 
                  7575 
                 0 
                 AGACTGATGGAAGGCATTGA 
               
               
                   
               
               
                 400001 
                 3-14-3 
                 131 
                  7565 
                  7584 
                 0 
                 GTGTTGAGCAGACTGATGGA 
               
               
                   
               
               
                 400002 
                 3-14-3 
                 145 
                  8836 
                  8855 
                 0 
                 TGACATCTTGTCTGGGAGCC 
               
               
                   
               
               
                 400003 
                 3-14-3 
                  90 
                  8948 
                  8967 
                 0 
                 AGACTAGGAGCCTGAGTTTT 
               
               
                   
               
               
                 400004 
                 3-14-3 
                 125 
                  9099 
                  9118 
                 0 
                 GGCCTGCAGAAGCCAGAGAG 
               
               
                   
               
               
                 400005 
                 3-14-3 
                 148 
                 10252 
                 10271 
                 0 
                 TGGCAGCAACTCAGACATAT 
               
               
                   
               
               
                 400006 
                 3-14-3 
                  79 
                 11472 
                 11491 
                 0 
                 AAATGCAGGGCTAAAATCAC 
               
               
                   
               
               
                 400007 
                 3-14-3 
                  88 
                 12715 
                 12734 
                 0 
                 ACTGGATACATTGGCAGACA 
               
               
                   
               
               
                 400008 
                 3-14-3 
                 111 
                 12928 
                 12947 
                 0 
                 CTAGAGGAACCACTAGATAT 
               
               
                   
               
               
                 400009 
                 3-14-3 
                  86 
                 15471 
                 15490 
                 0 
                 ACAGCATTCTTGGTTAGGAG 
               
               
                   
               
               
                 400010 
                 3-14-3 
                  97 
                 16134 
                 16153 
                 0 
                 AGTCAAGCTGCTGCCCAGAG 
               
               
                   
               
               
                 400011 
                 3-14-3 
                 120 
                 16668 
                 16687 
                 0 
                 GCTAGTTATTAAGCACCTGC 
               
               
                   
               
               
                 400012 
                 3-14-3 
                 150 
                 17267 
                 17286 
                 0 
                 TGTGAGCTCTGGCCCAGTGG 
               
               
                   
               
               
                 400013 
                 3-14-3 
                 115 
                 18377 
                 18396 
                 0 
                 GAGTAAGGCAGGTTACTCTC 
               
               
                   
               
               
                 400014 
                 3-14-3 
                 134 
                 18408 
                 18427 
                 0 
                 TAGATGTGACTAACATTTAA 
               
               
                   
               
               
                 400015 
                 3-14-3 
                 105 
                 19203 
                 19222 
                 0 
                 CACATTAGCCTTGCTCAAGT 
               
               
                   
               
               
                 400016 
                 3-14-3 
                 151 
                 19913 
                 19932 
                 0 
                 TGTGATGACCTGGAAAGGTG 
               
               
                   
               
               
                 400017 
                 3-14-3 
                 158 
                 20100 
                 20119 
                 0 
                 GTGGTGACTTACCAGCCACG 
               
               
                   
               
               
                 400018 
                 3-14-3 
                 109 
                 20188 
                 20207 
                 0 
                 CCCCTGCACAGAGCCTGGCA 
               
               
                   
               
               
                 400019 
                 3-14-3 
                 141 
                 20624 
                 20643 
                 0 
                 TCATGGCTGCAATGCCTGGT 
               
               
                   
               
               
                 400020 
                 3-14-3 
                  93 
                 20995 
                 21014 
                 0 
                 AGAGAGGAGGGCTTAAAGAA 
               
               
                   
               
               
                 400021 
                 3-14-3 
                  95 
                 21082 
                 21101 
                 0 
                 AGCTGCCAACCTGCAAAAAG 
               
               
                   
               
               
                 400022 
                 3-14-3 
                 143 
                 21481 
                 21500 
                 0 
                 TGAAAATCCATCCAGCACTG 
               
               
                   
               
               
                 400023 
                 3-14-3 
                  89 
                 21589 
                 21608 
                 0 
                 AGAACCATGGAGCACCTGAG 
               
               
                   
               
               
                 400024 
                 3-14-3 
                 123 
                 21696 
                 21715 
                 0 
                 GGCACTGCCCTTCCACCAAA 
               
               
                   
               
               
                 400025 
                 3-14-3 
                 118 
                 24907 
                 24926 
                 0 
                 GCACCATCCAGACCAGAATC 
               
               
                   
               
               
                 400026 
                 3-14-3 
                 114 
                 25413 
                 25432 
                 0 
                 GAGAGGTTCAGATCCAGGCC 
               
               
                   
               
               
                 405604 
                 3-14-3 
                 236 
                 15257 
                 15276 
                 0 
                 CCAGGTGGGTGCCATGACTG 
               
               
                   
               
               
                 405641 
                 3-14-3 
                 373 
                 21183 
                 21202 
                 0 
                 AACTGGAGCAGCTCAGCAGC 
               
               
                   
               
               
                 410574 
                 3-14-3 
                 184 
                  6534 
                  6553 
                 0 
                 TGAGGTATCCCCGGCGGGCA 
               
               
                   
               
               
                 410575 
                 3-14-3 
                 185 
                  6535 
                  6554 
                 0 
                 GTGAGGTATCCCCGGCGGGC 
               
               
                   
               
               
                 410576 
                 3-14-3 
                 186 
                  6536 
                  6555 
                 0 
                 GGTGAGGTATCCCCGGCGGG 
               
               
                   
               
               
                 410577 
                 3-14-3 
                 187 
                  6538 
                  6557 
                 0 
                 TTGGTGAGGTATCCCCGGCG 
               
               
                   
               
               
                 410578 
                 3-14-3 
                 188 
                  6539 
                  6558 
                 0 
                 CTTGGTGAGGTATCCCCGGC 
               
               
                   
               
               
                 410579 
                 3-14-3 
                 189 
                  6540 
                  6559 
                 0 
                 TCTTGGTGAGGTATCCCCGG 
               
               
                   
               
               
                 410580 
                 3-14-3 
                 190 
                  6541 
                  6560 
                 0 
                 ATCTTGGTGAGGTATCCCCG 
               
               
                   
               
               
                 410581 
                 3-14-3 
                 191 
                  6542 
                  6561 
                 0 
                 GATCTTGGTGAGGTATCCCC 
               
               
                   
               
               
                 410582 
                 3-14-3 
                 192 
                  6544 
                  6563 
                 0 
                 AGGATCTTGGTGAGGTATCC 
               
               
                   
               
               
                 410583 
                 3-14-3 
                 243 
                 15291 
                 15310 
                 0 
                 GCCACGCCGGCATCCCGGCC 
               
               
                   
               
               
                 410584 
                 3-14-3 
                 244 
                 15292 
                 15311 
                 0 
                 GGCCACGCCGGCATCCCGGC 
               
               
                   
               
               
                 410585 
                 3-14-3 
                 245 
                 15293 
                 15312 
                 0 
                 TGGCCACGCCGGCATCCCGG 
               
               
                   
               
               
                 410586 
                 3-14-3 
                 246 
                 15294 
                 15313 
                 0 
                 TTGGCCACGCCGGCATCCCG 
               
               
                   
               
               
                 410587 
                 3-14-3 
                 247 
                 15295 
                 15314 
                 0 
                 CTTGGCCACGCCGGCATCCC 
               
               
                   
               
               
                 410588 
                 3-14-3 
                 248 
                 15296 
                 15315 
                 0 
                 CCTTGGCCACGCCGGCATCC 
               
               
                   
               
               
                 410589 
                 3-14-3 
                 249 
                 15297 
                 15316 
                 0 
                 CCCTTGGCCACGCCGGCATC 
               
               
                   
               
               
                 410590 
                 3-14-3 
                 250 
                 15299 
                 15318 
                 0 
                 CACCCTTGGCCACGCCGGCA 
               
               
                   
               
               
                 410591 
                 3-14-3 
                 251 
                 15300 
                 15319 
                 0 
                 GCACCCTTGGCCACGCCGGC 
               
               
                   
               
               
                 410592 
                 3-14-3 
                 252 
                 15301 
                 15320 
                 0 
                 GGCACCCTTGGCCACGCCGG 
               
               
                   
               
               
                 410593 
                 3-14-3 
                 253 
                 15302 
                 15321 
                 0 
                 TGGCACCCTTGGCCACGCCG 
               
               
                   
               
               
                 410594 
                 3-14-3 
                 254 
                 15303 
                 15322 
                 0 
                 CTGGCACCCTTGGCCACGCC 
               
               
                   
               
               
                 410595 
                 3-14-3 
                 255 
                 15304 
                 15323 
                 0 
                 GCTGGCACCCTTGGCCACGC 
               
               
                   
               
               
                 410596 
                 3-14-3 
                 348 
                 20719 
                 20738 
                 0 
                 AGGGAACCAGGCCTCATTGA 
               
               
                   
               
               
                 410597 
                 3-14-3 
                 349 
                 20720 
                 20739 
                 0 
                 CAGGGAACCAGGCCTCATTG 
               
               
                   
               
               
                 410598 
                 3-14-3 
                 350 
                 20722 
                 20741 
                 0 
                 CTCAGGGAACCAGGCCTCAT 
               
               
                   
               
               
                 410599 
                 3-14-3 
                 351 
                 20723 
                 20742 
                 0 
                 CCTCAGGGAACCAGGCCTCA 
               
               
                   
               
               
                 410600 
                 3-14-3 
                 352 
                 20724 
                 20743 
                 0 
                 TCCTCAGGGAACCAGGCCTC 
               
               
                   
               
               
                 410601 
                 3-14-3 
                 353 
                 20725 
                 20744 
                 0 
                 GTCCTCAGGGAACCAGGCCT 
               
               
                   
               
               
                 410602 
                 3-14-3 
                 354 
                 20727 
                 20746 
                 0 
                 TGGTCCTCAGGGAACCAGGC 
               
               
                   
               
               
                 410603 
                 3-14-3 
                 355 
                 20728 
                 20747 
                 0 
                 CTGGTCCTCAGGGAACCAGG 
               
               
                   
               
               
                 410604 
                 3-14-3 
                 356 
                 20729 
                 20748 
                 0 
                 GCTGGTCCTCAGGGAACCAG 
               
               
                   
               
               
                 410605 
                 3-14-3 
                 376 
                 22133 
                 22152 
                 0 
                 CACCTGGCAATGGCGTAGAC 
               
               
                   
               
               
                 410606 
                 3-14-3 
                 377 
                 22134 
                 22153 
                 0 
                 GCACCTGGCAATGGCGTAGA 
               
               
                   
               
               
                 410607 
                 3-14-3 
                 378 
                 22135 
                 22154 
                 0 
                 AGCACCTGGCAATGGCGTAG 
               
               
                   
               
               
                 410608 
                 3-14-3 
                 379 
                 22136 
                 22155 
                 0 
                 CAGCACCTGGCAATGGCGTA 
               
               
                   
               
               
                 410609 
                 3-14-3 
                 380 
                 22137 
                 22156 
                 0 
                 GCAGCACCTGGCAATGGCGT 
               
               
                   
               
               
                 410610 
                 3-14-3 
                 381 
                 22138 
                 22157 
                 0 
                 GGCAGCACCTGGCAATGGCG 
               
               
                   
               
               
                 410611 
                 3-14-3 
                 382 
                 22139 
                 22158 
                 0 
                 AGGCAGCACCTGGCAATGGC 
               
               
                   
               
               
                 410612 
                 3-14-3 
                 383 
                 22140 
                 22159 
                 0 
                 CAGGCAGCACCTGGCAATGG 
               
               
                   
               
               
                 410613 
                 3-14-3 
                 384 
                 22141 
                 22160 
                 0 
                 GCAGGCAGCACCTGGCAATG 
               
               
                   
               
               
                 410614 
                 3-14-3 
                 385 
                 22143 
                 22162 
                 0 
                 TAGCAGGCAGCACCTGGCAA 
               
               
                   
               
               
                 410615 
                 3-14-3 
                 388 
                 22199 
                 22218 
                 0 
                 GTCCCCATGCTGGCCTCAGC 
               
               
                   
               
               
                 410616 
                 3-14-3 
                 389 
                 22200 
                 22219 
                 0 
                 GGTCCCCATGCTGGCCTCAG 
               
               
                   
               
               
                 410617 
                 3-14-3 
                 390 
                 22201 
                 22220 
                 0 
                 GGGTCCCCATGCTGGCCTCA 
               
               
                   
               
               
                 410618 
                 3-14-3 
                 391 
                 22202 
                 22221 
                 0 
                 CGGGTCCCCATGCTGGCCTC 
               
               
                   
               
               
                 410619 
                 3-14-3 
                 392 
                 22203 
                 22222 
                 0 
                 ACGGGTCCCCATGCTGGCCT 
               
               
                   
               
               
                 410620 
                 3-14-3 
                 393 
                 22205 
                 22224 
                 0 
                 ACACGGGTCCCCATGCTGGC 
               
               
                   
               
               
                 410621 
                 3-14-3 
                 394 
                 22206 
                 22225 
                 0 
                 GACACGGGTCCCCATGCTGG 
               
               
                   
               
               
                 410622 
                 3-14-3 
                 395 
                 22207 
                 22226 
                 0 
                 GGACACGGGTCCCCATGCTG 
               
               
                   
               
               
                 410623 
                 3-14-3 
                 396 
                 22208 
                 22227 
                 0 
                 TGGACACGGGTCCCCATGCT 
               
               
                   
               
               
                 410624 
                 3-14-3 
                 397 
                 22209 
                 22228 
                 0 
                 GTGGACACGGGTCCCCATGC 
               
               
                   
               
               
                 410625 
                 3-14-3 
                 398 
                 22210 
                 22229 
                 0 
                 AGTGGACACGGGTCCCCATG 
               
               
                   
               
               
                 410626 
                 3-14-3 
                 399 
                 22211 
                 22230 
                 0 
                 CAGTGGACACGGGTCCCCAT 
               
               
                   
               
               
                 410627 
                 3-14-3 
                 400 
                 22212 
                 22231 
                 0 
                 GCAGTGGACACGGGTCCCCA 
               
               
                   
               
               
                 410628 
                 3-14-3 
                 401 
                 22213 
                 22232 
                 0 
                 GGCAGTGGACACGGGTCCCC 
               
               
                   
               
               
                 410629 
                 3-14-3 
                 402 
                 22214 
                 22233 
                 0 
                 TGGCAGTGGACACGGGTCCC 
               
               
                   
               
               
                 410630 
                 3-14-3 
                 403 
                 22215 
                 22234 
                 0 
                 GTGGCAGTGGACACGGGTCC 
               
               
                   
               
               
                 410631 
                 3-14-3 
                 404 
                 22216 
                 22235 
                 0 
                 GGTGGCAGTGGACACGGGTC 
               
               
                   
               
               
                 410632 
                 3-14-3 
                 405 
                 22217 
                 22236 
                 0 
                 TGGTGGCAGTGGACACGGGT 
               
               
                   
               
               
                 410633 
                 3-14-3 
                 411 
                 24096 
                 24115 
                 0 
                 ACTTTGCATTCCAGACCTGG 
               
               
                   
               
               
                 410634 
                 3-14-3 
                 412 
                 24097 
                 24116 
                 0 
                 GACTTTGCATTCCAGACCTG 
               
               
                   
               
               
                 410635 
                 3-14-3 
                 413 
                 24098 
                 24117 
                 0 
                 TGACTTTGCATTCCAGACCT 
               
               
                   
               
               
                 410636 
                 3-14-3 
                 414 
                 24099 
                 24118 
                 0 
                 TTGACTTTGCATTCCAGACC 
               
               
                   
               
               
                 410637 
                 3-14-3 
                 419 
                 26112 
                 26131 
                 0 
                 CAGATGGCAACGGCTGTCAC 
               
               
                   
               
               
                 410638 
                 3-14-3 
                 420 
                 26113 
                 26132 
                 0 
                 GCAGATGGCAACGGCTGTCA 
               
               
                   
               
               
                 410639 
                 3-14-3 
                 421 
                 26114 
                 26133 
                 0 
                 AGCAGATGGCAACGGCTGTC 
               
               
                   
               
               
                 410640 
                 3-14-3 
                 422 
                 26115 
                 26134 
                 0 
                 CAGCAGATGGCAACGGCTGT 
               
               
                   
               
               
                 410641 
                 3-14-3 
                 423 
                 26116 
                 26135 
                 0 
                 GCAGCAGATGGCAACGGCTG 
               
               
                   
               
               
                 410642 
                 3-14-3 
                 424 
                 26118 
                 26137 
                 0 
                 CGGCAGCAGATGGCAACGGC 
               
               
                   
               
               
                 410643 
                 3-14-3 
                 425 
                 26119 
                 26138 
                 0 
                 CCGGCAGCAGATGGCAACGG 
               
               
                   
               
               
                 410644 
                 3-14-3 
                 426 
                 26120 
                 26139 
                 0 
                 TCCGGCAGCAGATGGCAACG 
               
               
                   
               
               
                 410645 
                 3-14-3 
                 427 
                 26121 
                 26140 
                 0 
                 CTCCGGCAGCAGATGGCAAC 
               
               
                   
               
               
                 410646 
                 3-14-3 
                 428 
                 26122 
                 26141 
                 0 
                 GCTCCGGCAGCAGATGGCAA 
               
               
                   
               
            
           
         
       
     
     In certain embodiments, gap-widened antisense compounds are targeted to a PCSK9 nucleic acid. In certain such embodiments, gap-widened antisense compounds are targeted to SEQ ID NO: 2. In certain such embodiments, the nucleotide sequences illustrated in Table 7 have a 2-13-5 gap-widened motif. Table 10 illustrates gap-widened antisense compounds targeted to SEQ ID NO: 2, having a 2-13-5 motif, where the gap segment comprises 2′-deoxynucleotides and each wing segment comprises nucleotides comprising a 2′-O-methoxyethyl sugar modification. Internucleoside linkages are phosphorthioate, and cytidines are 5-methylcytidines. 
     
       
         
           
               
             
               
                 TABLE 10 
               
             
            
               
                   
               
               
                 Gapmer antisense compounds having a 2-13-5  
               
               
                 motif targeted to SEQ ID NO: 2 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                   
                   
                 5′ 
                 3′ 
                   
                   
               
               
                   
                   
                   
                 Target 
                 Target 
                   
                   
               
               
                   
                   
                   
                 Site 
                 Site 
                   
                   
               
               
                   
                   
                   
                 on 
                 on 
                   
                   
               
               
                   
                   
                   
                 SEQ 
                 SEQ 
                   
                   
               
               
                   
                   
                 SEQ 
                 ID 
                 ID 
                   
                   
               
               
                 Isis 
                   
                 ID 
                 NO: 
                 NO: 
                   
                   
               
               
                 No 
                 Motif 
                 NO 
                 2 
                 2 
                 Mismatches 
                 Sequence (5′-3′) 
               
               
                   
               
               
                 410647 
                 2-13-5 
                 184 
                  6534 
                  6553 
                 0 
                 TGAGGTATCCCCGGCGG 
               
               
                   
                   
                   
                   
                   
                   
                 GCA 
               
               
                   
               
               
                 410648 
                 2-13-5 
                 185 
                  6535 
                  6554 
                 0 
                 GTGAGGTATCCCCGGCG 
               
               
                   
                   
                   
                   
                   
                   
                 GGC 
               
               
                   
               
               
                 410649 
                 2-13-5 
                 186 
                  6536 
                  6555 
                 0 
                 GGTGAGGTATCCCCGGC 
               
               
                   
                   
                   
                   
                   
                   
                 GGG 
               
               
                   
               
               
                 410650 
                 2-13-5 
                  11 
                  6537 
                  6556 
                 0 
                 TGGTGAGGTATCCCCGG 
               
               
                   
                   
                   
                   
                   
                   
                 CGG 
               
               
                   
               
               
                 410651 
                 2-13-5 
                 187 
                  6538 
                  6557 
                 0 
                 TTGGTGAGGTATCCCCG 
               
               
                   
                   
                   
                   
                   
                   
                 GCG 
               
               
                   
               
               
                 410652 
                 2-13-5 
                 188 
                  6539 
                  6558 
                 0 
                 CTTGGTGAGGTATCCCC 
               
               
                   
                   
                   
                   
                   
                   
                 GGC 
               
               
                   
               
               
                 410653 
                 2-13-5 
                 189 
                  6540 
                  6559 
                 0 
                 TCTTGGTGAGGTATCCC 
               
               
                   
                   
                   
                   
                   
                   
                 CGG 
               
               
                   
               
               
                 410654 
                 2-13-5 
                 190 
                  6541 
                  6560 
                 0 
                 ATCTTGGTGAGGTATCC 
               
               
                   
                   
                   
                   
                   
                   
                 CCG 
               
               
                   
               
               
                 410655 
                 2-13-5 
                 191 
                  6542 
                  6561 
                 0 
                 GATCTTGGTGAGGTATC 
               
               
                   
                   
                   
                   
                   
                   
                 CCC 
               
               
                   
               
               
                 410656 
                 2-13-5 
                  12 
                  6543 
                  6562 
                 0 
                 GGATCTTGGTGAGGTAT 
               
               
                   
                   
                   
                   
                   
                   
                 CCC 
               
               
                   
               
               
                 410657 
                 2-13-5 
                 192 
                  6544 
                  6563 
                 0 
                 AGGATCTTGGTGAGGTA 
               
               
                   
                   
                   
                   
                   
                   
                 TCC 
               
               
                   
               
               
                 410658 
                 2-13-5 
                 243 
                 15291 
                 15310 
                 0 
                 GCCACGCCGGCATCCCG 
               
               
                   
                   
                   
                   
                   
                   
                 GCC 
               
               
                   
               
               
                 410659 
                 2-13-5 
                 244 
                 15292 
                 15311 
                 0 
                 GGCCACGCCGGCATCCC 
               
               
                   
                   
                   
                   
                   
                   
                 GGC 
               
               
                   
               
               
                 410660 
                 2-13-5 
                 245 
                 15293 
                 15312 
                 0 
                 TGGCCACGCCGGCATCC 
               
               
                   
                   
                   
                   
                   
                   
                 CGG 
               
               
                   
               
               
                 410661 
                 2-13-5 
                 246 
                 15294 
                 15313 
                 0 
                 TTGGCCACGCCGGCATC 
               
               
                   
                   
                   
                   
                   
                   
                 CCG 
               
               
                   
               
               
                 410662 
                 2-13-5 
                 247 
                 15295 
                 15314 
                 0 
                 CTTGGCCACGCCGGCAT 
               
               
                   
                   
                   
                   
                   
                   
                 CCC 
               
               
                   
               
               
                 410663 
                 2-13-5 
                 248 
                 15296 
                 15315 
                 0 
                 CCTTGGCCACGCCGGCA 
               
               
                   
                   
                   
                   
                   
                   
                 TCC 
               
               
                   
               
               
                 410664 
                 2-13-5 
                 249 
                 15297 
                 15316 
                 0 
                 CCCTTGGCCACGCCGGC 
               
               
                   
                   
                   
                   
                   
                   
                 ATC 
               
               
                   
               
               
                 410665 
                 2-13-5 
                  28 
                 15298 
                 15317 
                 0 
                 ACCCTTGGCCACGCCGG 
               
               
                   
                   
                   
                   
                   
                   
                 CAT 
               
               
                   
               
               
                 410666 
                 2-13-5 
                 250 
                 15299 
                 15318 
                 0 
                 CACCCTTGGCCACGCCG 
               
               
                   
                   
                   
                   
                   
                   
                 GCA 
               
               
                   
               
               
                 410667 
                 2-13-5 
                 251 
                 15300 
                 15319 
                 0 
                 GCACCCTTGGCCACGCC 
               
               
                   
                   
                   
                   
                   
                   
                 GGC 
               
               
                   
               
               
                 410668 
                 2-13-5 
                 252 
                 15301 
                 15320 
                 0 
                 GGCACCCTTGGCCACGC 
               
               
                   
                   
                   
                   
                   
                   
                 CGG 
               
               
                   
               
               
                 410669 
                 2-13-5 
                 253 
                 15302 
                 15321 
                 0 
                 TGGCACCCTTGGCCACG 
               
               
                   
                   
                   
                   
                   
                   
                 CCG 
               
               
                   
               
               
                 410670 
                 2-13-5 
                 254 
                 15303 
                 15322 
                 0 
                 CTGGCACCCTTGGCCAC 
               
               
                   
                   
                   
                   
                   
                   
                 GCC 
               
               
                   
               
               
                 410671 
                 2-13-5 
                 255 
                 15304 
                 15323 
                 0 
                 GCTGGCACCCTTGGCCA 
               
               
                   
                   
                   
                   
                   
                   
                 CGC 
               
               
                   
               
               
                 410672 
                 2-13-5 
                 348 
                 20719 
                 20738 
                 0 
                 AGGGAACCAGGCCTCAT 
               
               
                   
                   
                   
                   
                   
                   
                 TGA 
               
               
                   
               
               
                 410673 
                 2-13-5 
                 349 
                 20720 
                 20739 
                 0 
                 CAGGGAACCAGGCCTCA 
               
               
                   
                   
                   
                   
                   
                   
                 TTG 
               
               
                   
               
               
                 410674 
                 2-13-5 
                  49 
                 20721 
                 20740 
                 0 
                 TCAGGGAACCAGGCCTC 
               
               
                   
                   
                   
                   
                   
                   
                 ATT 
               
               
                   
               
               
                 410675 
                 2-13-5 
                 350 
                 20722 
                 20741 
                 0 
                 CTCAGGGAACCAGGCCT 
               
               
                   
                   
                   
                   
                   
                   
                 CAT 
               
               
                   
               
               
                 410676 
                 2-13-5 
                 351 
                 20723 
                 20742 
                 0 
                 CCTCAGGGAACCAGGCC 
               
               
                   
                   
                   
                   
                   
                   
                 TCA 
               
               
                   
               
               
                 410677 
                 2-13-5 
                 352 
                 20724 
                 20743 
                 0 
                 TCCTCAGGGAACCAGGC 
               
               
                   
                   
                   
                   
                   
                   
                 CTC 
               
               
                   
               
               
                 410678 
                 2-13-5 
                 353 
                 20725 
                 20744 
                 0 
                 GTCCTCAGGGAACCAGG 
               
               
                   
                   
                   
                   
                   
                   
                 CCT 
               
               
                   
               
               
                 410679 
                 2-13-5 
                  50 
                 20726 
                 20745 
                 0 
                 GGTCCTCAGGGAACCAG 
               
               
                   
                   
                   
                   
                   
                   
                 GCC 
               
               
                   
               
               
                 410680 
                 2-13-5 
                 354 
                 20727 
                 20746 
                 0 
                 TGGTCCTCAGGGAACCA 
               
               
                   
                   
                   
                   
                   
                   
                 GGC 
               
               
                   
               
               
                 410681 
                 2-13-5 
                 355 
                 20728 
                 20747 
                 0 
                 CTGGTCCTCAGGGAACC 
               
               
                   
                   
                   
                   
                   
                   
                 AGG 
               
               
                   
               
               
                 410682 
                 2-13-5 
                 356 
                 20729 
                 20748 
                 0 
                 GCTGGTCCTCAGGGAAC 
               
               
                   
                   
                   
                   
                   
                   
                 CAG 
               
               
                   
               
               
                 410683 
                 2-13-5 
                 376 
                 22133 
                 22152 
                 0 
                 CACCTGGCAATGGCGTA 
               
               
                   
                   
                   
                   
                   
                   
                 GAC 
               
               
                   
               
               
                 410684 
                 2-13-5 
                 377 
                 22134 
                 22153 
                 0 
                 GCACCTGGCAATGGCGT 
               
               
                   
                   
                   
                   
                   
                   
                 AGA 
               
               
                   
               
               
                 410685 
                 2-13-5 
                 378 
                 22135 
                 22154 
                 0 
                 AGCACCTGGCAATGGCG 
               
               
                   
                   
                   
                   
                   
                   
                 TAG 
               
               
                   
               
               
                 410686 
                 2-13-5 
                 379 
                 22136 
                 22155 
                 0 
                 CAGCACCTGGCAATGGC 
               
               
                   
                   
                   
                   
                   
                   
                 GTA 
               
               
                   
               
               
                 410687 
                 2-13-5 
                 380 
                 22137 
                 22156 
                 0 
                 GCAGCACCTGGCAATGG 
               
               
                   
                   
                   
                   
                   
                   
                 CGT 
               
               
                   
               
               
                 410688 
                 2-13-5 
                 381 
                 22138 
                 22157 
                 0 
                 GGCAGCACCTGGCAATG 
               
               
                   
                   
                   
                   
                   
                   
                 GCG 
               
               
                   
               
               
                 410689 
                 2-13-5 
                 382 
                 22139 
                 22158 
                 0 
                 AGGCAGCACCTGGCAAT 
               
               
                   
                   
                   
                   
                   
                   
                 GGC 
               
               
                   
               
               
                 410690 
                 2-13-5 
                 383 
                 22140 
                 22159 
                 0 
                 CAGGCAGCACCTGGCAA 
               
               
                   
                   
                   
                   
                   
                   
                 TGG 
               
               
                   
               
               
                 410691 
                 2-13-5 
                 384 
                 22141 
                 22160 
                 0 
                 GCAGGCAGCACCTGGCA 
               
               
                   
                   
                   
                   
                   
                   
                 ATG 
               
               
                   
               
               
                 410692 
                 2-13-5 
                  58 
                 22142 
                 22161 
                 0 
                 AGCAGGCAGCACCTGGC 
               
               
                   
                   
                   
                   
                   
                   
                 AAT 
               
               
                   
               
               
                 410693 
                 2-13-5 
                 385 
                 22143 
                 22162 
                 0 
                 TAGCAGGCAGCACCTGG 
               
               
                   
                   
                   
                   
                   
                   
                 CAA 
               
               
                   
               
               
                 410694 
                 2-13-5 
                 388 
                 22199 
                 22218 
                 0 
                 GTCCCCATGCTGGCCTC 
               
               
                   
                   
                   
                   
                   
                   
                 AGC 
               
               
                   
               
               
                 410695 
                 2-13-5 
                 389 
                 22200 
                 22219 
                 0 
                 GGTCCCCATGCTGGCCT 
               
               
                   
                   
                   
                   
                   
                   
                 CAG 
               
               
                   
               
               
                 410696 
                 2-13-5 
                 390 
                 22201 
                 22220 
                 0 
                 GGGTCCCCATGCTGGCC 
               
               
                   
                   
                   
                   
                   
                   
                 TCA 
               
               
                   
               
               
                 410697 
                 2-13-5 
                 391 
                 22202 
                 22221 
                 0 
                 CGGGTCCCCATGCTGGC 
               
               
                   
                   
                   
                   
                   
                   
                 CTC 
               
               
                   
               
               
                 410698 
                 2-13-5 
                 392 
                 22203 
                 22222 
                 0 
                 ACGGGTCCCCATGCTGG 
               
               
                   
                   
                   
                   
                   
                   
                 CCT 
               
               
                   
               
               
                 410699 
                 2-13-5 
                 59 
                 22204 
                 22223 
                 0 
                 CACGGGTCCCCATGCTG 
               
               
                   
                   
                   
                   
                   
                   
                 GCC 
               
               
                   
               
               
                 410700 
                 2-13-5 
                 393 
                 22205 
                 22224 
                 0 
                 ACACGGGTCCCCATGCT 
               
               
                   
                   
                   
                   
                   
                   
                 GGC 
               
               
                   
               
               
                 410701 
                 2-13-5 
                 394 
                 22206 
                 22225 
                 0 
                 GACACGGGTCCCCATGC 
               
               
                   
                   
                   
                   
                   
                   
                 TGG 
               
               
                   
               
               
                 410702 
                 2-13-5 
                 395 
                 22207 
                 22226 
                 0 
                 GGACACGGGTCCCCATG 
               
               
                   
                   
                   
                   
                   
                   
                 CTG 
               
               
                   
               
               
                 410703 
                 2-13-5 
                 396 
                 22208 
                 22227 
                 0 
                 TGGACACGGGTCCCCAT 
               
               
                   
                   
                   
                   
                   
                   
                 GCT 
               
               
                   
               
               
                 410704 
                 2-13-5 
                 397 
                 22209 
                 22228 
                 0 
                 GTGGACACGGGTCCCCA 
               
               
                   
                   
                   
                   
                   
                   
                 TGC 
               
               
                   
               
               
                 410705 
                 2-13-5 
                 398 
                 22210 
                 22229 
                 0 
                 AGTGGACACGGGTCCCC 
               
               
                   
                   
                   
                   
                   
                   
                 ATG 
               
               
                   
               
               
                 410706 
                 2-13-5 
                 399 
                 22211 
                 22230 
                 0 
                 CAGTGGACACGGGTCCC 
               
               
                   
                   
                   
                   
                   
                   
                 CAT 
               
               
                   
               
               
                 410707 
                 2-13-5 
                 400 
                 22212 
                 22231 
                 0 
                 GCAGTGGACACGGGTCC 
               
               
                   
                   
                   
                   
                   
                   
                 CCA 
               
               
                   
               
               
                 410708 
                 2-13-5 
                 401 
                 22213 
                 22232 
                 0 
                 GGCAGTGGACACGGGTC 
               
               
                   
                   
                   
                   
                   
                   
                 CCC 
               
               
                   
               
               
                 410709 
                 2-13-5 
                 402 
                 22214 
                 22233 
                 0 
                 TGGCAGTGGACACGGGT 
               
               
                   
                   
                   
                   
                   
                   
                 CCC 
               
               
                   
               
               
                 410710 
                 2-13-5 
                 403 
                 22215 
                 22234 
                 0 
                 GTGGCAGTGGACACGGG 
               
               
                   
                   
                   
                   
                   
                   
                 TCC 
               
               
                   
               
               
                 410711 
                 2-13-5 
                 404 
                 22216 
                 22235 
                 0 
                 GGTGGCAGTGGACACGG 
               
               
                   
                   
                   
                   
                   
                   
                 GTC 
               
               
                   
               
               
                 410712 
                 2-13-5 
                 405 
                 22217 
                 22236 
                 0 
                 TGGTGGCAGTGGACACG 
               
               
                   
                   
                   
                   
                   
                   
                 GGT 
               
               
                   
               
               
                 410713 
                 2-13-5 
                 60 
                 24095 
                 24114 
                 0 
                 CTTTGCATTCCAGACCT 
               
               
                   
                   
                   
                   
                   
                   
                 GGG 
               
               
                   
               
               
                 410714 
                 2-13-5 
                 411 
                 24096 
                 24115 
                 0 
                 ACTTTGCATTCCAGACC 
               
               
                   
                   
                   
                   
                   
                   
                 TGG 
               
               
                   
               
               
                 410715 
                 2-13-5 
                 412 
                 24097 
                 24116 
                 0 
                 GACTTTGCATTCCAGAC 
               
               
                   
                   
                   
                   
                   
                   
                 CTG 
               
               
                   
               
               
                 410716 
                 2-13-5 
                 413 
                 24098 
                 24117 
                 0 
                 TGACTTTGCATTCCAGA 
               
               
                   
                   
                   
                   
                   
                   
                 CCT 
               
               
                   
               
               
                 410717 
                 2-13-5 
                 414 
                 24099 
                 24118 
                 0 
                 TTGACTTTGCATTCCAG 
               
               
                   
                   
                   
                   
                   
                   
                 ACC 
               
               
                   
               
               
                 410718 
                 2-13-5 
                 61 
                 24100 
                 24119 
                 0 
                 CTTGACTTTGCATTCCA 
               
               
                   
                   
                   
                   
                   
                   
                 GAC 
               
               
                   
               
               
                 410719 
                 2-13-5 
                 419 
                 26112 
                 26131 
                 0 
                 CAGATGGCAACGGCTGT 
               
               
                   
                   
                   
                   
                   
                   
                 CAC 
               
               
                   
               
               
                 410720 
                 2-13-5 
                 420 
                 26113 
                 26132 
                 0 
                 GCAGATGGCAACGGCTG 
               
               
                   
                   
                   
                   
                   
                   
                 TCA 
               
               
                   
               
               
                 410721 
                 2-13-5 
                 421 
                 26114 
                 26133 
                 0 
                 AGCAGATGGCAACGGCT 
               
               
                   
                   
                   
                   
                   
                   
                 GTC 
               
               
                   
               
               
                 410722 
                 2-13-5 
                 422 
                 26115 
                 26134 
                 0 
                 CAGCAGATGGCAACGGC 
               
               
                   
                   
                   
                   
                   
                   
                 TGT 
               
               
                   
               
               
                 410723 
                 2-13-5 
                 423 
                 26116 
                 26135 
                 0 
                 GCAGCAGATGGCAACGG 
               
               
                   
                   
                   
                   
                   
                   
                 CTG 
               
               
                   
               
               
                 410724 
                 2-13-5 
                 62 
                 26117 
                 26136 
                 0 
                 GGCAGCAGATGGCAACG 
               
               
                   
                   
                   
                   
                   
                   
                 GCT 
               
               
                   
               
               
                 410725 
                 2-13-5 
                 424 
                 26118 
                 26137 
                 0 
                 CGGCAGCAGATGGCAAC 
               
               
                   
                   
                   
                   
                   
                   
                 GGC 
               
               
                   
               
               
                 410726 
                 2-13-5 
                 425 
                 26119 
                 26138 
                 0 
                 CCGGCAGCAGATGGCAA 
               
               
                   
                   
                   
                   
                   
                   
                 CGG 
               
               
                   
               
               
                 410727 
                 2-13-5 
                 426 
                 26120 
                 26139 
                 0 
                 TCCGGCAGCAGATGGCA 
               
               
                   
                   
                   
                   
                   
                   
                 ACG 
               
               
                   
               
               
                 410728 
                 2-13-5 
                 427 
                 26121 
                 26140 
                 0 
                 CTCCGGCAGCAGATGGC 
               
               
                   
                   
                   
                   
                   
                   
                 AAC 
               
               
                   
               
               
                 410729 
                 2-13-5 
                 428 
                 26122 
                 26141 
                 0 
                 GCTCCGGCAGCAGATGG 
               
               
                   
                   
                   
                   
                   
                   
                 CAA 
               
               
                   
               
            
           
         
       
     
     In certain embodiments, gap-widened antisense compounds are targeted to a PCSK9 nucleic acid. In certain such embodiments, gap-widened antisense compounds are targeted to SEQ ID NO: 2. In certain such embodiments, the nucleotide sequences illustrated in Table 7 have a 3-13-4 gap-widened motif. Table 11 illustrates gap-widened antisense compounds targeted to SEQ ID NO: 2, having a 3-13-4 motif, where the gap segment comprises 2′-deoxynucleotides and each wing segment comprises nucleotides comprising a 2′-O-methoxyethyl sugar modification. Internucleoside linkages are phosphorthioate, and cytidines are 5-methylcytidines. 
     
       
         
           
               
             
               
                 TABLE 11 
               
             
            
               
                   
               
               
                 Gapmer antisense compounds having a 3-13-4 motif 
               
               
                 targeted to SEQ ID NO: 2 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                   
                   
                 5′ 
                 3′ 
                   
                   
               
               
                   
                   
                   
                 Tar- 
                 Tar- 
                   
                   
               
               
                   
                   
                   
                 get 
                 get 
                   
                   
               
               
                   
                   
                   
                 Site 
                 Site 
                   
                   
               
               
                   
                   
                   
                 on 
                 on 
                   
                   
               
               
                   
                   
                   
                 SEQ 
                 SEQ 
                   
                   
               
               
                   
                   
                 SEQ 
                 ID 
                 ID 
                 Mis- 
                   
               
               
                 Isis 
                   
                 ID 
                 NO: 
                 NO: 
                 match- 
                   
               
               
                 No 
                 Motif 
                 NO 
                 2 
                 2 
                 es 
                 Sequence (5′-3′) 
               
               
                   
               
               
                 405526 
                 3-13-4 
                 236 
                 15257 
                 15276 
                 0 
                 CCAGGTGGGTGCCATGA 
               
               
                   
                   
                   
                   
                   
                   
                 CTG 
               
               
                   
               
               
                 405557 
                 3-13-4 
                  50 
                 20726 
                 20745 
                 0 
                 GGTCCTCAGGGAACCAG 
               
               
                   
                   
                   
                   
                   
                   
                 GCC 
               
               
                   
               
               
                 405564 
                 3-13-4 
                 373 
                 21183 
                 21202 
                 0 
                 AACTGGAGCAGCTCAGC 
               
               
                   
                   
                   
                   
                   
                   
                 AGC 
               
               
                   
               
            
           
         
       
     
     The following embodiments set forth target regions of PCSK9 nucleic acids. Also illustrated are examples of antisense compounds targeted to the target regions. It is understood that the sequence set forth in each SEQ ID NO is independent of any modification to a sugar moiety, an internucleoside linkage, or a nucleobase. As such, antisense compounds defined by a SEQ ID NO may comprise, independently, one or more modifications to a sugar moiety, an internucleoside linkage, or a nucleobase. Antisense compounds described by Isis Number (Isis No) indicate a combination of nucleobase sequence and motif. 
     In certain embodiments, antisense compounds target a range of a PCSK9 nucleic acid. In certain embodiment, such compounds contain at least an 8 nucleotide core sequence in common. In certain embodiments, such compounds sharing at least an 8 nucleotide core sequence targets the following nucleotide regions of SEQ ID NO: 2: 2274-2400, 2274-2575, 2433-2570, 2433-2579, 2549-2575, 2552-2579, 2585-2638, 2605-2638, 3056-3075, 4150-5159, 4306-4325, 5590-5618, 5667-5686, 6444-6463, 6482-6518, 6492-6518, 6528-6555, 6528-6623, 6534-6561, 6535-6562, 6536-6563, 6537-6563, 6538-6565, 6539-6565, 6540-6567, 6541-6567, 6542-6569, 6546-6573, 6557-6584, 6575-6602, 6585-6611, 6594-6621, 6596-6623, 6652-6671, 7099-7118, 7556-7584, 8836-8855, 8948-8967, 9099-9118, 9099-9168, 9130-9168, 9207-9233, 9207-9235, 9209-9235, 10252-10271, 10633-10652, 11308-11491, 12715-12734, 12928-12947, 13681-13700, 13746-13779, 13816-13847, 13903-13945, 13977-14141, 14179-14198, 14267-14286, 14397-14423, 14441-14460, 14494-14513, 14494-14543, 14524-14543, 14601-14650, 14670-14700, 14675-14700, 14801-14828, 14877-14912, 14877-14915, 14877-14973, 14916-14943, 14916-14973, 14925-14951, 14934-14963, 14946-14973, 14979-14998, 15254-15280, 15254-15328, 15264-15290, 15279-15305, 15291-15318, 15292-15319, 15293-15320, 15294-15321, 15294-15321, 15295-15322, 15296-15315, 15296-15323, 15297-15323, 15298-15323, 15299-15323, 15300-15323, 15301-15328, 15330-15355, 15330-15490, 15339-15366, 15358-15490, 16134-16153, 16668-16687, 17267-17286, 18377-18427, 18561-18580, 18591-18618, 18591-18646, 18591-18668, 18695-18746, 18705-18730, 18709-18736, 18719-18746, 19203-20080, 19931-19952, 19954-19981, 19964-19990, 19973-19999, 19982-20009, 19992-20016, 20016-20042, 20025-20052, 20036-20062, 20045-20070, 20100-20119, 20188-20207, 20624-20650, 20624-20759, 20629-20804, 20633-20660, 20635-20781, 20643-20662, 20657-20676, 20670-20697, 20680-20706, 20683-20781, 20689-20715, 20698-20725, 20709-20736, 20717-20744, 20718-20745, 20719-20746, 20720-20747, 20721-20748, 20722-20749, 20727-20752, 20735-20759, 20762-21014, 20785-21014, 21082-21107, 21082-21152, 21091-21114, 21118-21144, 21127-21152, 21181-21209, 21181-21211, 21183-21211, 21481-21500, 21589-21608, 21692-21719, 22000-22227, 22096-22115, 22096-22223, 22096-22311, 22133-22160, 22133-22163, 22134-22161, 22135-22162, 22136-22163, 22137-22163, 22138-22163, 22189-22239, 22199-22226, 22199-22227, 22200-22227, 22201-22228, 22202-22229, 22203-22230, 22204-22231, 22205-22232, 22206-22233, 22207-22234, 22208-22235, 22209-22236, 22210-22236, 22210-22239, 22211-22236, 22212-22239, 22292-22311, 23985-24054, 24035-24134, 24095-24121, 24858-24877, 24907-24926, 25413-25432, 25994-26013, 26112-26139, 26112-26161, 26112-27303, 26113-26140, 26114-26141, 26115-26141, 26116-26141, 26117-26141, 26117-26475, 26118-26141, 26120-26141, 26132-26151, 26142-26161, 26217-26241, 26311-26335, 26389-26432, 26456-26576, 26635-26662, 26707-26734, 26707-26736, 26790-26820, 27034-27263, 27279-27303, or 27350-27376. 
     In certain embodiments, a target region is nucleotides 2274-2400 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 2274-2400 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 4 or 5. In certain such embodiments, an antisense compound targeted to nucleotides 2274-2400 of SEQ ID NO: 2 is selected from ISIS NOs: 395149, 399871, 395150 or 399872. 
     In certain embodiments, a target region is nucleotides 2274-2575 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 2274-2575 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 4, 5, 6, 7, 8, 159, 160, 162, 163, 164, 165, 166, 167, 168 or 169. In certain such embodiments, an antisense compound targeted to nucleotides 2274-2575 of SEQ ID NO: 2 is selected from ISIS NOs: 395149, 399871, 395150, 399872, 410742, 405999, 395151, 399873, 405861, 405862, 405863, 405864, 395152, 399874, 405865, 405866, 405867, 405868, 399793, or 399949. 
     In certain embodiments, a target region is nucleotides 2433-2570 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 2433-2570 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 6, 7, 159, 160, 162, 163, 164, 165, 166, or 167. In certain such embodiments, an antisense compound targeted to nucleotides 2433-2570 of SEQ ID NO: 2 is selected from ISIS NOs: 395151, 395152, 399873, 399874, 405861, 405862, 405863, 405864, 405865, 405866, 405999, or 410742. 
     In certain embodiments, a target region is nucleotides 2433-2579 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 2433-2579 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 6, 7, 8, 159, 160, 162, 163, 164, 165, 166, 167, 168, 169, or 170. In certain such embodiments, an antisense compound targeted to nucleotides 2433-2579 of SEQ ID NO: 2 is selected from ISIS NOs: 395151, 395152, 399793, 399873, 399874, 399949, 405861, 405862, 405863, 405864, 405865, 405866, 405867, 405868, 405999, 410742, or 410743. 
     In certain embodiments, a target region is nucleotides 2549-2575 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 2549-2575 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 7, 8, 166, 167, 168 or 169. In certain such embodiments, an antisense compound targeted to nucleotides 2549-2575 of SEQ ID NO: 2 is selected from ISIS NOs: 395152, 399793, 399874, 399949, 405865, 405866, 405867, or 405868. 
     In certain embodiments, a target region is nucleotides 2552-2579 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 2552-2579 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 8, 168, 169 or 170. In certain such embodiments, an antisense compound targeted to nucleotides 2552-2579 of SEQ ID NO: 2 is selected from ISIS NOs: 399793, 399949, 405867, 405868, or 410743. 
     In certain embodiments, a target region is nucleotides 2585-2638 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 2585-2638 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 9, 171 or 172. In certain such embodiments, an antisense compound targeted to nucleotides 2585-2638 of SEQ ID NO: 2 is selected from ISIS NOs: 395153, 399875, 410744, or 410745. 
     In certain embodiments, a target region is nucleotides 2605-2638 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 2605-2638 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 8, 168 or 169. In certain such embodiments, an antisense compound targeted to nucleotides 2605-2638 of SEQ ID NO: 2 is selected from ISIS NOs: 410745, 395153, or 399875. 
     In certain embodiments, a target region is nucleotides 3056-3075 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 3056-3075 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 107. In certain such embodiments, an antisense compound targeted to nucleotides 3056-3075 of SEQ ID NO: 2 is selected from ISIS NOs: 399837 or 399993. 
     In certain embodiments, a target region is nucleotides 4150-5159 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 4150-5159 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 106. In certain such embodiments, an antisense compound targeted to nucleotides 4150-5159 of SEQ ID NO: 2 is selected from ISIS NOs: 399839 or 399995. 
     In certain embodiments, a target region is nucleotides 4306-4325 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 4306-4325 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 80. In certain such embodiments, an antisense compound targeted to nucleotides 4306-4325 of SEQ ID NO: 2 is selected from ISIS NOs: 399838 or 399994. 
     In certain embodiments, a target region is nucleotides 5590-5618 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 5590-5618 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 102 or 121. In certain such embodiments, an antisense compound targeted to nucleotides 5590-5618 of SEQ ID NO: 2 is selected from ISIS NOs: 395221, 399840, 399943, or 399996. 
     In certain embodiments, a target region is nucleotides 5667-5686 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 5667-5686 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 94. In certain such embodiments, an antisense compound targeted to nucleotides 5667-5686 of SEQ ID NO: 2 is selected from ISIS NOs: 399841 or 399997. 
     In certain embodiments, a target region is nucleotides 6444-6463 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 6444-6463 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 176. In certain such embodiments, an antisense compound targeted to nucleotides 6444-6463 of SEQ ID NO: 2 is selected from ISIS NOs: 410746. 
     In certain embodiments, a target region is nucleotides 6482-6518 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 6482-6518 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 10, 177, 178, 179, 180 or 181. In certain such embodiments, an antisense compound targeted to nucleotides 6482-6518 of SEQ ID NO: 2 is selected from ISIS NOs: 395154, 399876, 406003, 406004, 406005, 406006 or 410747. 
     In certain embodiments, a target region is nucleotides 6492-6518 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 6492-6518 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 10, 178, 179, 180 or 181. In certain such embodiments, an antisense compound targeted to nucleotides 6492-6518 of SEQ ID NO: 2 is selected from ISIS NOs: 395154, 399876, 406003, 406004, 406005 or 406006. 
     In certain embodiments, a target region is nucleotides 6528-6555 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 6528-6555 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 182, 183, 184, 185 or 186. In certain such embodiments, an antisense compound targeted to nucleotides 6528-6555 of SEQ ID NO: 2 is selected from ISIS NOs: 406007, 410529, 410530, 410531, 410574, 410575, 410576, 410647, 410648, 410649 or 410748. 
     In certain embodiments, a target region is nucleotides 6528-6623 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 6528-6623 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 11, 12, 13, 13, 14, 15, 16, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, or 207. In certain such embodiments, an antisense compound targeted to nucleotides 6528-6623 of SEQ ID NO: 2 is selected from ISIS NOs: 395155, 395156, 395157, 399794, 399795, 399796, 399877, 399878, 399879, 399950, 399951, 399952, 406007, 406008, 406009, 406010, 406011, 406012, 406013, 406014, 406015, 406016, 406017, 406018, 406019, 406020, 410529, 410530, 410531, 410532, 410533, 410534, 410535, 410574, 410575, 410576, 410577, 410578, 410579, 410580, 410581, 410582, 410647, 410648, 410649, 410650, 410651, 410652, 410653, 410654, 410655, 410656, 410657, 410730, 410731, 410748, 410749, or 410750. 
     In certain embodiments, a target region is nucleotides 6534-6561 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 6534-6561 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 11, 184, 185, 186, 187, 188, 189, 190 or 191. In certain such embodiments, an antisense compound targeted to nucleotides 6534-6561 of SEQ ID NO: 2 is selected from ISIS NOs: 395155, 399877, 406008, 406009, 410529, 410530, 410531, 410532, 410533, 410534, 410574, 410575, 410576, 410577, 410578, 410579, 410580, 410581, 410647, 410648, 410649, 410650, 410651, 410652, 410653, 410654, or 410655. 
     In certain embodiments, a target region is nucleotides 6535-6562 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 6535-6562 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 11, 12, 185, 186, 187, 188, 189, 190 or 191. In certain such embodiments, an antisense compound targeted to nucleotides 6535-6562 of SEQ ID NO: 2 is selected from ISIS NOs: 395155, 399794, 399877, 399950, 406008, 406009, 410530, 410531, 410532, 410533, 410534, 410575, 410576, 410577, 410578, 410579, 410580, 410581, 410648, 410649, 410650, 410651, 410652, 410653, 410654, 410655 or 410656. 
     In certain embodiments, a target region is nucleotides 6536-6563 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 6536-6563 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 11, 12, 186, 187, 188, 189, 190, 191 or 192. In certain such embodiments, an antisense compound targeted to nucleotides 6536-6563 of SEQ ID NO: 2 is selected from ISIS NOs: 395155, 399794, 399877, 399950, 406008, 406009, 410531, 410532, 410533, 410534, 410535, 410576, 410577, 410578, 410579, 410580, 410581, 410582, 410649, 410650, 410651, 410652, 410653, 410654, 410655, 410656 or 410657. 
     In certain embodiments, a target region is nucleotides 6537-6563 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 6537-6563 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 11, 12, 187, 188, 189, 190, 191 or 192. In certain such embodiments, an antisense compound targeted to nucleotides 6537-6563 of SEQ ID NO: 2 is selected from ISIS NOs: 395155, 399794, 399877, 399950, 406008, 406009, 410532, 410533, 410534, 410535, 410577, 410578, 410579, 410580, 410581, 410582, 410650, 410651, 410652, 410653, 410654, 410655, 410656 or 410657. 
     In certain embodiments, a target region is nucleotides 6538-6565 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 6538-6565 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 12, 187, 188, 189, 190, 191, 192 or 193. In certain such embodiments, an antisense compound targeted to nucleotides 6538-6565 of SEQ ID NO: 2 is selected from ISIS NOs: 399794, 399950, 406008, 406009, 406010, 410532, 410533, 410534, 410535, 410577, 410578, 410579, 410580, 410581, 410582, 410651, 410652, 410653, 410654, 410655, 410656 or 410657. 
     In certain embodiments, a target region is nucleotides 6539-6565 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 6539-6565 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 12, 188, 189, 190, 191, 192 or 193. In certain such embodiments, an antisense compound targeted to nucleotides 6539-6565 of SEQ ID NO: 2 is selected from ISIS NOs: 399794, 399950, 406008, 406009, 406010, 410533, 410534, 410535, 410578, 410579, 410580, 410581, 410582, 410652, 410653, 410654, 410655, 410656 or 410657. 
     In certain embodiments, a target region is nucleotides 6540-6567 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 6540-6567 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 12, 189, 190, 191, 192, 193 or 194. In certain such embodiments, an antisense compound targeted to nucleotides 6540-6567 of SEQ ID NO: 2 is selected from ISIS NOs: 399794, 399950, 406009, 406010, 406011, 410533, 410534, 410535, 410579, 410580, 410581, 410582, 410653, 410654, 410655, 410656 or 410657. 
     In certain embodiments, a target region is nucleotides 6541-6567 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 6541-6567 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 12, 190, 191, 192, 193 or 194. In certain such embodiments, an antisense compound targeted to nucleotides 6541-6567 of SEQ ID NO: 2 is selected from ISIS NOs: 399794, 399950, 406009, 406010, 406011, 410534, 410535, 410580, 410581, 410582, 410654, 410655, 410656 or 410657. 
     In certain embodiments, a target region is nucleotides 6542-6569 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 6542-6569 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 12, 191, 192, 193, 194 or 195. In certain such embodiments, an antisense compound targeted to nucleotides 6542-6569 of SEQ ID NO: 2 is selected from ISIS NOs: 399794, 399950, 406010, 406011, 406012, 410534, 410535, 410581, 410582, 410655, 410656 or 410657. 
     In certain embodiments, a target region is nucleotides 6546-6573 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 6546-6573 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 13, 193, 194, 195 or 196. In certain such embodiments, an antisense compound targeted to nucleotides 6546-6573 of SEQ ID NO: 2 is selected from ISIS NOs: 399795, 399951, 406010, 406011, 406012 or 406013. 
     In certain embodiments, a target region is nucleotides 6557-6584 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 6557-6584 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 14, 197 or 198. In certain such embodiments, an antisense compound targeted to nucleotides 6557-6584 of SEQ ID NO: 2 is selected from ISIS NOs: 395156, 399878, 410749 or 410750. 
     In certain embodiments, a target region is nucleotides 6575-6602 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 6575-6602 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 15 or 198. In certain such embodiments, an antisense compound targeted to nucleotides 6575-6602 of SEQ ID NO: 2 is selected from ISIS NOs: 395157, 399879 or 410750. 
     In certain embodiments, a target region is nucleotides 6585-6611 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 6585-6611 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 16, 199, 200 or 201. In certain such embodiments, an antisense compound targeted to nucleotides 6585-6611 of SEQ ID NO: 2 is selected from ISIS NOs: 399796, 399952, 406014, 406015 or 406016. 
     In certain embodiments, a target region is nucleotides 6594-6621 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 6594-6621 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 202, 203, 204, 205 or 206. In certain such embodiments, an antisense compound targeted to nucleotides 6594-6621 of SEQ ID NO: 2 is selected from ISIS NOs: 406017, 406018, 406019, 406020 or 410730. 
     In certain embodiments, a target region is nucleotides 6596-6623 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 6596-6623 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 203, 204, 205, 206 or 207. In certain such embodiments, an antisense compound targeted to nucleotides 6596-6623 of SEQ ID NO: 2 is selected from ISIS NOs: 406017, 406018, 406019, 406020 or 410731. 
     In certain embodiments, a target region is nucleotides 6652-6671 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 6652-6671 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 108. In certain such embodiments, an antisense compound targeted to nucleotides 6652-6671 of SEQ ID NO: 2 is selected from ISIS NOs: 399842 or 399998. 
     In certain embodiments, a target region is nucleotides 7099-7118 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 7099-7118 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 114. In certain such embodiments, an antisense compound targeted to nucleotides 7099-7118 of SEQ ID NO: 2 is selected from ISIS NOs: 399843 or 399999. 
     In certain embodiments, a target region is nucleotides 7556-7584 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 7556-7584 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 91 or 131. In certain such embodiments, an antisense compound targeted to nucleotides 7556-7584 of SEQ ID NO: 2 is selected from ISIS NOs: 399844, 399845, 400000 or 400001. 
     In certain embodiments, a target region is nucleotides 8836-8855 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 8836-8855 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 145. In certain such embodiments, an antisense compound targeted to nucleotides 8836-8855 of SEQ ID NO: 2 is selected from ISIS NOs: 399846 or 400002. 
     In certain embodiments, a target region is nucleotides 8948-8967 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 8948-8967 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 90. In certain such embodiments, an antisense compound targeted to nucleotides 8948-8967 of SEQ ID NO: 2 is selected from ISIS NOs: 399847 or 400003. 
     In certain embodiments, a target region is nucleotides 9099-9118 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 9099-9118 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 125. In certain such embodiments, an antisense compound targeted to nucleotides 9099-9118 of SEQ ID NO: 2 is selected from ISIS NOs: 399848 or 400004. 
     In certain embodiments, a target region is nucleotides 9099-9168 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 9099-9168 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 17, 125 or 209. In certain such embodiments, an antisense compound targeted to nucleotides 9099-9168 of SEQ ID NO: 2 is selected from ISIS NOs: 395158, 399848, 399880, 400004 or 410752. 
     In certain embodiments, a target region is nucleotides 9130-9168 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 9130-9168 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 17. In certain such embodiments, an antisense compound targeted to nucleotides 9130-9168 of SEQ ID NO: 2 is selected from ISIS NOs: 395158 or 399880. 
     In certain embodiments, a target region is nucleotides 9207-9233 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 9207-9233 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 18, 210, 211, 212 or 213. In certain such embodiments, an antisense compound targeted to nucleotides 9207-9233 of SEQ ID NO: 2 is selected from ISIS NOs: 395159, 399881, 406021, 406022, 406023 or 406024. 
     In certain embodiments, a target region is nucleotides 9207-9235 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 9207-9235 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 18, 210, 211, 212, 213 or 214. In certain such embodiments, an antisense compound targeted to nucleotides 9207-9235 of SEQ ID NO: 2 is selected from ISIS NOs: 395159, 399881, 406021, 406022, 406023, 406024 or 410732. 
     In certain embodiments, a target region is nucleotides 9209-9235 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 9209-9235 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 18, 211, 212, 213 or 214. In certain such embodiments, an antisense compound targeted to nucleotides 9209-9235 of SEQ ID NO: 2 is selected from ISIS NOs: 395159, 399881, 406022, 406023, 406024 or 410732. 
     In certain embodiments, a target region is nucleotides 10252-10271 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 10252-10271 of SEQ ID 5 NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 148. In certain such embodiments, an antisense compound targeted to nucleotides 10252-10271 of SEQ ID NO: 2 is selected from ISIS NOs: 399849 or 400005. 
     In certain embodiments, a target region is nucleotides 10633-10652 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 10633-10652 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 127. In certain such embodiments, an antisense compound targeted to nucleotides 10633-10652 of SEQ ID NO: 2 is selected from ISIS NOs: 395222 or 399944. 
     In certain embodiments, a target region is nucleotides 11308-11491 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 11308-11491 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 79 or 84. In certain such embodiments, an antisense compound targeted to nucleotides 11308-11491 of SEQ ID NO: 2 is selected from ISIS NOs: 395223, 399850, 399945 or 400006. 
     In certain embodiments, a target region is nucleotides 12715-12734 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 12715-12734 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 88. In certain such embodiments, an antisense compound targeted to nucleotides 12715-12734 of SEQ ID NO: 2 is selected from ISIS NOs: 399851 or 400007. 
     In certain embodiments, a target region is nucleotides 12928-12947 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 12928-12947 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 111. In certain such embodiments, an antisense compound targeted to nucleotides 12928-12947 of SEQ ID NO: 2 is selected from ISIS NOs: 399852 or 400008. 
     In certain embodiments, a target region is nucleotides 13681-13700 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 13681-13700 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 85. In certain such embodiments, an antisense compound targeted to nucleotides 13681-13700 of SEQ ID NO: 2 is selected from ISIS NOs: 395201 or 399923. 
     In certain embodiments, a target region is nucleotides 13746-13779 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 13746-13779 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 100 or 116. In certain such embodiments, an antisense compound targeted to nucleotides 13746-13779 of SEQ ID NO: 2 is selected from ISIS NOs: 399827, 399828, 399983 or 399984. 
     In certain embodiments, a target region is nucleotides 13816-13847 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 13816-13847 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 117 or 129. In certain such embodiments, an antisense compound targeted to nucleotides 13816-13847 of SEQ ID NO: 2 is selected from ISIS NOs: 395202, 399829, 399924 or 399985. 
     In certain embodiments, a target region is nucleotides 13903-13945 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 13903-13945 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 81 or 110. In certain such embodiments, an antisense compound targeted to nucleotides 13903-13945 of SEQ ID NO: 2 is selected from ISIS NOs: 395203, 399830, 399925 or 399986. 
     In certain embodiments, a target region is nucleotides 13977-14141 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 13977-14141 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 83, 136, 137, 140 or 152. In certain such embodiments, an antisense compound targeted to nucleotides 13977-14141 of SEQ ID NO: 2 is selected from ISIS NOs: 395204, 395205, 395206, 399831, 399832, 399926, 399927, 399928, 399987 or 399988. 
     In certain embodiments, a target region is nucleotides 14179-14198 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 14179-14198 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 132. In certain such embodiments, an antisense compound targeted to nucleotides 14179-14198 of SEQ ID NO: 2 is selected from ISIS NOs: 395207 or 399929. 
     In certain embodiments, a target region is nucleotides 14267-14286 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 14267-14286 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 139. In certain such embodiments, an antisense compound targeted to nucleotides 14267-14286 of SEQ ID NO: 2 is selected from ISIS NOs: 395208 or 399930. 
     In certain embodiments, a target region is nucleotides 14397-14423 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 14397-14423 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 92 or 142. In certain such embodiments, an antisense compound targeted to nucleotides 14397-14423 of SEQ ID NO: 2 is selected from ISIS NOs: 395209, 399833, 399931 or 399989. 
     In certain embodiments, a target region is nucleotides 14441-14460 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 14441-14460 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 113. In certain such embodiments, an antisense compound targeted to nucleotides 14441-14460 of SEQ ID NO: 2 is selected from ISIS NOs: 395210 or 399932. 
     In certain embodiments, a target region is nucleotides 14494-14513 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 14494-14513 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 138. In certain such embodiments, an antisense compound targeted to nucleotides 14494-14513 of SEQ ID NO: 2 is selected from ISIS NOs: 395211 or 399933. 
     In certain embodiments, a target region is nucleotides 14494-14543 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 14494-14543 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 98 or 138. In certain such embodiments, an antisense compound targeted to nucleotides 14494-14543 of SEQ ID NO: 2 is selected from ISIS NOs: 395211, 395212, 399933 or 399934. 
     In certain embodiments, a target region is nucleotides 14524-14543 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 14524-14543 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 98. In certain such embodiments, an antisense compound targeted to nucleotides 14524-14543 of SEQ ID NO: 2 is selected from ISIS NOs: 395212 or 399934. 
     In certain embodiments, a target region is nucleotides 14601-14650 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 14601-14650 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 96 or 124. In certain such embodiments, an antisense compound targeted to nucleotides 14601-14650 of SEQ ID NO: 2 is selected from ISIS NOs: 395213, 395214, 399935 or 399936. 
     In certain embodiments, a target region is nucleotides 14670-14700 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 14670-14700 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 82, 103 or 133. In certain such embodiments, an antisense compound targeted to nucleotides 14670-14700 of SEQ ID NO: 2 is selected from ISIS NOs: 395215, 395216, 399834, 399937, 399938 or 399990. 
     In certain embodiments, a target region is nucleotides 14675-14700 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 14675-14700 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 103 or 133. In certain such embodiments, an antisense compound targeted to nucleotides 14675-14700 of SEQ ID NO: 2 is selected from ISIS NOs: 395215, 395216, 399937 or 399938. 
     In certain embodiments, a target region is nucleotides 14801-14828 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 14801-14828 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 155 or 156. In certain such embodiments, an antisense compound targeted to nucleotides 14801-14828 of SEQ ID NO: 2 is selected from ISIS NOs: 395217, 399835, 399939 or 399991. 
     In certain embodiments, a target region is nucleotides 14877-14912 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 14877-14912 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 19, 215, 216 or 217. In certain such embodiments, an antisense compound targeted to nucleotides 14877-14912 of SEQ ID NO: 2 is selected from ISIS NOs: 395160, 399882, 406025, 406026 or 410753. 
     In certain embodiments, a target region is nucleotides 14877-14915 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 14877-14915 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 19, 20, 215, 216 or 217. In certain such embodiments, an antisense compound targeted to nucleotides 14877-14915 of SEQ ID NO: 2 is selected from ISIS NOs: 395160, 399797, 399882, 399953, 406025, 406026 or 410753. 
     In certain embodiments, a target region is nucleotides 14877-14973 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 14877-14973 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 19, 20, 21, 22, 23, 24, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, or 233. In certain such embodiments, an antisense compound targeted to nucleotides 14877-14973 of SEQ ID NO: 2 is selected from ISIS NOs: 395160, 395161, 395162, 399797, 399798, 399799, 399882, 399883, 399884, 399953, 399954, 399955, 405869, 405870, 405871, 405872, 405873, 405874, 405875, 405876, 406025, 406026, 406027, 406028, 406029, 406030, 406031, 406032, 410733, 410753, or 410754. 
     In certain embodiments, a target region is nucleotides 14916-14943 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 14916-14943 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 21, 22, 218, 219, 220, 221, 222 or 223. In certain such embodiments, an antisense compound targeted to nucleotides 14916-14943 of SEQ ID NO: 2 is selected from ISIS NOs: 395161, 399798, 399883, 399954, 405869, 405870, 405871, 405872, 405873 or 405874. 
     In certain embodiments, a target region is nucleotides 14916-14973 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 14916-14973 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 21, 22, 23, 24, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, or 223. In certain such embodiments, an antisense compound targeted to nucleotides 14916-14973 of SEQ ID NO: 2 is selected from ISIS NOs: 395161, 395162, 399798, 399799, 399883, 399884, 399954, 399955, 405869, 405870, 405871, 405872, 405873, 405874, 405875, 405876, 406027, 406028, 406029, 406030, 406031, 406032, 410733, or 410754. 
     In certain embodiments, a target region is nucleotides 14925-14951 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 14925-14951 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 224, 225, 226 or 227. In certain such embodiments, an antisense compound targeted to nucleotides 14925-14951 of SEQ ID NO: 2 is selected from ISIS NOs: 405875, 405876, 406027 or 406028. 
     In certain embodiments, a target region is nucleotides 14934-14963 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 14934-14963 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 23, 228, 229, 230, 231 or 232. In certain such embodiments, an antisense compound targeted to nucleotides 14934-14963 of SEQ ID NO: 2 is selected from ISIS NOs: 399799, 399955, 406029, 406030, 406031, 406032 or 410733. 
     In certain embodiments, a target region is nucleotides 14946-14973 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 14946-14973 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 24 or 233. In certain such embodiments, an antisense compound targeted to nucleotides 14946-14973 of SEQ ID NO: 2 is selected from ISIS NOs: 395162, 399884 or 410754. 
     In certain embodiments, a target region is nucleotides 14979-14998 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 14979-14998 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 25. In certain such embodiments, an antisense compound targeted to nucleotides 14979-14998 of SEQ ID NO: 2 is selected from ISIS NOs: 395163 or 399885. 
     In certain embodiments, a target region is nucleotides 15254-15280 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 15254-15280 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 235, 236 or 237. In certain such embodiments, an antisense compound targeted to nucleotides 15254-15280 of SEQ ID NO: 2 is selected from ISIS NOs: 405526, 405604, 406033 or 410756. 
     In certain embodiments, a target region is nucleotides 15254-15328 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 15254-15328 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 26, 27, 28, 235, 236, 237, 238, 239, 240, 241, 242, 243, 243, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, or 447. In certain such embodiments, an antisense compound targeted to nucleotides 15254-15328 of SEQ ID NO: 2 is selected from ISIS NOs: 395164, 395165, 399800, 399886, 399887, 399956, 405526, 405604, 405877, 405878, 405879, 405880, 405881, 405882, 405883, 405884, 406033, 406034, 406035, 406036, 406037, 406038, 409126, 410536, 410537, 410538, 410539, 410583, 410584, 410585, 410586, 410587, 410588, 410589, 410590, 410591, 410592, 410593, 410594, 410595, 410658, 410659, 410660, 410661, 410662, 410663, 410664, 410665, 410666, 410667, 410668, 410669, 410670, 410671, 410756, 410757, or 410758. 
     In certain embodiments, a target region is nucleotides 15264-15290 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 15264-15290 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 26, 27, 238 or 239. In certain such embodiments, an antisense compound targeted to nucleotides 15264-15290 of SEQ ID NO: 2 is selected from ISIS NOs: 395164, 399800, 399886, 399956, 406034, or 406035. 
     In certain embodiments, a target region is nucleotides 15279-15305 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 15279-15305 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 240, 241 or 242. In certain such embodiments, an antisense compound targeted to nucleotides 15279-15305 of SEQ ID NO: 2 is selected from ISIS NOs: 406036, 406037, or 410757. 
     In certain embodiments, a target region is nucleotides 15291-15318 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 15291-15318 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 28, 243, 244, 245, 246, 247, 248, 249, 250, or 447. In certain such embodiments, an antisense compound targeted to nucleotides 15291-15318 of SEQ ID NO: 2 is selected from ISIS NOs: 395165, 399887, 405877, 405878, 405879, 405880, 405881, 406038, 409126, 410536, 410537, 410583, 410584, 410585, 410586, 410587, 410588, 410589, 410590, 410658, 410659, 410660, 410661, 410662, 410663, 410664, 410665, or 410666. 
     In certain embodiments, a target region is nucleotides 15292-15319 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 15292-15319 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 28, 244, 245, 246, 247, 248, 249, 250 or 447. In certain such embodiments, an antisense compound targeted to nucleotides 15292-15319 of SEQ ID NO: 2 is selected from ISIS NOs: 395165, 399887, 405877, 405878, 405879, 405880, 405881, 406038, 409126, 410537, 410584, 410585, 410586, 410587, 410588, 410589, 410590, 410659, 410660, 410661, 410662, 410663, 410664, 410665, or 410666. 
     In certain embodiments, a target region is nucleotides 15293-15320 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 15293-15320 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 28, 245, 246, 247, 248, 249, 250, 251, 252 or 447. In certain such embodiments, an antisense compound targeted to nucleotides 15293-15320 of SEQ ID NO: 2 is selected from ISIS NOs: 395165, 399887, 405877, 405878, 405879, 405880, 405881, 405882, 405883, 406038, 409126, 410585, 410586, 410587, 410588, 410589, 410590, 410591, 410592, 410660, 410661, 410662, 410663, 410664, 410665, 410666, 410667, or 410668. 
     In certain embodiments, a target region is nucleotides 15294-15321 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 15294-15321 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 28, 246, 247, 248, 249, 250, 251, 252, 253 or 447. In certain such embodiments, an antisense compound targeted to nucleotides 15294-15321 of SEQ ID NO: 2 is selected from ISIS NOs: 395165, 399887, 405877, 405878, 405879, 405880, 405881, 405882, 405883, 405884, 409126, 410586, 410587, 410588, 410589, 410590, 410591, 410592, 410593, 410661, 410662, 410663, 410664, 410665, 410666, 410667, 410668 or 410669. 
     In certain embodiments, a target region is nucleotides 15294-15321 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 15294-15321 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 28, 246, 247, 248, 249, 250, 251, 252, 253 or 447. In certain such embodiments, an antisense compound targeted to nucleotides 15294-15321 of SEQ ID NO: 2 is selected from ISIS NOs: 395165, 399887, 405877, 405878, 405879, 405880, 405881, 405882, 405883, 405884, 409126, 410586, 410587, 410588, 410589, 410590, 410591, 410592, 410593, 410661, 410662, 410663, 410664, 410665, 410666, 410667, 410668 or 410669. 
     In certain embodiments, a target region is nucleotides 15295-15322 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 15295-15322 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 28, 247, 248, 249, 250, 250, 251, 252, 253, 254 or 447. In certain such embodiments, an antisense compound targeted to nucleotides 15295-15322 of SEQ ID NO: 2 is selected from ISIS NOs: 395165, 399887, 405878, 405879, 405880, 405881, 405882, 405883, 405884, 409126, 410538, 410587, 410588, 410589, 410590, 410591, 410592, 410593, 410594, 410662, 410663, 410664, 410665, 410666, 410667, 410668, 410669 or 410670. 
     In certain embodiments, a target region is nucleotides 15296-15315 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 15296-15315 of SEQ ID NO: 2. In one such embodiment, an antisense compound targeted to nucleotides 15296-15315 of SEQ ID NO: 2 is ISIS NO: 405879. 
     In certain embodiments, a target region is nucleotides 15296-15323 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 15296-15323 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 28, 248, 249, 250, 251, 252, 253, 254, 255 or 447. In certain such embodiments, an antisense compound targeted to nucleotides 15296-15323 of SEQ ID NO: 2 is selected from ISIS NOs: 395165, 399887, 405879, 405880, 405881, 405882, 405883, 405884, 409126, 410538, 410539, 410588, 410589, 410590, 410591, 410592, 410593, 410594, 410595, 410663, 410664, 410665, 410666, 410667, 410668, 410669, 410670 or 410671. 
     In certain embodiments, a target region is nucleotides 15297-15323 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 15297-15323 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 28, 249, 250, 251, 252, 253, 254, 255 or 447. In certain such embodiments, an antisense compound targeted to nucleotides 15297-15323 of SEQ ID NO: 2 is selected from ISIS NOs: 395165, 399887, 405880, 405881, 405882, 405883, 405884, 409126, 410538, 410539, 410589, 410590, 410591, 410592, 410593, 410594, 410595, 410664, 410665, 410666, 410667, 410668, 410669, 410670 or 410671. 
     In certain embodiments, a target region is nucleotides 15298-15323 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 15298-15323 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 28, 250, 251, 252, 253, 254, 255 or 447. In certain such embodiments, an antisense compound targeted to nucleotides 15298-15323 of SEQ ID NO: 2 is selected from ISIS NOs: 395165, 399887, 405881, 405882, 405883, 405884, 409126, 410538, 410539, 410590, 410591, 410592, 410593, 410594, 410595, 410665, 410666, 410667, 410668, 410669, 410670 or 410671. 
     In certain embodiments, a target region is nucleotides 15299-15323 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 15299-15323 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 250, 251, 252, 253, 254 or 255. In certain such embodiments, an antisense compound targeted to nucleotides 15299-15323 of SEQ ID NO: 2 is selected from ISIS NOs: 405881, 405882, 405883, 405884, 410538, 410539, 410590, 410591, 410592, 410593, 410594, 410595, 410666, 410667, 410668, 410669, 410670 or 410671. 
     In certain embodiments, a target region is nucleotides 15300-15323 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 15300-15323 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 251, 252, 253, 254 or 255. In certain such embodiments, an antisense compound targeted to nucleotides 15300-15323 of SEQ ID NO: 2 is selected from ISIS NOs: 405882, 405883, 405884, 410538, 410539, 410591, 410592, 410593, 410594, 410595, 410667, 410668, 410669, 410670 or 410671. 
     In certain embodiments, a target region is nucleotides 15301-15328 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 15301-15328 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 252, 253, 254, 255 or 256. In certain such embodiments, an antisense compound targeted to nucleotides 15301-15328 of SEQ ID NO: 2 is selected from ISIS NOs: 405883, 405884, 410538, 410539, 410592, 410593, 410594, 410595, 410668, 410669, 410670, 410671 or 410758. 
     In certain embodiments, a target region is nucleotides 15330-15355 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 15330-15355 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 29, 257, 258 or 259. In certain such embodiments, an antisense compound targeted to nucleotides 15330-15355 of SEQ ID NO: 2 is selected from ISIS NOs: 395166, 399888, 406039, 406040 or 406041. 
     In certain embodiments, a target region is nucleotides 15330-15490 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 15330-15490 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 29, 30, 86, 257, 258, 259, 260, 261, 262 or 263. In certain such embodiments, an antisense compound targeted to nucleotides 15330-15490 of SEQ ID NO: 2 is selected from ISIS NOs: 395166, 399801, 399853, 399888, 399957, 400009, 406039, 406040, 406041, 406042, 406043, 406044 or 410759. 
     In certain embodiments, a target region is nucleotides 15339-15366 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 15339-15366 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 30, 260, 261 or 262. In certain such embodiments, an antisense compound targeted to nucleotides 15339-15366 of SEQ ID NO: 2 is selected from ISIS NOs: 399801, 399957, 406042, 406043 or 406044. 
     In certain embodiments, a target region is nucleotides 15358-15490 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 15358-15490 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 86 or 263. In certain such embodiments, an antisense compound targeted to nucleotides 15358-15490 of SEQ ID NO: 2 is selected from ISIS NOs: 399853, 400009 or 410759. 
     In certain embodiments, a target region is nucleotides 16134-16153 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 16134-16153 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 97. In certain such embodiments, an antisense compound targeted to nucleotides 16134-16153 of SEQ ID NO: 2 is selected from ISIS NOs: 399854 or 400010. 
     In certain embodiments, a target region is nucleotides 16668-16687 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 16668-16687 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 120. In certain such embodiments, an antisense compound targeted to nucleotides 16668-16687 of SEQ ID NO: 2 is selected from ISIS NOs: 399855 or 400011. 
     In certain embodiments, a target region is nucleotides 17267-17286 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 17267-17286 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 150. In certain such embodiments, an antisense compound targeted to nucleotides 17267-17286 of SEQ ID NO: 2 is selected from ISIS NOs: 399856 or 400012. 
     In certain embodiments, a target region is nucleotides 18377-18427 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 18377-18427 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 115 or 134. In certain such embodiments, an antisense compound targeted to nucleotides 18377-18427 of SEQ ID NO: 2 is selected from ISIS NOs: 399857, 399858, 400013 or 400014. 
     In certain embodiments, a target region is nucleotides 18561-18580 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 18561-18580 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 157. In certain such embodiments, an antisense compound targeted to nucleotides 18561-18580 of SEQ ID NO: 2 is selected from ISIS NOs: 395224 or 399946. 
     In certain embodiments, a target region is nucleotides 18591-18618 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 18591-18618 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 32, 266, 267, 268 or 269. In certain such embodiments, an antisense compound targeted to nucleotides 18591-18618 of SEQ ID NO: 2 is selected from ISIS NOs: 395168, 399890, 405909, 405910, 405911 or 406045. 
     In certain embodiments, a target region is nucleotides 18591-18646 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 18591-18646 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 32, 32, 266, 267, 268, 269, 270, 271 or 272. In certain such embodiments, an antisense compound targeted to nucleotides 18591-18646 of SEQ ID NO: 2 is selected from ISIS NOs: 395168, 399890, 405909, 405910, 405911, 405912, 406045, 410761 or 410762. 
     In certain embodiments, a target region is nucleotides 18591-18668 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 18591-18668 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 32, 266, 267, 268, 269, 270, 271, 272 or 273. In certain such embodiments, an antisense compound targeted to nucleotides 18591-18668 of SEQ ID NO: 2 is selected from ISIS NOs: 395168, 399890, 405909, 405910, 405911, 405912, 406045, 410761, 410762 or 410763. 
     In certain embodiments, a target region is nucleotides 18695-18746 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 18695-18746 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 33, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284 or 285. In certain such embodiments, an antisense compound targeted to nucleotides 18695-18746 of SEQ ID NO: 2 is selected from ISIS NOs: 395169, 399891, 405913, 405914, 405915, 405916, 405917, 405918, 405919, 405920, 405921, 405922, 410734 or 410764. 
     In certain embodiments, a target region is nucleotides 18705-18730 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 18705-18730 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 33, 275, 276 or 277. In certain such embodiments, an antisense compound targeted to nucleotides 18705-18730 of SEQ ID NO: 2 is selected from ISIS NOs: 395169, 399891, 405913, 405914 or 405915. 
     In certain embodiments, a target region is nucleotides 18709-18736 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 18709-18736 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 276, 277, 278, 279 or 280. In certain such embodiments, an antisense compound targeted to nucleotides 18709-18736 of SEQ ID NO: 2 is selected from ISIS NOs: 405914, 405915, 405916, 405917 or 410734. 
     In certain embodiments, a target region is nucleotides 18719-18746 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 18719-18746 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 281, 282, 283, 284 or 285. In certain such embodiments, an antisense compound targeted to nucleotides 18719-18746 of SEQ ID NO: 2 is selected from ISIS NOs: 405918, 405919, 405920, 405921 or 405922. 
     In certain embodiments, a target region is nucleotides 19203-20080 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 19203-20080 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 34, 35, 36, 37, 38, 39, 40, 41, 105, 128, 149, 151, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317 or 318. In certain such embodiments, an antisense compound targeted to nucleotides 19203-20080 of SEQ ID NO: 2 is selected from ISIS NOs: 395170, 395171, 395172, 395173, 395174, 395175, 399802, 399803, 399804, 399805, 399859, 399860, 399892, 399893, 399894, 399895, 399896, 399897, 399958, 399959, 399960, 399961, 400015, 400016, 405923, 405924, 405925, 405926, 405927, 405928, 405929, 405930, 405931, 405932, 405933, 405934, 405935, 405936, 405937, 405938, 405939, 405940, 405941, 405942, 405943, 405944, 405945, 405946, 405947, 410735, 410736, 410737, 410767, 410768 or 410769. 
     In certain embodiments, a target region is nucleotides 19931-19952 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 19931-19952 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 149 or 188. In certain such embodiments, an antisense compound targeted to nucleotides 19931-19952 of SEQ ID NO: 2 is selected from ISIS NOs: 395170, 399892 or 405923. 
     In certain embodiments, a target region is nucleotides 19954-19981 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 19954-19981 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 34, 290, 291, 292 or 293. In certain such embodiments, an antisense compound targeted to nucleotides 19954-19981 of SEQ ID NO: 2 is selected from ISIS NOs: 395171, 399893, 405924, 405925, 405926 or 410735. 
     In certain embodiments, a target region is nucleotides 19964-19990 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 19964-19990 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 35, 128, 128, 294 or 295. In certain such embodiments, an antisense compound targeted to nucleotides 19964-19990 of SEQ ID NO: 2 is selected from ISIS NOs: 395172, 399802, 399894, 399958, 405927 or 405928. 
     In certain embodiments, a target region is nucleotides 19973-19999 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 19973-19999 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 36, 296, 297 or 298. In certain such embodiments, an antisense compound targeted to nucleotides 19973-19999 of SEQ ID NO: 2 is selected from ISIS NOs: 395173, 399895, 405929, 405930 or 405931. 
     In certain embodiments, a target region is nucleotides 19982-20009 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 19982-20009 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 37, 299, 300, 301 or 302. In certain such embodiments, an antisense compound targeted to nucleotides 19982-20009 of SEQ ID NO: 2 is selected from ISIS NOs: 399803, 399959, 405932, 405933, 405934 or 405935. 
     In certain embodiments, a target region is nucleotides 19992-20016 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 19992-20016 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 38, 303 or 304. In certain such embodiments, an antisense compound targeted to nucleotides 19992-20016 of SEQ ID NO: 2 is selected from ISIS NOs: 395174, 399896, 405936 or 410736. 
     In certain embodiments, a target region is nucleotides 20016-20042 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 20016-20042 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 305 or 306. In certain such embodiments, an antisense compound targeted to nucleotides 20016-20042 of SEQ ID NO: 2 is selected from ISIS NOs: 405937 or 410768. 
     In certain embodiments, a target region is nucleotides 20025-20052 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 20025-20052 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 39, 307, 308, 309 or 310. In certain such embodiments, an antisense compound targeted to nucleotides 20025-20052 of SEQ ID NO: 2 is selected from ISIS NOs: 395175, 399897, 405938, 405939, 405940 or 405941. 
     In certain embodiments, a target region is nucleotides 20036-20062 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 20036-20062 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 40, 311, 312, 313 or 314. In certain such embodiments, an antisense compound targeted to nucleotides 20036-20062 of SEQ ID NO: 2 is selected from ISIS NOs: 399804, 399960, 405942, 405943, 405944 or 410737. 
     In certain embodiments, a target region is nucleotides 20045-20070 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 20045-20070 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 41, 315, 316 or 317. In certain such embodiments, an antisense compound targeted to nucleotides 20045-20070 of SEQ ID NO: 2 is selected from ISIS NOs: 399805, 399961, 405945, 405946 or 405947. 
     In certain embodiments, a target region is nucleotides 20100-20119 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 20100-20119 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 158. In certain such embodiments, an antisense compound targeted to nucleotides 20100-20119 of SEQ ID NO: 2 is selected from ISIS NOs: 399861 or 400017. 
     In certain embodiments, a target region is nucleotides 20188-20207 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 20188-20207 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 109. In certain such embodiments, an antisense compound targeted to nucleotides 20188-20207 of SEQ ID NO: 2 is selected from ISIS NOs: 399862 or 400018. 
     In certain embodiments, a target region is nucleotides 20624-20650 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 20624-20650 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 141, 320 or 321. In certain such embodiments, an antisense compound targeted to nucleotides 20624-20650 of SEQ ID NO: 2 is selected from ISIS NOs: 399863, 400019, 405949 or 405950. 
     In certain embodiments, a target region is nucleotides 20624-20759 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 20624-20759 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 43, 44, 45, 46, 47, 48, 49, 50, 51, 87, 141, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358 or 359. In 5 certain such embodiments, an antisense compound targeted to nucleotides 20624-20759 of SEQ ID NO: 2 is selected from ISIS NOs: 395177, 395178, 395179, 399807, 399808, 399809, 399810, 399811, 399812, 399813, 399863, 399899, 399900, 399901, 399963, 399964, 399965, 399966, 399967, 399968, 399969, 400019, 405557, 405885, 405886, 405887, 405888, 405889, 405890, 405891, 405892, 405949, 405950, 405951, 405952, 405953, 405954, 405955, 405956, 405957, 405958, 405959, 405960, 405961, 405962, 405963, 405964, 405965, 405966, 405967, 405968, 405969, 405970, 405971, 405972, 405973, 405974, 408653, 410540, 410596, 410597, 410598, 410599, 410600, 410601, 410602, 410603, 410604, 410672, 410673, 410674, 410675, 410676, 410677, 410678, 410679, 410680, 410681, 410682, 410738, 410739, 410740 or 410770. 
     In certain embodiments, a target region is nucleotides 20629-20804 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 20629-20804 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 43, 44, 45, 46, 47, 48, 49, 50, 51, 87, 119, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 356, 357, 358, 359 or 360. In certain such embodiments, an antisense compound targeted to nucleotides 20629-20804 of SEQ ID NO: 2 is selected from ISIS NOs: 395177, 395178, 395179, 395180, 399807, 399808, 399809, 399810, 399811, 399812, 399813, 399899, 399900, 399901, 399902, 399963, 399964, 399965, 399966, 399967, 399968, 399969, 405557, 405885, 405886, 405887, 405888, 405889, 405890, 405891, 405892, 405949, 405950, 405951, 405952, 405953, 405954, 405955, 405956, 405957, 405958, 405959, 405960, 405961, 405962, 405963, 405964, 405965, 405966, 405967, 405968, 405969, 405970, 405971, 405972, 405973, 405974, 408653, 410540, 410596, 410597, 410598, 410599, 410600, 410601, 410602, 410603, 410604, 410672, 410673, 410674, 410675, 410676, 410677, 410678, 410679, 410680, 410681, 410682, 410738, 410739, 410740, 410770 or 410771. 
     In certain embodiments, a target region is nucleotides 20633-20660 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 20633-20660 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 43, 322, 323, 324 or 325. In certain such embodiments, an antisense compound targeted to nucleotides 20633-20660 of SEQ ID NO: 2 is selected from ISIS NOs: 399807, 399963, 405951, 405952, 405953 or 410738. 
     In certain embodiments, a target region is nucleotides 20635-20781 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 20635-20781 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 43, 44, 45, 46, 47, 48, 49, 50, 51, 87, 119, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358 or 359. In certain such embodiments, an antisense compound targeted to nucleotides 20635-20781 of SEQ ID NO: 2 is selected from ISIS NOs: 395177, 395178, 395179, 395180, 399807, 399808, 399809, 399810, 399811, 399812, 399813, 399899, 399900, 399901, 399902, 399963, 399964, 399965, 399966, 399967, 399968, 399969, 405557, 405885, 405886, 405887, 405888, 405889, 405890, 405891, 405892, 405952, 405953, 405954, 405955, 405956, 405957, 405958, 405959, 405960, 405961, 405962, 405963, 405964, 405965, 405966, 405967, 405968, 405969, 405970, 405971, 405972, 405973, 405974, 408653, 410540, 410596, 410597, 410598, 410599, 410600, 410601, 410602, 410603, 410604, 410672, 410673, 410674, 410675, 410676, 410677, 410678, 410679, 410680, 410681, 410682, 410738, 410739, 410740 or 410770. 
     In certain embodiments, a target region is nucleotides 20643-20662 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 20643-20662 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 326. In certain such embodiments, an antisense compound targeted to nucleotides 20643-20662 of SEQ ID NO: 2 is selected from ISIS NOs: 405954. 
     In certain embodiments, a target region is nucleotides 20657-20676 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 20657-20676 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 327. In certain such embodiments, an antisense compound targeted to nucleotides 20657-20676 of SEQ ID NO: 2 is selected from ISIS NOs: 410770. 
     In certain embodiments, a target region is nucleotides 20670-20697 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 20670-20697 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 328, 329, 330, 331 or 332. In certain such embodiments, an antisense compound targeted to nucleotides 20670-20697 of SEQ ID NO: 2 is selected from ISIS NOs: 405955, 405956, 405957, 405958 or 405959. 
     In certain embodiments, a target region is nucleotides 20680-20706 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 20680-20706 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 44, 333, 334, 335 or 336. In certain such embodiments, an antisense compound targeted to nucleotides 20680-20706 of SEQ ID NO: 2 is selected from ISIS NOs: 399808, 399964, 405960, 405961, 405962 or 410739. 
     In certain embodiments, a target region is nucleotides 20683-20781 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 20683-20781 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 44, 45, 46, 47, 48, 49, 50, 51, 87, 119, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358 or 359. In certain such embodiments, an antisense compound targeted to nucleotides 20683-20781 of SEQ ID NO: 2 is selected from ISIS NOs: 395177, 395178, 395179, 395180, 399808, 399809, 399810, 399811, 399812, 399813, 399899, 399900, 399901, 399902, 399964, 399965, 399966, 399967, 399968, 399969, 405557, 405885, 405886, 405887, 405888, 405889, 405890, 405891, 405892, 405962, 405963, 405964, 405965, 405966, 405967, 405968, 405969, 405970, 405971, 405972, 405973, 405974, 408653, 410540, 410596, 410597, 410598, 410599, 410600, 410601, 410602, 410603, 410604, 410672, 410673, 410674, 410675, 410676, 410677, 410678, 410679, 410680, 410681, 410682, 410739 or 410740. 
     In certain embodiments, a target region is nucleotides 20689-20715 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 20689-20715 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 45, 46, 337 or 338. In certain such embodiments, an antisense compound targeted to nucleotides 20689-20715 of SEQ ID NO: 2 is selected from ISIS NOs: 395177, 399809, 399899, 399965, 405963 or 405964. 
     In certain embodiments, a target region is nucleotides 20698-20725 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 20698-20725 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 47, 47, 339, 340, 341 or 342. In certain such embodiments, an antisense compound targeted to nucleotides 20698-20725 of SEQ ID NO: 2 is selected from ISIS NOs: 399810, 399966, 405965, 405966, 405967 or 405968. 
     In certain embodiments, a target region is nucleotides 20709-20736 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 20709-20736 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 48, 48, 343, 344, 345 or 346. In certain such embodiments, an antisense compound targeted to nucleotides 20709-20736 of SEQ ID NO: 2 is selected from ISIS NOs: 399811, 399967, 405885, 405969, 405970 or 410740. 
     In certain embodiments, a target region is nucleotides 20717-20744 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 20717-20744 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 49, 346, 347, 348, 349, 350, 351, 352 or 353. In certain such embodiments, an antisense compound targeted to nucleotides 20717-20744 of SEQ ID NO: 2 is selected from ISIS NOs: 399812, 399968, 405885, 405886, 405887, 405888, 405889, 405890, 405891, 405892, 410596, 410597, 410598, 410599, 410600, 410601, 410672, 410673, 410674, 410675, 410676, 410677 or 410678. 
     In certain embodiments, a target region is nucleotides 20718-20745 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 20718-20745 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 49, 50, 347, 348, 349, 350, 351, 352 or 353. In certain such embodiments, an antisense compound targeted to nucleotides 20718-20745 of SEQ ID NO: 2 is selected from ISIS NOs: 395178, 399812, 399900, 399968, 405557, 405886, 405887, 405888, 405889, 405890, 405891, 405892, 410596, 410597, 410598, 410599, 410600, 410601, 410672, 410673, 410674, 410675, 410676, 410677, 410678 or 410679. 
     In certain embodiments, a target region is nucleotides 20719-20746 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 20719-20746 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 49, 50, 348, 349, 350, 351, 352, 353 or 354. In certain such embodiments, an antisense compound targeted to nucleotides 20719-20746 of SEQ ID NO: 2 is selected from ISIS NOs: 395178, 399812, 399900, 399968, 405557, 405887, 405888, 405889, 405890, 405891, 405892, 408653, 410596, 410597, 410598, 410599, 410600, 410601, 410602, 410672, 410673, 410674, 410675, 410676, 410677, 410678, 410679 or 410680. 
     In certain embodiments, a target region is nucleotides 20720-20747 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 20720-20747 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 49, 50, 349, 350, 351, 352, 353, 354 or 355. In certain such embodiments, an antisense compound targeted to nucleotides 20720-20747 of SEQ ID NO: 2 is selected from ISIS NOs: 395178, 399812, 399900, 399968, 405557, 405888, 405889, 405890, 405891, 405892, 405971, 408653, 410597, 410598, 410599, 410600, 410601, 410602, 410603, 410673, 410674, 410675, 410676, 410677, 410678, 410679, 410680 or 410681. 
     In certain embodiments, a target region is nucleotides 20721-20748 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 20721-20748 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 49, 50, 350, 351, 352, 353, 354, 355 or 356. In certain such embodiments, an antisense compound targeted to nucleotides 20721-20748 of SEQ ID NO: 2 is selected from ISIS NOs: 395178, 399812, 399900, 399968, 405557, 405889, 405890, 405891, 405892, 405971, 408653, 410540, 410598, 410599, 410600, 410601, 410602, 410603, 410604, 410674, 410675, 410676, 410677, 410678, 410679, 410680, 410681 or 410682. 
     In certain embodiments, a target region is nucleotides 20722-20749 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 20722-20749 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 50, 350, 351, 352, 353, 354, 355, 356 or 357. In certain such embodiments, an antisense compound targeted to nucleotides 20722-20749 of SEQ ID NO: 2 is selected from ISIS NOs: 395178, 399900, 405557, 405889, 405890, 405891, 405892, 405971, 405972, 408653, 410540, 410598, 410599, 410600, 410601, 410602, 410603, 410604, 410675, 410676, 410677, 410678, 410679, 410680, 410681 or 410682. 
     In certain embodiments, a target region is nucleotides 20727-20752 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 20727-20752 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 87, 354, 355, 356 or 357. In certain such embodiments, an antisense compound targeted to nucleotides 20727-20752 of SEQ ID NO: 2 is selected from ISIS NOs: 395179, 399901, 405971, 405972, 408653, 410540, 410602, 410603, 410604, 410680, 410681 or 410682. 
     In certain embodiments, a target region is nucleotides 20735-20759 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 20735-20759 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 51, 358 or 359. In certain such embodiments, an antisense compound targeted to nucleotides 20735-20759 of SEQ ID NO: 2 is selected from ISIS NOs: 399813, 399969, 405973 or 405974. 
     In certain embodiments, a target region is nucleotides 20762-21014 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 20762-21014 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 93, 119 or 360. In certain such embodiments, an antisense compound targeted to nucleotides 20762-21014 of SEQ ID NO: 2 is selected from ISIS NOs: 395180, 399864, 399902, 400020 or 410771. 
     In certain embodiments, a target region is nucleotides 20785-21014 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 20785-21014 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 93 or 360. In certain such embodiments, an antisense compound targeted to nucleotides 20785-21014 of SEQ ID NO: 2 is selected from ISIS NOs: 399864, 400020 or 410771. 
     In certain embodiments, a target region is nucleotides 21082-21107 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 21082-21107 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 95 or 361. In certain such embodiments, an antisense compound targeted to nucleotides 21082-21107 of SEQ ID NO: 2 is selected from ISIS NOs: 399865, 400021 or 405975. 
     In certain embodiments, a target region is nucleotides 21082-21152 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 21082-21152 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 53, 54, 95, 361, 362, 363, 364, 365, 366, 367, 368, 369, 370 or 371. In certain such embodiments, an antisense compound targeted to nucleotides 21082-21152 of SEQ ID NO: 2 is selected from ISIS NOs: 395182, 399814, 399865, 399904, 399970, 400021, 405975, 405976, 405977, 405978, 405979, 405980, 405981, 405982, 405983, 410741 or 410772. 
     In certain embodiments, a target region is nucleotides 21091-21114 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 21091-21114 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 53, 362 or 363. In certain such embodiments, an antisense compound targeted to nucleotides 21091-21114 of SEQ ID NO: 2 is selected from ISIS NOs: 399814, 399970, 405976 or 405977. 
     In certain embodiments, a target region is nucleotides 21118-21144 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 21118-21144 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 54, 365, 366 or 367. In certain such embodiments, an antisense compound targeted to nucleotides 21118-21144 of SEQ ID NO: 2 is selected from ISIS NOs: 395182, 399904, 405978, 405979 or 405980. 
     In certain embodiments, a target region is nucleotides 21127-21152 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 21127-21152 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 368, 369, 370 or 371. In certain such embodiments, an antisense compound targeted to nucleotides 21127-21152 of SEQ ID NO: 2 is selected from ISIS NOs: 405981, 405982, 405983 or 410741. 
     In certain embodiments, a target region is nucleotides 21181-21209 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 21181-21209 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 55, 372, 373, 374 or 375. In certain such embodiments, an antisense compound targeted to nucleotides 21181-21209 of SEQ ID NO: 2 is selected from ISIS NOs: 399815, 399971, 405564, 405641, 405984, 405985, 405986 or 405987. 
     In certain embodiments, a target region is nucleotides 21181-21211 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 21181-21211 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 55, 56, 372, 373, 374 or 375. In certain such embodiments, an antisense compound targeted to nucleotides 21181-21211 of SEQ ID NO: 2 is selected from ISIS NOs: 399815, 399816, 399971, 399972, 405564, 405641, 405984, 405985, 405986 or 405987. 
     In certain embodiments, a target region is nucleotides 21183-21211 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 21183-21211 of SEQ ID 5 NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 55, 56, 373, 374 or 375. In certain such embodiments, an antisense compound targeted to nucleotides 21183-21211 of SEQ ID NO: 2 is selected from ISIS NOs: 399815, 399816, 399971, 399972, 405564, 405641, 405985, 405986 or 405987. 
     In certain embodiments, a target region is nucleotides 21481-21500 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 21481-21500 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 143. In certain such embodiments, an antisense compound targeted to nucleotides 21481-21500 of SEQ ID NO: 2 is selected from ISIS NOs: 399866 or 400022. 
     In certain embodiments, a target region is nucleotides 21589-21608 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 21589-21608 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 89. In certain such embodiments, an antisense compound targeted to nucleotides 21589-21608 of SEQ ID NO: 2 is selected from ISIS NOs: 399867 or 400023. 
     In certain embodiments, a target region is nucleotides 21692-21719 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 21692-21719 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 123, 448, 449, 450, 451, 452, 453, 454 or 455. In certain such embodiments, an antisense compound targeted to nucleotides 21692-21719 of SEQ ID NO: 2 is selected from ISIS NOs: 399868, 400024, 406478, 406479, 406480, 406481, 406482, 406483, 406484 or 406485. 
     In certain embodiments, a target region is nucleotides 22000-22227 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 22000-22227 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 59, 389, 390, 391, 392, 393, 394, 395 or 396. In certain such embodiments, an antisense compound targeted to nucleotides 22000-22227 of SEQ ID NO: 2 is selected from ISIS NOs: 395185, 399907, 405991, 405992, 410550, 410551, 410552, 410553, 410554, 410555, 410616, 410617, 410618, 410619, 410620, 410621, 410622, 410623, 410695, 410696, 410697, 410698, 410699, 410700, 410701, 410702 or 410703. 
     In certain embodiments, a target region is nucleotides 22096-22115 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 22096-22115 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 57. In certain such embodiments, an antisense compound targeted to nucleotides 22096-22115 of SEQ ID NO: 2 is selected from ISIS NOs: 395183 or 399905. 
     In certain embodiments, a target region is nucleotides 22096-22223 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 22096-22223 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 57, 58, 59, 376, 377, 378, 379, 380, 381, 382, 383, 384, 385, 386, 387, 388, 389, 390, 391 or 392. In certain such embodiments, an antisense compound targeted to nucleotides 22096-22223 of SEQ ID NO: 2 is selected from ISIS NOs: 395183, 395184, 395185, 399905, 399906, 399907, 405988, 405989, 405990, 410541, 410542, 410543, 410544, 410545, 410546, 410547, 410548, 410549, 410550, 410551, 410552, 410553, 410605, 410606, 410607, 410608, 410609, 410610, 410611, 410612, 410613, 410614, 410615, 410616, 410617, 410618, 410619, 410683, 410684, 410685, 410686, 410687, 410688, 410689, 410690, 410691, 410692, 410693, 410694, 410695, 410696, 410697, 410698, 410699 or 410773. 
     In certain embodiments, a target region is nucleotides 22096-22311 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 22096-22311 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 57, 58, 59, 126, 126, 376, 377, 378, 379, 380, 381, 382, 383, 384, 385, 386, 387, 388, 389, 390, 391, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 401, 401, 402, 402, 402, 403, 403, 403, 404, 404, 404, 405, 405, 405 or 406. In certain such embodiments, an antisense compound targeted to nucleotides 22096-22311 of SEQ ID NO: 2 is selected from ISIS NOs: 395183, 395184, 395185, 395225, 399905, 399906, 399907, 399947, 405988, 405989, 405990, 405991, 405992, 405993, 405994, 405995, 410541, 410542, 410543, 410544, 410545, 410546, 410547, 410548, 410549, 410550, 410551, 410552, 410553, 410554, 410555, 410556, 410557, 410558, 410559, 410560, 410561, 410605, 410606, 410607, 410608, 410609, 410610, 410611, 410612, 410613, 410614, 410615, 410616, 410617, 410618, 410619, 410620, 410621, 410622, 410623, 410624, 410625, 410626, 410627, 410628, 410629, 410630, 410631, 410632, 410683, 410684, 410685, 410686, 410687, 410688, 410689, 410690, 410691, 410692, 410693, 410694, 410695, 410696, 410697, 410698, 410699, 410700, 410701, 410702, 410703, 410704, 410705, 410706, 410707, 410708, 410709, 410710, 410711, 410712, 410773 or 410774. 
     In certain embodiments, a target region is nucleotides 22133-22160 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 22133-22160 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 376, 377, 378, 379, 380, 381, 382, 383 or 384. In certain such embodiments, an antisense compound targeted to nucleotides 22133-22160 of SEQ ID NO: 2 is selected from ISIS NOs: 405988, 405989, 410541, 410542, 410543, 410544, 410545, 410546, 410547, 410605, 410606, 410607, 410608, 410609, 410610, 410611, 410612, 410613, 410683, 410684, 410685, 410686, 410687, 410688, 410689, 410690 or 410691. 
     In certain embodiments, a target region is nucleotides 22133-22163 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 22133-22163 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 58, 376, 377, 378, 379, 380, 381, 382, 383, 384, 385 or 386. In certain such embodiments, an antisense compound targeted to nucleotides 22133-22163 of SEQ ID NO: 2 is selected from ISIS NOs: 395184, 399906, 405988, 405989, 405990, 410541, 410542, 410543, 410544, 410545, 410546, 410547, 410548, 410605, 410606, 410607, 410608, 410609, 410610, 410611, 410612, 410613, 410614, 410683, 410684, 410685, 410686, 410687, 410688, 410689, 410690, 410691, 410692 or 410693. 
     In certain embodiments, a target region is nucleotides 22134-22161 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 22134-22161 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 58, 377, 378, 379, 380, 381, 382, 383 or 384. In certain such embodiments, an antisense compound targeted to nucleotides 22134-22161 of SEQ ID NO: 2 is selected from ISIS NOs: 395184, 399906, 405988, 405989, 410542, 410543, 410544, 410545, 410546, 410547, 410606, 410607, 410608, 410609, 410610, 410611, 410612, 410613, 410684, 410685, 410686, 410687, 410688, 410689, 410690, 410691 or 410692. 
     In certain embodiments, a target region is nucleotides 22135-22162 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 22135-22162 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 58, 378, 379, 380, 381, 382, 383, 384 or 385. In certain such embodiments, an antisense compound targeted to nucleotides 22135-22162 of SEQ ID NO: 2 is selected from ISIS NOs: 395184, 399906, 405988, 405989, 410543, 410544, 410545, 410546, 410547, 410548, 410607, 410608, 410609, 410610, 410611, 410612, 410613, 410614, 410685, 410686, 410687, 410688, 410689, 410690, 410691, 410692 or 410693. 
     In certain embodiments, a target region is nucleotides 22136-22163 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 22136-22163 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 58, 379, 380, 381, 382, 383, 384, 385 or 386. In certain such embodiments, an antisense compound targeted to nucleotides 22136-22163 of SEQ ID NO: 2 is selected from ISIS NOs: 395184, 399906, 405988, 405989, 405990, 410544, 410545, 410546, 410547, 410548, 410608, 410609, 410610, 410611, 410612, 410613, 410614, 410686, 410687, 410688, 410689, 410690, 410691, 410692 or 410693. 
     In certain embodiments, a target region is nucleotides 22137-22163 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 22137-22163 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 58, 380, 381, 382, 383, 384, 385 or 386. In certain such embodiments, an antisense compound targeted to nucleotides 22137-22163 of SEQ ID NO: 2 is selected from ISIS NOs: 395184, 399906, 405988, 405989, 405990, 410545, 410546, 410547, 410548, 410609, 410610, 410611, 410612, 410613, 410614, 410687, 410688, 410689, 410690, 410691, 410692 or 410693. 
     In certain embodiments, a target region is nucleotides 22138-22163 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 22138-22163 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 58, 381, 382, 383, 384, 385 or 386. In certain such embodiments, an antisense compound targeted to nucleotides 22138-22163 of SEQ ID NO: 2 is selected from ISIS NOs: 395184, 399906, 405988, 405989, 405990, 410546, 410547, 410548, 410610, 410611, 410612, 410613, 410614, 410688, 410689, 410690, 410691, 410692 or 410693. 
     In certain embodiments, a target region is nucleotides 22189-22239 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 22189-22239 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 59, 387, 388, 389, 390, 391, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405 or 406. In certain such embodiments, an antisense compound targeted to nucleotides 22189-22239 of SEQ ID NO: 2 is selected from ISIS NOs: 395185, 399907, 405991, 405992, 405993, 405994, 405995, 410549, 410550, 410551, 410552, 410553, 410554, 410555, 410556, 410557, 410558, 410559, 410560, 410561, 410615, 410616, 410617, 410618, 410619, 410620, 410621, 410622, 410623, 410624, 410625, 410626, 410627, 410628, 410629, 410630, 410631, 410632, 410694, 410695, 410696, 410697, 410698, 410699, 410700, 410701, 410702, 410703, 410704, 410705, 410706, 410707, 410708, 410709, 410710, 410711, 410712, 410773 or 410774. 
     In certain embodiments, a target region is nucleotides 22199-22226 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 22199-22226 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 59, 388, 389, 390, 391, 392, 393, 394 or 395. In certain such embodiments, an antisense compound targeted to nucleotides 22199-22226 of SEQ ID NO: 2 is selected from ISIS NOs: 395185, 399907, 405991, 410549, 410550, 410551, 410552, 410553, 410554, 410555, 410615, 410616, 410617, 410618, 410619, 410620, 410621, 410622, 410694, 410695, 410696, 410697, 410698, 410699, 410700, 410701 or 410702. 
     In certain embodiments, a target region is nucleotides 22199-22227 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 22199-22227 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 59, 388, 389, 390, 391, 392, 393, 394, 395 or 396. In certain such embodiments, an antisense compound targeted to nucleotides 22199-22227 of SEQ ID NO: 2 is selected from ISIS NOs: 395185, 399907, 405991, 405992, 410549, 410550, 410551, 410552, 410553, 410554, 410555, 410615, 410616, 410617, 410618, 410619, 410620, 410621, 410622, 410623, 410694, 410695, 410696, 410697, 410698, 410699, 410700, 410701, 410702 or 410703. 
     In certain embodiments, a target region is nucleotides 22200-22227 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 22200-22227 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 59, 389, 390, 391, 392, 393, 394, 395 or 396. In certain such embodiments, an antisense compound targeted to nucleotides 22200-22227 of SEQ ID NO: 2 is selected from ISIS NOs: 395185, 399907, 405991, 405992, 410550, 410551, 410552, 410553, 410554, 410555, 410616, 410617, 410618, 410619, 410620, 410621, 410622, 410623, 410695, 410696, 410697, 410698, 410699, 410700, 410701, 410702 or 410703. 
     In certain embodiments, a target region is nucleotides 22201-22228 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 22201-22228 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 59, 390, 391, 392, 393, 394, 395, 396 or 397. In certain such embodiments, an antisense compound targeted to nucleotides 22201-22228 of SEQ ID NO: 2 is selected from ISIS NOs: 395185, 399907, 405991, 405992, 410551, 410552, 410553, 410554, 410555, 410556, 410617, 410618, 410619, 410620, 410621, 410622, 410623, 410624, 410696, 410697, 410698, 410699, 410700, 410701, 410702, 410703 or 410704. 
     In certain embodiments, a target region is nucleotides 22202-22229 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 22202-22229 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 59, 391, 392, 393, 394, 395, 396, 397 or 398. In certain such embodiments, an antisense compound targeted to nucleotides 22202-22229 of SEQ ID NO: 2 is selected from ISIS NOs: 395185, 399907, 405991, 405992, 405993, 410552, 410553, 410554, 410555, 410556, 410618, 410619, 410620, 410621, 410622, 410623, 410624, 410625, 410697, 410698, 410699, 410700, 410701, 410702, 410703, 410704 or 410705. 
     In certain embodiments, a target region is nucleotides 22203-22230 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 22203-22230 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 59, 392, 393, 394, 395, 396, 397, 398 or 399. In certain such embodiments, an antisense compound targeted to nucleotides 22203-22230 of SEQ ID NO: 2 is selected from ISIS NOs: 395185, 399907, 405991, 405992, 405993, 410553, 410554, 410555, 410556, 410557, 410619, 410620, 410621, 410622, 410623, 410624, 410625, 410626, 410698, 410699, 410700, 410701, 410702, 410703, 410704, 410705 or 410706. 
     In certain embodiments, a target region is nucleotides 22204-22231 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 22204-22231 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 59, 393, 394, 395, 396, 397, 398, 399 or 400. In certain such embodiments, an antisense compound targeted to nucleotides 22204-22231 of SEQ ID NO: 2 is selected from ISIS NOs: 395185, 399907, 405991, 405992, 405993, 405994, 410554, 410555, 410556, 410557, 410620, 410621, 410622, 410623, 410624, 410625, 410626, 410627, 410699, 410700, 410701, 410702, 410703, 410704, 410705, 410706 or 410707. 
     In certain embodiments, a target region is nucleotides 22205-22232 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 22205-22232 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 393, 394, 395, 396, 397, 398, 399, 400 or 401. In certain such embodiments, an antisense compound targeted to nucleotides 22205-22232 of SEQ ID NO: 2 is selected from ISIS NOs: 405991, 405992, 405993, 405994, 410554, 410555, 410556, 410557, 410558, 410620, 410621, 410622, 410623, 410624, 410625, 410626, 410627, 410628, 410700, 410701, 410702, 410703, 410704, 410705, 410706, 410707 or 410708. 
     In certain embodiments, a target region is nucleotides 22206-22233 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 22206-22233 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 394, 395, 396, 397, 398, 399, 400, 401 or 402. In certain such embodiments, an antisense compound targeted to nucleotides 22206-22233 of SEQ ID NO: 2 is selected from ISIS NOs: 405991, 405992, 405993, 405994, 405995, 410555, 410556, 410557, 410558, 410621, 410622, 410623, 410624, 410625, 410626, 410627, 410628, 410629, 410701, 410702, 410703, 410704, 410705, 410706, 410707, 410708 or 410709. 
     In certain embodiments, a target region is nucleotides 22207-22234 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 22207-22234 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 395, 396, 397, 398, 399, 400, 401, 402 or 403. In certain such embodiments, an antisense compound targeted to nucleotides 22207-22234 of SEQ ID NO: 2 is selected from ISIS NOs: 405992, 405993, 405994, 405995, 410555, 410556, 410557, 410558, 410559, 410622, 410623, 410624, 410625, 410626, 410627, 410628, 410629, 410630, 410702, 410703, 410704, 410705, 410706, 410707, 410708, 410709 or 410710. 
     In certain embodiments, a target region is nucleotides 22208-22235 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 22208-22235 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 396, 397, 398, 399, 400, 401, 402, 403 or 404. In certain such embodiments, an antisense compound targeted to nucleotides 22208-22235 of SEQ ID NO: 2 is selected from ISIS NOs: 405992, 405993, 405994, 405995, 410556, 410557, 410558, 410559, 410560, 410623, 410624, 410625, 410626, 410627, 410628, 410629, 410630, 410631, 410703, 410704, 410705, 410706, 410707, 410708, 410709, 410710 or 410711. 
     In certain embodiments, a target region is nucleotides 22209-22236 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 22209-22236 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 397, 398, 399, 400, 401, 402, 403, 404 or 405. In certain such embodiments, an antisense compound targeted to nucleotides 22209-22236 of SEQ ID NO: 2 is selected from ISIS NOs: 405993, 405994, 405995, 410556, 410557, 410558, 410559, 410560, 410561, 410624, 410625, 410626, 410627, 410628, 410629, 410630, 410631, 410632, 410704, 410705, 410706, 410707, 410708, 410709, 410710, 410711 or 410712. 
     In certain embodiments, a target region is nucleotides 22210-22236 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 22210-22236 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 398, 399, 400, 401, 402, 403, 404 or 405. In certain such embodiments, an antisense compound targeted to nucleotides 22210-22236 of SEQ ID NO: 2 is selected from ISIS NOs: 405993, 405994, 405995, 410557, 410558, 410559, 410560, 410561, 410625, 410626, 410627, 410628, 410629, 410630, 410631, 410632, 410705, 410706, 410707, 410708, 410709, 410710, 410711 or 410712. 
     In certain embodiments, a target region is nucleotides 22210-22239 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 22210-22239 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 398, 399, 400, 401, 402, 403, 404, 405 or 405. In certain such embodiments, an antisense compound targeted to nucleotides 22210-22239 of SEQ ID NO: 2 is selected from ISIS NOs: 405993, 405994, 405995, 410557, 410558, 410559, 410560, 410561, 410625, 410626, 410627, 410628, 410629, 410630, 410631, 410632, 410705, 410706, 410707, 410708, 410709, 410710, 410711, 410712 or 410774. 
     In certain embodiments, a target region is nucleotides 22211-22236 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 22211-22236 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 399, 400, 401, 402, 403, 404 or 405. In certain such embodiments, an antisense compound targeted to nucleotides 22211-22236 of SEQ ID NO: 2 is selected from ISIS NOs: 405994, 405995, 410557, 410558, 410559, 410560, 410561, 410626, 410627, 410628, 410629, 410630, 410631, 410632, 410706, 410707, 410708, 410709, 410710, 410711 or 410712. 
     In certain embodiments, a target region is nucleotides 22212-22239 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 22212-22239 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 400, 401, 402, 403, 404, 405 or 406. In certain such embodiments, an antisense compound targeted to nucleotides 22212-22239 of SEQ ID NO: 2 is selected from ISIS NOs: 405994, 405995, 410558, 410559, 410560, 410561, 410627, 410628, 410629, 410630, 410631, 410632, 410707, 410708, 410709, 410710, 410711, 410712 or 410774. 
     In certain embodiments, a target region is nucleotides 22292-22311 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 22292-22311 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 126. In certain such embodiments, an antisense compound targeted to nucleotides 22292-22311 of SEQ ID NO: 2 is selected from ISIS NOs: 395225 or 399947. 
     In certain embodiments, a target region is nucleotides 23985-24054 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 23985-24054 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 408, 409 or 410. In certain such embodiments, an antisense compound targeted to nucleotides 23985-24054 of SEQ ID NO: 2 is selected from ISIS NOs: 410776, 410777 or 410778. 
     In certain embodiments, a target region is nucleotides 24035-24134 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 24035-24134 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 60, 61, 410, 411, 412, 413, 414, 415 or 416. In certain such embodiments, an antisense compound targeted to nucleotides 24035-24134 of SEQ ID NO: 2 is selected from ISIS NOs: 395186, 399817, 399908, 399973, 405996, 405997, 410562, 410563, 410564, 410633, 410634, 410635, 410636, 410713, 410714, 410715, 410716, 410717, 410718, 410778 or 410779. 
     In certain embodiments, a target region is nucleotides 24095-24121 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 24095-24121 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 60, 61, 411, 412, 413, 414 or 415. In certain such embodiments, an antisense compound targeted to nucleotides 24095-24121 of SEQ ID NO: 2 is selected from ISIS NOs: 395186, 399817, 399908, 399973, 405996, 405997, 410562, 410563, 410564, 410633, 410634, 410635, 410636, 410713, 410714, 410715, 410716, 410717 or 410718. 
     In certain embodiments, a target region is nucleotides 24858-24877 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 24858-24877 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 147. In certain such embodiments, an antisense compound targeted to nucleotides 24858-24877 of SEQ ID NO: 2 is selected from ISIS NOs: 395226 or 399948. 
     In certain embodiments, a target region is nucleotides 24907-24926 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 24907-24926 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 118. In certain such embodiments, an antisense compound targeted to nucleotides 24907-24926 of SEQ ID NO: 2 is selected from ISIS NOs: 399869 or 400025. 
     In certain embodiments, a target region is nucleotides 25413-25432 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 25413-25432 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 114. In certain such embodiments, an antisense compound targeted to nucleotides 25413-25432 of SEQ ID NO: 2 is selected from ISIS NOs: 399870 or 400026. 
     In certain embodiments, a target region is nucleotides 25994-26013 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 25994-26013 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 418. In certain such embodiments, an antisense compound targeted to nucleotides 25994-26013 of SEQ ID NO: 2 is selected from ISIS NOs: 410781. 
     In certain embodiments, a target region is nucleotides 26112-26139 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 26112-26139 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 62, 419, 420, 421, 422, 423, 424, 425 or 426. In certain such embodiments, an antisense compound targeted to nucleotides 26112-26139 of SEQ ID NO: 2 is selected from ISIS NOs: 395187, 399909, 405998, 410565, 410566, 410567, 410568, 410569, 410570, 410571, 410637, 410638, 410639, 410640, 410641, 410642, 410643, 410644, 410719, 410720, 410721, 410722, 410723, 410724, 410725, 410726 or 410727. 
     In certain embodiments, a target region is nucleotides 26112-26161 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 26112-26161 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 62, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429 or 430. In certain such embodiments, an antisense compound targeted to nucleotides 26112-26161 of SEQ ID NO: 2 is selected from ISIS NOs: 395187, 399909, 405998, 410565, 410566, 410567, 410568, 410569, 410570, 410571, 410572, 410573, 410637, 410638, 410639, 410640, 410641, 410642, 410643, 410644, 410645, 410646, 410719, 410720, 410721, 410722, 410723, 410724, 410725, 410726, 410727, 410728, 410729, 410782 or 410783. 
     In certain embodiments, a target region is nucleotides 26112-27303 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 26112-27303 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 112, 122, 135, 153, 154, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 432, 433, 434, 435, 436, 437, 438, 439, 440, 441, 442, 443, 444, 445 or 446. In certain such embodiments, an antisense compound targeted to nucleotides 26112-27303 of SEQ ID NO: 2 is selected from ISIS NOs: 395187, 395188, 395189, 395190, 395191, 395192, 395193, 395194, 395195, 395196, 395197, 395198, 395199, 399818, 399819, 399820, 399821, 399822, 399823, 399824, 399825, 399909, 399910, 399911, 399912, 399913, 399914, 399915, 399916, 399917, 399918, 399919, 399920, 399921, 399974, 399975, 399976, 399977, 399978, 399979, 399980, 399981, 405893, 405894, 405895, 405896, 405897, 405898, 405899, 405900, 405901, 405902, 405903, 405904, 405905, 405906, 405907, 405908, 405998, 410565, 410566, 410567, 410568, 410569, 410570, 410571, 410572, 410573, 410637, 410638, 410639, 410640, 410641, 410642, 410643, 410644, 410645, 410646, 410719, 410720, 410721, 410722, 410723, 410724, 410725, 410726, 410727, 410728, 410729, 410782 or 410783. 
     In certain embodiments, a target region is nucleotides 26113-26140 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 26113-26140 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 62, 420, 421, 422, 423, 424, 425, 426 or 427. In certain such embodiments, an antisense compound targeted to nucleotides 26113-26140 of SEQ ID NO: 2 is selected from ISIS NOs: 395187, 399909, 405998, 410566, 410567, 410568, 410569, 410570, 410571, 410572, 410638, 410639, 410640, 410641, 410642, 410643, 410644, 410645, 410720, 410721, 410722, 410723, 410724, 410725, 410726, 410727 or 410728. 
     In certain embodiments, a target region is nucleotides 26114-26141 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 26114-26141 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 62, 421, 422, 423, 424, 425, 426, 427 or 248. In certain such embodiments, an antisense compound targeted to nucleotides 26114-26141 of SEQ ID NO: 2 is selected from ISIS NOs: 395187, 399909, 405998, 410567, 410568, 410569, 410570, 410571, 410572, 410573, 410639, 410640, 410641, 410642, 410643, 410644, 410645, 410646, 410721, 410722, 410723, 410724, 410725, 410726, 410727, 410728 or 410729. 
     In certain embodiments, a target region is nucleotides 26115-26141 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 26115-26141 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 62, 422, 423, 424, 425, 426, 427 or 248. In certain such embodiments, an antisense compound targeted to nucleotides 26115-26141 of SEQ ID NO: 2 is selected from ISIS NOs: 395187, 399909, 405998, 410568, 410569, 410570, 410571, 410572, 410573, 410640, 410641, 410642, 410643, 410644, 410645, 410646, 410722, 410723, 410724, 410725, 410726, 410727, 410728 or 410729. 
     In certain embodiments, a target region is nucleotides 26116-26141 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 26116-26141 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 62, 423, 424, 425, 426, 427 or 428. In certain such embodiments, an antisense compound targeted to nucleotides 26116-26141 of SEQ ID NO: 2 is selected from ISIS NOs: 395187, 399909, 405998, 410569, 410570, 410571, 410572, 410573, 410641, 410642, 410643, 410644, 410645, 410646, 410723, 410724, 410725, 410726, 410727 or 410728. 
     In certain embodiments, a target region is nucleotides 26117-26141 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 26117-26141 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 62, 424, 425, 426, 427 or 428. In certain such embodiments, an antisense compound targeted to nucleotides 26117-26141 of SEQ ID NO: 2 is selected from ISIS NOs: 395187, 399909, 405998, 410570, 410571, 410572, 410573, 410642, 410643, 410644, 410645, 410646, 410724, 410725, 410726, 410727, 410728 or 410729. 
     In certain embodiments, a target region is nucleotides 26117-26475 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 26117-26475 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 62, 63, 64, 65, 66, 67, 122, 153, 154, 424, 425, 426, 427, 428, 429 or 430. In certain such embodiments, an antisense compound targeted to nucleotides 26117-26475 of SEQ ID NO: 2 is selected from ISIS NOs: 395187, 395188, 395189, 395190, 395191, 395192, 399818, 399819, 399820, 399909, 399910, 399911, 399912, 399913, 399914, 399974, 399975, 399976, 405998, 410570, 410571, 410572, 410573, 410642, 410643, 410644, 410645, 410646, 410724, 410725, 410726, 410727, 410728, 410729, 410782 or 410783. 
     In certain embodiments, a target region is nucleotides 26118-26141 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 26118-26141 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 424, 425, 426, 427 or 428. In certain such embodiments, an antisense compound targeted to nucleotides 26118-26141 of SEQ ID NO: 2 is selected from ISIS NOs: 405998, 410570, 410571, 410572, 410573, 410642, 410643, 410644, 410645, 410646, 410725, 410726, 410727, 410728 or 410729. 
     In certain embodiments, a target region is nucleotides 26120-26141 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 26120-26141 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 426, 427 or 428. In certain such embodiments, an antisense compound targeted to nucleotides 26120-26141 of SEQ ID NO: 2 is selected from ISIS NOs: 405998, 410572, 410573, 410644, 410645, 410646, 410727, 410728 or 410729. 
     In certain embodiments, a target region is nucleotides 26132-26151 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 26132-26151 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 429. In certain such embodiments, an antisense compound targeted to nucleotides 26132-26151 of SEQ ID NO: 2 is selected from ISIS NOs: 410782. 
     In certain embodiments, a target region is nucleotides 26142-26161 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 26142-26161 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 430. In certain such embodiments, an antisense compound targeted to nucleotides 26142-26161 of SEQ ID NO: 2 is selected from ISIS NOs: 410783. 
     In certain embodiments, a target region is nucleotides 26217-26241 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 26217-26241 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 63 or 154. In certain such embodiments, an antisense compound targeted to nucleotides 26217-26241 of SEQ ID NO: 2 is selected from ISIS NOs: 395188, 399818 or 399910. 
     In certain embodiments, a target region is nucleotides 26311-26335 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 26311-26335 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 64 or 65. In certain such embodiments, an antisense compound targeted to nucleotides 26311-26335 of SEQ ID NO: 2 is selected from ISIS NOs: 395189, 399819, 399911 or 399975. 
     In certain embodiments, a target region is nucleotides 26389-26432 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 26389-26432 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 66, 67 or 122. In certain such embodiments, an antisense compound targeted to nucleotides 26389-26432 of SEQ ID NO: 2 is selected from ISIS NOs: 395190, 395191, 399820, 399912, 399913 or 399976. 
     In certain embodiments, a target region is nucleotides 26456-26576 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 26456-26576 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 68 or 153. In certain such embodiments, an antisense compound targeted to nucleotides 26456-26576 of SEQ ID NO: 2 is selected from ISIS NOs: 395192, 395193, 399914 or 399915. 
     In certain embodiments, a target region is nucleotides 26635-26662 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 26635-26662 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 69, 431, 432, 433, 434, 435, 436, 437 or 438. In certain such embodiments, an antisense compound targeted to nucleotides 26635-26662 of SEQ ID NO: 2 is selected from ISIS NOs: 395194, 399916, 405893, 405894, 405895, 405896, 405897, 405898, 405899 or 405900. 
     In certain embodiments, a target region is nucleotides 26707-26734 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 26707-26734 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 70, 71, 439, 440, 441, 442, 443 or 444. In certain such embodiments, an antisense compound targeted to nucleotides 26707-26734 of SEQ ID NO: 2 is selected from ISIS NOs: 395195, 399821, 399917, 399977, 405901, 405902, 405903, 405904, 405905 or 405906. 
     In certain embodiments, a target region is nucleotides 26707-26736 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 26707-26736 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 70, 71, 439, 440, 441, 442, 443, 444, 445 or 446. In certain such embodiments, an antisense compound targeted to nucleotides 26707-26736 of SEQ ID NO: 2 is selected from ISIS NOs: 395195, 399821, 399917, 399977, 405901, 405902, 405903, 405904, 405905, 405906, 405907 or 405908. 
     In certain embodiments, a target region is nucleotides 26790-26820 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 26790-26820 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 72, 73 or 135. In certain such embodiments, an antisense compound targeted to nucleotides 26790-26820 of SEQ ID NO: 2 is selected from ISIS NOs: 395196, 399822, 399823, 399918, 399978 or 399979. 
     In certain embodiments, a target region is nucleotides 27034-27263 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 27034-27263 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 74, 75 or 112. In certain such embodiments, an antisense compound targeted to nucleotides 27034-27263 of SEQ ID NO: 2 is selected from ISIS NOs: 395197, 395198, 399824, 399919, 399920 or 399980. 
     In certain embodiments, a target region is nucleotides 27279-27303 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 27279-27303 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 76 or 77. In certain such embodiments, an antisense compound targeted to nucleotides 27279-27303 of SEQ ID NO: 2 is selected from ISIS NOs: 395199, 399825, 399921 or 399981. 
     In certain embodiments, a target region is nucleotides 27350-27376 of SEQ ID NO: 2. In certain embodiments, an antisense compound is targeted to nucleotides 27350-27376 of SEQ ID NO: 2. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 78 or 99. In certain such embodiments, an antisense compound targeted to nucleotides 27350-27376 of SEQ ID NO: 2 is selected from ISIS NOs: 395200, 399826, 399922 or 399982. 
     In certain embodiments, antisense compounds target a PCSK9 nucleic acid having the sequence of GENBANK® Accession No. AK124635.1, first deposited with GENBANK® on Sep. 8, 2003, and incorporated herein as SEQ ID NO: 3. In certain such embodiments, an antisense oligonucleotide is targeted to SEQ ID NO: 3. In certain such embodiments, an antisense oligonucleotide that is targeted to SEQ ID NO: 3 is at least 90% complementary to SEQ ID NO: 1. In certain such embodiments, an antisense oligonucleotide that is targeted to SEQ ID NO: 3 is at least 95% complementary to SEQ ID NO: 3. In certain such embodiments, an antisense oligonucleotide that is targeted to SEQ ID NO: 3 is 100% complementary to SEQ ID NO: 3. In certain such embodiments, an antisense oligonucleotide comprises a nucleotide sequence selected from a nucleotide sequence set forth in Table 12. 
     
       
         
           
               
             
               
                 TABLE 12 
               
             
            
               
                   
               
               
                 Nucleotide sequences targeted to AK124635.1 
               
               
                 (SEQ ID NO: 3) 
               
            
           
           
               
               
               
               
            
               
                   
                 5′ Target 
                 3′ Target 
                   
               
               
                 SEQ 
                 Site on 
                 Site on 
                   
               
               
                 ID 
                 SEQ ID 
                 SEQ ID 
                   
               
               
                 NO 
                 NO: 3 
                 NO: 3 
                 Sequences (5′-3′) 
               
               
                   
               
               
                  85 
                  155 
                  174 
                 ACAAATTCCCAGACTCAGCA 
               
               
                   
               
               
                 100 
                  220 
                  239 
                 ATCTCAGGACAGGTGAGCAA 
               
               
                   
               
               
                 116 
                  234 
                  253 
                 GAGTAGAGATTCTCATCTCA 
               
               
                   
               
               
                 129 
                  290 
                  309 
                 GTGCCATCTGAACAGCACCT 
               
               
                   
               
               
                 117 
                  302 
                  321 
                 GAGTCTTCTGAAGTGCCATC 
               
               
                   
               
               
                  81 
                  377 
                  396 
                 AAGCAGGGCCTCAGGTGGAA 
               
               
                   
               
               
                 110 
                  400 
                  419 
                 CCTGGAACCCCTGCAGCCAG 
               
               
                   
               
               
                 152 
                  451 
                  470 
                 TTCAGGCAGGTTGCTGCTAG 
               
               
                   
               
               
                  83 
                  460 
                  479 
                 AAGGAAGACTTCAGGCAGGT 
               
               
                   
               
               
                 140 
                  472 
                  491 
                 TCAGCCAGGCCAAAGGAAGA 
               
               
                   
               
               
                 137 
                  586 
                  605 
                 TAGGGAGAGCTCACAGATGC 
               
               
                   
               
               
                 136 
                  596 
                  615 
                 TAGGAGAAAGTAGGGAGAGC 
               
               
                   
               
               
                 132 
                  653 
                  672 
                 TAAAAGCTGCAAGAGACTCA 
               
               
                   
               
               
                 139 
                 741 
                  760 
                 TCAGAGAAAACAGTCACCGA 
               
               
                   
               
               
                  92 
                  871 
                  890 
                 AGAGACAGGAAGCTGCAGCT 
               
               
                   
               
               
                 142 
                  878 
                  897 
                 TCATTTTAGAGACAGGAAGC 
               
               
                   
               
               
                 113 
                  915 
                  934 
                 GAATAACAGTGATGTCTGGC 
               
               
                   
               
               
                 138 
                  968 
                  987 
                 TCACAGCTCACCGAGTCTGC 
               
               
                   
               
               
                  98 
                  998 
                 1017 
                 AGTGTAAAATAAAGCCCCTA 
               
               
                   
               
               
                  96 
                 1075 
                 1094 
                 AGGACCCAAGTCATCCTGCT 
               
               
                   
               
               
                 124 
                 1105 
                 1124 
                 GGCCATCAGCTGGCAATGCT 
               
               
                   
               
               
                  82 
                 1144 
                 1163 
                 AAGGAAAGGGAGGCCTAGAG 
               
               
                   
               
               
                 133 
                 1149 
                 1168 
                 TAGACAAGGAAAGGGAGGCC 
               
               
                   
               
               
                 103 
                 1155 
                 1174 
                 ATTTCATAGACAAGGAAAGG 
               
               
                   
               
               
                 155 
                 1275 
                 1294 
                 CTTATAGTTAACACACAGAA 
               
               
                   
               
               
                 156 
                 1283 
                 1302 
                 AAGTCAACCTTATAGTTAAC 
               
               
                   
               
               
                 146 
                 1315 
                 1334 
                 TGACATTTGTGGGAGAGGAG 
               
               
                   
               
               
                 161 
                 1322 
                 1341 
                 TCCAAGGTGACATTTGTGGG 
               
               
                   
               
               
                 215 
                 1351 
                 1370 
                 ATACACCTCCACCAGGCTGC 
               
               
                   
               
               
                 216 
                 1362 
                 1381 
                 GTGTCTAGGAGATACACCTC 
               
               
                   
               
               
                  19 
                 1365 
                 1384 
                 CTGGTGTCTAGGAGATACAC 
               
               
                   
               
               
                 217 
                 1367 
                 1386 
                 TGCTGGTGTCTAGGAGATAC 
               
               
                   
               
               
                  20 
                 1370 
                 1389 
                 GTATGCTGGTGTCTAGGAGA 
               
               
                   
               
               
                  21 
                 1390 
                 1409 
                 GATTTCCCGGTGGTCACTCT 
               
               
                   
               
               
                 218 
                 1392 
                 1411 
                 TCGATTTCCCGGTGGTCACT 
               
               
                   
               
               
                 219 
                 1393 
                 1412 
                 CTCGATTTCCCGGTGGTCAC 
               
               
                   
               
               
                 220 
                 1394 
                 1413 
                 CCTCGATTTCCCGGTGGTCA 
               
               
                   
               
               
                 221 
                 1395 
                 1414 
                 CCCTCGATTTCCCGGTGGTC 
               
               
                   
               
               
                  22 
                 1396 
                 1415 
                 GCCCTCGATTTCCCGGTGGT 
               
               
                   
               
               
                 222 
                 1397 
                 1416 
                 TGCCCTCGATTTCCCGGTGG 
               
               
                   
               
               
                 223 
                 1398 
                 1417 
                 CTGCCCTCGATTTCCCGGTG 
               
               
                   
               
               
                 224 
                 1399 
                 1418 
                 CCTGCCCTCGATTTCCCGGT 
               
               
                   
               
               
                 225 
                 1400 
                 1419 
                 CCCTGCCCTCGATTTCCCGG 
               
               
                   
               
               
                 226 
                 1404 
                 1423 
                 ATGACCCTGCCCTCGATTTC 
               
               
                   
               
               
                 227 
                 1406 
                 1425 
                 CCATGACCCTGCCCTCGATT 
               
               
                   
               
               
                 228 
                 1408 
                 1427 
                 GACCATGACCCTGCCCTCGA 
               
               
                   
               
               
                  23 
                 1410 
                 1429 
                 GTGACCATGACCCTGCCCTC 
               
               
                   
               
               
                 229 
                 1412 
                 1431 
                 CGGTGACCATGACCCTGCCC 
               
               
                   
               
               
                 230 
                 1414 
                 1433 
                 GTCGGTGACCATGACCCTGC 
               
               
                   
               
               
                 231 
                 1416 
                 1435 
                 AAGTCGGTGACCATGACCCT 
               
               
                   
               
               
                 232 
                 1418 
                 1437 
                 CGAAGTCGGTGACCATGACC 
               
               
                   
               
               
                  24 
                 1420 
                 1439 
                 CTCGAAGTCGGTGACCATGA 
               
               
                   
               
               
                 233 
                 1428 
                 1447 
                 GGCACATTCTCGAAGTCGGT 
               
               
                   
               
               
                  25 
                 1453 
                 1472 
                 GTGGAAGCGGGTCCCGTCCT 
               
               
                   
               
               
                 234 
                 1463 
                 1482 
                 TGGCCTGTCTGTGGAAGCGG 
               
               
                   
               
               
                 235 
                 1490 
                 1509 
                 GGTGGGTGCCATGACTGTCA 
               
               
                   
               
               
                 236 
                 1493 
                 1512 
                 CCAGGTGGGTGCCATGACTG 
               
               
                   
               
               
                 237 
                 1497 
                 1516 
                 CCTGCCAGGTGGGTGCCATG 
               
               
                   
               
               
                  26 
                 1500 
                 1519 
                 ACCCCTGCCAGGTGGGTGCC 
               
               
                   
               
               
                 238 
                 1502 
                 1521 
                 CCACCCCTGCCAGGTGGGTG 
               
               
                   
               
               
                  27 
                 1505 
                 1524 
                 TGACCACCCCTGCCAGGTGG 
               
               
                   
               
               
                 239 
                 1507 
                 1526 
                 GCTGACCACCCCTGCCAGGT 
               
               
                   
               
               
                 240 
                 1515 
                 1534 
                 TCCCGGCCGCTGACCACCCC 
               
               
                   
               
               
                 241 
                 1519 
                 1538 
                 GGCATCCCGGCCGCTGACCA 
               
               
                   
               
               
                 242 
                 1522 
                 1541 
                 GCCGGCATCCCGGCCGCTGA 
               
               
                   
               
               
                 243 
                 1527 
                 1546 
                 GCCACGCCGGCATCCCGGCC 
               
               
                   
               
               
                 244 
                 1528 
                 1547 
                 GGCCACGCCGGCATCCCGGC 
               
               
                   
               
               
                 245 
                 1529 
                 1548 
                 TGGCCACGCCGGCATCCCGG 
               
               
                   
               
               
                 246 
                 1530 
                 1549 
                 TTGGCCACGCCGGCATCCCG 
               
               
                   
               
               
                 247 
                 1531 
                 1550 
                 CTTGGCCACGCCGGCATCCC 
               
               
                   
               
               
                 248 
                 1532 
                 1551 
                 CCTTGGCCACGCCGGCATCC 
               
               
                   
               
               
                 249 
                 1533 
                 1552 
                 CCCTTGGCCACGCCGGCATC 
               
               
                   
               
               
                  28 
                 1534 
                 1553 
                 ACCCTTGGCCACGCCGGCAT 
               
               
                   
               
               
                 447 
                 1534 
                 1553 
                 ACCCTTGGTCACGCCGGCAT 
               
               
                   
               
               
                 250 
                 1535 
                 1554 
                 CACCCTTGGCCACGCCGGCA 
               
               
                   
               
               
                 251 
                 1536 
                 1555 
                 GCACCCTTGGCCACGCCGGC 
               
               
                   
               
               
                 252 
                 1537 
                 1556 
                 GGCACCCTTGGCCACGCCGG 
               
               
                   
               
               
                 253 
                 1538 
                 1557 
                 TGGCACCCTTGGCCACGCCG 
               
               
                   
               
               
                 254 
                 1539 
                 1558 
                 CTGGCACCCTTGGCCACGCC 
               
               
                   
               
               
                 255 
                 1540 
                 1559 
                 GCTGGCACCCTTGGCCACGC 
               
               
                   
               
               
                 256 
                 1545 
                 1564 
                 CGCATGCTGGCACCCTTGGC 
               
               
                   
               
               
                 257 
                 1566 
                 1585 
                 CAGTTGAGCACGCGCAGGCT 
               
               
                   
               
               
                 258 
                 1568 
                 1587 
                 GGCAGTTGAGCACGCGCAGG 
               
               
                   
               
               
                  29 
                 1570 
                 1589 
                 TTGGCAGTTGAGCACGCGCA 
               
               
                   
               
               
                 259 
                 1572 
                 1591 
                 CCTTGGCAGTTGAGCACGCG 
               
               
                   
               
               
                  30 
                 1575 
                 1594 
                 TTCCCTTGGCAGTTGAGCAC 
               
               
                   
               
               
                 260 
                 1577 
                 1596 
                 CCTTCCCTTGGCAGTTGAGC 
               
               
                   
               
               
                 261 
                 1581 
                 1600 
                 GTGCCCTTCCCTTGGCAGTT 
               
               
                   
               
               
                 262 
                 1583 
                 1602 
                 CCGTGCCCTTCCCTTGGCAG 
               
               
                   
               
               
                 263 
                 1594 
                 1613 
                 GGTGCCGCTAACCGTGCCCT 
               
               
                   
               
               
                 264 
                 1606 
                 1625 
                 CAGGCCTATGAGGGTGCCGC 
               
               
                   
               
               
                  31 
                 1607 
                 1626 
                 CCAGGCCTATGAGGGTGCCG 
               
               
                   
               
               
                 458 
                 1609 
                 1622 
                 GCCTATGAGGGTGC 
               
               
                   
               
               
                 459 
                 1614 
                 1627 
                 TCCAGGCCTATGAG 
               
               
                   
               
               
                 265 
                 1618 
                 1637 
                 CCGAATAAACTCCAGGCCTA 
               
               
                   
               
               
                 266 
                 1626 
                 1645 
                 TGGCTTTTCCGAATAAACTC 
               
               
                   
               
               
                  32 
                 1628 
                 1647 
                 GCTGGCTTTTCCGAATAAAC 
               
               
                   
               
               
                 267 
                 1630 
                 1649 
                 CAGCTGGCTTTTCCGAATAA 
               
               
                   
               
               
                 268 
                 1632 
                 1651 
                 ACCAGCTGGCTTTTCCGAAT 
               
               
                   
               
               
                 269 
                 1634 
                 1653 
                 GGACCAGCTGGCTTTTCCGA 
               
               
                   
               
               
                 270 
                 1638 
                 1657 
                 GGCTGGACCAGCTGGCTTTT 
               
               
                   
               
               
                 271 
                 1649 
                 1668 
                 GTGGCCCCACAGGCTGGACC 
               
               
                   
               
               
                 272 
                 1662 
                 1681 
                 AGCAGCACCACCAGTGGCCC 
               
               
                   
               
               
                 273 
                 1684 
                 1703 
                 GCTGTACCCACCCGCCAGGG 
               
               
                   
               
               
                 274 
                 1730 
                 1749 
                 CGACCCCAGCCCTCGCCAGG 
               
               
                   
               
               
                  33 
                 1740 
                 1759 
                 GTGACCAGCACGACCCCAGC 
               
               
                   
               
               
                 275 
                 1742 
                 1761 
                 CGGTGACCAGCACGACCCCA 
               
               
                   
               
               
                 276 
                 1744 
                 1763 
                 AGCGGTGACCAGCACGACCC 
               
               
                   
               
               
                 277 
                 1746 
                 1765 
                 GCAGCGGTGACCAGCACGAC 
               
               
                   
               
               
                 278 
                 1748 
                 1767 
                 CGGCAGCGGTGACCAGCACG 
               
               
                   
               
               
                 279 
                 1749 
                 1768 
                 CCGGCAGCGGTGACCAGCAC 
               
               
                   
               
               
                 280 
                 1752 
                 1771 
                 TTGCCGGCAGCGGTGACCAG 
               
               
                   
               
               
                 281 
                 1754 
                 1773 
                 AGTTGCCGGCAGCGGTGACC 
               
               
                   
               
               
                 282 
                 1756 
                 1775 
                 GAAGTTGCCGGCAGCGGTGA 
               
               
                   
               
               
                 283 
                 1758 
                 1777 
                 CGGAAGTTGCCGGCAGCGGT 
               
               
                   
               
               
                 284 
                 1760 
                 1779 
                 CCCGGAAGTTGCCGGCAGCG 
               
               
                   
               
               
                 285 
                 1762 
                 1781 
                 GTCCCGGAAGTTGCCGGCAG 
               
               
                   
               
               
                 306 
                 1820 
                 1839 
                 GAGGCACCAATGATGTCCTC 
               
               
                   
               
               
                  39 
                 1822 
                 1841 
                 TGGAGGCACCAATGATGTCC 
               
               
                   
               
               
                 307 
                 1824 
                 1843 
                 GCTGGAGGCACCAATGATGT 
               
               
                   
               
               
                 308 
                 1826 
                 1845 
                 TCGCTGGAGGCACCAATGAT 
               
               
                   
               
               
                 309 
                 1828 
                 1847 
                 AGTCGCTGGAGGCACCAATG 
               
               
                   
               
               
                 310 
                 1830 
                 1849 
                 GCAGTCGCTGGAGGCACCAA 
               
               
                   
               
               
                  40 
                 1833 
                 1852 
                 GCTGCAGTCGCTGGAGGCAC 
               
               
                   
               
               
                 311 
                 1835 
                 1854 
                 GTGCTGCAGTCGCTGGAGGC 
               
               
                   
               
               
                 312 
                 1837 
                 1856 
                 AGGTGCTGCAGTCGCTGGAG 
               
               
                   
               
               
                 313 
                 1839 
                 1858 
                 GCAGGTGCTGCAGTCGCTGG 
               
               
                   
               
               
                 314 
                 1840 
                 1859 
                 AGCAGGTGCTGCAGTCGCTG 
               
               
                   
               
               
                 315 
                 1842 
                 1861 
                 AAAGCAGGTGCTGCAGTCGC 
               
               
                   
               
               
                  41 
                 1844 
                 1863 
                 ACAAAGCAGGTGCTGCAGTC 
               
               
                   
               
               
                 316 
                 1846 
                 1865 
                 ACACAAAGCAGGTGCTGCAG 
               
               
                   
               
               
                 317 
                 1848 
                 1867 
                 TGACACAAAGCAGGTGCTGC 
               
               
                   
               
               
                 318 
                 1858 
                 1877 
                 TCCCACTCTGTGACACAAAG 
               
               
                   
               
               
                 101 
                 1898 
                 1917 
                 ATGGCTGCAATGCCAGCCAC 
               
               
                   
               
               
                 319 
                 1900 
                 1919 
                 TCATGGCTGCAATGCCAGCC 
               
               
                   
               
               
                  42 
                 1903 
                 1922 
                 GCATCATGGCTGCAATGCCA 
               
               
                   
               
               
                 320 
                 1905 
                 1924 
                 CAGCATCATGGCTGCAATGC 
               
               
                   
               
               
                 321 
                 1907 
                 1926 
                 GACAGCATCATGGCTGCAAT 
               
               
                   
               
               
                 322 
                 1909 
                 1928 
                 CAGACAGCATCATGGCTGCA 
               
               
                   
               
               
                  43 
                 1911 
                 1930 
                 GGCAGACAGCATCATGGCTG 
               
               
                   
               
               
                 323 
                 1913 
                 1932 
                 TCGGCAGACAGCATCATGGC 
               
               
                   
               
               
                 324 
                 1915 
                 1934 
                 GCTCGGCAGACAGCATCATG 
               
               
                   
               
               
                 325 
                 1917 
                 1936 
                 CGGCTCGGCAGACAGCATCA 
               
               
                   
               
               
                 326 
                 1919 
                 1938 
                 TCCGGCTCGGCAGACAGCAT 
               
               
                   
               
               
                 327 
                 1933 
                 1952 
                 CGGCCAGGGTGAGCTCCGGC 
               
               
                   
               
               
                 328 
                 1946 
                 1965 
                 CTCTGCCTCAACTCGGCCAG 
               
               
                   
               
               
                 329 
                 1948 
                 1967 
                 GTCTCTGCCTCAACTCGGCC 
               
               
                   
               
               
                 330 
                 1950 
                 1969 
                 CAGTCTCTGCCTCAACTCGG 
               
               
                   
               
               
                 331 
                 1952 
                 1971 
                 ATCAGTCTCTGCCTCAACTC 
               
               
                   
               
               
                 332 
                 1954 
                 1973 
                 GGATCAGTCTCTGCCTCAAC 
               
               
                   
               
               
                 333 
                 1956 
                 1975 
                 GTGGATCAGTCTCTGCCTCA 
               
               
                   
               
               
                 334 
                 1958 
                 1977 
                 AAGTGGATCAGTCTCTGCCT 
               
               
                   
               
               
                  44 
                 1959 
                 1978 
                 GAAGTGGATCAGTCTCTGCC 
               
               
                   
               
               
                 335 
                 1961 
                 1980 
                 GAGAAGTGGATCAGTCTCTG 
               
               
                   
               
               
                 336 
                 1963 
                 1982 
                 CAGAGAAGTGGATCAGTCTC 
               
               
                   
               
               
                 337 
                 1965 
                 1984 
                 GGCAGAGAAGTGGATCAGTC 
               
               
                   
               
               
                  45 
                 1967 
                 1986 
                 TTGGCAGAGAAGTGGATCAG 
               
               
                   
               
               
                 338 
                 1969 
                 1988 
                 CTTTGGCAGAGAAGTGGATC 
               
               
                   
               
               
                  46 
                 1972 
                 1991 
                 CATCTTTGGCAGAGAAGTGG 
               
               
                   
               
               
                 339 
                 1974 
                 1993 
                 GACATCTTTGGCAGAGAAGT 
               
               
                   
               
               
                 340 
                 1976 
                 1995 
                 ATGACATCTTTGGCAGAGAA 
               
               
                   
               
               
                  47 
                 1978 
                 1997 
                 TGATGACATCTTTGGCAGAG 
               
               
                   
               
               
                 341 
                 1980 
                 1999 
                 ATTGATGACATCTTTGGCAG 
               
               
                   
               
               
                 342 
                 1982 
                 2001 
                 TCATTGATGACATCTTTGGC 
               
               
                   
               
               
                  48 
                 1985 
                 2004 
                 GCCTCATTGATGACATCTTT 
               
               
                   
               
               
                 343 
                 1987 
                 2006 
                 AGGCCTCATTGATGACATCT 
               
               
                   
               
               
                 344 
                 1989 
                 2008 
                 CCAGGCCTCATTGATGACAT 
               
               
                   
               
               
                 345 
                 1991 
                 2010 
                 AACCAGGCCTCATTGATGAC 
               
               
                   
               
               
                 346 
                 1993 
                 2012 
                 GGAACCAGGCCTCATTGATG 
               
               
                   
               
               
                 347 
                 1994 
                 2013 
                 GGGAACCAGGCCTCATTGAT 
               
               
                   
               
               
                 348 
                 1995 
                 2014 
                 AGGGAACCAGGCCTCATTGA 
               
               
                   
               
               
                 349 
                 1996 
                 2015 
                 CAGGGAACCAGGCCTCATTG 
               
               
                   
               
               
                  49 
                 1997 
                 2016 
                 TCAGGGAACCAGGCCTCATT 
               
               
                   
               
               
                 350 
                 1998 
                 2017 
                 CTCAGGGAACCAGGCCTCAT 
               
               
                   
               
               
                 351 
                 1999 
                 2018 
                 CCTCAGGGAACCAGGCCTCA 
               
               
                   
               
               
                 352 
                 2000 
                 2019 
                 TCCTCAGGGAACCAGGCCTC 
               
               
                   
               
               
                 353 
                 2001 
                 2020 
                 GTCCTCAGGGAACCAGGCCT 
               
               
                   
               
               
                  50 
                 2002 
                 2021 
                 GGTCCTCAGGGAACCAGGCC 
               
               
                   
               
               
                 354 
                 2003 
                 2022 
                 TGGTCCTCAGGGAACCAGGC 
               
               
                   
               
               
                 355 
                 2004 
                 2023 
                 CTGGTCCTCAGGGAACCAGG 
               
               
                   
               
               
                 356 
                 2005 
                 2024 
                 GCTGGTCCTCAGGGAACCAG 
               
               
                   
               
               
                 357 
                 2006 
                 2025 
                 CGCTGGTCCTCAGGGAACCA 
               
               
                   
               
               
                  87 
                 2009 
                 2028 
                 ACCCGCTGGTCCTCAGGGAA 
               
               
                   
               
               
                 358 
                 2011 
                 2030 
                 GTACCCGCTGGTCCTCAGGG 
               
               
                   
               
               
                 359 
                 2013 
                 2032 
                 CAGTACCCGCTGGTCCTCAG 
               
               
                   
               
               
                  51 
                 2016 
                 2035 
                 GGTCAGTACCCGCTGGTCCT 
               
               
                   
               
               
                 119 
                 2038 
                 2057 
                 GCAGGGCGGCCACCAGGTTG 
               
               
                   
               
               
                 360 
                 2061 
                 2080 
                 ACCTGCCCCATGGGTGCTGG 
               
               
                   
               
               
                  52 
                 2073 
                 2092 
                 AAACAGCTGCCAACCTGCCC 
               
               
                   
               
               
                 361 
                 2075 
                 2094 
                 CAAAACAGCTGCCAACCTGC 
               
               
                   
               
               
                  53 
                 2078 
                 2097 
                 CTGCAAAACAGCTGCCAACC 
               
               
                   
               
               
                 362 
                 2080 
                 2099 
                 TCCTGCAAAACAGCTGCCAA 
               
               
                   
               
               
                 363 
                 2082 
                 2101 
                 AGTCCTGCAAAACAGCTGCC 
               
               
                   
               
               
                 104 
                 2085 
                 2104 
                 CACAGTCCTGCAAAACAGCT 
               
               
                   
               
               
                 130 
                 2095 
                 2114 
                 GTGCTGACCACACAGTCCTG 
               
               
                   
               
               
                 365 
                 2105 
                 2124 
                 GGCCCCGAGTGTGCTGACCA 
               
               
                   
               
               
                  54 
                 2108 
                 2127 
                 GTAGGCCCCGAGTGTGCTGA 
               
               
                   
               
               
                 366 
                 2110 
                 2129 
                 GTGTAGGCCCCGAGTGTGCT 
               
               
                   
               
               
                 367 
                 2112 
                 2131 
                 CCGTGTAGGCCCCGAGTGTG 
               
               
                   
               
               
                 368 
                 2114 
                 2133 
                 ATCCGTGTAGGCCCCGAGTG 
               
               
                   
               
               
                 369 
                 2116 
                 2135 
                 CCATCCGTGTAGGCCCCGAG 
               
               
                   
               
               
                 370 
                 2118 
                 2137 
                 GGCCATCCGTGTAGGCCCCG 
               
               
                   
               
               
                 371 
                 2120 
                 2139 
                 GTGGCCATCCGTGTAGGCCC 
               
               
                   
               
               
                 372 
                 2168 
                 2187 
                 CTGGAGCAGCTCAGCAGCTC 
               
               
                   
               
               
                 460 
                 2168 
                 2181 
                 CAGCTCAGCAGCTC 
               
               
                   
               
               
                 373 
                 2170 
                 2189 
                 AACTGGAGCAGCTCAGCAGC 
               
               
                   
               
               
                  55 
                 2173 
                 2192 
                 AGAAACTGGAGCAGCTCAGC 
               
               
                   
               
               
                 374 
                 2175 
                 2194 
                 GGAGAAACTGGAGCAGCTCA 
               
               
                   
               
               
                 375 
                 2177 
                 2196 
                 CTGGAGAAACTGGAGCAGCT 
               
               
                   
               
               
                  56 
                 2179 
                 2198 
                 TCCTGGAGAAACTGGAGCAG 
               
               
                   
               
               
                 408 
                 2245 
                 2264 
                 GTGCCAAGGTCCTCCACCTC 
               
               
                   
               
               
                 409 
                 2265 
                 2284 
                 TCAGCACAGGCGGCTTGTGG 
               
               
                   
               
               
                 410 
                 2295 
                 2314 
                 CCACGCACTGGTTGGGCTGA 
               
               
                   
               
               
                  60 
                 2355 
                 2374 
                 CTTTGCATTCCAGACCTGGG 
               
               
                   
               
               
                 411 
                 2356 
                 2375 
                 ACTTTGCATTCCAGACCTGG 
               
               
                   
               
               
                 412 
                 2357 
                 2376 
                 GACTTTGCATTCCAGACCTG 
               
               
                   
               
               
                 413 
                 2358 
                 2377 
                 TGACTTTGCATTCCAGACCT 
               
               
                   
               
               
                 414 
                 2359 
                 2378 
                 TTGACTTTGCATTCCAGACC 
               
               
                   
               
               
                  61 
                 2360 
                 2379 
                 CTTGACTTTGCATTCCAGAC 
               
               
                   
               
               
                 415 
                 2362 
                 2381 
                 TCCTTGACTTTGCATTCCAG 
               
               
                   
               
               
                 416 
                 2375 
                 2394 
                 CGGGATTCCATGCTCCTTGA 
               
               
                   
               
               
                 417 
                 2405 
                 2424 
                 GCAGGCCACGGTCACCTGCT 
               
               
                   
               
               
                 418 
                 2442 
                 2461 
                 GGAGGGCACTGCAGCCAGTC 
               
               
                   
               
               
                 419 
                 2560 
                 2579 
                 CAGATGGCAACGGCTGTCAC 
               
               
                   
               
               
                 420 
                 2561 
                 2580 
                 GCAGATGGCAACGGCTGTCA 
               
               
                   
               
               
                 421 
                 2562 
                 2581 
                 AGCAGATGGCAACGGCTGTC 
               
               
                   
               
               
                 422 
                 2563 
                 2582 
                 CAGCAGATGGCAACGGCTGT 
               
               
                   
               
               
                 423 
                 2564 
                 2583 
                 GCAGCAGATGGCAACGGCTG 
               
               
                   
               
               
                  62 
                 2565 
                 2584 
                 GGCAGCAGATGGCAACGGCT 
               
               
                   
               
               
                 424 
                 2566 
                 2585 
                 CGGCAGCAGATGGCAACGGC 
               
               
                   
               
               
                 425 
                 2567 
                 2586 
                 CCGGCAGCAGATGGCAACGG 
               
               
                   
               
               
                 426 
                 2568 
                 2587 
                 TCCGGCAGCAGATGGCAACG 
               
               
                   
               
               
                 427 
                 2569 
                 2588 
                 CTCCGGCAGCAGATGGCAAC 
               
               
                   
               
               
                 428 
                 2570 
                 2589 
                 GCTCCGGCAGCAGATGGCAA 
               
               
                   
               
               
                 429 
                 2580 
                 2599 
                 CCAGGTGCCGGCTCCGGCAG 
               
               
                   
               
               
                 430 
                 2590 
                 2609 
                 GAGGCCTGCGCCAGGTGCCG 
               
               
                   
               
               
                 154 
                 2665 
                 2684 
                 TTTTAAAGCTCAGCCCCAGC 
               
               
                   
               
               
                  63 
                 2670 
                 2689 
                 AACCATTTTAAAGCTCAGCC 
               
               
                   
               
               
                  64 
                 2759 
                 2778 
                 TCAAGGGCCAGGCCAGCAGC 
               
               
                   
               
               
                  65 
                 2764 
                 2783 
                 CCCACTCAAGGGCCAGGCCA 
               
               
                   
               
               
                 122 
                 2837 
                 2856 
                 GGAGGGAGCTTCCTGGCACC 
               
               
                   
               
               
                  66 
                 2852 
                 2871 
                 ATGCCCCACAGTGAGGGAGG 
               
               
                   
               
               
                  67 
                 2861 
                 2880 
                 AATGGTGAAATGCCCCACAG 
               
               
                   
               
               
                 153 
                 2904 
                 2923 
                 TTGGGAGCAGCTGGCAGCAC 
               
               
                   
               
               
                  68 
                 3005 
                 3024 
                 CATGGGAAGAATCCTGCCTC 
               
               
                   
               
               
                 431 
                 3083 
                 3102 
                 ATGAGGGCCATCAGCACCTT 
               
               
                   
               
               
                 432 
                 3084 
                 3103 
                 GATGAGGGCCATCAGCACCT 
               
               
                   
               
               
                 433 
                 3085 
                 3104 
                 AGATGAGGGCCATCAGCACC 
               
               
                   
               
               
                 434 
                 3086 
                 3105 
                 GAGATGAGGGCCATCAGCAC 
               
               
                   
               
               
                  69 
                 3087 
                 3106 
                 GGAGATGAGGGCCATCAGCA 
               
               
                   
               
               
                 435 
                 3088 
                 3107 
                 TGGAGATGAGGGCCATCAGC 
               
               
                   
               
               
                 436 
                 3089 
                 3108 
                 CTGGAGATGAGGGCCATCAG 
               
               
                   
               
               
                 437 
                 3090 
                 3109 
                 GCTGGAGATGAGGGCCATCA 
               
               
                   
               
               
                 438 
                 3091 
                 3110 
                 AGCTGGAGATGAGGGCCATC 
               
               
                   
               
               
                 461 
                 3132 
                 3145 
                 TTAATCAGGGAGCC 
               
               
                   
               
               
                  70 
                 3155 
                 3174 
                 TAGATGCCATCCAGAAAGCT 
               
               
                   
               
               
                 439 
                 3157 
                 3176 
                 GCTAGATGCCATCCAGAAAG 
               
               
                   
               
               
                 440 
                 3158 
                 3177 
                 GGCTAGATGCCATCCAGAAA 
               
               
                   
               
               
                 441 
                 3159 
                 3178 
                 TGGCTAGATGCCATCCAGAA 
               
               
                   
               
               
                 442 
                 3160 
                 3179 
                 CTGGCTAGATGCCATCCAGA 
               
               
                   
               
               
                  71 
                 3161 
                 3180 
                 TCTGGCTAGATGCCATCCAG 
               
               
                   
               
               
                 443 
                 3162 
                 3181 
                 CTCTGGCTAGATGCCATCCA 
               
               
                   
               
               
                 444 
                 3163 
                 3182 
                 CCTCTGGCTAGATGCCATCC 
               
               
                   
               
               
                 445 
                 3164 
                 3183 
                 GCCTCTGGCTAGATGCCATC 
               
               
                   
               
               
                 446 
                 3165 
                 3184 
                 AGCCTCTGGCTAGATGCCAT 
               
               
                   
               
               
                  72 
                 3238 
                 3257 
                 GGCATAGAGCAGAGTAAAGG 
               
               
                   
               
               
                  73 
                 3243 
                 3262 
                 AGCCTGGCATAGAGCAGAGT 
               
               
                   
               
               
                 135 
                 3249 
                 3268 
                 TAGCACAGCCTGGCATAGAG 
               
               
                   
               
               
                 112 
                 3482 
                 3501 
                 GAAGAGGCTTGGCTTCAGAG 
               
               
                   
               
               
                  74 
                 3488 
                 3507 
                 AAGTAAGAAGAGGCTTGGCT 
               
               
                   
               
               
                  75 
                 3692 
                 3711 
                 GCTCAAGGAGGGACAGTTGT 
               
               
                   
               
               
                  76 
                 3727 
                 3746 
                 AAAGATAAATGTCTGCTTGC 
               
               
                   
               
               
                  77 
                 3732 
                 3751 
                 ACCCAAAAGATAAATGTCTG 
               
               
                   
               
               
                  78 
                 3798 
                 3817 
                 TCTTCAAGTTACAAAAGCAA 
               
               
                   
               
               
                  99 
                 3805 
                 3824 
                 ATAAATATCTTCAAGTTACA 
               
               
                   
               
            
           
         
       
     
     In certain embodiments, gapmer antisense compounds are targeted to a PCSK9 nucleic acid. In certain such embodiments, gapmer antisense compounds are targeted to SEQ ID NO: 3. In certain such embodiments, the nucleotide sequences illustrated in Table 12 have a 5-10-5 gapmer motif. Table 13 illustrates gapmer antisense compounds targeted to SEQ ID NO: 3, having a 5-10-5 motif, where the gap segment comprises 2′-deoxynucleotides and each wing segment comprises nucleotides comprising a 2′-O-methoxyethyl sugar modification. Internucleoside linkages are phosphorthioate, and cytidines are 5-methylcytidines. 
     
       
         
           
               
             
               
                 TABLE 13 
               
             
            
               
                   
               
               
                 Gapmer antisense compounds having a 5-10-5 motif targeted to SEQ ID NO: 3 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                   
                   
                 5′ Target 
                 3′ Target 
                   
                   
               
               
                   
                   
                   
                 Site on 
                 Site on 
                   
                   
               
               
                   
                   
                 SEQ ID 
                 SEQ ID 
                 SEQ ID 
                   
                   
               
               
                 Isis No 
                 Motif 
                 NO 
                 NO: 3 
                 NO: 3 
                 Mismatches 
                 Sequence (5′-3′) 
               
               
                   
               
               
                 395201 
                 5-10-5 
                  85 
                  155 
                  174 
                 0 
                 ACAAATTCCCAGACTCAGCA 
               
               
                   
               
               
                 399827 
                 5-10-5 
                 100 
                  220 
                  239 
                 0 
                 ATCTCAGGACAGGTGAGCAA 
               
               
                   
               
               
                 399828 
                 5-10-5 
                 116 
                  234 
                  253 
                 0 
                 GAGTAGAGATTCTCATCTCA 
               
               
                   
               
               
                 395202 
                 5-10-5 
                 129 
                  290 
                  309 
                 0 
                 GTGCCATCTGAACAGCACCT 
               
               
                   
               
               
                 399829 
                 5-10-5 
                 117 
                  302 
                  321 
                 0 
                 GAGTCTTCTGAAGTGCCATC 
               
               
                   
               
               
                 399830 
                 5-10-5 
                  81 
                  377 
                  396 
                 0 
                 AAGCAGGGCCTCAGGTGGAA 
               
               
                   
               
               
                 395203 
                 5-10-5 
                 110 
                  400 
                  419 
                 0 
                 CCTGGAACCCCTGCAGCCAG 
               
               
                   
               
               
                 395204 
                 5-10-5 
                 152 
                  451 
                  470 
                 0 
                 TTCAGGCAGGTTGCTGCTAG 
               
               
                   
               
               
                 399831 
                 5-10-5 
                  83 
                  460 
                  479 
                 0 
                 AAGGAAGACTTCAGGCAGGT 
               
               
                   
               
               
                 395205 
                 5-10-5 
                 140 
                  472 
                  491 
                 0 
                 TCAGCCAGGCCAAAGGAAGA 
               
               
                   
               
               
                 399832 
                 5-10-5 
                 137 
                  586 
                  605 
                 0 
                 TAGGGAGAGCTCACAGATGC 
               
               
                   
               
               
                 395206 
                 5-10-5 
                 136 
                  596 
                  615 
                 0 
                 TAGGAGAAAGTAGGGAGAGC 
               
               
                   
               
               
                 395207 
                 5-10-5 
                 132 
                  653 
                  672 
                 0 
                 TAAAAGCTGCAAGAGACTCA 
               
               
                   
               
               
                 395208 
                 5-10-5 
                 139 
                  741 
                  760 
                 0 
                 TCAGAGAAAACAGTCACCGA 
               
               
                   
               
               
                 399833 
                 5-10-5 
                  92 
                  871 
                  890 
                 0 
                 AGAGACAGGAAGCTGCAGCT 
               
               
                   
               
               
                 395209 
                 5-10-5 
                 142 
                  878 
                  897 
                 0 
                 TCATTTTAGAGACAGGAAGC 
               
               
                   
               
               
                 395210 
                 5-10-5 
                 113 
                  915 
                  934 
                 0 
                 GAATAACAGTGATGTCTGGC 
               
               
                   
               
               
                 395211 
                 5-10-5 
                 138 
                  968 
                  987 
                 0 
                 TCACAGCTCACCGAGTCTGC 
               
               
                   
               
               
                 395212 
                 5-10-5 
                  98 
                  998 
                 1017 
                 0 
                 AGTGTAAAATAAAGCCCCTA 
               
               
                   
               
               
                 395213 
                 5-10-5 
                  96 
                 1075 
                 1094 
                 0 
                 AGGACCCAAGTCATCCTGCT 
               
               
                   
               
               
                 395214 
                 5-10-5 
                 124 
                 1105 
                 1124 
                 0 
                 GGCCATCAGCTGGCAATGCT 
               
               
                   
               
               
                 399834 
                 5-10-5 
                  82 
                 1144 
                 1163 
                 0 
                 AAGGAAAGGGAGGCCTAGAG 
               
               
                   
               
               
                 395215 
                 5-10-5 
                 133 
                 1149 
                 1168 
                 0 
                 TAGACAAGGAAAGGGAGGCC 
               
               
                   
               
               
                 395216 
                 5-10-5 
                 103 
                 1155 
                 1174 
                 0 
                 ATTTCATAGACAAGGAAAGG 
               
               
                   
               
               
                 395217 
                 5-10-5 
                 155 
                 1275 
                 1294 
                 0 
                 CTTATAGTTAACACACAGAA 
               
               
                   
               
               
                 399835 
                 5-10-5 
                 156 
                 1283 
                 1302 
                 0 
                 AAGTCAACCTTATAGTTAAC 
               
               
                   
               
               
                 395218 
                 5-10-5 
                 146 
                 1315 
                 1334 
                 0 
                 TGACATTTGTGGGAGAGGAG 
               
               
                   
               
               
                 395219 
                 5-10-5 
                 161 
                 1322 
                 1341 
                 0 
                 TCCAAGGTGACATTTGTGGG 
               
               
                   
               
               
                 395160 
                 5-10-5 
                  19 
                 1365 
                 1384 
                 0 
                 CTGGTGTCTAGGAGATACAC 
               
               
                   
               
               
                 399797 
                 5-10-5 
                  20 
                 1370 
                 1389 
                 0 
                 GTATGCTGGTGTCTAGGAGA 
               
               
                   
               
               
                 395161 
                 5-10-5 
                  21 
                 1390 
                 1409 
                 0 
                 GATTTCCCGGTGGTCACTCT 
               
               
                   
               
               
                 399798 
                 5-10-5 
                  22 
                 1396 
                 1415 
                 0 
                 GCCCTCGATTTCCCGGTGGT 
               
               
                   
               
               
                 399799 
                 5-10-5 
                  23 
                 1410 
                 1429 
                 0 
                 GTGACCATGACCCTGCCCTC 
               
               
                   
               
               
                 395162 
                 5-10-5 
                  24 
                 1420 
                 1439 
                 0 
                 CTCGAAGTCGGTGACCATGA 
               
               
                   
               
               
                 395163 
                 5-10-5 
                  25 
                 1453 
                 1472 
                 0 
                 GTGGAAGCGGGTCCCGTCCT 
               
               
                   
               
               
                 395164 
                 5-10-5 
                  26 
                 1500 
                 1519 
                 0 
                 ACCCCTGCCAGGTGGGTGCC 
               
               
                   
               
               
                 399800 
                 5-10-5 
                  27 
                 1505 
                 1524 
                 0 
                 TGACCACCCCTGCCAGGTGG 
               
               
                   
               
               
                 395165 
                 5-10-5 
                  28 
                 1534 
                 1553 
                 0 
                 ACCCTTGGCCACGCCGGCAT 
               
               
                   
               
               
                 395166 
                 5-10-5 
                  29 
                 1570 
                 1589 
                 0 
                 TTGGCAGTTGAGCACGCGCA 
               
               
                   
               
               
                 399801 
                 5-10-5 
                  30 
                 1575 
                 1594 
                 0 
                 TTCCCTTGGCAGTTGAGCAC 
               
               
                   
               
               
                 395167 
                 5-10-5 
                  31 
                 1607 
                 1626 
                 0 
                 CCAGGCCTATGAGGGTGCCG 
               
               
                   
               
               
                 395168 
                 5-10-5 
                  32 
                 1628 
                 1647 
                 0 
                 GCTGGCTTTTCCGAATAAAC 
               
               
                   
               
               
                 395169 
                 5-10-5 
                  33 
                 1740 
                 1759 
                 0 
                 GTGACCAGCACGACCCCAGC 
               
               
                   
               
               
                 395175 
                 5-10-5 
                  39 
                 1822 
                 1841 
                 0 
                 TGGAGGCACCAATGATGTCC 
               
               
                   
               
               
                 399804 
                 5-10-5 
                  40 
                 1833 
                 1852 
                 0 
                 GCTGCAGTCGCTGGAGGCAC 
               
               
                   
               
               
                 399805 
                 5-10-5 
                  41 
                 1844 
                 1863 
                 0 
                 ACAAAGCAGGTGCTGCAGTC 
               
               
                   
               
               
                 395176 
                 5-10-5 
                 101 
                 1898 
                 1917 
                 0 
                 ATGGCTGCAATGCCAGCCAC 
               
               
                   
               
               
                 399806 
                 5-10-5 
                  42 
                 1903 
                 1922 
                 0 
                 GCATCATGGCTGCAATGCCA 
               
               
                   
               
               
                 399807 
                 5-10-5 
                  43 
                 1911 
                 1930 
                 0 
                 GGCAGACAGCATCATGGCTG 
               
               
                   
               
               
                 399808 
                 5-10-5 
                  44 
                 1959 
                 1978 
                 0 
                 GAAGTGGATCAGTCTCTGCC 
               
               
                   
               
               
                 395177 
                 5-10-5 
                  45 
                 1967 
                 1986 
                 0 
                 TTGGCAGAGAAGTGGATCAG 
               
               
                   
               
               
                 399809 
                 5-10-5 
                  46 
                 1972 
                 1991 
                 0 
                 CATCTTTGGCAGAGAAGTGG 
               
               
                   
               
               
                 399810 
                 5-10-5 
                  47 
                 1978 
                 1997 
                 0 
                 TGATGACATCTTTGGCAGAG 
               
               
                   
               
               
                 399811 
                 5-10-5 
                  48 
                 1985 
                 2004 
                 0 
                 GCCTCATTGATGACATCTTT 
               
               
                   
               
               
                 399812 
                 5-10-5 
                  49 
                 1997 
                 2016 
                 0 
                 TCAGGGAACCAGGCCTCATT 
               
               
                   
               
               
                 395178 
                 5-10-5 
                  50 
                 2002 
                 2021 
                 0 
                 GGTCCTCAGGGAACCAGGCC 
               
               
                   
               
               
                 395179 
                 5-10-5 
                  87 
                 2009 
                 2028 
                 0 
                 ACCCGCTGGTCCTCAGGGAA 
               
               
                   
               
               
                 399813 
                 5-10-5 
                  51 
                 2016 
                 2035 
                 0 
                 GGTCAGTACCCGCTGGTCCT 
               
               
                   
               
               
                 395180 
                 5-10-5 
                 119 
                 2038 
                 2057 
                 0 
                 GCAGGGCGGCCACCAGGTTG 
               
               
                   
               
               
                 395181 
                 5-10-5 
                  52 
                 2073 
                 2092 
                 0 
                 AAACAGCTGCCAACCTGCCC 
               
               
                   
               
               
                 399814 
                 5-10-5 
                  53 
                 2078 
                 2097 
                 0 
                 CTGCAAAACAGCTGCCAACC 
               
               
                   
               
               
                 395220 
                 5-10-5 
                 104 
                 2085 
                 2104 
                 0 
                 CACAGTCCTGCAAAACAGCT 
               
               
                   
               
               
                 399836 
                 5-10-5 
                 130 
                 2095 
                 2114 
                 0 
                 GTGCTGACCACACAGTCCTG 
               
               
                   
               
               
                 395182 
                 5-10-5 
                  54 
                 2108 
                 2127 
                 0 
                 GTAGGCCCCGAGTGTGCTGA 
               
               
                   
               
               
                 399815 
                 5-10-5 
                  55 
                 2173 
                 2192 
                 0 
                 AGAAACTGGAGCAGCTCAGC 
               
               
                   
               
               
                 399816 
                 5-10-5 
                  56 
                 2179 
                 2198 
                 0 
                 TCCTGGAGAAACTGGAGCAG 
               
               
                   
               
               
                 395186 
                 5-10-5 
                  60 
                 2355 
                 2374 
                 0 
                 CTTTGCATTCCAGACCTGGG 
               
               
                   
               
               
                 399817 
                 5-10-5 
                  61 
                 2360 
                 2379 
                 0 
                 CTTGACTTTGCATTCCAGAC 
               
               
                   
               
               
                 395187 
                 5-10-5 
                  62 
                 2565 
                 2584 
                 0 
                 GGCAGCAGATGGCAACGGCT 
               
               
                   
               
               
                 395188 
                 5-10-5 
                 154 
                 2665 
                 2684 
                 0 
                 TTTTAAAGCTCAGCCCCAGC 
               
               
                   
               
               
                 399818 
                 5-10-5 
                  63 
                 2670 
                 2689 
                 0 
                 AACCATTTTAAAGCTCAGCC 
               
               
                   
               
               
                 395189 
                 5-10-5 
                  64 
                 2759 
                 2778 
                 0 
                 TCAAGGGCCAGGCCAGCAGC 
               
               
                   
               
               
                 399819 
                 5-10-5 
                  65 
                 2764 
                 2783 
                 0 
                 CCCACTCAAGGGCCAGGCCA 
               
               
                   
               
               
                 399820 
                 5-10-5 
                 122 
                 2837 
                 2856 
                 0 
                 GGAGGGAGCTTCCTGGCACC 
               
               
                   
               
               
                 395190 
                 5-10-5 
                  66 
                 2852 
                 2871 
                 0 
                 ATGCCCCACAGTGAGGGAGG 
               
               
                   
               
               
                 395191 
                 5-10-5 
                  67 
                 2861 
                 2880 
                 0 
                 AATGGTGAAATGCCCCACAG 
               
               
                   
               
               
                 395192 
                 5-10-5 
                 153 
                 2904 
                 2923 
                 0 
                 TTGGGAGCAGCTGGCAGCAC 
               
               
                   
               
               
                 395193 
                 5-10-5 
                  68 
                 3005 
                 3024 
                 0 
                 CATGGGAAGAATCCTGCCTC 
               
               
                   
               
               
                 395194 
                 5-10-5 
                  69 
                 3087 
                 3106 
                 0 
                 GGAGATGAGGGCCATCAGCA 
               
               
                   
               
               
                 395195 
                 5-10-5 
                  70 
                 3155 
                 3174 
                 0 
                 TAGATGCCATCCAGAAAGCT 
               
               
                   
               
               
                 399821 
                 5-10-5 
                  71 
                 3161 
                 3180 
                 0 
                 TCTGGCTAGATGCCATCCAG 
               
               
                   
               
               
                 395196 
                 5-10-5 
                  72 
                 3238 
                 3257 
                 0 
                 GGCATAGAGCAGAGTAAAGG 
               
               
                   
               
               
                 399822 
                 5-10-5 
                  73 
                 3243 
                 3262 
                 0 
                 AGCCTGGCATAGAGCAGAGT 
               
               
                   
               
               
                 399823 
                 5-10-5 
                 135 
                 3249 
                 3268 
                 0 
                 TAGCACAGCCTGGCATAGAG 
               
               
                   
               
               
                 395197 
                 5-10-5 
                 112 
                 3482 
                 3501 
                 0 
                 GAAGAGGCTTGGCTTCAGAG 
               
               
                   
               
               
                 399824 
                 5-10-5 
                  74 
                 3488 
                 3507 
                 0 
                 AAGTAAGAAGAGGCTTGGCT 
               
               
                   
               
               
                 395198 
                 5-10-5 
                  75 
                 3692 
                 3711 
                 0 
                 GCTCAAGGAGGGACAGTTGT 
               
               
                   
               
               
                 395199 
                 5-10-5 
                  76 
                 3727 
                 3746 
                 0 
                 AAAGATAAATGTCTGCTTGC 
               
               
                   
               
               
                 399825 
                 5-10-5 
                  77 
                 3732 
                 3751 
                 0 
                 ACCCAAAAGATAAATGTCTG 
               
               
                   
               
               
                 395200 
                 5-10-5 
                  78 
                 3798 
                 3817 
                 0 
                 TCTTCAAGTTACAAAAGCAA 
               
               
                   
               
               
                 399826 
                 5-10-5 
                  99 
                 3805 
                 3824 
                 0 
                 ATAAATATCTTCAAGTTACA 
               
               
                   
               
               
                 405869 
                 5-10-5 
                 218 
                 1392 
                 1411 
                 0 
                 TCGATTTCCCGGTGGTCACT 
               
               
                   
               
               
                 405870 
                 5-10-5 
                 219 
                 1393 
                 1412 
                 0 
                 CTCGATTTCCCGGTGGTCAC 
               
               
                   
               
               
                 405871 
                 5-10-5 
                 220 
                 1394 
                 1413 
                 0 
                 CCTCGATTTCCCGGTGGTCA 
               
               
                   
               
               
                 405872 
                 5-10-5 
                 221 
                 1395 
                 1414 
                 0 
                 CCCTCGATTTCCCGGTGGTC 
               
               
                   
               
               
                 405873 
                 5-10-5 
                 222 
                 1397 
                 1416 
                 0 
                 TGCCCTCGATTTCCCGGTGG 
               
               
                   
               
               
                 405874 
                 5-10-5 
                 223 
                 1398 
                 1417 
                 0 
                 CTGCCCTCGATTTCCCGGTG 
               
               
                   
               
               
                 405875 
                 5-10-5 
                 224 
                 1399 
                 1418 
                 0 
                 CCTGCCCTCGATTTCCCGGT 
               
               
                   
               
               
                 405876 
                 5-10-5 
                 225 
                 1400 
                 1419 
                 0 
                 CCCTGCCCTCGATTTCCCGG 
               
               
                   
               
               
                 405877 
                 5-10-5 
                 246 
                 1530 
                 1549 
                 0 
                 TTGGCCACGCCGGCATCCCG 
               
               
                   
               
               
                 405878 
                 5-10-5 
                 247 
                 1531 
                 1550 
                 0 
                 CTTGGCCACGCCGGCATCCC 
               
               
                   
               
               
                 405879 
                 5-10-5 
                 248 
                 1532 
                 1551 
                 0 
                 CCTTGGCCACGCCGGCATCC 
               
               
                   
               
               
                 405880 
                 5-10-5 
                 249 
                 1533 
                 1552 
                 0 
                 CCCTTGGCCACGCCGGCATC 
               
               
                   
               
               
                 405881 
                 5-10-5 
                 250 
                 1535 
                 1554 
                 0 
                 CACCCTTGGCCACGCCGGCA 
               
               
                   
               
               
                 405882 
                 5-10-5 
                 251 
                 1536 
                 1555 
                 0 
                 GCACCCTTGGCCACGCCGGC 
               
               
                   
               
               
                 405883 
                 5-10-5 
                 252 
                 1537 
                 1556 
                 0 
                 GGCACCCTTGGCCACGCCGG 
               
               
                   
               
               
                 405884 
                 5-10-5 
                 253 
                 1538 
                 1557 
                 0 
                 TGGCACCCTTGGCCACGCCG 
               
               
                   
               
               
                 405885 
                 5-10-5 
                 346 
                 1993 
                 2012 
                 0 
                 GGAACCAGGCCTCATTGATG 
               
               
                   
               
               
                 405886 
                 5-10-5 
                 347 
                 1994 
                 2013 
                 0 
                 GGGAACCAGGCCTCATTGAT 
               
               
                   
               
               
                 405887 
                 5-10-5 
                 348 
                 1995 
                 2014 
                 0 
                 AGGGAACCAGGCCTCATTGA 
               
               
                   
               
               
                 405888 
                 5-10-5 
                 349 
                 1996 
                 2015 
                 0 
                 CAGGGAACCAGGCCTCATTG 
               
               
                   
               
               
                 405889 
                 5-10-5 
                 350 
                 1998 
                 2017 
                 0 
                 CTCAGGGAACCAGGCCTCAT 
               
               
                   
               
               
                 405890 
                 5-10-5 
                 351 
                 1999 
                 2018 
                 0 
                 CCTCAGGGAACCAGGCCTCA 
               
               
                   
               
               
                 405891 
                 5-10-5 
                 352 
                 2000 
                 2019 
                 0 
                 TCCTCAGGGAACCAGGCCTC 
               
               
                   
               
               
                 405892 
                 5-10-5 
                 353 
                 2001 
                 2020 
                 0 
                 GTCCTCAGGGAACCAGGCCT 
               
               
                   
               
               
                 405893 
                 5-10-5 
                 431 
                 3083 
                 3102 
                 0 
                 ATGAGGGCCATCAGCACCTT 
               
               
                   
               
               
                 405894 
                 5-10-5 
                 432 
                 3084 
                 3103 
                 0 
                 GATGAGGGCCATCAGCACCT 
               
               
                   
               
               
                 405895 
                 5-10-5 
                 433 
                 3085 
                 3104 
                 0 
                 AGATGAGGGCCATCAGCACC 
               
               
                   
               
               
                 405896 
                 5-10-5 
                 434 
                 3086 
                 3105 
                 0 
                 GAGATGAGGGCCATCAGCAC 
               
               
                   
               
               
                 405897 
                 5-10-5 
                 435 
                 3088 
                 3107 
                 0 
                 TGGAGATGAGGGCCATCAGC 
               
               
                   
               
               
                 405898 
                 5-10-5 
                 436 
                 3089 
                 3108 
                 0 
                 CTGGAGATGAGGGCCATCAG 
               
               
                   
               
               
                 405899 
                 5-10-5 
                 437 
                 3090 
                 3109 
                 0 
                 GCTGGAGATGAGGGCCATCA 
               
               
                   
               
               
                 405900 
                 5-10-5 
                 438 
                 3091 
                 3110 
                 0 
                 AGCTGGAGATGAGGGCCATC 
               
               
                   
               
               
                 405901 
                 5-10-5 
                 439 
                 3157 
                 3176 
                 0 
                 GCTAGATGCCATCCAGAAAG 
               
               
                   
               
               
                 405902 
                 5-10-5 
                 440 
                 3158 
                 3177 
                 0 
                 GGCTAGATGCCATCCAGAAA 
               
               
                   
               
               
                 405903 
                 5-10-5 
                 441 
                 3159 
                 3178 
                 0 
                 TGGCTAGATGCCATCCAGAA 
               
               
                   
               
               
                 405904 
                 5-10-5 
                 442 
                 3160 
                 3179 
                 0 
                 CTGGCTAGATGCCATCCAGA 
               
               
                   
               
               
                 405905 
                 5-10-5 
                 443 
                 3162 
                 3181 
                 0 
                 CTCTGGCTAGATGCCATCCA 
               
               
                   
               
               
                 405906 
                 5-10-5 
                 444 
                 3163 
                 3182 
                 0 
                 CCTCTGGCTAGATGCCATCC 
               
               
                   
               
               
                 405907 
                 5-10-5 
                 445 
                 3164 
                 3183 
                 0 
                 GCCTCTGGCTAGATGCCATC 
               
               
                   
               
               
                 405908 
                 5-10-5 
                 446 
                 3165 
                 3184 
                 0 
                 AGCCTCTGGCTAGATGCCAT 
               
               
                   
               
               
                 405909 
                 5-10-5 
                 267 
                 1630 
                 1649 
                 0 
                 CAGCTGGCTTTTCCGAATAA 
               
               
                   
               
               
                 405910 
                 5-10-5 
                 268 
                 1632 
                 1651 
                 0 
                 ACCAGCTGGCTTTTCCGAAT 
               
               
                   
               
               
                 405911 
                 5-10-5 
                 269 
                 1634 
                 1653 
                 0 
                 GGACCAGCTGGCTTTTCCGA 
               
               
                   
               
               
                 405912 
                 5-10-5 
                 270 
                 1638 
                 1657 
                 0 
                 GGCTGGACCAGCTGGCTTTT 
               
               
                   
               
               
                 405913 
                 5-10-5 
                 275 
                 1742 
                 1761 
                 0 
                 CGGTGACCAGCACGACCCCA 
               
               
                   
               
               
                 405914 
                 5-10-5 
                 276 
                 1744 
                 1763 
                 0 
                 AGCGGTGACCAGCACGACCC 
               
               
                   
               
               
                 405915 
                 5-10-5 
                 277 
                 1746 
                 1765 
                 0 
                 GCAGCGGTGACCAGCACGAC 
               
               
                   
               
               
                 405916 
                 5-10-5 
                 278 
                 1748 
                 1767 
                 0 
                 CGGCAGCGGTGACCAGCACG 
               
               
                   
               
               
                 405917 
                 5-10-5 
                 280 
                 1752 
                 1771 
                 0 
                 TTGCCGGCAGCGGTGACCAG 
               
               
                   
               
               
                 405918 
                 5-10-5 
                 281 
                 1754 
                 1773 
                 0 
                 AGTTGCCGGCAGCGGTGACC 
               
               
                   
               
               
                 405919 
                 5-10-5 
                 282 
                 1756 
                 1775 
                 0 
                 GAAGTTGCCGGCAGCGGTGA 
               
               
                   
               
               
                 405920 
                 5-10-5 
                 283 
                 1758 
                 1777 
                 0 
                 CGGAAGTTGCCGGCAGCGGT 
               
               
                   
               
               
                 405921 
                 5-10-5 
                 284 
                 1760 
                 1779 
                 0 
                 CCCGGAAGTTGCCGGCAGCG 
               
               
                   
               
               
                 405922 
                 5-10-5 
                 285 
                 1762 
                 1781 
                 0 
                 GTCCCGGAAGTTGCCGGCAG 
               
               
                   
               
               
                 405937 
                 5-10-5 
                 306 
                 1820 
                 1839 
                 0 
                 GAGGCACCAATGATGTCCTC 
               
               
                   
               
               
                 405938 
                 5-10-5 
                 307 
                 1824 
                 1843 
                 0 
                 GCTGGAGGCACCAATGATGT 
               
               
                   
               
               
                 405939 
                 5-10-5 
                 308 
                 1826 
                 1845 
                 0 
                 TCGCTGGAGGCACCAATGAT 
               
               
                   
               
               
                 405940 
                 5-10-5 
                 309 
                 1828 
                 1847 
                 0 
                 AGTCGCTGGAGGCACCAATG 
               
               
                   
               
               
                 405941 
                 5-10-5 
                 310 
                 1830 
                 1849 
                 0 
                 GCAGTCGCTGGAGGCACCAA 
               
               
                   
               
               
                 405942 
                 5-10-5 
                 311 
                 1835 
                 1854 
                 0 
                 GTGCTGCAGTCGCTGGAGGC 
               
               
                   
               
               
                 405943 
                 5-10-5 
                 312 
                 1837 
                 1856 
                 0 
                 AGGTGCTGCAGTCGCTGGAG 
               
               
                   
               
               
                 405944 
                 5-10-5 
                 314 
                 1840 
                 1859 
                 0 
                 AGCAGGTGCTGCAGTCGCTG 
               
               
                   
               
               
                 405945 
                 5-10-5 
                 315 
                 1842 
                 1861 
                 0 
                 AAAGCAGGTGCTGCAGTCGC 
               
               
                   
               
               
                 405946 
                 5-10-5 
                 316 
                 1846 
                 1865 
                 0 
                 ACACAAAGCAGGTGCTGCAG 
               
               
                   
               
               
                 405947 
                 5-10-5 
                 317 
                 1848 
                 1867 
                 0 
                 TGACACAAAGCAGGTGCTGC 
               
               
                   
               
               
                 405948 
                 5-10-5 
                 319 
                 1900 
                 1919 
                 0 
                 TCATGGCTGCAATGCCAGCC 
               
               
                   
               
               
                 405949 
                 5-10-5 
                 320 
                 1905 
                 1924 
                 0 
                 CAGCATCATGGCTGCAATGC 
               
               
                   
               
               
                 405950 
                 5-10-5 
                 321 
                 1907 
                 1926 
                 0 
                 GACAGCATCATGGCTGCAAT 
               
               
                   
               
               
                 405951 
                 5-10-5 
                 322 
                 1909 
                 1928 
                 0 
                 CAGACAGCATCATGGCTGCA 
               
               
                   
               
               
                 405952 
                 5-10-5 
                 323 
                 1913 
                 1932 
                 0 
                 TCGGCAGACAGCATCATGGC 
               
               
                   
               
               
                 405953 
                 5-10-5 
                 325 
                 1917 
                 1936 
                 0 
                 CGGCTCGGCAGACAGCATCA 
               
               
                   
               
               
                 405954 
                 5-10-5 
                 326 
                 1919 
                 1938 
                 0 
                 TCCGGCTCGGCAGACAGCAT 
               
               
                   
               
               
                 405955 
                 5-10-5 
                 328 
                 1946 
                 1965 
                 0 
                 CTCTGCCTCAACTCGGCCAG 
               
               
                   
               
               
                 405956 
                 5-10-5 
                 329 
                 1948 
                 1967 
                 0 
                 GTCTCTGCCTCAACTCGGCC 
               
               
                   
               
               
                 405957 
                 5-10-5 
                 330 
                 1950 
                 1969 
                 0 
                 CAGTCTCTGCCTCAACTCGG 
               
               
                   
               
               
                 405958 
                 5-10-5 
                 331 
                 1952 
                 1971 
                 0 
                 ATCAGTCTCTGCCTCAACTC 
               
               
                   
               
               
                 405959 
                 5-10-5 
                 332 
                 1954 
                 1973 
                 0 
                 GGATCAGTCTCTGCCTCAAC 
               
               
                   
               
               
                 405960 
                 5-10-5 
                 333 
                 1956 
                 1975 
                 0 
                 GTGGATCAGTCTCTGCCTCA 
               
               
                   
               
               
                 405961 
                 5-10-5 
                 334 
                 1958 
                 1977 
                 0 
                 AAGTGGATCAGTCTCTGCCT 
               
               
                   
               
               
                 405962 
                 5-10-5 
                 335 
                 1961 
                 1980 
                 0 
                 GAGAAGTGGATCAGTCTCTG 
               
               
                   
               
               
                 405963 
                 5-10-5 
                 337 
                 1965 
                 1984 
                 0 
                 GGCAGAGAAGTGGATCAGTC 
               
               
                   
               
               
                 405964 
                 5-10-5 
                 338 
                 1969 
                 1988 
                 0 
                 CTTTGGCAGAGAAGTGGATC 
               
               
                   
               
               
                 405965 
                 5-10-5 
                 339 
                 1974 
                 1993 
                 0 
                 GACATCTTTGGCAGAGAAGT 
               
               
                   
               
               
                 405966 
                 5-10-5 
                 340 
                 1976 
                 1995 
                 0 
                 ATGACATCTTTGGCAGAGAA 
               
               
                   
               
               
                 405967 
                 5-10-5 
                 341 
                 1980 
                 1999 
                 0 
                 ATTGATGACATCTTTGGCAG 
               
               
                   
               
               
                 405968 
                 5-10-5 
                 342 
                 1982 
                 2001 
                 0 
                 TCATTGATGACATCTTTGGC 
               
               
                   
               
               
                 405969 
                 5-10-5 
                 343 
                 1987 
                 2006 
                 0 
                 AGGCCTCATTGATGACATCT 
               
               
                   
               
               
                 405970 
                 5-10-5 
                 344 
                 1989 
                 2008 
                 0 
                 CCAGGCCTCATTGATGACAT 
               
               
                   
               
               
                 405971 
                 5-10-5 
                 355 
                 2004 
                 2023 
                 0 
                 CTGGTCCTCAGGGAACCAGG 
               
               
                   
               
               
                 405972 
                 5-10-5 
                 357 
                 2006 
                 2025 
                 0 
                 CGCTGGTCCTCAGGGAACCA 
               
               
                   
               
               
                 405973 
                 5-10-5 
                 358 
                 2011 
                 2030 
                 0 
                 GTACCCGCTGGTCCTCAGGG 
               
               
                   
               
               
                 405974 
                 5-10-5 
                 359 
                 2013 
                 2032 
                 0 
                 CAGTACCCGCTGGTCCTCAG 
               
               
                   
               
               
                 405975 
                 5-10-5 
                 361 
                 2075 
                 2094 
                 0 
                 CAAAACAGCTGCCAACCTGC 
               
               
                   
               
               
                 405976 
                 5-10-5 
                 362 
                 2080 
                 2099 
                 0 
                 TCCTGCAAAACAGCTGCCAA 
               
               
                   
               
               
                 405977 
                 5-10-5 
                 363 
                 2082 
                 2101 
                 0 
                 AGTCCTGCAAAACAGCTGCC 
               
               
                   
               
               
                 405978 
                 5-10-5 
                 365 
                 2105 
                 2124 
                 0 
                 GGCCCCGAGTGTGCTGACCA 
               
               
                   
               
               
                 405979 
                 5-10-5 
                 366 
                 2110 
                 2129 
                 0 
                 GTGTAGGCCCCGAGTGTGCT 
               
               
                   
               
               
                 405980 
                 5-10-5 
                 367 
                 2112 
                 2131 
                 0 
                 CCGTGTAGGCCCCGAGTGTG 
               
               
                   
               
               
                 405981 
                 5-10-5 
                 368 
                 2114 
                 2133 
                 0 
                 ATCCGTGTAGGCCCCGAGTG 
               
               
                   
               
               
                 405982 
                 5-10-5 
                 370 
                 2118 
                 2137 
                 0 
                 GGCCATCCGTGTAGGCCCCG 
               
               
                   
               
               
                 405983 
                 5-10-5 
                 371 
                 2120 
                 2139 
                 0 
                 GTGGCCATCCGTGTAGGCCC 
               
               
                   
               
               
                 405984 
                 5-10-5 
                 372 
                 2168 
                 2187 
                 0 
                 CTGGAGCAGCTCAGCAGCTC 
               
               
                   
               
               
                 405985 
                 5-10-5 
                 373 
                 2170 
                 2189 
                 0 
                 AACTGGAGCAGCTCAGCAGC 
               
               
                   
               
               
                 405986 
                 5-10-5 
                 374 
                 2175 
                 2194 
                 0 
                 GGAGAAACTGGAGCAGCTCA 
               
               
                   
               
               
                 405987 
                 5-10-5 
                 375 
                 2177 
                 2196 
                 0 
                 CTGGAGAAACTGGAGCAGCT 
               
               
                   
               
               
                 405996 
                 5-10-5 
                 412 
                 2357 
                 2376 
                 0 
                 GACTTTGCATTCCAGACCTG 
               
               
                   
               
               
                 405997 
                 5-10-5 
                 415 
                 2362 
                 2381 
                 0 
                 TCCTTGACTTTGCATTCCAG 
               
               
                   
               
               
                 405998 
                 5-10-5 
                 426 
                 2568 
                 2587 
                 0 
                 TCCGGCAGCAGATGGCAACG 
               
               
                   
               
               
                 406025 
                 5-10-5 
                 216 
                 1362 
                 1381 
                 0 
                 GTGTCTAGGAGATACACCTC 
               
               
                   
               
               
                 406026 
                 5-10-5 
                 217 
                 1367 
                 1386 
                 0 
                 TGCTGGTGTCTAGGAGATAC 
               
               
                   
               
               
                 406027 
                 5-10-5 
                 226 
                 1404 
                 1423 
                 0 
                 ATGACCCTGCCCTCGATTTC 
               
               
                   
               
               
                 406028 
                 5-10-5 
                 227 
                 1406 
                 1425 
                 0 
                 CCATGACCCTGCCCTCGATT 
               
               
                   
               
               
                 406029 
                 5-10-5 
                 228 
                 1408 
                 1427 
                 0 
                 GACCATGACCCTGCCCTCGA 
               
               
                   
               
               
                 406030 
                 5-10-5 
                 229 
                 1412 
                 1431 
                 0 
                 CGGTGACCATGACCCTGCCC 
               
               
                   
               
               
                 406031 
                 5-10-5 
                 230 
                 1414 
                 1433 
                 0 
                 GTCGGTGACCATGACCCTGC 
               
               
                   
               
               
                 406032 
                 5-10-5 
                 232 
                 1418 
                 1437 
                 0 
                 CGAAGTCGGTGACCATGACC 
               
               
                   
               
               
                 406033 
                 5-10-5 
                 237 
                 1497 
                 1516 
                 0 
                 CCTGCCAGGTGGGTGCCATG 
               
               
                   
               
               
                 406034 
                 5-10-5 
                 238 
                 1502 
                 1521 
                 0 
                 CCACCCCTGCCAGGTGGGTG 
               
               
                   
               
               
                 406035 
                 5-10-5 
                 239 
                 1507 
                 1526 
                 0 
                 GCTGACCACCCCTGCCAGGT 
               
               
                   
               
               
                 406036 
                 5-10-5 
                 241 
                 1519 
                 1538 
                 0 
                 GGCATCCCGGCCGCTGACCA 
               
               
                   
               
               
                 406037 
                 5-10-5 
                 242 
                 1522 
                 1541 
                 0 
                 GCCGGCATCCCGGCCGCTGA 
               
               
                   
               
               
                 406038 
                 5-10-5 
                 245 
                 1529 
                 1548 
                 0 
                 TGGCCACGCCGGCATCCCGG 
               
               
                   
               
               
                 406039 
                 5-10-5 
                 257 
                 1566 
                 1585 
                 0 
                 CAGTTGAGCACGCGCAGGCT 
               
               
                   
               
               
                 406040 
                 5-10-5 
                 258 
                 1568 
                 1587 
                 0 
                 GGCAGTTGAGCACGCGCAGG 
               
               
                   
               
               
                 406041 
                 5-10-5 
                 259 
                 1572 
                 1591 
                 0 
                 CCTTGGCAGTTGAGCACGCG 
               
               
                   
               
               
                 406042 
                 5-10-5 
                 260 
                 1577 
                 1596 
                 0 
                 CCTTCCCTTGGCAGTTGAGC 
               
               
                   
               
               
                 406043 
                 5-10-5 
                 261 
                 1581 
                 1600 
                 0 
                 GTGCCCTTCCCTTGGCAGTT 
               
               
                   
               
               
                 406044 
                 5-10-5 
                 262 
                 1583 
                 1602 
                 0 
                 CCGTGCCCTTCCCTTGGCAG 
               
               
                   
               
               
                 406045 
                 5-10-5 
                 266 
                 1626 
                 1645 
                 0 
                 TGGCTTTTCCGAATAAACTC 
               
               
                   
               
               
                 408642 
                 5-10-5 
                 264 
                 1606 
                 1625 
                 0 
                 CAGGCCTATGAGGGTGCCGC 
               
               
                   
               
               
                 408653 
                 5-10-5 
                 354 
                 2003 
                 2022 
                 0 
                 TGGTCCTCAGGGAACCAGGC 
               
               
                   
               
               
                 409126 
                 5-10-5 
                 447 
                 1534 
                 1553 
                 1 
                 ACCCTTGGTCACGCCGGCAT 
               
               
                   
               
               
                 410536 
                 5-10-5 
                 243 
                 1527 
                 1546 
                 0 
                 GCCACGCCGGCATCCCGGCC 
               
               
                   
               
               
                 410537 
                 5-10-5 
                 244 
                 1528 
                 1547 
                 0 
                 GGCCACGCCGGCATCCCGGC 
               
               
                   
               
               
                 410538 
                 5-10-5 
                 254 
                 1539 
                 1558 
                 0 
                 CTGGCACCCTTGGCCACGCC 
               
               
                   
               
               
                 410539 
                 5-10-5 
                 255 
                 1540 
                 1559 
                 0 
                 GCTGGCACCCTTGGCCACGC 
               
               
                   
               
               
                 410540 
                 5-10-5 
                 356 
                 2005 
                 2024 
                 0 
                 GCTGGTCCTCAGGGAACCAG 
               
               
                   
               
               
                 410562 
                 5-10-5 
                 411 
                 2356 
                 2375 
                 0 
                 ACTTTGCATTCCAGACCTGG 
               
               
                   
               
               
                 410563 
                 5-10-5 
                 413 
                 2358 
                 2377 
                 0 
                 TGACTTTGCATTCCAGACCT 
               
               
                   
               
               
                 410564 
                 5-10-5 
                 414 
                 2359 
                 2378 
                 0 
                 TTGACTTTGCATTCCAGACC 
               
               
                   
               
               
                 410565 
                 5-10-5 
                 419 
                 2560 
                 2579 
                 0 
                 CAGATGGCAACGGCTGTCAC 
               
               
                   
               
               
                 410566 
                 5-10-5 
                 420 
                 2561 
                 2580 
                 0 
                 GCAGATGGCAACGGCTGTCA 
               
               
                   
               
               
                 410567 
                 5-10-5 
                 421 
                 2562 
                 2581 
                 0 
                 AGCAGATGGCAACGGCTGTC 
               
               
                   
               
               
                 410568 
                 5-10-5 
                 422 
                 2563 
                 2582 
                 0 
                 CAGCAGATGGCAACGGCTGT 
               
               
                   
               
               
                 410569 
                 5-10-5 
                 423 
                 2564 
                 2583 
                 0 
                 GCAGCAGATGGCAACGGCTG 
               
               
                   
               
               
                 410570 
                 5-10-5 
                 424 
                 2566 
                 2585 
                 0 
                 CGGCAGCAGATGGCAACGGC 
               
               
                   
               
               
                 410571 
                 5-10-5 
                 425 
                 2567 
                 2586 
                 0 
                 CCGGCAGCAGATGGCAACGG 
               
               
                   
               
               
                 410572 
                 5-10-5 
                 427 
                 2569 
                 2588 
                 0 
                 CTCCGGCAGCAGATGGCAAC 
               
               
                   
               
               
                 410573 
                 5-10-5 
                 428 
                 2570 
                 2589 
                 0 
                 GCTCCGGCAGCAGATGGCAA 
               
               
                   
               
               
                 410733 
                 5-10-5 
                 231 
                 1416 
                 1435 
                 0 
                 AAGTCGGTGACCATGACCCT 
               
               
                   
               
               
                 410734 
                 5-10-5 
                 279 
                 1749 
                 1768 
                 0 
                 CCGGCAGCGGTGACCAGCAC 
               
               
                   
               
               
                 410737 
                 5-10-5 
                 313 
                 1839 
                 1858 
                 0 
                 GCAGGTGCTGCAGTCGCTGG 
               
               
                   
               
               
                 410738 
                 5-10-5 
                 324 
                 1915 
                 1934 
                 0 
                 GCTCGGCAGACAGCATCATG 
               
               
                   
               
               
                 410739 
                 5-10-5 
                 336 
                 1963 
                 1982 
                 0 
                 CAGAGAAGTGGATCAGTCTC 
               
               
                   
               
               
                 410740 
                 5-10-5 
                 345 
                 1991 
                 2010 
                 0 
                 AACCAGGCCTCATTGATGAC 
               
               
                   
               
               
                 410741 
                 5-10-5 
                 369 
                 2116 
                 2135 
                 0 
                 CCATCCGTGTAGGCCCCGAG 
               
               
                   
               
               
                 410753 
                 5-10-5 
                 215 
                 1351 
                 1370 
                 0 
                 ATACACCTCCACCAGGCTGC 
               
               
                   
               
               
                 410754 
                 5-10-5 
                 233 
                 1428 
                 1447 
                 0 
                 GGCACATTCTCGAAGTCGGT 
               
               
                   
               
               
                 410755 
                 5-10-5 
                 234 
                 1463 
                 1482 
                 0 
                 TGGCCTGTCTGTGGAAGCGG 
               
               
                   
               
               
                 410756 
                 5-10-5 
                 235 
                 1490 
                 1509 
                 0 
                 GGTGGGTGCCATGACTGTCA 
               
               
                   
               
               
                 410757 
                 5-10-5 
                 240 
                 1515 
                 1534 
                 0 
                 TCCCGGCCGCTGACCACCCC 
               
               
                   
               
               
                 410758 
                 5-10-5 
                 256 
                 1545 
                 1564 
                 0 
                 CGCATGCTGGCACCCTTGGC 
               
               
                   
               
               
                 410759 
                 5-10-5 
                 263 
                 1594 
                 1613 
                 0 
                 GGTGCCGCTAACCGTGCCCT 
               
               
                   
               
               
                 410760 
                 5-10-5 
                 265 
                 1618 
                 1637 
                 0 
                 CCGAATAAACTCCAGGCCTA 
               
               
                   
               
               
                 410761 
                 5-10-5 
                 271 
                 1649 
                 1668 
                 0 
                 GTGGCCCCACAGGCTGGACC 
               
               
                   
               
               
                 410762 
                 5-10-5 
                 272 
                 1662 
                 1681 
                 0 
                 AGCAGCACCACCAGTGGCCC 
               
               
                   
               
               
                 410763 
                 5-10-5 
                 273 
                 1684 
                 1703 
                 0 
                 GCTGTACCCACCCGCCAGGG 
               
               
                   
               
               
                 410764 
                 5-10-5 
                 274 
                 1730 
                 1749 
                 0 
                 CGACCCCAGCCCTCGCCAGG 
               
               
                   
               
               
                 410769 
                 5-10-5 
                 318 
                 1858 
                 1877 
                 0 
                 TCCCACTCTGTGACACAAAG 
               
               
                   
               
               
                 410770 
                 5-10-5 
                 327 
                 1933 
                 1952 
                 0 
                 CGGCCAGGGTGAGCTCCGGC 
               
               
                   
               
               
                 410771 
                 5-10-5 
                 360 
                 2061 
                 2080 
                 0 
                 ACCTGCCCCATGGGTGCTGG 
               
               
                   
               
               
                 410776 
                 5-10-5 
                 408 
                 2245 
                 2264 
                 0 
                 GTGCCAAGGTCCTCCACCTC 
               
               
                   
               
               
                 410777 
                 5-10-5 
                 409 
                 2265 
                 2284 
                 0 
                 TCAGCACAGGCGGCTTGTGG 
               
               
                   
               
               
                 410778 
                 5-10-5 
                 410 
                 2295 
                 2314 
                 0 
                 CCACGCACTGGTTGGGCTGA 
               
               
                   
               
               
                 410779 
                 5-10-5 
                 416 
                 2375 
                 2394 
                 0 
                 CGGGATTCCATGCTCCTTGA 
               
               
                   
               
               
                 410780 
                 5-10-5 
                 417 
                 2405 
                 2424 
                 0 
                 GCAGGCCACGGTCACCTGCT 
               
               
                   
               
               
                 410781 
                 5-10-5 
                 418 
                 2442 
                 2461 
                 0 
                 GGAGGGCACTGCAGCCAGTC 
               
               
                   
               
               
                 410782 
                 5-10-5 
                 429 
                 2580 
                 2599 
                 0 
                 CCAGGTGCCGGCTCCGGCAG 
               
               
                   
               
               
                 410783 
                 5-10-5 
                 430 
                 2590 
                 2609 
                 0 
                 GAGGCCTGCGCCAGGTGCCG 
               
               
                   
               
            
           
         
       
     
     In certain embodiments, gap-widened antisense compounds are targeted to a PCSK9 nucleic acid. In certain such embodiments, gap-widened antisense compounds are targeted to SEQ ID NO: 3. In certain such embodiments, the nucleotide sequences illustrated in Table 12 have a 3-14-3 gap-widened motif. Table 14 illustrates gap-widened antisense compounds targeted to SEQ ID NO: 3, having a 3-14-3 motif, where the gap segment comprises 2′-deoxynucleotides and each wing segment comprises nucleotides comprising a 2′-O-methoxyethyl sugar modification. Internucleoside linkages are phosphorthioate, and cytidines are 5-methylcytidines. 
     
       
         
           
               
             
               
                 TABLE 14 
               
             
            
               
                   
               
               
                 Gapmer antisense compounds having a 3-14-3 motif targeted to SEQ ID NO: 3 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                   
                   
                 5′ Target 
                 3′ Target 
                   
                   
               
               
                   
                   
                   
                 Site on 
                 Site on 
                   
                   
               
               
                   
                   
                 SEQ ID 
                 SEQ ID 
                 SEQ ID 
                   
                   
               
               
                 Isis No 
                 Motif 
                 NO 
                 NO: 3 
                 NO: 3 
                 Mismatches 
                 Sequence (5′-3′) 
               
               
                   
               
               
                 399923 
                 3-14-3 
                  85 
                  155 
                  174 
                 0 
                 ACAAATTCCCAGACTCAGCA 
               
               
                   
               
               
                 399983 
                 3-14-3 
                 100 
                  220 
                  239 
                 0 
                 ATCTCAGGACAGGTGAGCAA 
               
               
                   
               
               
                 399984 
                 3-14-3 
                 116 
                  234 
                  253 
                 0 
                 GAGTAGAGATTCTCATCTCA 
               
               
                   
               
               
                 399924 
                 3-14-3 
                 129 
                  290 
                  309 
                 0 
                 GTGCCATCTGAACAGCACCT 
               
               
                   
               
               
                 399985 
                 3-14-3 
                 117 
                  302 
                  321 
                 0 
                 GAGTCTTCTGAAGTGCCATC 
               
               
                   
               
               
                 399986 
                 3-14-3 
                  81 
                  377 
                  396 
                 0 
                 AAGCAGGGCCTCAGGTGGAA 
               
               
                   
               
               
                 399925 
                 3-14-3 
                 110 
                  400 
                  419 
                 0 
                 CCTGGAACCCCTGCAGCCAG 
               
               
                   
               
               
                 399926 
                 3-14-3 
                 152 
                  451 
                  470 
                 0 
                 TTCAGGCAGGTTGCTGCTAG 
               
               
                   
               
               
                 399987 
                 3-14-3 
                  83 
                  460 
                  479 
                 0 
                 AAGGAAGACTTCAGGCAGGT 
               
               
                   
               
               
                 399927 
                 3-14-3 
                 140 
                  472 
                  491 
                 0 
                 TCAGCCAGGCCAAAGGAAGA 
               
               
                   
               
               
                 399988 
                 3-14-3 
                 137 
                  586 
                  605 
                 0 
                 TAGGGAGAGCTCACAGATGC 
               
               
                   
               
               
                 399928 
                 3-14-3 
                 136 
                  596 
                  615 
                 0 
                 TAGGAGAAAGTAGGGAGAGC 
               
               
                   
               
               
                 399929 
                 3-14-3 
                 132 
                  653 
                  672 
                 0 
                 TAAAAGCTGCAAGAGACTCA 
               
               
                   
               
               
                 399930 
                 3-14-3 
                 139 
                  741 
                  760 
                 0 
                 TCAGAGAAAACAGTCACCGA 
               
               
                   
               
               
                 399989 
                 3-14-3 
                  92 
                  871 
                  890 
                 0 
                 AGAGACAGGAAGCTGCAGCT 
               
               
                   
               
               
                 399931 
                 3-14-3 
                 142 
                  878 
                  897 
                 0 
                 TCATTTTAGAGACAGGAAGC 
               
               
                   
               
               
                 399932 
                 3-14-3 
                 113 
                  915 
                  934 
                 0 
                 GAATAACAGTGATGTCTGGC 
               
               
                   
               
               
                 399933 
                 3-14-3 
                 138 
                  968 
                  987 
                 0 
                 TCACAGCTCACCGAGTCTGC 
               
               
                   
               
               
                 399934 
                 3-14-3 
                  98 
                  998 
                 1017 
                 0 
                 AGTGTAAAATAAAGCCCCTA 
               
               
                   
               
               
                 399935 
                 3-14-3 
                  96 
                 1075 
                 1094 
                 0 
                 AGGACCCAAGTCATCCTGCT 
               
               
                   
               
               
                 399936 
                 3-14-3 
                 124 
                 1105 
                 1124 
                 0 
                 GGCCATCAGCTGGCAATGCT 
               
               
                   
               
               
                 399990 
                 3-14-3 
                  82 
                 1144 
                 1163 
                 0 
                 AAGGAAAGGGAGGCCTAGAG 
               
               
                   
               
               
                 399937 
                 3-14-3 
                 133 
                 1149 
                 1168 
                 0 
                 TAGACAAGGAAAGGGAGGCC 
               
               
                   
               
               
                 399938 
                 3-14-3 
                 103 
                 1155 
                 1174 
                 0 
                 ATTTCATAGACAAGGAAAGG 
               
               
                   
               
               
                 399939 
                 3-14-3 
                 155 
                 1275 
                 1294 
                 0 
                 CTTATAGTTAACACACAGAA 
               
               
                   
               
               
                 399991 
                 3-14-3 
                 156 
                 1283 
                 1302 
                 0 
                 AAGTCAACCTTATAGTTAAC 
               
               
                   
               
               
                 399940 
                 3-14-3 
                 146 
                 1315 
                 1334 
                 0 
                 TGACATTTGTGGGAGAGGAG 
               
               
                   
               
               
                 399941 
                 3-14-3 
                 161 
                 1322 
                 1341 
                 0 
                 TCCAAGGTGACATTTGTGGG 
               
               
                   
               
               
                 399882 
                 3-14-3 
                  19 
                 1365 
                 1384 
                 0 
                 CTGGTGTCTAGGAGATACAC 
               
               
                   
               
               
                 399953 
                 3-14-3 
                  20 
                 1370 
                 1389 
                 0 
                 GTATGCTGGTGTCTAGGAGA 
               
               
                   
               
               
                 399883 
                 3-14-3 
                  21 
                 1390 
                 1409 
                 0 
                 GATTTCCCGGTGGTCACTCT 
               
               
                   
               
               
                 399954 
                 3-14-3 
                  22 
                 1396 
                 1415 
                 0 
                 GCCCTCGATTTCCCGGTGGT 
               
               
                   
               
               
                 399955 
                 3-14-3 
                  23 
                 1410 
                 1429 
                 0 
                 GTGACCATGACCCTGCCCTC 
               
               
                   
               
               
                 399884 
                 3-14-3 
                  24 
                 1420 
                 1439 
                 0 
                 CTCGAAGTCGGTGACCATGA 
               
               
                   
               
               
                 399885 
                 3-14-3 
                  25 
                 1453 
                 1472 
                 0 
                 GTGGAAGCGGGTCCCGTCCT 
               
               
                   
               
               
                 399886 
                 3-14-3 
                  26 
                 1500 
                 1519 
                 0 
                 ACCCCTGCCAGGTGGGTGCC 
               
               
                   
               
               
                 399956 
                 3-14-3 
                  27 
                 1505 
                 1524 
                 0 
                 TGACCACCCCTGCCAGGTGG 
               
               
                   
               
               
                 399887 
                 3-14-3 
                  28 
                 1534 
                 1553 
                 0 
                 ACCCTTGGCCACGCCGGCAT 
               
               
                   
               
               
                 399888 
                 3-14-3 
                  29 
                 1570 
                 1589 
                 0 
                 TTGGCAGTTGAGCACGCGCA 
               
               
                   
               
               
                 399957 
                 3-14-3 
                  30 
                 1575 
                 1594 
                 0 
                 TTCCCTTGGCAGTTGAGCAC 
               
               
                   
               
               
                 399889 
                 3-14-3 
                  31 
                 1607 
                 1626 
                 0 
                 CCAGGCCTATGAGGGTGCCG 
               
               
                   
               
               
                 399890 
                 3-14-3 
                  32 
                 1628 
                 1647 
                 0 
                 GCTGGCTTTTCCGAATAAAC 
               
               
                   
               
               
                 399891 
                 3-14-3 
                  33 
                 1740 
                 1759 
                 0 
                 GTGACCAGCACGACCCCAGC 
               
               
                   
               
               
                 399897 
                 3-14-3 
                  39 
                 1822 
                 1841 
                 0 
                 TGGAGGCACCAATGATGTCC 
               
               
                   
               
               
                 399960 
                 3-14-3 
                  40 
                 1833 
                 1852 
                 0 
                 GCTGCAGTCGCTGGAGGCAC 
               
               
                   
               
               
                 399961 
                 3-14-3 
                  41 
                 1844 
                 1863 
                 0 
                 ACAAAGCAGGTGCTGCAGTC 
               
               
                   
               
               
                 399898 
                 3-14-3 
                 101 
                 1898 
                 1917 
                 0 
                 ATGGCTGCAATGCCAGCCAC 
               
               
                   
               
               
                 399962 
                 3-14-3 
                  42 
                 1903 
                 1922 
                 0 
                 GCATCATGGCTGCAATGCCA 
               
               
                   
               
               
                 399963 
                 3-14-3 
                  43 
                 1911 
                 1930 
                 0 
                 GGCAGACAGCATCATGGCTG 
               
               
                   
               
               
                 399964 
                 3-14-3 
                  44 
                 1959 
                 1978 
                 0 
                 GAAGTGGATCAGTCTCTGCC 
               
               
                   
               
               
                 399899 
                 3-14-3 
                  45 
                 1967 
                 1986 
                 0 
                 TTGGCAGAGAAGTGGATCAG 
               
               
                   
               
               
                 399965 
                 3-14-3 
                  46 
                 1972 
                 1991 
                 0 
                 CATCTTTGGCAGAGAAGTGG 
               
               
                   
               
               
                 399966 
                 3-14-3 
                  47 
                 1978 
                 1997 
                 0 
                 TGATGACATCTTTGGCAGAG 
               
               
                   
               
               
                 399967 
                 3-14-3 
                  48 
                 1985 
                 2004 
                 0 
                 GCCTCATTGATGACATCTTT 
               
               
                   
               
               
                 399968 
                 3-14-3 
                  49 
                 1997 
                 2016 
                 0 
                 TCAGGGAACCAGGCCTCATT 
               
               
                   
               
               
                 399900 
                 3-14-3 
                  50 
                 2002 
                 2021 
                 0 
                 GGTCCTCAGGGAACCAGGCC 
               
               
                   
               
               
                 399901 
                 3-14-3 
                  87 
                 2009 
                 2028 
                 0 
                 ACCCGCTGGTCCTCAGGGAA 
               
               
                   
               
               
                 399969 
                 3-14-3 
                  51 
                 2016 
                 2035 
                 0 
                 GGTCAGTACCCGCTGGTCCT 
               
               
                   
               
               
                 399902 
                 3-14-3 
                 119 
                 2038 
                 2057 
                 0 
                 GCAGGGCGGCCACCAGGTTG 
               
               
                   
               
               
                 399903 
                 3-14-3 
                   52 
                 2073 
                 2092 
                 0 
                 AAACAGCTGCCAACCTGCCC 
               
               
                   
               
               
                 399970 
                 3-14-3 
                   53 
                 2078 
                 2097 
                 0 
                 CTGCAAAACAGCTGCCAACC 
               
               
                   
               
               
                 399942 
                 3-14-3 
                 104 
                 2085 
                 2104 
                 0 
                 CACAGTCCTGCAAAACAGCT 
               
               
                   
               
               
                 399992 
                 3-14-3 
                 130 
                 2095 
                 2114 
                 0 
                 GTGCTGACCACACAGTCCTG 
               
               
                   
               
               
                 399904 
                 3-14-3 
                  54 
                 2108 
                 2127 
                 0 
                 GTAGGCCCCGAGTGTGCTGA 
               
               
                   
               
               
                 399971 
                 3-14-3 
                  55 
                 2173 
                 2192 
                 0 
                 AGAAACTGGAGCAGCTCAGC 
               
               
                   
               
               
                 399972 
                 3-14-3 
                  56 
                 2179 
                 2198 
                 0 
                 TCCTGGAGAAACTGGAGCAG 
               
               
                   
               
               
                 399908 
                 3-14-3 
                  60 
                 2355 
                 2374 
                 0 
                 CTTTGCATTCCAGACCTGGG 
               
               
                   
               
               
                 399973 
                 3-14-3 
                  61 
                 2360 
                 2379 
                 0 
                 CTTGACTTTGCATTCCAGAC 
               
               
                   
               
               
                 399909 
                 3-14-3 
                  62 
                 2565 
                 2584 
                 0 
                 GGCAGCAGATGGCAACGGCT 
               
               
                   
               
               
                 399910 
                 3-14-3 
                 154 
                 2665 
                 2684 
                 0 
                 TTTTAAAGCTCAGCCCCAGC 
               
               
                   
               
               
                 399974 
                 3-14-3 
                  63 
                 2670 
                 2689 
                 0 
                 AACCATTTTAAAGCTCAGCC 
               
               
                   
               
               
                 399911 
                 3-14-3 
                  64 
                 2759 
                 2778 
                 0 
                 TCAAGGGCCAGGCCAGCAGC 
               
               
                   
               
               
                 399975 
                 3-14-3 
                  65 
                 2764 
                 2783 
                 0 
                 CCCACTCAAGGGCCAGGCCA 
               
               
                   
               
               
                 399976 
                 3-14-3 
                 122 
                 2837 
                 2856 
                 0 
                 GGAGGGAGCTTCCTGGCACC 
               
               
                   
               
               
                 399912 
                 3-14-3 
                  66 
                 2852 
                 2871 
                 0 
                 ATGCCCCACAGTGAGGGAGG 
               
               
                   
               
               
                 399913 
                 3-14-3 
                  67 
                 2861 
                 2880 
                 0 
                 AATGGTGAAATGCCCCACAG 
               
               
                   
               
               
                 399914 
                 3-14-3 
                 153 
                 2904 
                 2923 
                 0 
                 TTGGGAGCAGCTGGCAGCAC 
               
               
                   
               
               
                 399915 
                 3-14-3 
                  68 
                 3005 
                 3024 
                 0 
                 CATGGGAAGAATCCTGCCTC 
               
               
                   
               
               
                 399916 
                 3-14-3 
                  69 
                 3087 
                 3106 
                 0 
                 GGAGATGAGGGCCATCAGCA 
               
               
                   
               
               
                 399917 
                 3-14-3 
                  70 
                 3155 
                 3174 
                 0 
                 TAGATGCCATCCAGAAAGCT 
               
               
                   
               
               
                 399977 
                 3-14-3 
                  71 
                 3161 
                 3180 
                 0 
                 TCTGGCTAGATGCCATCCAG 
               
               
                   
               
               
                 399918 
                 3-14-3 
                  72 
                 3238 
                 3257 
                 0 
                 GGCATAGAGCAGAGTAAAGG 
               
               
                   
               
               
                 399978 
                 3-14-3 
                  73 
                 3243 
                 3262 
                 0 
                 AGCCTGGCATAGAGCAGAGT 
               
               
                   
               
               
                 399979 
                 3-14-3 
                 135 
                 3249 
                 3268 
                 0 
                 TAGCACAGCCTGGCATAGAG 
               
               
                   
               
               
                 399919 
                 3-14-3 
                 112 
                 3482 
                 3501 
                 0 
                 GAAGAGGCTTGGCTTCAGAG 
               
               
                   
               
               
                 399980 
                 3-14-3 
                  74 
                 3488 
                 3507 
                 0 
                 AAGTAAGAAGAGGCTTGGCT 
               
               
                   
               
               
                 399920 
                 3-14-3 
                  75 
                 3692 
                 3711 
                 0 
                 GCTCAAGGAGGGACAGTTGT 
               
               
                   
               
               
                 399921 
                 3-14-3 
                  76 
                 3727 
                 3746 
                 0 
                 AAAGATAAATGTCTGCTTGC 
               
               
                   
               
               
                 399981 
                 3-14-3 
                  77 
                 3732 
                 3751 
                 0 
                 ACCCAAAAGATAAATGTCTG 
               
               
                   
               
               
                 399922 
                 3-14-3 
                  78 
                 3798 
                 3817 
                 0 
                 TCTTCAAGTTACAAAAGCAA 
               
               
                   
               
               
                 399982 
                 3-14-3 
                  99 
                 3805 
                 3824 
                 0 
                 ATAAATATCTTCAAGTTACA 
               
               
                   
               
               
                 405604 
                 3-14-3 
                 236 
                 1493 
                 1512 
                 0 
                 CCAGGTGGGTGCCATGACTG 
               
               
                   
               
               
                 405641 
                 3-14-3 
                 373 
                 2170 
                 2189 
                 0 
                 AACTGGAGCAGCTCAGCAGC 
               
               
                   
               
               
                 410583 
                 3-14-3 
                 243 
                 1527 
                 1546 
                 0 
                 GCCACGCCGGCATCCCGGCC 
               
               
                   
               
               
                 410584 
                 3-14-3 
                 244 
                 1528 
                 1547 
                 0 
                 GGCCACGCCGGCATCCCGGC 
               
               
                   
               
               
                 410585 
                 3-14-3 
                 245 
                 1529 
                 1548 
                 0 
                 TGGCCACGCCGGCATCCCGG 
               
               
                   
               
               
                 410586 
                 3-14-3 
                 246 
                 1530 
                 1549 
                 0 
                 TTGGCCACGCCGGCATCCCG 
               
               
                   
               
               
                 410587 
                 3-14-3 
                 247 
                 1531 
                 1550 
                 0 
                 CTTGGCCACGCCGGCATCCC 
               
               
                   
               
               
                 410588 
                 3-14-3 
                 248 
                 1532 
                 1551 
                 0 
                 CCTTGGCCACGCCGGCATCC 
               
               
                   
               
               
                 410589 
                 3-14-3 
                 249 
                 1533 
                 1552 
                 0 
                 CCCTTGGCCACGCCGGCATC 
               
               
                   
               
               
                 410590 
                 3-14-3 
                 250 
                 1535 
                 1554 
                 0 
                 CACCCTTGGCCACGCCGGCA 
               
               
                   
               
               
                 410591 
                 3-14-3 
                 251 
                 1536 
                 1555 
                 0 
                 GCACCCTTGGCCACGCCGGC 
               
               
                   
               
               
                 410592 
                 3-14-3 
                 252 
                 1537 
                 1556 
                 0 
                 GGCACCCTTGGCCACGCCGG 
               
               
                   
               
               
                 410593 
                 3-14-3 
                 253 
                 1538 
                 1557 
                 0 
                 TGGCACCCTTGGCCACGCCG 
               
               
                   
               
               
                 410594 
                 3-14-3 
                 254 
                 1539 
                 1558 
                 0 
                 CTGGCACCCTTGGCCACGCC 
               
               
                   
               
               
                 410595 
                 3-14-3 
                 255 
                 1540 
                 1559 
                 0 
                 GCTGGCACCCTTGGCCACGC 
               
               
                   
               
               
                 410596 
                 3-14-3 
                 348 
                 1995 
                 2014 
                 0 
                 AGGGAACCAGGCCTCATTGA 
               
               
                   
               
               
                 410597 
                 3-14-3 
                 349 
                 1996 
                 2015 
                 0 
                 CAGGGAACCAGGCCTCATTG 
               
               
                   
               
               
                 410598 
                 3-14-3 
                 350 
                 1998 
                 2017 
                 0 
                 CTCAGGGAACCAGGCCTCAT 
               
               
                   
               
               
                 410599 
                 3-14-3 
                 351 
                 1999 
                 2018 
                 0 
                 CCTCAGGGAACCAGGCCTCA 
               
               
                   
               
               
                 410600 
                 3-14-3 
                 352 
                 2000 
                 2019 
                 0 
                 TCCTCAGGGAACCAGGCCTC 
               
               
                   
               
               
                 410601 
                 3-14-3 
                 353 
                 2001 
                 2020 
                 0 
                 GTCCTCAGGGAACCAGGCCT 
               
               
                   
               
               
                 410602 
                 3-14-3 
                 354 
                 2003 
                 2022 
                 0 
                 TGGTCCTCAGGGAACCAGGC 
               
               
                   
               
               
                 410603 
                 3-14-3 
                 355 
                 2004 
                 2023 
                 0 
                 CTGGTCCTCAGGGAACCAGG 
               
               
                   
               
               
                 410604 
                 3-14-3 
                 356 
                 2005 
                 2024 
                 0 
                 GCTGGTCCTCAGGGAACCAG 
               
               
                   
               
               
                 410633 
                 3-14-3 
                 411 
                 2356 
                 2375 
                 0 
                 ACTTTGCATTCCAGACCTGG 
               
               
                   
               
               
                 410634 
                 3-14-3 
                 412 
                 2357 
                 2376 
                 0 
                 GACTTTGCATTCCAGACCTG 
               
               
                   
               
               
                 410635 
                 3-14-3 
                 413 
                 2358 
                 2377 
                 0 
                 TGACTTTGCATTCCAGACCT 
               
               
                   
               
               
                 410636 
                 3-14-3 
                 414 
                 2359 
                 2378 
                 0 
                 TTGACTTTGCATTCCAGACC 
               
               
                   
               
               
                 410637 
                 3-14-3 
                 419 
                 2560 
                 2579 
                 0 
                 CAGATGGCAACGGCTGTCAC 
               
               
                   
               
               
                 410638 
                 3-14-3 
                 420 
                 2561 
                 2580 
                 0 
                 GCAGATGGCAACGGCTGTCA 
               
               
                   
               
               
                 410639 
                 3-14-3 
                 421 
                 2562 
                 2581 
                 0 
                 AGCAGATGGCAACGGCTGTC 
               
               
                   
               
               
                 410640 
                 3-14-3 
                 422 
                 2563 
                 2582 
                 0 
                 CAGCAGATGGCAACGGCTGT 
               
               
                   
               
               
                 410641 
                 3-14-3 
                 423 
                 2564 
                 2583 
                 0 
                 GCAGCAGATGGCAACGGCTG 
               
               
                   
               
               
                 410642 
                 3-14-3 
                 424 
                 2566 
                 2585 
                 0 
                 CGGCAGCAGATGGCAACGGC 
               
               
                   
               
               
                 410643 
                 3-14-3 
                 425 
                 2567 
                 2586 
                 0 
                 CCGGCAGCAGATGGCAACGG 
               
               
                   
               
               
                 410644 
                 3-14-3 
                 426 
                 2568 
                 2587 
                 0 
                 TCCGGCAGCAGATGGCAACG 
               
               
                   
               
               
                 410645 
                 3-14-3 
                 427 
                 2569 
                 2588 
                 0 
                 CTCCGGCAGCAGATGGCAAC 
               
               
                   
               
               
                 410646 
                 3-14-3 
                 428 
                 2570 
                 2589 
                 0 
                 GCTCCGGCAGCAGATGGCAA 
               
               
                   
               
            
           
         
       
     
     In certain embodiments, gap-widened antisense compounds are targeted to a PCSK9 nucleic acid. In certain such embodiments, gap-widened antisense compounds are targeted to SEQ ID NO: 3. In certain such embodiments, the nucleotide sequences illustrated in Table 12 have a 2-13-5 gap-widened motif. Table 15 illustrates gap-widened antisense compounds targeted to SEQ ID NO: 3, having a 2-13-5 motif, where the gap segment comprises 2′-deoxynucleotides and each wing segment comprises nucleotides comprising a 2′-O-methoxyethyl sugar modification. Internucleoside linkages are phosphorthioate, and cytidines are 5-methylcytidines. 
     
       
         
           
               
             
               
                 TABLE 15 
               
             
            
               
                   
               
               
                 Gapmer antisense compounds having a 2-13-5  
               
               
                 motif targeted to SEQ ID NO: 3 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                   
                   
                 5′ 
                 3′ 
                   
                   
               
               
                   
                   
                   
                 Tar- 
                 Tar- 
                   
                   
               
               
                   
                   
                   
                 get 
                 get 
                   
                   
               
               
                   
                   
                   
                 Site 
                 Site 
                   
                   
               
               
                   
                   
                   
                 to 
                 to 
                   
                   
               
               
                   
                   
                   
                 SEQ 
                 SEQ 
                   
                   
               
               
                   
                   
                 SEQ 
                 ID 
                 ID 
                 Mis- 
                   
               
               
                 ISIS 
                   
                 ID 
                 NO: 
                 NO: 
                 match- 
                 Sequences 
               
               
                 No 
                 Motiff 
                 NO 
                 3 
                 3 
                 es 
                  (5′-3′) 
               
               
                   
               
               
                 410658 
                 2-13-5 
                 243 
                 1527 
                 1546 
                 0 
                 GCCACGCCGGCATC 
               
               
                   
                   
                   
                   
                   
                   
                 CCGGCC 
               
               
                   
               
               
                 410659 
                 2-13-5 
                 244 
                 1528 
                 1547 
                 0 
                 GGCCACGCCGGCAT 
               
               
                   
                   
                   
                   
                   
                   
                 CCCGGC 
               
               
                   
               
               
                 410660 
                 2-13-5 
                 245 
                 1529 
                 1548 
                 0 
                 TGGCCACGCCGGCA 
               
               
                   
                   
                   
                   
                   
                   
                 TCCCGG 
               
               
                   
               
               
                 410661 
                 2-13-5 
                 246 
                 1530 
                 1549 
                 0 
                 TTGGCCACGCCGGC 
               
               
                   
                   
                   
                   
                   
                   
                 ATCCCG 
               
               
                   
               
               
                 410662 
                 2-13-5 
                 247 
                 1531 
                 1550 
                 0 
                 CTTGGCCACGCCGG 
               
               
                   
                   
                   
                   
                   
                   
                 CATCCC 
               
               
                   
               
               
                 410663 
                 2-13-5 
                 248 
                 1532 
                 1551 
                 0 
                 CCTTGGCCACGCCG 
               
               
                   
                   
                   
                   
                   
                   
                 GCATCC 
               
               
                   
               
               
                 410664 
                 2-13-5 
                 249 
                 1533 
                 1552 
                 0 
                 CCCTTGGCCACGCC 
               
               
                   
                   
                   
                   
                   
                   
                 GGCATC 
               
               
                   
               
               
                 410665 
                 2-13-5 
                 28 
                 1534 
                 1553 
                 0 
                 ACCCTTGGCCACGC 
               
               
                   
                   
                   
                   
                   
                   
                 CGGCAT 
               
               
                   
               
               
                 410666 
                 2-13-5 
                 250 
                 1535 
                 1554 
                 0 
                 CACCCTTGGCCACG 
               
               
                   
                   
                   
                   
                   
                   
                 CCGGCA 
               
               
                   
               
               
                 410667 
                 2-13-5 
                 251 
                 1536 
                 1555 
                 0 
                 GCACCCTTGGCCAC 
               
               
                   
                   
                   
                   
                   
                   
                 GCCGGC 
               
               
                   
               
               
                 410668 
                 2-13-5 
                 252 
                 1537 
                 1556 
                 0 
                 GGCACCCTTGGCCA 
               
               
                   
                   
                   
                   
                   
                   
                 CGCCGG 
               
               
                   
               
               
                 410669 
                 2-13-5 
                 253 
                 1538 
                 1557 
                 0 
                 TGGCACCCTTGGCC 
               
               
                   
                   
                   
                   
                   
                   
                 ACGCCG 
               
               
                   
               
               
                 410670 
                 2-13-5 
                 254 
                 1539 
                 1558 
                 0 
                 CTGGCACCCTTGGC 
               
               
                   
                   
                   
                   
                   
                   
                 CACGCC 
               
               
                   
               
               
                 410671 
                 2-13-5 
                 255 
                 1540 
                 1559 
                 0 
                 GCTGGCACCCTTGG 
               
               
                   
                   
                   
                   
                   
                   
                 CCACGC 
               
               
                   
               
               
                 410672 
                 2-13-5 
                 348 
                 1995 
                 2014 
                 0 
                 AGGGAACCAGGCCT 
               
               
                   
                   
                   
                   
                   
                   
                 CATTGA 
               
               
                   
               
               
                 410673 
                 2-13-5 
                 349 
                 1996 
                 2015 
                 0 
                 CAGGGAACCAGGCC 
               
               
                   
                   
                   
                   
                   
                   
                 TCATTG 
               
               
                   
               
               
                 410674 
                 2-13-5 
                  49 
                 1997 
                 2016 
                 0 
                 TCAGGGAACCAGGC 
               
               
                   
                   
                   
                   
                   
                   
                 CTCATT 
               
               
                   
               
               
                 410675 
                 2-13-5 
                 350 
                 1998 
                 2017 
                 0 
                 CTCAGGGAACCAGG 
               
               
                   
                   
                   
                   
                   
                   
                 CCTCAT 
               
               
                   
               
               
                 410676 
                 2-13-5 
                 351 
                 1999 
                 2018 
                 0 
                 CCTCAGGGAACCAG 
               
               
                   
                   
                   
                   
                   
                   
                 GCCTCA 
               
               
                   
               
               
                 410677 
                 2-13-5 
                 352 
                 2000 
                 2019 
                 0 
                 TCCTCAGGGAACCA 
               
               
                   
                   
                   
                   
                   
                   
                 GGCCTC 
               
               
                   
               
               
                 410678 
                 2-13-5 
                 353 
                 2001 
                 2020 
                 0 
                 GTCCTCAGGGAACC 
               
               
                   
                   
                   
                   
                   
                   
                 AGGCCT 
               
               
                   
               
               
                 410679 
                 2-13-5 
                  50 
                 2002 
                 2021 
                 0 
                 GGTCCTCAGGGAAC 
               
               
                   
                   
                   
                   
                   
                   
                 CAGGCC 
               
               
                   
               
               
                 410680 
                 2-13-5 
                 354 
                 2003 
                 2022 
                 0 
                 TGGTCCTCAGGGAA 
               
               
                   
                   
                   
                   
                   
                   
                 CCAGGC 
               
               
                   
               
               
                 410681 
                 2-13-5 
                 355 
                 2004 
                 2023 
                 0 
                 CTGGTCCTCAGGGA 
               
               
                   
                   
                   
                   
                   
                   
                 ACCAGG 
               
               
                   
               
               
                 410682 
                 2-13-5 
                 356 
                 2005 
                 2024 
                 0 
                 GCTGGTCCTCAGGG 
               
               
                   
                   
                   
                   
                   
                   
                 AACCAG 
               
               
                   
               
               
                 410713 
                 2-13-5 
                  60 
                 2355 
                 2374 
                 0 
                 CTTTGCATTCCAGA 
               
               
                   
                   
                   
                   
                   
                   
                 CCTGGG 
               
               
                   
               
               
                 410714 
                 2-13-5 
                 411 
                 2356 
                 2375 
                 0 
                 ACTTTGCATTCCAG 
               
               
                   
                   
                   
                   
                   
                   
                 ACCTGG 
               
               
                   
               
               
                 410715 
                 2-13-5 
                 412 
                 2357 
                 2376 
                 0 
                 GACTTTGCATTCCA 
               
               
                   
                   
                   
                   
                   
                   
                 GACCTG 
               
               
                   
               
               
                 410716 
                 2-13-5 
                 413 
                 2358 
                 2377 
                 0 
                 TGACTTTGCATTCC 
               
               
                   
                   
                   
                   
                   
                   
                 AGACCT 
               
               
                   
               
               
                 410717 
                 2-13-5 
                 414 
                 2359 
                 2378 
                 0 
                 TTGACTTTGCATTC 
               
               
                   
                   
                   
                   
                   
                   
                 CAGACC 
               
               
                   
               
               
                 410718 
                 2-13-5 
                  61 
                 2360 
                 2379 
                 0 
                 CTTGACTTTGCATT 
               
               
                   
                   
                   
                   
                   
                   
                 CCAGAC 
               
               
                   
               
               
                 410719 
                 2-13-5 
                 419 
                 2560 
                 2579 
                 0 
                 CAGATGGCAACGGC 
               
               
                   
                   
                   
                   
                   
                   
                 TGTCAC 
               
               
                   
               
               
                 410720 
                 2-13-5 
                 420 
                 2561 
                 2580 
                 0 
                 GCAGATGGCAACGG 
               
               
                   
                   
                   
                   
                   
                   
                 CTGTCA 
               
               
                   
               
               
                 410721 
                 2-13-5 
                 421 
                 2562 
                 2581 
                 0 
                 AGCAGATGGCAACG 
               
               
                   
                   
                   
                   
                   
                   
                 GCTGTC 
               
               
                   
               
               
                 410722 
                 2-13-5 
                 422 
                 2563 
                 2582 
                 0 
                 CAGCAGATGGCAAC 
               
               
                   
                   
                   
                   
                   
                   
                 GGCTGT 
               
               
                   
               
               
                 410723 
                 2-13-5 
                 423 
                 2564 
                 2583 
                 0 
                 GCAGCAGATGGCAA 
               
               
                   
                   
                   
                   
                   
                   
                 CGGCTG 
               
               
                   
               
               
                 410724 
                 2-13-5 
                  62 
                 2565 
                 2584 
                 0 
                 GGCAGCAGATGGCA 
               
               
                   
                   
                   
                   
                   
                   
                 ACGGCT 
               
               
                   
               
               
                 410725 
                 2-13-5 
                 424 
                 2566 
                 2585 
                 0 
                 CGGCAGCAGATGGC 
               
               
                   
                   
                   
                   
                   
                   
                 AACGGC 
               
               
                   
               
               
                 410726 
                 2-13-5 
                 425 
                 2567 
                 2586 
                 0 
                 CCGGCAGCAGATGG 
               
               
                   
                   
                   
                   
                   
                   
                 CAACGG 
               
               
                   
               
               
                 410727 
                 2-13-5 
                 426 
                 2568 
                 2587 
                 0 
                 TCCGGCAGCAGATG 
               
               
                   
                   
                   
                   
                   
                   
                 GCAACG 
               
               
                   
               
               
                 410728 
                 2-13-5 
                 427 
                 2569 
                 2588 
                 0 
                 CTCCGGCAGCAGAT 
               
               
                   
                   
                   
                   
                   
                   
                 GGCAAC 
               
               
                   
               
               
                 410729 
                 2-13-5 
                 428 
                 2570 
                 2589 
                 0 
                 GCTCCGGCAGCAGA 
               
               
                   
                   
                   
                   
                   
                   
                 TGGCAA 
               
               
                   
               
            
           
         
       
     
     The following embodiments set forth target regions of PCSK9 nucleic acids. Also illustrated are examples of antisense compounds targeted to the target regions. It is understood that the sequence set forth in each SEQ ID NO is independent of any modification to a sugar moiety, an internucleoside linkage, or a nucleobase. As such, antisense compounds defined by a SEQ ID NO may comprise, independently, one or more modifications to a sugar moiety, an internucleoside linkage, or a nucleobase. Antisense compounds described by Isis Number (Isis No) indicate a combination of nucleobase sequence and motif. 
     In certain embodiments, antisense compounds target a range of a PCSK9 nucleic acid. In certain embodiment, such compounds contain at least an 8 nucleotide core sequence in common. In certain embodiments, such compounds sharing at least an 8 nucleotide core sequence targets the following nucleotide regions of SEQ ID NO: 3: 220-253, 290-321, 377-419, 451-615, 653-672, 741-760, 871-897, 915-934, 968-1017, 1075-1124, 1075-1174, 1144-1174, 1275-1302, 1315-1341, 1351-1389, 1351-1447, 1365-1439, 1390-1417, 1390-1429, 1390-1439, 1399-1425, 1408-1435, 1420-1447, 1453-1482, 1490-1516, 1490-1564, 1500-1526, 1515-1541, 1527-1553, 1527-1554, 1528-1554, 1529-1555, 1529-1556, 1530-1556, 1530-1557, 1531-1557, 1532-1551, 1532-1558, 1533-1559, 1534-1559, 1535-1559, 1536-1559, 1537-1564, 1566-1602, 1566-1681, 1606-1626, 1618-1645, 1626-1653, 1684-1703, 1730-1781, 1740-1767, 1749-1775, 1758-1781, 1820-1847, 1820-1877, 1822-2198, 1830-1856, 1839-1865, 1840-1867, 1898-1924, 1898-2035, 1903-2127, 1907-1934, 1911-1938, 1946-1971, 1954-1980, 1959-2035, 1959-2057, 1963-1988, 1967-2035, 1972-1999, 1982-2008, 1991-2018, 1993-2019, 1995-2022, 1996-2023, 1997-2024, 1998-2025, 1999-2025, 2000-2025, 2009-2035, 2038-2139, 2061-2139, 2073-2099, 2078-2104, 2105-2131, 2112-2139, 2168-2198, 2170-2177, 2245-2284, 2295-2394, 2355-2381, 2355-2394, 2405-2461, 2560-2587, 2560-2609, 2561-2588, 2562-2589, 2563-2589, 2564-2589, 2565-2589, 2566-2589, 2567-2589, 2568-2589, 2665-2689, 2759-2783, 2837-2880, 2904-2923, 3005-3024, 3005-3174, 3083-3110, 3155-3184, 3238-3268, 3482-3711, or 3727-3751, or 3798-3824. 
     In certain embodiments, a target region is nucleotides 290-321 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 290-321 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 117 or 129. In certain such embodiments, an antisense compound targeted to nucleotides 290-321 of SEQ ID NO: 3 is selected from ISIS NOs: 395202, 399924, 399829 or 399985. 
     In certain embodiments, a target region is nucleotides 220-253 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 220-253 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 100 or 116. In certain such embodiments, an antisense compound targeted to nucleotides 220-253 of SEQ ID NO: 3 is selected from ISIS NOs: 399827, 399983, 399828 or 399984. 
     In certain embodiments, a target region is nucleotides 377-419 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 377-419 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 81 or 110. In certain such embodiments, an antisense compound targeted to nucleotides 377-419 of SEQ ID NO: 3 is selected from ISIS NOs: 399830, 399986, 395203 or 399925. 
     In certain embodiments, a target region is nucleotides 451-615 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 451-615 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 152, 140, 137 or 136. In certain such embodiments, an antisense compound targeted to nucleotides 451-615 of SEQ ID NO: 3 is selected from ISIS NOs: 395204, 399926, 399831, 399987, 395205, 399927, 399832, 399988, 395206 or 399928. 
     In certain embodiments, a target region is nucleotides 653-672 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 653-672 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 132. In certain such embodiments, an antisense compound targeted to nucleotides 653-672 of SEQ ID NO: 3 is selected from ISIS NOs: 395207 or 399929. 
     In certain embodiments, a target region is nucleotides 741-760 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 741-760 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 139. In certain such embodiments, an antisense compound targeted to nucleotides 741-760 of SEQ ID NO: 3 is selected from ISIS NOs: 395208 or 399930. 
     In certain embodiments, a target region is nucleotides 871-897 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 871-897 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 92 or 142. In certain such embodiments, an antisense compound targeted to nucleotides 871-897 of SEQ ID NO: 3 is selected from ISIS NOs: 399833, 399989, 395209 or 399931. 
     In certain embodiments, a target region is nucleotides 915-934 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 915-934 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 113. In certain such embodiments, an antisense compound targeted to nucleotides 915-934 of SEQ ID NO: 3 is selected from ISIS NOs: 395210 or 399932. 
     In certain embodiments, a target region is nucleotides 968-1017 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 968-1017 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 98 or 138. In certain such embodiments, an antisense compound targeted to nucleotides 968-1017 of SEQ ID NO: 3 is selected from ISIS NOs: 395211, 399933, 395212, or 399934. 
     In certain embodiments, a target region is nucleotides 1075-1124 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 1075-1124 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 96 or 124. In certain such embodiments, an antisense compound targeted to nucleotides 1075-1124 of SEQ ID NO: 3 is selected from ISIS NOs: 395213, 399935, 395214, or 399936. 
     In certain embodiments, a target region is nucleotides 1075-1174 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 1075-1174 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 82, 96, 103, 124, or 133. In certain such embodiments, an antisense compound targeted to nucleotides 1075-1174 of SEQ ID NO: 3 is selected from ISIS NOs: 395213, 399935, 395214, 399936, 399834, 399990, 395215, 399937, 395216, or 399938. 
     In certain embodiments, a target region is nucleotides 1144-1174 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 1144-1174 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 82, 133 or 103. In certain such embodiments, an antisense compound targeted to nucleotides 1144-1174 of SEQ ID NO: 3 is selected from ISIS NOs: 399834, 399990, 395215, 399937, 395216 or 399938. 
     In certain embodiments, a target region is nucleotides 1275-1302 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 1275-1302 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 155 or 156. In certain such embodiments, an antisense compound targeted to nucleotides 1275-1302 of SEQ ID NO: 3 is selected from ISIS NOs: 395217, 399939, 399835 or 399991. 
     In certain embodiments, a target region is nucleotides 1315-1341 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 1315-1341 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 146 or 161. In certain such embodiments, an antisense compound targeted to nucleotides 1315-1341 of SEQ ID NO: 3 is selected from ISIS NOs: 395218, 399940, 395219 or 399941. 
     In certain embodiments, a target region is nucleotides 1351-1389 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 1351-1389 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 215, 216, 19, 217 or 20. In certain such embodiments, an antisense compound targeted to nucleotides 1351-1389 of SEQ ID NO: 3 is selected from ISIS NOs: 410753, 406025, 395160, 399882, 406026, 399797 or 399953. 
     In certain embodiments, a target region is nucleotides 1351-1447 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 1351-1447 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 215, 216, 19, 217, 20, 21, 218, 219, 220, 221, 22,222, 223, 224, 225, 226, 227, 228, 23, 229, 230,231, 232, 24, or 233. In certain such embodiments, an antisense compound targeted to nucleotides 1351-1447 of SEQ ID NO: 3 is selected from ISIS NOs: 410753, 406025, 395160, 399882, 406026, 399797, 399953, 395161, 399883, 405869, 405870, 405871, 405872, 399798, 399954, 405873, 405874, 405875, 405876, 406027, 406028, 406029, 399799, 399955, 406030, 406031, 410733, 406032, 395162, 399884 or 410754. 
     In certain embodiments, a target region is nucleotides 1365-1439 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 1365-1439 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 19, 20, 21, 22, 23, 24, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, or 232. In certain such embodiments, an antisense compound targeted to nucleotides 1365-1439 of SEQ ID NO: 3 is selected from ISIS NOs: 395160, 399882, 406026, 399797, 399953, 395161, 399883, 405869, 405870, 405871, 405872, 399798, 399954, 405873, 405874, 405875, 405876, 406027, 406028, 406029, 399799, 399955, 406030, 406031, 410733, 406032, 395162, or 399884. 
     In certain embodiments, a target region is nucleotides 1390-1417 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 1390-1417 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 21, 218, 219, 220, 221, 22, 222 or 223. In certain such embodiments, an antisense compound targeted to nucleotides 1390-1417 of SEQ ID NO: 3 is selected from ISIS NOs: 395161, 399883, 405869, 405870, 405871, 405872, 399798, 399954, 405873 or 405874. 
     In certain embodiments, a target region is nucleotides 1390-1429 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 1390-1429 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 21, 22, 23, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, or 228. In certain such embodiments, an antisense compound targeted to nucleotides 1390-1429 of SEQ ID NO: 3 is selected from ISIS NOs: 395160, 399882, 406026, 399797, 399953, 395161, 399883, 405869, 405870, 405871, 405872, 399798, 399954, 405873, 405874, 405875, 405876, 406027, 406028, 406029, 399799, or 399955. 
     In certain embodiments, a target region is nucleotides 1390-1439 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 1390-1439 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 21, 22, 23, 24, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, or 232. In certain such embodiments, an antisense compound targeted to nucleotides 1390-1439 of SEQ ID NO: 3 is selected from ISIS NOs: 395160, 399882, 406026, 399797, 399953, 395161, 399883, 405869, 405870, 405871, 405872, 399798, 399954, 405873, 405874, 405875, 405876, 406027, 406028, 406029, 399799, 399955, 406030, 406031, 410733, 406032, 395162, or 399884. 
     In certain embodiments, a target region is nucleotides 1399-1425 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 1399-1425 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 224, 225, 226 or 227. In certain such embodiments, an antisense compound targeted to nucleotides 1399-1425 of SEQ ID NO: 3 is selected from ISIS NOs: 405875, 405876, 406027 or 406028. 
     In certain embodiments, a target region is nucleotides 1408-1435 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 1408-1435 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 228, 23, 229, 230 or 231. In certain such embodiments, an antisense compound targeted to nucleotides 1408-1435 of SEQ ID NO: 3 is selected from ISIS NOs: 406029, 399799, 399955, 406030, 406031 or 410733. 
     In certain embodiments, a target region is nucleotides 1420-1447 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 1420-1447 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 24 or 233. In certain such embodiments, an antisense compound targeted to nucleotides 1420-1447 of SEQ ID NO: 3 is selected from ISIS NOs: 395162, 399884 or 410754. 
     In certain embodiments, a target region is nucleotides 1453-1482 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 1453-1482 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 25 or 234. In certain such embodiments, an antisense compound targeted to nucleotides 1453-1482 of SEQ ID NO: 3 is selected from ISIS NOs: 395163, 399885 or 410755. 
     In certain embodiments, a target region is nucleotides 1490-1516 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 1490-1516 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 235, 236, or 237. In certain such embodiments, an antisense compound targeted to nucleotides 1490-1516 of SEQ ID NO: 3 is selected from ISIS NOs: 410756, 405604, or 406033. 
     In certain embodiments, a target region is nucleotides 1490-1564 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 1490-1564 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 235, 236, 237, 26, 238, 27, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 447, 28, 250, 251, 252, 253, 254, 255, or 256. In certain such embodiments, an antisense compound targeted to nucleotides 1490-1564 of SEQ ID NO: 3 is selected from ISIS NOs: 410756, 405604, 406033, 395164, 399886, 406034, 399800, 399956, 406035, 410757, 406036, 406037, 410536, 410583, 410658, 410537, 410584, 410659, 406038, 410585, 410660, 405877, 410586, 410661, 405878, 410587, 410662, 405879, 410588, 410663, 405880, 410589, or 410758. 
     In certain embodiments, a target region is nucleotides 1500-1526 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 1500-1526 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 26, 238, 27, or 239. In certain such embodiments, an antisense compound targeted to nucleotides 1500-1526 of SEQ ID NO: 3 is selected from ISIS NOs: 395164, 399886, 406034, 399800, 399956, or 406035. 
     In certain embodiments, a target region is nucleotides 1515-1541 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 1515-1541 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 240, 241, or 242. In certain such embodiments, an antisense compound targeted to nucleotides 1515-1541 of SEQ ID NO: 3 is selected from ISIS NOs: 399886, 406034, 399800, 399956, or 406035. 
     In certain embodiments, a target region is nucleotides 1527-1553 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 1527-1553 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 243, 244, 245, 246, 247, 248, 447, 28 or 249. In certain such embodiments, an antisense compound targeted to nucleotides 1527-1553 of SEQ ID NO: 3 is selected from ISIS NOs: 410536, 410583, 410658, 410537, 410584, 410659, 406038, 410585, 410660, 405877, 410586, 410661, 405878, 410587, 410662, 405879, 410588, 410663, 405880, 410589, 410664, 395165, 399887, or 410665. 
     In certain embodiments, a target region is nucleotides 1527-1554 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 1527-1554 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 243, 244, 245, 246, 247, 248, 249, 447, 28, or 250. In certain such embodiments, an antisense compound targeted to nucleotides 1527-1554 of SEQ ID NO: 3 is selected from ISIS NOs: 410536, 410583, 410658, 410537, 410584, 410659, 406038, 410585, 410660, 405877, 410586, 410661, 405878, 410587, 410662, 405879, 410588, 410663, 405880, 410589, 410664, 395165, 399887, 405881, 410590, 410666, or 410665. 
     In certain embodiments, a target region is nucleotides 1528-1554 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 1528-1554 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 244, 245, 246, 247, 248, 249, 447, 28, or 250. In certain such embodiments, an antisense compound targeted to nucleotides 1528-1554 of SEQ ID NO: 3 is selected from ISIS NOs: 410537, 410584, 410659, 406038, 410585, 410660, 405877, 410586, 410661, 405878, 410587, 410662, 405879, 410588, 410663, 405880, 410589, 410664, 395165, 399887, 409126, 410665, or 405881. 
     In certain embodiments, a target region is nucleotides 1529-1555 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 1529-1555 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 245, 246, 247, 248, 249, 447, 28, 250 or 251. In certain such embodiments, an antisense compound targeted to nucleotides 1529-1555 of SEQ ID NO: 3 is selected from ISIS NOs: 406038, 395165, 399887, 405877, 405878, 405879, 405880, 405881, 405882, 409126, 410585, 410586, 410587, 410588, 410589, 410590, 410591, 410660, 410661, 410662, 410663, 410664, 410665, 410666, 410667, or 410667. 
     In certain embodiments, a target region is nucleotides 1529-1556 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 1529-1556 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 245, 246, 247, 248, 249, 447, 28, 250, 251, or 252. In certain such embodiments, an antisense compound targeted to nucleotides 1529-1556 of SEQ ID NO: 3 is selected from ISIS NOs: 406038, 395165, 399887, 405877, 405878, 405879, 405880, 405881, 405882, 405883, 409126, 410585, 410586, 410587, 410588, 410589, 410590, 410591, 410592, 410660, 410661, 410662, 410663, 410664, 410665, 410666, 410667, or 410668. 
     In certain embodiments, a target region is nucleotides 1530-1556 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 1530-1556 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 246, 247, 248, 249, 447, 28, 250, 251, or 252. In certain such embodiments, an antisense compound targeted to nucleotides 1530-1556 of SEQ ID NO: 3 is selected from ISIS NOs: 406038, 395165, 399887, 405877, 405878, 405879, 405880, 405881, 405882, 405883, 409126, 410585, 410586, 410587, 410588, 410589, 410590, 410591, 410592, 410660, 410661, 410662, 410663, 410664, 410665, 410666, 410667, 405884, 410593, 410669 or 410668. 
     In certain embodiments, a target region is nucleotides 1530-1557 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 1530-1557 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 28, 246, 247, 248, 249, 250, 251, 252, 253, or 447. In certain such embodiments, an antisense compound targeted to nucleotides 1530-1557 of SEQ ID NO: 3 is selected from ISIS NOs: 395165, 399887, 405877, 405878, 405879, 405880, 405881, 405882, 405883, 405884, 409126, 410586, 410587, 410588, 410589, 410590, 410591, 410592, 410593, 410661, 410662, 410663, 410664, 410665, 410666, 410667, 410668, or 410669. 
     In certain embodiments, a target region is nucleotides 1531-1557 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 1531-1557 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 28, 247, 248, 249, 250, 251, 252, 253, or 447. In certain such embodiments, an antisense compound targeted to nucleotides 1531-1557 of SEQ ID NO: 3 is selected from ISIS NOs: 395165, 399887, 405878, 405879, 405880, 405881, 405882, 405883, 405884, 409126, 410587, 410588, 410589, 410590, 410591, 410592, 410593, 410662, 410663, 410664, 410665, 410666, 410667, 410668, or 410669. 
     In certain embodiments, a target region is nucleotides 1532-1551 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 1532-1551 of SEQ ID NO: 3. In one such embodiment, an antisense compound targeted to nucleotides 1532-1551 of SEQ ID NO: 3 is ISIS NO: 405879. 
     In certain embodiments, a target region is nucleotides 1532-1558 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 1532-1558 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 28, 248, 249, 250, 251, 252, 253, 254 or 447. In certain such embodiments, an antisense compound targeted to nucleotides 1532-1558 of SEQ ID NO: 3 is selected from ISIS NOs: 405879, 410588, 410663, 405880, 410589, 410664, 395165, 399887, 410665, 405881, 410590, 410666, 405882, 410591, 410667, 405883, 410592, 410668, 405884, 410593, 410669, 410538, 410594, or 410670. 
     In certain embodiments, a target region is nucleotides 1533-1559 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 1533-1559 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 28, 249, 250, 251, 252, 253, 254, 255 or 447. In certain such embodiments, an antisense compound targeted to nucleotides 1533-1559 of SEQ ID NO: 3 is selected from ISIS NOs: 405880, 410589, 410664, 395165, 399887, 410665, 405881, 410590, 410666, 405882, 410591, 410667, 405883, 410592, 410668, 405884, 410593, 410669, 410538, 410594, 410670, 410539, 410595, or 410671. 
     In certain embodiments, a target region is nucleotides 1534-1559 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 1534-1559 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 28, 250, 251, 252, 253, 254, 255 or 447. In certain such embodiments, an antisense compound targeted to nucleotides 1534-1559 of SEQ ID NO: 3 is selected from ISIS NOs: 395165, 399887, 410665, 405881, 410590, 410666, 405882, 410591, 410667, 405883, 410592, 410668, 405884, 410593, 410669, 410538, 410594, 410670, or 410671. 
     In certain embodiments, a target region is nucleotides 1535-1559 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 1535-1559 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 250, 251, 252, 253, 254, 255 or 447. In certain such embodiments, an antisense compound targeted to nucleotides 1535-1559 of SEQ ID NO: 3 is selected from ISIS NOs: 405881, 410590, 410666, 405882, 410591, 410667, 405883, 410592, 410668, 405884, 410593, 410669, 410538, 410594 or 410671. 
     In certain embodiments, a target region is nucleotides 1536-1559 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 1536-1559 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 251, 252, 253, 254, or 255. In certain such embodiments, an antisense compound targeted to nucleotides 1536-1559 of SEQ ID NO: 3 is selected from ISIS NOs: 405882, 410591, 410667, 405883, 410592, 410668, 405884, 410593, 410669, 410538, 410594, 410670, 410539, 410595, or 410671. 
     In certain embodiments, a target region is nucleotides 1537-1564 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 1537-1564 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 251, 252, 253, 254, 255, or 256. In certain such embodiments, an antisense compound targeted to nucleotides 1537-1564 of SEQ ID NO: 3 is selected from ISIS NOs: 405882, 410591, 410667, 405883, 410592, 410668, 405884, 410593, 410669, 410538, 410594, 410670, 410539, 410595, 410671, or 410758. 
     In certain embodiments, a target region is nucleotides 1566-1602 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 1566-1602 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 29, 30, 31, 32, 257, 258, 259, 260, 261, or 262. In certain such embodiments, an antisense compound targeted to nucleotides 1566-1602 of SEQ ID NO: 3 is selected from ISIS NOs: 395166, 395167, 395168, 399801, 399888, 399889, 399890, 399957, 405909, 405910, 405911, 405912, 406039, 406040, 406041, 406042, 406043, or 406044. 
     In certain embodiments, a target region is nucleotides 1566-1681 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 1566-1681 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 29, 30, 31, 32, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, or 272. In certain such embodiments, an antisense compound targeted to nucleotides 1566-1681 of SEQ ID NO: 3 is selected from ISIS NOs: 395166, 395167, 395168, 399801, 399888, 399889, 399890, 399957, 405909, 405910, 405911, 405912, 406039, 406040, 406041, 406042, 406043, 406044, 406045, 408642, 410759, 410760, 410761, or 410762. 
     In certain embodiments, a target region is nucleotides 1606-1626 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 1606-1626 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 264 or 31. In certain such embodiments, an antisense compound targeted to nucleotides 1606-1626 of SEQ ID NO: 3 is selected from ISIS NOs: 408642, 395167, or 399889. 
     In certain embodiments, a target region is nucleotides 1618-1645 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 1618-1645 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 265 or 266. In certain such embodiments, an antisense compound targeted to nucleotides 1618-1645 of SEQ ID NO: 3 is selected from ISIS NOs: 410760 or 406045. 
     In certain embodiments, a target region is nucleotides 1626-1653 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 1626-1653 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 32, 266, 267, 268, or 269. In certain such embodiments, an antisense compound targeted to nucleotides 1626-1653 of SEQ ID NO: 3 is selected from ISIS NOs: 395168, 399890, 405909, 405910, 405911, or 406045. 
     In certain embodiments, a target region is nucleotides 1684-1703 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 1684-1703 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 273. In certain such embodiments, an antisense compound targeted to nucleotides 1684-1703 of SEQ ID NO: 3 is selected from ISIS NOs: 410763. 
     In certain embodiments, a target region is nucleotides 1730-1781 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 1730-1781 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 33, 33, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, or 285. In certain such embodiments, an antisense compound targeted to nucleotides 1730-1781 of SEQ ID NO: 3 is selected from ISIS NOs: 395169, 399891, 405913, 405914, 405915, 405916, 405917, 405918, 405919, 405920, 405921, 405922, 410734, or 410764. 
     In certain embodiments, a target region is nucleotides 1740-1767 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 1740-1767 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 33, 275, 276, 277, or 278. In certain such embodiments, an antisense compound targeted to nucleotides 1740-1767 of SEQ ID NO: 3 is selected from ISIS NOs: 395169, 399891, 405913, 405914, 405915, or 405916. 
     In certain embodiments, a target region is nucleotides 1749-1775 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 1749-1775 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 279, 280, 281 or 282. In certain such embodiments, an antisense compound targeted to nucleotides 1749-1775 of SEQ ID NO: 3 is selected from ISIS NOs: 410734, 405917, 405918 or 405919. 
     In certain embodiments, a target region is nucleotides 1758-1781 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 1758-1781 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 283, 284, or 285. In certain such embodiments, an antisense compound targeted to nucleotides 1758-1781 of SEQ ID NO: 3 is selected from ISIS NOs: 405920, 405921, or 405922. 
     In certain embodiments, a target region is nucleotides 1820-1847 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 1820-1847 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 39, 306, 307, 308, or 309. In certain such embodiments, an antisense compound targeted to nucleotides 1820-1847 of SEQ ID NO: 3 is selected from ISIS NOs: 395175, 399897, 405937, 405938, 405939, or 405940. 
     In certain embodiments, a target region is nucleotides 1820-1877 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 1820-1877 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 39, 40, 41, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, or 318. In certain such embodiments, an antisense compound targeted to nucleotides 1820-1877 of SEQ ID NO: 3 is selected from ISIS NOs: 395175, 399804, 399805, 399897, 399960, 399961, 405937, 405938, 405939, 405940, 405941, 405942, 405943, 405944, 405945, 405946, 405947, 410737, or 410769. 
     In certain embodiments, a target region is nucleotides 1822-2198 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 1822-2198 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 39, 307, 308, 309, 310, 40, 311, 312, 313, 314, 315, 41, 41, 316, 317, 318, 101, 319, 42, 320, 321, 322, 43, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 44, 335, 336, 337, 45, 338, 46, 339, 340, 47, 341, 342, 48, 343, 344, 345, 346, 347, 3, or 366. In certain such embodiments, an antisense compound targeted to nucleotides 1822-2198 of SEQ ID NO: 3 is selected from ISIS NOs: 395175, 399897, 405938, 405939, 405940, 405941, 399804, 399960, 405942, 405943, 410737, 405944, 405945, 399805, 399961, 405946, 405947, 410769, 395176, 399898, 405948, 399806, 399962, 405949, 405950, 405951, 399807, 399963, 405952, 410738, 405953, 405954, or 405979. 
     In certain embodiments, a target region is nucleotides 1830-1856 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 1830-1856 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 40, 310, 311, or 312. In certain such embodiments, an antisense compound targeted to nucleotides 1830-1856 of SEQ ID NO: 3 is selected from ISIS NOs: 399804, 399960, 405941, 405942, or 405943. 
     In certain embodiments, a target region is nucleotides 1839-1865 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 1839-1865 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 41, 313, 314, 315, or 316. In certain such embodiments, an antisense compound targeted to nucleotides 1839-1865 of SEQ ID NO: 3 is selected from ISIS NOs: 399805, 399961, 405944, 405945, 405946, or 410737. 
     In certain embodiments, a target region is nucleotides 1840-1867 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 1840-1867 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 314, 315, 316, or 317. In certain such embodiments, an antisense compound targeted to nucleotides 1840-1867 of SEQ ID NO: 3 is selected from ISIS NOs: 399961, 405944, 405945, 405946, 410737, or 405947. 
     In certain embodiments, a target region is nucleotides 1898-1924 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 1898-1924 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 42, 101, 319, or 320. In certain such embodiments, an antisense compound targeted to nucleotides 1898-1924 of SEQ ID NO: 3 is selected from ISIS NOs: 395176, 399898, 405948, 399806, 399962, 405949, or 405949. 
     In certain embodiments, a target region is nucleotides 1898-2035 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 1898-2035 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 87, 101, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, or 359. In certain such embodiments, an antisense compound targeted to nucleotides 1898-2035 of SEQ ID NO: 3 is selected from ISIS NOs: 395176, 395177, 395178, 395179, 399806, 399807, 399808, 399809, 399810, 399811, 399812, 399813, 399898, 399899, 399900, 399901, 399962, 399963, 399964, 399965, 399966, 399967, 399968, 399969, 405885, 405886, 405887, 405888, 405889, 405890, 405891, 405892, 405948, 405949, 405950, 405951, 405952, 405953, 405954, 405955, 405956, 405957, 405958, 405959, 405960, 405961, 405962, 405963, 405964, 405965, 405966, 405967, 405968, 405969, 405970, 405971, 405972, 405973, 405974, 408653, 410540, 410596, 410597, 410598, 410599, 410600, 410601, 410602, 410603, 410604, 410672, 410673, 410674, 410675, 410676, 410677, 410678, 410679, 410680, 410681, 410682, 410738, 410739, 410740, or 410770. 
     In certain embodiments, a target region is nucleotides 1903-2127 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 1903-2127 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 42, 320, 321, 322, 43, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 44, 335, 336, 337, 45, 338, 46, 339, 340, 47, 341, 342, 48, 343, 344, 345, 346, 347, 348, 349, 49, 350, 351, 352, 353, 50, 354, 355, 356, 357, 87, 358, 359, 51, 119, 360, or 54. In certain such embodiments, an antisense compound targeted to nucleotides 1903-2127 of SEQ ID NO: 3 is selected from ISIS NOs: 399806, 399962, 405949, 405950, 405951, 399807, 399963, 405952, 410738, 405953, 405954, 410770, 405955, 405956, 405957, 405958, 405959, 405960, 405961, 399808, 399964, 405962, 410739, 405963, 395177, 399899, 405964, 399809, 399965, 405965, 405966, 399810, or 399967. 
     In certain embodiments, a target region is nucleotides 1907-1934 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 1907-1934 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 43, 321, 322, 323, or 324. In certain such embodiments, an antisense compound targeted to nucleotides 1907-1934 of SEQ ID NO: 3 is selected from ISIS NOs: 405950, 405951, 399807, 399963, 405952, or 410738. 
     In certain embodiments, a target region is nucleotides 1911-1938 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 1911-1938 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 43, 323, 324, 325, or 326. In certain such embodiments, an antisense compound targeted to nucleotides 1911-1938 of SEQ ID NO: 3 is selected from ISIS NOs: 399807, 399963, 405952, 410738, 405953, or 405954. 
     In certain embodiments, a target region is nucleotides 1946-1971 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 1946-1971 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 328, 329, 330, or 331. In certain such embodiments, an antisense compound targeted to nucleotides 1946-1971 of SEQ ID NO: 3 is selected from ISIS NOs: 405955, 405956, 405957, or 405958. 
     In certain embodiments, a target region is nucleotides 1954-1980 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 1954-1980 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 44, 332, 333, 334, or 335. In certain such embodiments, an antisense compound targeted to nucleotides 1954-1980 of SEQ ID NO: 3 is selected from ISIS NOs: 405959, 405960, 405961, 399808, 399964, or 405962. 
     In certain embodiments, a target region is nucleotides 1959-2035 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 1959-2035 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 44, 335, 336, 337, 45, 338, 46, 339, 340, 47, 341, 342, 48, 343, 344, 345, 346, 347, 348, 349, 49, 350, 351, 352, 353, 50, 354, 355, 356, 357, 87, 358, 359, or 51. In certain such embodiments, an antisense compound targeted to nucleotides 1959-2035 of SEQ ID NO: 3 is selected from ISIS NOs: 399808, 399964, 405962, 410739, 405963, 395177, 399899, 405964, 399809, 399965, 405965, 405966, 399810, 399966, 405967, 405968, 399811, 399967, 405969, 405970, 410740, 405885, 405886, 405887, 410596, 410672, 405888, 410597, 410673, 399812, 399968, 410674, or 399969. 
     In certain embodiments, a target region is nucleotides 1959-2057 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 1959-2057 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 44, 335, 336, 337, 45, 338, 46, 339, 340, 47, 341, 342, 48, 343, 344, 345, 346, 347, 348, 349, 49, 350, 351, 352, 353, 50, 354, 355, 356, 357, 87, 358, 359, 51, or 119. In certain such embodiments, an antisense compound targeted to nucleotides 1959-2057 of SEQ ID NO: 3 is selected from ISIS NOs: 399808, 399964, 405962, 410739, 405963, 395177, 399899, 405964, 399809, 399965, 405965, 405966, 399810, 399966, 405967, 405968, 399811, 399967, 405969, 405970, 410740, 405885, 405886, 405887, 410596, 410672, 405888, 410597, 410673, 399812, 399968, 410674, or 399902. 
     In certain embodiments, a target region is nucleotides 1963-1988 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 1963-1988 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 45, 336, 337 or 338. In certain such embodiments, an antisense compound targeted to nucleotides 1963-1988 of SEQ ID NO: 3 is selected from ISIS NOs: 410739, 405963, 395177, 399899, or 405964. 
     In certain embodiments, a target region is nucleotides 1967-2035 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 1967-2035 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 45, 338, 46, 339, 340, 47, 341, 342, 48, 343, 344, 345, 346, 347, 348, 349, 49, 350, 351, 352, 353, 50, 354, 355, 356, 357, 87, 358, 359 or 51. In certain such embodiments, an antisense compound targeted to nucleotides 1967-2035 of SEQ ID NO: 3 is selected from ISIS NOs: 395177, 399899, 405964, 399809, 399965, 405965, 405966, 399810, 399966, 405967, 405968, 399811, 399967, 405969, 405970, 410740, 405885, 405886, 405887, 410596, 410672, 405888, 410597, 410673, 399812, 399968, 410674, 405889, 410598, 410675, 405890, 410599, or 399969. 
     In certain embodiments, a target region is nucleotides 1972-1999 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 1972-1999 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 46, 47, 339, 340, or 341. In certain such embodiments, an antisense compound targeted to nucleotides 1972-1999 of SEQ ID NO: 3 is selected from ISIS NOs: 399809, 399965, 405965, 405966, 399810, 399966, or 405967. 
     In certain embodiments, a target region is nucleotides 1982-2008 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 1982-2008 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 48, 342, 343, or 344. In certain such embodiments, an antisense compound targeted to nucleotides 1982-2008 of SEQ ID NO: 3 is selected from ISIS NOs: 405968, 399811, 399967, 405969, or 405970. 
     In certain embodiments, a target region is nucleotides 1991-2018 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 1991-2018 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 49, 345, 346, 347, 348, 349, 350, or 351. In certain such embodiments, an antisense compound targeted to nucleotides 1991-2018 of SEQ ID NO: 3 is selected from ISIS NOs: 399812, 399968, 405885, 405886, 405887, 405888, 405889, 405890, 410596, 410597, 410598, 410599, 410672, 410673, 410674, 410675, 410676, or 410740. 
     In certain embodiments, a target region is nucleotides 1993-2019 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 1993-2019 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 49, 346, 347, 348, 349, 350, or 354. In certain such embodiments, an antisense compound targeted to nucleotides 1993-2019 of SEQ ID NO: 3 is selected from ISIS NOs: 405885, 405887, 410596, 410672, 405888, 410597, 410673, 399812, 399968, 410674, 405889, 410598, 410675, 405890, 410599, 410676, 405891, 410600, or 410677. 
     In certain embodiments, a target region is nucleotides 1995-2022 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 1995-2022 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 348, 349, 350, 351, 352, 353, 50, or 351 In certain such embodiments, an antisense compound targeted to nucleotides 1995-2022 of SEQ ID NO: 3 is selected from ISIS NOs: 405887, 410596, 410672, 405888, 410597, 410673, 399812, 399968, 410674, 405889, 410598, 410675, 405890, 410599, 410676, 405891, 410600, 405892, 410601, 410678, 395178, 399900, 410679, 408653, 410602, or 410680. 
     In certain embodiments, a target region is nucleotides 1996-2023 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 1996-2023 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 49, 50, 349, 350, 351, 352, 353, 354, or 355. In certain such embodiments, an antisense compound targeted to nucleotides 1996-2023 of SEQ ID NO: 3 is selected from ISIS NOs: 395178, 399812, 399900, 399968, 405888, 405889, 405890, 405891, 405892, 405971, 408653, 410597, 410598, 410599, 410600, 410601, 410602, 410603, 410673, 410674, 410675, 410676, 410677, 410678, 410679, 410680, or 410681. 
     In certain embodiments, a target region is nucleotides 1997-2024 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 1997-2024 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 49, 50, 350, 351, 352, 353, 354, 355, or 356. In certain such embodiments, an antisense compound targeted to nucleotides 1997-2024 of SEQ ID NO: 3 is selected from ISIS NOs: 399812, 399968, 410674, 405889, 410598, 410675, 405890, 410599, 410676, 405891, 410600, 410677, 405892, 410601, 410678, 395178, 399900, 410679, 408653, 410602, 410680, 405971, 410603, 410681, 410540, 410604, or 410682. 
     In certain embodiments, a target region is nucleotides 1998-2025 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 1998-2025 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 50, 350, 351, 352, 353, 354, 355, 356 or 357. In certain such embodiments, an antisense compound targeted to nucleotides 1998-2025 of SEQ ID NO: 3 is selected from ISIS NOs: 405889, 410598, 410675, 405890, 410599, 410676, 405891, 410600, 410677, 405892, 410601, 410678, 395178, 399900, 410679, 408653, 410602, 410680, 405971, 410603, 410681, 410540, 410604, 410682, or 405972. 
     In certain embodiments, a target region is nucleotides 1999-2025 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 1999-2025 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 50, 351, 352, 353, 354, 355, 356, or 357. In certain such embodiments, an antisense compound targeted to nucleotides 1999-2025 of SEQ ID NO: 3 is selected from ISIS NOs: 405889, 410598, 410675, 405890, 410599, 410676, 405891, 410600, 410677, 405892, 410601, 410678, 395178, 399900, 410679, 408653, 410602, 410680, 405971, 410603, 410681, 410540, 410604, 410682, or 405972. 
     In certain embodiments, a target region is nucleotides 2000-2025 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 2000-2025 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 351, 352, 353, 354, 355, 356, or 357. In certain such embodiments, an antisense compound targeted to nucleotides 2000-2025 of SEQ ID NO: 3 is selected from ISIS NOs: 405890, 410599, 410676, 405891, 410600, 410677, 405892, 410601, 410678, 395178, 399900, 410679, 408653, 410602, 410680, 405971, 410603, 410681, 410540, 410604, 410682, or 405972. 
     In certain embodiments, a target region is nucleotides 2009-2035 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 2009-2035 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 51, 87, 358, or 359. In certain such embodiments, an antisense compound targeted to nucleotides 2009-2035 of SEQ ID NO: 3 is selected from ISIS NOs: 395179, 399813, 399901, 399969, 405973, or 405974. 
     In certain embodiments, a target region is nucleotides 2038-2139 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 2038-2139 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 52, 53, 54, 104, 119, 130, 360, 361, 362, 363, 365, 366, 367, 368, 369, 370, or 371. In certain such embodiments, an antisense compound targeted to nucleotides 2038-2139 of SEQ ID NO: 3 is selected from ISIS NOs: 395180, 395181, 395182, 395220, 399814, 399836, 399902, 399903, 399904, 399942, 399970, 399992, 405975, 405976, 405977, 405978, 405979, 405980, 405981, 405982, 405983, 410741, or 410771. 
     In certain embodiments, a target region is nucleotides 2061-2139 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 2061-2139 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 52, 53, 54, 104, 130, 360, 361, 362, 363, 365, 366, 367, 368, 369, 370, or 371. In certain such embodiments, an antisense compound targeted to nucleotides 2061-2139 of SEQ ID NO: 3 is selected from ISIS NOs: 395181, 395182, 395220, 399814, 399836, 399903, 399904, 399942, 399970, 399992, 405975, 405976, 405977, 405978, 405979, 405980, 405981, 405982, 405983, 410741, or 410771. 
     In certain embodiments, a target region is nucleotides 2073-2099 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 2073-2099 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 52, 53, 361, or 362. In certain such embodiments, an antisense compound targeted to nucleotides 2073-2099 of SEQ ID NO: 3 is selected from ISIS NOs: 395181, 399814, 399903, 399970, 405975, or 405976. 
     In certain embodiments, a target region is nucleotides 2078-2104 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 2078-2104 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 53, 104, 362, or 363. In certain such embodiments, an antisense compound targeted to nucleotides 2078-2104 of SEQ ID NO: 3 is selected from ISIS NOs: 395220, 399814, 399942, 399970, 405976, or 405977. 
     In certain embodiments, a target region is nucleotides 2105-2131 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 2105-2131 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 54, 365, 366, or 367. In certain such embodiments, an antisense compound targeted to nucleotides 2105-2131 of SEQ ID NO: 3 is selected from ISIS NOs: 395182, 399904, 405978, 405979, or 405980. 
     In certain embodiments, a target region is nucleotides 2112-2139 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 2112-2139 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 367, 368, 369, 370, or 371. In certain such embodiments, an antisense compound targeted to nucleotides 2112-2139 of SEQ ID NO: 3 is selected from ISIS NOs: 405980, 405981, 410741, 405982, or 405983. 
     In certain embodiments, a target region is nucleotides 2168-2198 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 2168-2198 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 55, 56, 372, 373, 374, or 375. In certain such embodiments, an antisense compound targeted to nucleotides 2168-2198 of SEQ ID NO: 3 is selected from ISIS NOs: 399815, 399816, 399971, 399972, 405641, 405984, 405985, 405986, or 405987. 
     In certain embodiments, a target region is nucleotides 2170-2177 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 2170-2177 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 55, 373, 374, or 375. In certain such embodiments, an antisense compound targeted to nucleotides 2170-2177 of SEQ ID NO: 3 is selected from ISIS NOs: 399815, 399971, 405641, 405985, 405986, or 405987. 
     In certain embodiments, a target region is nucleotides 2245-2284 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 2245-2284 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 408 or 409. In certain such embodiments, an antisense compound targeted to nucleotides 2245-2284 of SEQ ID NO: 3 is selected from ISIS NOs: 410776 or 410777. 
     In certain embodiments, a target region is nucleotides 2295-2394 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 2295-2394 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 60, 61, 410, 411, 412, 413, 414, 415, or 416. In certain such embodiments, an antisense compound targeted to nucleotides 2295-2394 of SEQ ID NO: 3 is selected from ISIS NOs: 395186, 399817, 399908, 399973, 405996, 405997, 410562, 410563, 410564, 410633, 410634, 410635, 410636, 410713, 410714, 410715, 410716, 410717, 410718, 410778, or 410779. 
     In certain embodiments, a target region is nucleotides 2355-2381 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 2355-2381 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 60, 61, 411, 412, 413, 414, or 415. In certain such embodiments, an antisense compound targeted to nucleotides 2355-2381 of SEQ ID NO: 3 is selected from ISIS NOs: 395186, 399817, 399908, 399973, 405996, 405997, 410562, 410563, 410564, 410633, 410634, 410635, 410636, 410713, 410714, 410715, 410716, 410717, or 410718. 
     In certain embodiments, a target region is nucleotides 2355-2394 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 2355-2394 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 60, 61, 411, 412, 413, 414, 415, or 416. In certain such embodiments, an antisense compound targeted to nucleotides 2355-2394 of SEQ ID NO: 3 is selected from ISIS NOs: 395186, 399817, 399908, 399973, 405996, 405997, 410562, 410563, 410564, 410633, 410634, 410635, 410636, 410713, 410714, 410715, 410716, 410717, 410718, or 410779. 
     In certain embodiments, a target region is nucleotides 2405-2461 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 2405-2461 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 417 or 418. In certain such embodiments, an antisense compound targeted to nucleotides 2405-2461 of SEQ ID NO: 3 is selected from ISIS NOs: 410780 or 410781. 
     In certain embodiments, a target region is nucleotides 2560-2587 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 2560-2587 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 62, 419, 420, 421, 422, 423, 424, 425, or 426. In certain such embodiments, an antisense compound targeted to nucleotides 2560-2587 of SEQ ID NO: 3 is selected from ISIS NOs: 395187, 399909, 405998, 410565, 410566, 410567, 410568, 410569, 410570, 410571, 410637, 410638, 410639, 410640, 410641, 410642, 410643, 410644, 410719, 410720, 410721, 410722, 410723, 410724, 410725, 410726, or 410727. 
     In certain embodiments, a target region is nucleotides 2560-2609 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 2560-2609 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 62, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, or 430. In certain such embodiments, an antisense compound targeted to nucleotides 2560-2609 of SEQ ID NO: 3 is selected from ISIS NOs: 395187, 399909, 405998, 410565, 410566, 410567, 410568, 410569, 410570, 410571, 410572, 410573, 410637, 410638, 410639, 410640, 410641, 410642, 410643, 410644, 410645, 410646, 410719, 410720, 410721, 410722, 410723, 410724, 410725, 410726, 410727, 410728, or 410783. 
     In certain embodiments, a target region is nucleotides 2561-2588 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 2561-2588 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 420, 421, 422, 423, 424, 425, 426, 427, or 62. In certain such embodiments, an antisense compound targeted to nucleotides 2561-2588 of SEQ ID NO: 3 is selected from ISIS NOs: 410566, 410638, 410720, 410567, 410639, 410721, 410568, 410640, 410722, 410569, 410641, 410723, 395187, 399909, 410724, 410570, 410642, 410725, 410571, 410643, 410726, 405988, 405998, 410644, 410727, 410572, 410645, or 410728. 
     In certain embodiments, a target region is nucleotides 2562-2589 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 2562-2589 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 62, 421, 422, 423, 424, 425, 426, 427, or 428. In certain such embodiments, an antisense compound targeted to nucleotides 2562-2589 of SEQ ID NO: 3 is selected from ISIS NOs: 395187, 399909, 405998, 410567, 410568, 410569, 410570, 410571, 410572, 410573, 410639, 410640, 410641, 410642, 410643, 410644, 410645, 410646, 410721, 410722, 410723, 410724, 410725, 410726, 410727, 410728, or 410729. 
     In certain embodiments, a target region is nucleotides 2563-2589 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 2563-2589 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 422, 423, 424, 425, 426, 427, 428 or 62. In certain such embodiments, an antisense compound targeted to nucleotides 2563-2589 of SEQ ID NO: 3 is selected from ISIS NOs: 410568, 410640, 410722, 410569, 410641, 410723, 395187, 399909, 410724, 410570, 410642, 410725, 410571, 410643, 410726, 405988, 405998, 410644, 410727, 410572, 410645, 410728, 410573, 410646, or 410729. 
     In certain embodiments, a target region is nucleotides 2564-2589 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 2564-2589 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 423, 424, 425, 426, 427, 428 or 62. In certain such embodiments, an antisense compound targeted to nucleotides 2564-2589 of SEQ ID NO: 3 is selected from ISIS NOs: 410569, 410641, 410723, 395187, 399909, 410724, 410570, 410642, 410725, 410571, 410643, 410726, 405988, 405998, 410644, 410727, 410572, 410645, 410728, 410573, 410646, or 410729. 
     In certain embodiments, a target region is nucleotides 2565-2589 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 2565-2589 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 424, 425, 426, 427, 428 or 62. In certain such embodiments, an antisense compound targeted to nucleotides 2565-2589 of SEQ ID NO: 3 is selected from ISIS NOs: 395187, 399909, 410724, 410570, 410642, 410725, 410571, 410643, 410726, 405988, 405998, 410644, 410727, 410572, 410645, 410728, 410573, 410646, or 410729. 
     In certain embodiments, a target region is nucleotides 2566-2589 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 2566-2589 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 424, 425, 426, 427, or 428. In certain such embodiments, an antisense compound targeted to nucleotides 2566-2589 of SEQ ID NO: 3 is selected from ISIS NOs: 410570, 410642, 410725, 410571, 410643, 410726, 405988, 405998, 410644, 410727, 410572, 410645, 410728, 410573, 410646, or 410729. 
     In certain embodiments, a target region is nucleotides 2567-2589 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 2567-2589 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 425, 426, 427, or 428. In certain such embodiments, an antisense compound targeted to nucleotides 2567-2589 of SEQ ID NO: 3 is selected from ISIS NOs: 410571, 410643, 410726, 405988, 405998, 410644, 410727, 410572, 410645, 410728, 410573, 410646, or 410729. 
     In certain embodiments, a target region is nucleotides 2568-2589 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 2568-2589 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 426, 427 or 428. In certain such embodiments, an antisense compound targeted to nucleotides 2568-2589 of SEQ ID NO: 3 is selected from ISIS NOs: 405988, 405998, 410644, 410727, 410572, 410645, 410728, 410573, 410646, or 410729. 
     In certain embodiments, a target region is nucleotides 2665-2689 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 2665-2689 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 63 or 154. In certain such embodiments, an antisense compound targeted to nucleotides 2665-2689 of SEQ ID NO: 3 is selected from ISIS NOs: 395188, 399910, 399818, or 399974. 
     In certain embodiments, a target region is nucleotides 2759-2783 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 2759-2783 SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 64 or 65. In certain such embodiments, an antisense compound targeted to nucleotides 2759-2783 of SEQ ID NO: 3 is selected from ISIS NOs: 395189, 399911, 399819, or 399975. 
     In certain embodiments, a target region is nucleotides 2837-2880 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 2837-2880 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 66, 67, or 122. In certain such embodiments, an antisense compound targeted to nucleotides 2837-2880 of SEQ ID NO: 3 is selected from ISIS NOs: 399820, 399976, 395190, 399912, 395191, or 399913. 
     In certain embodiments, a target region is nucleotides 2904-2923 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 2904-2923 SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 153. In certain such embodiments, an antisense compound targeted to nucleotides 2904-2923 of SEQ ID NO: 3 is selected from ISIS NOs: 395192 or 399914. 
     In certain embodiments, a target region is nucleotides 3005-3024 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 3005-3024 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 68. In certain such embodiments, an antisense compound targeted to nucleotides 3005-3024 of SEQ ID NO: 3 is selected from ISIS NOs: 395193 or 399915. 
     In certain embodiments, a target region is nucleotides 3005-3174 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 3005-3174 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 68, 431, 432, 433, 434, 69, 435, 436, 437, 438 or 70. In certain such embodiments, an antisense compound targeted to nucleotides 3005-3174 of SEQ ID NO: 3 is selected from ISIS NOs: 395193, 399915, 405893, 405894, 405895, 405896, 395194, 399916, 405897, 405898, 405899, 405900, 395195, or 399917. 
     In certain embodiments, a target region is nucleotides 3083-3110 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 3083-3110 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 69, 69, 431, 432, 433, 434, 435, 436, 437, or 438. In certain such embodiments, an antisense compound targeted to nucleotides 3083-3110 of SEQ ID NO: 3 is selected from ISIS NOs: 395194, 399916, 405893, 405894, 405895, 405896, 405897, 405898, 405899, or 405900. 
     In certain embodiments, a target region is nucleotides 3155-3184 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 3155-3184 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 70, 71, 439, 440, 441, 442, 443, 444, 445, or 446. In certain such embodiments, an antisense compound targeted to nucleotides 3155-3184 of SEQ ID NO: 3 is selected from ISIS NOs: 395195, 399821, 399917, 399977, 405901, 405902, 405903, 405904, 405905, 405906, 405907, or 405908. 
     In certain embodiments, a target region is nucleotides 3238-3268 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 3238-3268 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 72, 73, or 135. In certain such embodiments, an antisense compound targeted to nucleotides 3238-3268 of SEQ ID NO: 3 is selected from ISIS NOs: 395196, 399822, 399823, 399918, 399978, or 399979. 
     In certain embodiments, a target region is nucleotides 3482-3711 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 3482-3711 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 74, 75, or 112. In certain such embodiments, an antisense compound targeted to nucleotides 3482-3711 of SEQ ID NO: 3 is selected from ISIS NOs: 395197, 395198, 399824, 399919, 399920, or 399980. 
     In certain embodiments, a target region is nucleotides 3727-3751 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 3727-3751 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 76 or 77. In certain such embodiments, an antisense compound targeted to nucleotides 3727-3751 of SEQ ID NO: 3 is selected from ISIS NOs: 395199, 399921, 399825, or 399981. 
     In certain embodiments, a target region is nucleotides 3798-3824 of SEQ ID NO: 3. In certain embodiments, an antisense compound is targeted to nucleotides 3798-3824 of SEQ ID NO: 3. In certain embodiments, an antisense compound targeted to a PCSK9 nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 78 or 99. In certain such embodiments, an antisense compound targeted to nucleotides 3798-3824 of SEQ ID NO: 3 is selected from ISIS NOs: 395200, 399922, 399826, or 399982. 
     In certain embodiments, short gapmer antisense compounds are targeted to a PCSK9 nucleic acid. In certain such embodiments, gapmer antisense compounds are targeted to SEQ ID NO: 1, SEQ ID NO: 2 and/or SEQ ID NO: 3. In certain such embodiments, the nucleotide sequences illustrated in Table 15.1 have a 2-10-2 gapmer motif. Table 15.1 illustrates gapmer antisense compounds targeted to SEQ ID NO: 1, SEQ ID NO: 2 and/or SEQ ID NO: 3, having a 2-10-2 motif, where the gap segment comprises 2′-deoxynucleotides and each wing segment comprises nucleotides comprising a 2′-O-methoxyethyl sugar modification. Internucleoside linkages are phosphorthioate, and cytidines are 5-methylcytidines. 
     
       
         
           
               
             
               
                 TABLE 15.1 
               
             
            
               
                   
               
               
                 Gapmer antisense compounds having a 2-10-2  
               
               
                 motif targeted to SEQ ID NO: 1, SEQ ID NO: 2  
               
               
                 and/or SEQ ID NO: 3 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                   
                   
                   
                 5′ 
                 3′ 
                   
               
               
                   
                   
                   
                   
                 Tar- 
                 Tar- 
                   
               
               
                   
                   
                   
                   
                 get 
                 get 
                   
               
               
                 Tar- 
                   
                   
                   
                 Site 
                 Site 
                   
               
               
                 get 
                   
                   
                   
                 on 
                 on 
                   
               
               
                 SEQ 
                   
                   
                   
                 SEQ 
                 SEQ 
                 SEQ 
               
               
                 ID 
                 ISIS 
                   
                   
                 ID 
                 ID 
                 ID 
               
               
                 NO 
                 NO 
                 Motif 
                 OligoSeq 
                 NO: 1 
                 NO: 1 
                 NO 
               
               
                   
               
               
                 1 
                 406539 
                 2-10-2 
                 GCCTATGAGGGTGC 
                 1079 
                 1092 
                 458 
               
               
                   
               
               
                 1 
                 406540 
                 2-10-2 
                 TCCAGGCCTATGAG 
                 1084 
                 1097 
                 459 
               
               
                   
               
               
                 1 
                 406551 
                 2-10-2 
                 CAGCTCAGCAGCTC 
                 1735 
                 1748 
                 460 
               
               
                   
               
               
                 1 
                 406595 
                 2-10-2 
                 TTAATCAGGGAGCC 
                 2877 
                 2890 
                 461 
               
               
                   
               
               
                 2 
                 406551 
                 2-10-2 
                 CAGCTCAGCAGCTC 
                 21181 
                 21194 
                 460 
               
               
                   
               
               
                 2 
                 406595 
                 2-10-2 
                 TTAATCAGGGAGCC 
                 26684 
                 26697 
                 461 
               
               
                   
               
               
                 3 
                 406539 
                 2-10-2 
                 GCCTATGAGGGTGC 
                 1609 
                 1622 
                 458 
               
               
                   
               
               
                 3 
                 406540 
                 2-10-2 
                 TCCAGGCCTATGAG 
                 1614 
                 1627 
                 459 
               
               
                   
               
               
                 3 
                 406551 
                 2-10-2 
                 CAGCTCAGCAGCTC 
                 2168 
                 2181 
                 460 
               
               
                   
               
               
                 3 
                 406595 
                 2-10-2 
                 TTAATCAGGGAGCC 
                 3132 
                 3145 
                 461 
               
               
                   
               
            
           
         
       
     
     In a certain embodiment, a short antisense compound has increased potency compared to a 20 nucleotide compound. In a certain embodiment such short antisense compound and 20 nucleotide compound target the same region. In a certain embodiment, a short antisense compound has increased potency compared to a 20 nucleotide coumpound containing the sequence of the short antisense compound. 
     In certain embodiments, the desired effect is a reduction in mRNA target nucleic acid levels. In other embodiments, the desired effect is reduction of levels of protein encoded by the target nucleic acid or a phenotypic change associated with the target nucleic acid. 
     In one embodiment, a target region is a structurally defined region of the nucleic acid. For example, a target region may encompass a 3′ UTR, a 5′ UTR, an exon, an intron, a coding region, a translation initiation region, translation termination region, or other defined nucleic acid region. In other embodiments, a target region may encompass the sequence from a 5′ target site of one target segment within the target region to a 3′ target site of another target segment within the target region. 
     Targeting includes determination of at least one target segment to which an antisense compound hybridizes, such that a desired effect occurs. A target region may contain one or more target segments. Multiple target segments within a target region may be overlapping. Alternatively, they may be non-overlapping. In one embodiment, target segments within a target region are separated by no more than about 10 nucleotides on the target nucleic acid. In another embodiment, target segments within a target region are separated by no more than about 5 nucleotides on the target nucleic acid. In additional embodiments, target segments are contiguous. 
     Suitable target segments may be found within a 5′ UTR, a coding region, a 3′ UTR, an intron, or an exon. Target segments containing a start codon or a stop codon are also suitable target segments. 
     The determination of suitable target segments may include a comparison of the sequence of a target nucleic acid to other sequences throughout the genome. For example, the BLAST algorithm may be used to identify regions of similarity amongst different nucleic acids. This comparison can prevent the selection of antisense compound sequences that may hybridize in a non-specific manner to sequences other than a selected target nucleic acid (i.e., non-target or off-target sequences). 
     There may be variation in activity (e.g., as defined by percent reduction of target nucleic acid levels) of the antisense compounds within an active target region. In one embodiment, reductions in PCSK9 mRNA levels are indicative of inhibition of PCSK9 expression. Reductions in levels of a PCSK9 protein are also indicative of inhibition of target mRNA expression. Further, phenotypic changes are indicative of inhibition of PCSK9 expression. For example, a decrease in LDL-C levels is indicative of inhibition of PCSK9 expression. 
     Hybridization 
     For example, hybridization may occur between an antisense compound disclosed herein and a PCSK9 nucleic acid. The most common mechanism of hybridization involves hydrogen bonding (e.g., Watson-Crick, Hoogsteen or reversed Hoogsteen hydrogen bonding) between complementary nucleobases of the nucleic acid molecules. 
     Hybridization can occur under varying conditions. Stringent conditions are sequence-dependent and are determined by the nature and composition of the nucleic acid molecules to be hybridized. 
     Methods of determining whether a sequence is specifically hybridizable to a target nucleic acid are well known in the art. In one embodiment, the antisense compounds provided herein are specifically hybridizable with a PCSK9 nucleic acid. 
     The PCSK9 sequences targeted by some of the preferred antisense compounds disclosed in Table 1 are shown in  FIG.  1   . The antisense compounds are labeled with the corresponding Isis number. The bar in  FIG.  1    labeled “NM_174936.2” displays the relative position of the target sequences within GENBANK® Accession No. NM_174936.2, first deposited with GENBANK® on Jun. 1, 2003 (SEQ ID NO: 1). The bar below that shows the corresponding structural elements of the PCSK9 mRNA, where “CDS” is the protein-encoding region of the mRNA and “UTRs” are the 5′ and 3′ untranslated regions. As shown in  FIG.  1   , the sequences targeted by the present antisense compounds are found in the protein-encoding region of the PCSK9 mRNA. 
     Complementarity 
     An antisense compound and a target nucleic acid are complementary to each other when a sufficient number of nucleobases of the antisense compound can hydrogen bond with the corresponding nucleobases of the target nucleic acid, such that a desired effect will occur (e.g., antisense inhibition of a target nucleic acid, such as a PCSK9 nucleic acid). 
     Non-complementary nucleobases between an antisense compound and a PCSK9 nucleic acid may be tolerated provided that the antisense compound remains able to specifically hybridize to a target nucleic acid. Moreover, an antisense compound may hybridize over one or more segments of a PCSK9 nucleic acid such that intervening or adjacent segments are not involved in the hybridization event (e.g., a loop structure, mismatch or hairpin structure). 
     In some embodiments, the antisense compounds provided herein are at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% complementary to a PCSK9 nucleic acid. Percent complementarity of an antisense compound with a target nucleic acid can be determined using routine methods. 
     In other embodiments, the antisense compounds provided herein are fully complementary (i.e, 100% complementary) to a target nucleic acid. For example, antisense compound may be fully complementary to a PCSK9 nucleic acid. As used herein, “fully complementary” means each nucleobase of an antisense compound is capable of precise base pairing with the corresponding nucleobases of a target nucleic acid. 
     The location of a non-complementary nucleobase may be at the 5′ end or 3′ end of the antisense compound. Alternatively, the non-complementary nucleobase or nucleobases may be at an internal position of the antisense compound. When two or more non-complementary nucleobases are present, they may be contiguous (i.e., linked) or non-contiguous. In one embodiment, a non-complementary nucleobase is located in the wing segment of a gapmer antisense oligonucleotide. 
     In one embodiment, antisense compounds up to 20 nucleobases in length comprise no more than 4, no more than 3, no more than 2 or no more than 1 non-complementary nucleobase(s) relative to a target nucleic acid, such as a PCSK9 nucleic acid. 
     In another embodiment, antisense compounds up to 30 nucleobases in length comprise no more than 6, no more than 5, no more than 4, no more than 3, no more than 2 or no more than 1 non-complementary nucleobase(s) relative to a target nucleic acid, such as a PCSK9 nucleic acid. 
     The antisense compounds provided herein also include those which are complementary to a portion of a target nucleic acid. As used herein, “portion” refers to a defined number of contiguous (i.e., linked) nucleobases within a region or segment of a target nucleic acid. A “portion” can also refer to a defined number of contiguous nucleobases of an antisense compound. In one embodiment, the antisense compounds are complementary to at least an 8 nucleobase portion of a target segment. In another embodiment, the antisense compounds are complementary to at least a 12 nucleobase portion of a target segment. In yet another embodiment, the antisense compounds are complementary to at least a 15 nucleobase portion of a target segment. 
     Identity 
     The antisense compounds provided herein may also have a defined percent identity to a particular nucleotide sequence, SEQ ID NO, or compound represented by a specific Isis number. As used herein, an antisense compound is identical to the sequence disclosed herein if it has the same nucleobase pairing ability. For example, a RNA which contains uracil in place of thymidine in a disclosed DNA sequence would be considered identical to the DNA sequence since both uracil and thymidine pair with adenine. Shortened and lengthened versions of the antisense compounds described herein as well as compounds having non-identical bases relative to the antisense compounds provided herein also are contemplated. The non-identical bases may be adjacent to each other or dispersed throughout the antisense compound. Percent identity of an antisense compound is calculated according to the number of bases that have identical base pairing relative to the sequence to which it is being compared. 
     In one embodiment, the antisense compounds are at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or 100% identical to one or more of the antisense compounds disclosed herein. 
     Modifications 
     A nucleoside is a base-sugar combination. The nucleobase (also known as base) portion of the nucleoside is normally a heterocyclic base moiety. Nucleotides are nucleosides that further include a phosphate group covalently linked to the sugar portion of the nucleoside. For those nucleosides that include a pentofuranosyl sugar, the phosphate group can be linked to the 2′, 3′ or 5′ hydroxyl moiety of the sugar. Oligonucleotides are formed through the covalent linkage of adjacent nucleosides to one another, to form a linear polymeric oligonucleotide. Within the oligonucleotide structure, the phosphate groups are commonly referred to as forming the internucleoside linkages of the oligonucleotide. 
     Modifications to antisense compounds encompass substitutions or changes to internucleoside linkages, sugar moieties, or nucleobases. Modified antisense compounds are often preferred over native forms because of desirable properties such as, for example, enhanced cellular uptake, enhanced affinity for nucleic acid target, increased stability in the presence of nucleases, or increased inhibitory activity. 
     Chemically modified nucleosides may also be employed to increase the binding affinity of a shortened or truncated antisense oligonucleotide for its target nucleic acid. Consequently, comparable results can often be obtained with shorter antisense compounds that have such chemically modified nucleosides. 
     Modified Internucleoside Linkages 
     The naturally occurring internucleoside linkage of RNA and DNA is a 3′ to 5′ phosphodiester linkage. Antisense compounds having one or more modified, i.e., non-naturally occurring, internucleoside linkages are often selected over antisense compounds having naturally occurring internucleoside linkages because of desirable properties such as, for example, enhanced cellular uptake, enhanced affinity for target nucleic acids, and increased stability in the presence of nucleases. 
     Oligonucleotides having modified internucleoside linkages include internucleoside linkages that retain a phosphorus atom as well as internucleoside linkages that do not have a phosphorus atom. Representative phosphorus containing internucleoside linkages include, but are not limited to, phosphodiesters, phosphotriesters, methylphosphonates, phosphoramidate, and phosphorothioates. Methods of preparation of phosphorous-containing and non-phosphorous-containing linkages are well known. 
     In one embodiment, antisense compounds targeted to a PCSK9 nucleic acid comprise one or more modified internucleoside linkages. In some embodiments, the modified internucleoside linkages are phosphorothioate linkages. In other embodiments, each internucleoside linkage of an antisense compound is a phosphorothioate internucleoside linkage. 
     Modified Sugar Moieties 
     Antisense compounds targeted to a PCSK9 nucleic acid may contain one or more nucleotides having modified sugar moieties. Sugar modifications may impart nuclease stability, binding affinity or some other beneficial biological property to the antisense compounds. The furanosyl sugar ring of a nucleoside can be modified in a number of ways including, but not limited to: addition of a substituent group, particularly at the 2′ position; bridging of two non-geminal ring atoms to form a bicyclic nucleic acid (BNA); and substitution of an atom or group such as —S—, —N(R)— or —C(R 1 )(R 2 ) (R═H, C1-C12 alkyl or a protecting group) for the ring oxygen at the 4′-position and combinations of these such as for example a 2′-F-5′-methyl substituted nucleoside (see WO 2008/101157, published Aug. 21, 2008, for other disclosed 5′,2′-bis substituted nucleosides) or replacement of the ribosyl ring oxygen atom with S with further substitution at the 2′-position (see U.S. Published Application No. 2005/0130923, published on Jun. 16, 2005) or alternatively 5′-substitution of a BNA (see WO 2007/134181, published Nov. 22, 2007, wherein LNA is substituted with for example a 5′-methyl or a 5′-vinyl group). 
     Modified sugars include, but are not limited to: substituted sugars, especially 2′-substituted sugars having a 2′-F, 2′-OCH 3  (2′-OMe) or a 2′-O(CH 2 ) 2 —OCH 3  (2′-O-methoxyethyl or 2′-MOE) substituent group; and bicyclic modified sugars (BNAs), having a 4′-(CH 2 ) n —O-2′ bridge, where n=1 or n=2, including α-L-methyleneoxy (4′-CH2-O-2′ or 4′-α-L-(CH2)-O-2′ (α-L-LNA)) BNA, β-D-methyleneoxy (4′-CH2-O-2′ or 4′-β-D-(CH2)-O-2′ (β-D-LNA)) BNA and ethyleneoxy (4′-(CH 2 ) 2 —O-2′ (ENA)) BNA. BNAs also include 4′-(CH2)-S-2′ and 4′-C(CH3)2-O-2′ (see International Application No. PCT/US2008/068922); 4′-CH(CH3)-O-2′ and 4′-CH(CH2OCH3)-O-2′ (see U.S. Pat. No. 7,399,845, issued Jul. 15, 2008); 4′-CH2-N(OCH3)-2′ (see International Application No. PCT/US2008/064591); 4′-CH2-O—N(CH3)-2′ (see U.S. Published Application No. 2004/0171570, published Sep. 2, 2004); 4′-CH2-N(R)—O-2′ (see U.S. Pat. No. 7,427,672, issued Sep. 23, 2008); 4′-CH2-C(CH3)-2′ and 4′-CH2-C(═CH2)-2′ (see International Application No. PCT/US2008/066154); and wherein R is, independently, H, C1-C12 alkyl, or a protecting group. Bicyclic modified sugars also include (6&#39;S)-6′ methyl BNA, aminooxy (4′-CH2-O—N(R)-2′) BNA, oxyamino (4′-CH2-N(R)—O-2′) BNA wherein R is, independently, H, a protecting group or C1-C12 alkyl. Examples of nucleosides having modified sugar moieties also include without limitation nucleosides comprising 5′-vinyl, 5′-methyl (R or S) and 4′-S. 
     The substituent at the 2′ position can also be selected from allyl, amino, azido, thio, O-allyl, O—C1-C10 alkyl, OCF 3 , O(CH 2 ) 2 SCH 3 , O(CH 2 ) 2 —O—N(Rm)(Rn), and O—CH 2 —C(═O)—N(Rm)(Rn), where each Rm and Rn is, independently, H or substituted or unsubstituted C1-C10 alkyl. 
     In certain embodiments, such BNA modified nucleotides are high-affinity nucleotides and their incorporation into antisense compounds allows for increased potency and improved therapeutic index. Methods for the preparations of modified sugars are well known to those skilled in the art. 
     In certain embodiments, nucleosides are modified by substitution of the ribosyl ring with a sugar surrogate. Such modification includes without limitation, replacement of the ribosyl ring with a surrogate ring system (sometimes referred to as DNA analogs) such as a morpholino ring, a cyclohexenyl ring, a cyclohexyl ring or a tetrahydropyranyl ring such as one having one of the formula: 
     
       
         
         
             
             
         
       
     
     Many other bicyclo and tricyclo sugar surrogate ring systems are also know in the art that can be used to modify nucleosides for incorporation into antisense compounds. Such ring systems can undergo various additional substitutions to enhance activity. 
     Methods for the preparations of modified sugars are well known to those skilled in the art. 
     In nucleotides having modified sugar moieties (including substitution of a sugar surrogate), the nucleobase moieties (natural, modified or a combination thereof) are maintained for hybridization with an appropriate nucleic acid target. 
     In one embodiment, antisense compounds targeted to a PCSK9 nucleic acid comprise one or more nucleotides having modified sugar moieties. In a suitable embodiment, the modified sugar moiety is 2′-MOE. In other embodiments, the 2′-MOE modified nucleotides are arranged in a gapmer motif. 
     Modified Nucleobases 
     Nucleobase (or base) modifications or substitutions are structurally distinguishable from, yet functionally interchangeable with, naturally occurring or synthetic unmodified nucleobases. Both natural and modified nucleobases are capable of participating in hydrogen bonding. Such nucleobase modifications may impart nuclease stability, binding affinity or some other beneficial biological property to antisense compounds. Modified nucleobases include synthetic and natural nucleobases such as, for example, 5-methylcytosine (5-me-C). Certain nucleobase substitutions, including 5-methylcytosine substitutions, are particularly useful for increasing the binding affinity of an antisense compound for a target nucleic acid. For example, 5-methylcytosine substitutions have been shown to increase nucleic acid duplex stability by 0.6-1.2° C. (Sanghvi, Y. S., Crooke, S. T. and Lebleu, B., eds.,  Antisense Research and Applications , CRC Press, Boca Raton, 1993, pp. 276-278). 
     Additional unmodified nucleobases include 5-hydroxymethyl cytosine, xanthine, hypoxanthine, 2-aminoadenine, 6-methyl and other alkyl derivatives of adenine and guanine, 2-propyl and other alkyl derivatives of adenine and guanine, 2-thiouracil, 2-thiothymine and 2-thiocytosine, 5-halouracil and cytosine, 5-propynyl (—C≡C—CH 3 ) uracil and cytosine and other alkynyl derivatives of pyrimidine bases, 6-azo uracil, cytosine and thymine, 5-uracil (pseudouracil), 4-thiouracil, 8-halo, 8-amino, 8-thiol, 8-thioalkyl, 8-hydroxyl and other 8-substituted adenines and guanines, 5-halo particularly 5-bromo, 5-trifluoromethyl and other 5-substituted uracils and cytosines, 7-methylguanine and 7-methyladenine, 2-F-adenine, 2-amino-adenine, 8-azaguanine and 8-azaadenine, 7-deazaguanine and 7-deazaadenine and 3-deazaguanine and 3-deazaadenine. 
     Heterocyclic base moieties may also include those in which the purine or pyrimidine base is replaced with other heterocycles, for example 7-deaza-adenine, 7-deazaguanosine, 2-aminopyridine and 2-pyridone. Nucleobases that are particularly useful for increasing the binding affinity of antisense compounds include 5-substituted pyrimidines, 6-azapyrimidines and N-2, N-6 and O-6 substituted purines, including 2 aminopropyladenine, 5-propynyluracil and 5-propynylcytosine. 
     In one embodiment, antisense compounds targeted to a PCSK9 nucleic acid comprise one or more modified nucleobases. In an additional embodiment, gap-widened antisense oligonucleotides targeted to a PCSK9 nucleic acid comprise one or more modified nucleobases. In some embodiments, the modified nucleobase is 5-methylcytosine. In further embodiments, each cytosine is a 5-methylcytosine. 
     Compositions and Methods for Formulating Pharmaceutical Compositions 
     Antisense oligonucleotides may be admixed with pharmaceutically acceptable active and/or inert substances for the preparation of pharmaceutical compositions or formulations. Compositions and methods for the formulation of pharmaceutical compositions are dependent upon a number of criteria, including, but not limited to, route of administration, extent of disease, or dose to be administered. 
     Antisense compound targeted to a PCSK9 nucleic acid can be utilized in pharmaceutical compositions by combining the antisense compound with a suitable pharmaceutically acceptable diluent or carrier. A pharmaceutically acceptable diluent includes phosphate-buffered saline (PBS). PBS is a diluent suitable for use in compositions to be delivered parenterally. Accordingly, in one embodiment, employed in the methods described herein is a pharmaceutical composition comprising an antisense compound targeted to a PCSK9 nucleic acid and a pharmaceutically acceptable diluent. In one embodiment, the pharmaceutically acceptable diluent is PBS. In other embodiments, the antisense compound is an antisense oligonucleotide. 
     Pharmaceutical compositions comprising antisense compounds encompass any pharmaceutically acceptable salts, esters, or salts of such esters, or any other oligonucleotide which, upon administration to an animal, including a human, is capable of providing (directly or indirectly) the biologically active metabolite or residue thereof. Accordingly, for example, the disclosure is also drawn to pharmaceutically acceptable salts of antisense compounds, prodrugs, pharmaceutically acceptable salts of such prodrugs, and other bioequivalents. Suitable pharmaceutically acceptable salts include, but are not limited to, sodium and potassium salts. 
     A prodrug can include the incorporation of additional nucleosides at one or both ends of an antisense compound which are cleaved by endogenous nucleases within the body, to form the active antisense compound. 
     In certain embodiments, pharmaceutical compositions of the present invention comprise one or more oligonucleotides and one or more excipients. In certain such embodiments, excipients are selected from water, salt solutions, alcohol, polyethylene glycols, gelatin, lactose, amylase, magnesium stearate, talc, silicic acid, viscous paraffin, hydroxymethylcellulosem and polyvinylpyrrolidone. 
     In certain embodiments, a pharmaceutical composition of the present invention is prepared using known techniques, including, but not limited to mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tabletting processes. 
     In certain embodiments, a pharmaceutical composition of the present invention is a liquid (e.g., a suspension, elixir and/or solution). In certain of such embodiments, a liquid pharmaceutical composition is prepared using ingredients known in the art, including, but not limited to, water, glycols, oils, alcohols, flavoring agents, preservatives, and coloring agents. 
     In certain embodiments, a pharmaceutical composition of the present invention is a solid (e.g., a powder, tablet, and/or capsule). In certain of such embodiments, a solid pharmaceutical composition comprising one or more oligonucleotides is prepared using ingredients known in the art, including, but not limited to, starches, sugars, diluents, granulating agents, lubricants, binders, and disintegrating agents. 
     In certain embodiments, a pharmaceutical composition of the present invention is formulated as a depot preparation. Certain such depot preparations are typically longer acting than non-depot preparations. In certain embodiments, such preparations are administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. In certain embodiments, depot preparations are prepared using suitable polymeric or hydrophobic materials (for example an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt. 
     In certain embodiments, a pharmaceutical composition of the present invention comprises a delivery system. Examples of delivery systems include, but are not limited to, liposomes and emulsions. Certain delivery systems are useful for preparing certain pharmaceutical compositions including those comprising hydrophobic compounds. In certain embodiments, certain organic solvents such as dimethylsulfoxide are used. 
     In certain embodiments, a pharmaceutical composition of the present invention comprises one or more tissue-specific delivery molecules designed to deliver the one or more pharmaceutical agents of the present invention to specific tissues or cell types. For example, in certain embodiments, pharmaceutical compositions include liposomes coated with a tissue-specific antibody. 
     In certain embodiments, a pharmaceutical composition of the present invention comprises a co-solvent system. Certain of such co-solvent systems comprise, for example, benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase. In certain embodiments, such co-solvent systems are used for hydrophobic compounds. A non-limiting example of such a co-solvent system is the VPD co-solvent system, which is a solution of absolute ethanol comprising 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant Polysorbate 80™, and 65% w/v polyethylene glycol 300. The proportions of such co-solvent systems may be varied considerably without significantly altering their solubility and toxicity characteristics. Furthermore, the identity of co-solvent components may be varied: for example, other surfactants may be used instead of Polysorbate 80™; the fraction size of polyethylene glycol may be varied; other biocompatible polymers may replace polyethylene glycol, e.g., polyvinyl pyrrolidone; and other sugars or polysaccharides may substitute for dextrose. 
     In certain embodiments, a pharmaceutical composition of the present invention comprises a sustained-release system. A non-limiting example of such a sustained-release system is a semi-permeable matrix of solid hydrophobic polymers. In certain embodiments, sustained-release systems may, depending on their chemical nature, release pharmaceutical agents over a period of hours, days, weeks or months. 
     In certain embodiments, a pharmaceutical composition of the present invention is prepared for oral administration. In certain of such embodiments, a pharmaceutical composition is formulated by combining one or more oligonucleotides with one or more pharmaceutically acceptable carriers. Certain of such carriers enable pharmaceutical compositions to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a subject. In certain embodiments, pharmaceutical compositions for oral use are obtained by mixing oligonucleotide and one or more solid excipient. Suitable excipients include, but are not limited to, fillers, such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP). In certain embodiments, such a mixture is optionally ground and auxiliaries are optionally added. In certain embodiments, pharmaceutical compositions are formed to obtain tablets or dragee cores. In certain embodiments, disintegrating agents (e.g., cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate) are added. 
     In certain embodiments, dragee cores are provided with coatings. In certain such embodiments, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to tablets or dragee coatings. 
     In certain embodiments, pharmaceutical compositions for oral administration are push-fit capsules made of gelatin. Certain of such push-fit capsules comprise one or more pharmaceutical agents of the present invention in admixture with one or more filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In certain embodiments, pharmaceutical compositions for oral administration are soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. In certain soft capsules, one or more pharmaceutical agents of the present invention are be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. 
     In certain embodiments, pharmaceutical compositions are prepared for buccal administration. Certain of such pharmaceutical compositions are tablets or lozenges formulated in conventional manner. 
     In certain embodiments, a pharmaceutical composition is prepared for administration by injection (e.g., intravenous, subcutaneous, intramuscular, etc.). In certain of such embodiments, a pharmaceutical composition comprises a carrier and is formulated in aqueous solution, such as water or physiologically compatible buffers such as Hanks&#39;s solution, Ringer&#39;s solution, or physiological saline buffer. In certain embodiments, other ingredients are included (e.g., ingredients that aid in solubility or serve as preservatives). In certain embodiments, injectable suspensions are prepared using appropriate liquid carriers, suspending agents and the like. Certain pharmaceutical compositions for injection are presented in unit dosage form, e.g., in ampoules or in multi-dose containers. Certain pharmaceutical compositions for injection are suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Certain solvents suitable for use in pharmaceutical compositions for injection include, but are not limited to, lipophilic solvents and fatty oils, such as sesame oil, synthetic fatty acid esters, such as ethyl oleate or triglycerides, and liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, such suspensions may also contain suitable stabilizers or agents that increase the solubility of the pharmaceutical agents to allow for the preparation of highly concentrated solutions. 
     In certain embodiments, a pharmaceutical composition is prepared for transmucosal administration. In certain of such embodiments penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art. 
     In certain embodiments, a pharmaceutical composition is prepared for administration by inhalation. Certain of such pharmaceutical compositions for inhalation are prepared in the form of an aerosol spray in a pressurized pack or a nebulizer. Certain of such pharmaceutical compositions comprise a propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In certain embodiments using a pressurized aerosol, the dosage unit may be determined with a valve that delivers a metered amount. In certain embodiments, capsules and cartridges for use in an inhaler or insufflator may be formulated. Certain of such formulations comprise a powder mixture of a pharmaceutical agent of the invention and a suitable powder base such as lactose or starch. 
     In certain embodiments, a pharmaceutical composition is prepared for rectal administration, such as a suppositories or retention enema. Certain of such pharmaceutical compositions comprise known ingredients, such as cocoa butter and/or other glycerides. 
     In certain embodiments, a pharmaceutical composition is prepared for topical administration. Certain of such pharmaceutical compositions comprise bland moisturizing bases, such as ointments or creams. Exemplary suitable ointment bases include, but are not limited to, petrolatum, petrolatum plus volatile silicones, lanolin and water in oil emulsions such as Eucerin™, available from Beiersdorf (Cincinnati, Ohio). Exemplary suitable cream bases include, but are not limited to, Nivea™ Cream, available from Beiersdorf (Cincinnati, Ohio), cold cream (USP), Purpose Cream™, available from Johnson &amp; Johnson (New Brunswick, N.J.), hydrophilic ointment (USP) and Lubriderm™, available from Pfizer (Morris Plains, N.J.). 
     In certain embodiments, a pharmaceutical composition of the present invention comprises an oligonucleotide in a therapeutically effective amount. In certain embodiments, the therapeutically effective amount is sufficient to prevent, alleviate or ameliorate symptoms of a disease or to prolong the survival of the subject being treated. Determination of a therapeutically effective amount is well within the capability of those skilled in the art. 
     In certain embodiments, one or more oligonucleotides of the present invention is formulated as a prodrug. In certain embodiments, upon in vivo administration, a prodrug is chemically converted to the biologically, pharmaceutically or therapeutically more active form of the oligonucleotide. In certain embodiments, prodrugs are useful because they are easier to administer than the corresponding active form. For example, in certain instances, a prodrug may be more bioavailable (e.g., through oral administration) than is the corresponding active form. In certain instances, a prodrug may have improved solubility compared to the corresponding active form. In certain embodiments, prodrugs are less water soluble than the corresponding active form. In certain instances, such prodrugs possess superior transmittal across cell membranes, where water solubility is detrimental to mobility. In certain embodiments, a prodrug is an ester. In certain such embodiments, the ester is metabolically hydrolyzed to carboxylic acid upon administration. In certain instances the carboxylic acid containing compound is the corresponding active form. In certain embodiments, a prodrug comprises a short peptide (polyaminoacid) bound to an acid group. In certain of such embodiments, the peptide is cleaved upon administration to form the corresponding active form. 
     In certain embodiments, a prodrug is produced by modifying a pharmaceutically active compound such that the active compound will be regenerated upon in vivo administration. The prodrug can be designed to alter the metabolic stability or the transport characteristics of a drug, to mask side effects or toxicity, to improve the flavor of a drug or to alter other characteristics or properties of a drug. By virtue of knowledge of pharmacodynamic processes and drug metabolism in vivo, those of skill in this art, once a pharmaceutically active compound is known, can design prodrugs of the compound (see, e.g., Nogrady (1985) Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York, pages 388-392). 
     In certain embodiments, a pharmaceutical composition comprising one or more pharmaceutical agents of the present invention is useful for treating a conditions or disorders in a mammalian, and particularly in a human, subject. Suitable administration routes include, but are not limited to, oral, rectal, transmucosal, intestinal, enteral, topical, suppository, through inhalation, intrathecal, intraventricular, intraperitoneal, intranasal, intraocular and parenteral (e.g., intravenous, intramuscular, intramedullary, and subcutaneous). In certain embodiments, pharmaceutical intrathecals are administered to achieve local rather than systemic exposures. For example, pharmaceutical compositions may be injected directly in the area of desired effect (e.g., in the renal or cardiac area). 
     In certain embodiments, a pharmaceutical composition of the present invention is administered in the form of a dosage unit (e.g., tablet, capsule, bolus, etc.). In certain embodiments, such pharmaceutical compositions comprise an oligonucleotide in a dose selected from 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, 250 mg, 255 mg, 260 mg, 265 mg, 270 mg, 270 mg, 280 mg, 285 mg, 290 mg, 295 mg, 300 mg, 305 mg, 310 mg, 315 mg, 320 mg, 325 mg, 330 mg, 335 mg, 340 mg, 345 mg, 350 mg, 355 mg, 360 mg, 365 mg, 370 mg, 375 mg, 380 mg, 385 mg, 390 mg, 395 mg, 400 mg, 405 mg, 410 mg, 415 mg, 420 mg, 425 mg, 430 mg, 435 mg, 440 mg, 445 mg, 450 mg, 455 mg, 460 mg, 465 mg, 470 mg, 475 mg, 480 mg, 485 mg, 490 mg, 495 mg, 500 mg, 505 mg, 510 mg, 515 mg, 520 mg, 525 mg, 530 mg, 535 mg, 540 mg, 545 mg, 550 mg, 555 mg, 560 mg, 565 mg, 570 mg, 575 mg, 580 mg, 585 mg, 590 mg, 595 mg, 600 mg, 605 mg, 610 mg, 615 mg, 620 mg, 625 mg, 630 mg, 635 mg, 640 mg, 645 mg, 650 mg, 655 mg, 660 mg, 665 mg, 670 mg, 675 mg, 680 mg, 685 mg, 690 mg, 695 mg, 700 mg, 705 mg, 710 mg, 715 mg, 720 mg, 725 mg, 730 mg, 735 mg, 740 mg, 745 mg, 750 mg, 755 mg, 760 mg, 765 mg, 770 mg, 775 mg, 780 mg, 785 mg, 790 mg, 795 mg, and 800 mg. In certain such embodiments, a pharmaceutical composition of the present invention comprises a dose of oligonucleotide selected from 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 500 mg, 600 mg, 700 mg, and 800 mg. In certain embodiments, a pharmaceutical composition is comprises a dose of oligonucleotide selected from 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, and 400 mg. In certain embodiments the dose is administered at intervals ranging from more than once per day, once per day, once per week, twice per week, three times per week, four times per week, five times per week, 6 times per week, once per month to once per three months, for as long as needed to sustain the desired effect. 
     In a further aspect, a pharmaceutical agent is sterile lyophilized oligonucleotide that is reconstituted with a suitable diluent, e.g., sterile water for injection. The reconstituted product is administered as a subcutaneous injection or as an intravenous infusion after dilution into saline. The lyophilized drug product consists of the oligonucleotide which has been prepared in water for injection, adjusted to pH 7.0-9.0 with acid or base during preparation, and then lyophilized. The lyophilized oligonucleotide may be 25-800 mg of the oligonucleotide. It is understood that this encompasses 25, 50, 75, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 425, 450, 475, 500, 525, 550, 575, 600, 625, 650, 675, 700, 725, 750, 775, and 800 mg of lyophilized oligonucleotide. The lyophilized drug product may be packaged in a 2 mL Type I, clear glass vial (ammonium sulfate-treated), stoppered with a bromobutyl rubber closure and sealed with an aluminum FLIP-OFF® overseal. In one embodiment, the lyophilized pharmaceutical agent comprises ISIS 405879. 
     The compositions of the present invention may additionally contain other adjunct components conventionally found in pharmaceutical compositions, at their art-established usage levels. Thus, for example, the compositions may contain additional, compatible, pharmaceutically-active materials such as, for example, antipruritics, astringents, local anesthetics or anti-inflammatory agents, or may contain additional materials useful in physically formulating various dosage forms of the compositions of the present invention, such as dyes, flavoring agents, preservatives, antioxidants, opacifiers, thickening agents and stabilizers. However, such materials, when added, should not unduly interfere with the biological activities of the components of the compositions of the present invention. The formulations can be sterilized and, if desired, mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings, flavorings and/or aromatic substances and the like which do not deleteriously interact with the oligonucleotide(s) of the formulation. 
     Conjugated Antisense Compounds 
     Antisense compounds may be covalently linked to one or more moieties or conjugates which enhance the activity, visualization of cellular distribution, or cellular uptake of the resulting antisense oligonucleotides. Typical conjugate groups include cholesterol moieties and lipid moieties. Additional conjugate groups include carbohydrates, phospholipids, biotin, phenazine, folate, phenanthridine, anthraquinone, acridine, fluoresceins, rhodamines, coumarins, and dyes. 
     Antisense compounds can also be modified to have one or more stabilizing groups that are generally attached to one or both termini of antisense compounds to enhance properties such as, for example, nuclease stability. Included in stabilizing groups are cap structures. These terminal modifications protect the antisense compound having terminal nucleic acid from exonuclease degradation, and can help in delivery and/or localization within a cell. The cap can be present at the 5′-terminus (5′-cap), or at the 3′-terminus (3′-cap), or can be present on both termini. Cap structures are well known in the art and include, for example, inverted deoxy abasic caps. Further 3′ and 5′-stabilizing groups that can be used to cap one or both ends of an antisense compound to impart nuclease stability include those disclosed in WO 03/004602 published on Jan. 16, 2003. 
     Cell Culture and Antisense Compounds Treatment 
     The effects of antisense compounds on the level, activity or expression of PCSK9 nucleic acids can be tested in vitro in a variety of cell types. Cell types used for such analyses are available from commercial vendors (e.g., American Type Culture Collection, Manassas, Va.; Zen-Bio, Inc., Research Triangle Park, N.C.; Clonetics Corporation, Walkersville, Md.) and cells are cultured according to the vendor&#39;s instructions using commercially available reagents (e.g., Invitrogen Life Technologies, Carlsbad, Calif.). Illustrative cell types include, but are not limited to, HepG2 cells, Hep3B cells, and primary hepatocytes. 
     In Vitro Testing of Antisense Oligonucleotides 
     Described herein are methods for treatment of cells with antisense oligonucleotides, which can be modified appropriately for treatment with other antisense compounds. 
     In general, cells are treated with antisense oligonucleotides when they cells reach approximately 60-80% confluency in culture. 
     One reagent commonly used to introduce antisense oligonucleotides into cultured cells includes the cationic lipid transfection reagent LIPOFECTIN® (Invitrogen, Carlsbad, Calif.). Antisense oligonucleotides are mixed with LIPOFECTIN® in OPTI-MEM® 1 (Invitrogen, Carlsbad, Calif.) to achieve the desired final concentration of antisense oligonucleotide and a LIPOFECTIN® concentration that typically ranges 2 to 12 ug/mL per 100 nM antisense oligonucleotide. 
     Another reagent used to introduce antisense oligonucleotides into cultured cells includes LIPOFECTAMINE® (Invitrogen, Carlsbad, Calif.). Antisense oligonucleotide is mixed with LIPOFECTAMINE® in OPTI-MEM® 1 reduced serum medium (Invitrogen, Carlsbad, Calif.) to achieve the desired concentration of antisense oligonucleotide and a LIPOFECTAMINE® concentration that typically ranges 2 to 12 ug/mL per 100 nM antisense oligonucleotide. 
     Cells are treated with antisense oligonucleotides by routine methods. Cells are typically harvested 16-24 hours after antisense oligonucleotide treatment, at which time RNA or protein levels of target nucleic acids are measured by methods known in the art and described herein. In general, when treatments are performed in multiple replicates, the data are presented as the average of the replicate treatments. 
     The concentration of antisense oligonucleotide used varies from cell line to cell line. Methods to determine the optimal antisense oligonucleotide concentration for a particular cell line are well known in the art. Antisense oligonucleotides are typically used at concentrations ranging from 1 nM to 300 nM. 
     RNA Isolation 
     RNA analysis can be performed on total cellular RNA or poly(A)+ mRNA. Methods of RNA isolation are well known in the art. RNA is prepared using methods well known in the art, for example, using the TRIZOL® Reagent (Invitrogen, Carlsbad, Calif.) according to the manufacturer&#39;s recommended protocols. 
     Analysis of Inhibition of Target Levels or Expression 
     Inhibition of levels or expression of a PCSK9 nucleic acid can be assayed in a variety of ways known in the art. For example, target nucleic acid levels can be quantitated by, e.g., Northern blot analysis, competitive polymerase chain reaction (PCR), or quantitaive real-time PCR. RNA analysis can be performed on total cellular RNA or poly(A)+ mRNA. Methods of RNA isolation are well known in the art. Northern blot analysis is also routine in the art. Quantitative real-time PCR can be conveniently accomplished using the commercially available ABI PRISM® 7600, 7700, or 7900 Sequence Detection System, available from PE-Applied Biosystems, Foster City, Calif. and used according to manufacturer&#39;s instructions. 
     Quantitative Real-Time PCR Analysis of Target RNA Levels 
     Quantitation of target RNA levels may be accomplished by quantitative real-time PCR using the ABI PRISM® 7600, 7700, or 7900 Sequence Detection System (PE-Applied Biosystems, Foster City, Calif.) according to manufacturer&#39;s instructions. Methods of quantitative real-time PCR are well known in the art. 
     Prior to real-time PCR, the isolated RNA is subjected to a reverse transcriptase (RT) reaction, which produces complementary DNA (cDNA) that is then used as the substrate for the real-time PCR amplification. The RT and real-time PCR reactions are performed sequentially in the same sample well. RT and real-time PCR reagents are obtained from Invitrogen (Carlsbad, Calif.). RT, real-time-PCR reactions are carried out by methods well known to those skilled in the art. 
     Gene (or RNA) target quantities obtained by real time PCR are normalized using either the expression level of a gene whose expression is constant, such as GAPDH, or by quantifying total RNA using RIBOGREEN® (Invitrogen, Inc. Carlsbad, Calif.). GAPDH expression is quantified by real time PCR, by being run simultaneously with the target, multiplexing, or separately. Total RNA is quantified using RIBOGREEN® RNA quantification reagent (Invitrogen, Inc. Carlsbad, Calif.). Methods of RNA quantification by RIBOGREEN® are taught in Jones, L. J., et al, (Analytical Biochemistry, 1998, 265, 368-374). A CYTOFLUOR® 4000 instrument (PE Applied Biosystems) is used to measure RIBOGREEN® fluorescence. 
     Probes and primers are designed to hybridize to a PCSK9 nucleic acid. Methods for designing real-time PCR probes and primers are well known in the art, and may include the use of software such as PRIMER EXPRESS® Software (Applied Biosystems, Foster City, Calif.). 
     Analysis of Protein Levels 
     Antisense inhibition of PCSK9 nucleic acids can be assessed by measuring PCSK9 protein levels. Protein levels of PCSK9 can be evaluated or quantitated in a variety of ways well known in the art, such as immunoprecipitation, Western blot analysis (immunoblotting), enzyme-linked immunosorbent assay (ELISA), quantitative protein assays, protein activity assays (for example, caspase activity assays), immunohistochemistry, immunocytochemistry or fluorescence-activated cell sorting (FACS). Antibodies directed to a target can be identified and obtained from a variety of sources, such as the MSRS catalog of antibodies (Aerie Corporation, Birmingham, Mich.), or can be prepared via conventional monoclonal or polyclonal antibody generation methods well known in the art. Antibodies useful for the detection of human and rat PCSK9 are commercially available. 
     Serum Lipid Analysis 
     Plasma concentrations of total cholesterol, LDL-C, HDL-C, free cholesterol, triglycerides, glucose, ketones, transaminases, and phospholipids can be measured using an automated clinical chemistry analyzer (Hitachi Olympus AU400e, Melville, N.Y.). Serum lipoprotein and cholesterol profiling can be performed as described by Crooke et al.,  Lipid Res . (2005) 46: 872-884, using a Beckman System Gold 126 HPLC system, a 507e refrigerated autosampler, a 126 photodiode array detector (Beckman Instruments, Fullerton, Calif.), and a Superose 6 HR 10/30 column (Pfizer, Chicago, Ill.). HDL, LDL and VLDL fractions are measured at a wavelength of 505 nm and validated with a cholesterol calibration kit. (Sigma). 
     Liver Triglyceride Analysis 
     Liver triglyceride content can be measured according to routine experimental procedures, for example, per procedures described by Desai et al.,  Diabetes  (2001) 50: 2287-2295. Liver triglyceride content may be measured after antisense inhibition of PCSK9 for 6 weeks. 
     In Vivo Testing of Antisense Compounds 
     Antisense compounds, for example, antisense oligonucleotides, are tested in animals to assess their ability to inhibit expression of PCSK9 and produce phenotypic changes, such as decreases in LDL-C. Testing may be performed in normal animals, or in experimental disease models. For administration to animals, antisense oligonucleotides are formulated in a pharmaceutically acceptable diluent, such as phosphate-buffered saline. Administration includes parenteral routes of administration, such as intraperitoneal, intravenous, and subcutaneous. Calculation of antisense oligonucleotide dosage and dosing frequency is within the abilities of those skilled in the art, and depends upon factors such as route of administration and animal body weight. Following a period of treatment with antisense oligonucleotides, RNA is isolated from various tissues and changes in PCSK9 nucleic acid expression are measured. Changes in PCSK9 protein levels may also be measured. 
     Nonlimiting Disclosure and Incorporation by Reference 
     The following examples serve only to illustrate the methods, antisense oligonucleotides, and compositions provided and are not intended to limit the same. Each of the references, GENBANK® accession numbers, and the like recited in the present application is incorporated herein by reference in its entirety. 
     EXAMPLES 
     Example 1: Antisense Inhibition of Human PCSK9: A549 Cells 
     Antisense oligonucleotides targeted to a PCSK9 nucleic acid were tested for their effects on PCSK9 mRNA in vitro. Cultured A549 cells at a density of 4000 cells per well in a 96-well plate were treated with 60 nM of antisense oligonucleotide. After a treatment period of approximately 24 hours, RNA was isolated from the cells and PCSK9 mRNA levels were measured by quantitative real-time PCR, as described herein. PCSK9 mRNA levels were adjusted according to total RNA content as measured by RIBOGREEN®. Results are presented as percent inhibition of PCSK9, relative to untreated control cells. Antisense oligonucleotides that exhibited at least 30% inhibition of PCSK9 expression are shown in Table 16. 
     The motif column indicates the wing-gap-wing motif of each antisense oligonucleotide. Antisense oligonucleotides were designed as 5-10-5 gapmers, or alternatively as 3-14-3 gapmers, where the gap segment comprises 2′-deoxynucleotides and each wing segment comprises 2′-MOE nucleotides. As illustrated in Table 16, a single nucleobase sequence may be represented by a 5-10-5 motif as well as a 3-14-3 motif “5′ target site” indicates the 5′-most nucleotide which the antisense oligonucleotide is targeted on the indicated GENBANK Accession No. 
     
       
         
           
               
             
               
                 TABLE 16 
               
             
            
               
                   
               
               
                 Antisense inhibition of PCSK9 in human cells (Cell type A549) 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                 SEQ 
                 5′ 
                 Target 
                   
                   
                   
               
               
                   
                 ID 
                 Target 
                 Nucleic 
                   
                   
                 % 
               
               
                 IsisNo 
                 NO 
                 Site 
                 Acid 
                 Sequence 
                 Motif 
                 Inhibition 
               
               
                   
               
               
                 395150 
                   5 
                   242 
                 NM_174936.2 
                 GAGGAGACCTAGAGGCCGTG 
                 5-10-5 
                 57 
               
               
                   
               
               
                 395151 
                   6 
                   300 
                 NM_174936.2 
                 AGGACCGCCTGGAGCTGACG 
                 5-10-5 
                 77 
               
               
                   
               
               
                 395152 
                   7 
                   410 
                 NM_174936.2 
                 ACGCAAGGCTAGCACCAGCT 
                 5-10-5 
                 81 
               
               
                   
               
               
                 395153 
                   9 
                   480 
                 NM_174936.2 
                 CCTTGGCGCAGCGGTGGAAG 
                 5-10-5 
                 51 
               
               
                   
               
               
                 395154 
                  10 
                   561 
                 NM_174936.2 
                 GGCGGGCAGTGCGCTCTGAC 
                 5-10-5 
                 40 
               
               
                   
               
               
                 395155 
                  11 
                   600 
                 NM_174936.2 
                 TGGTGAGGTATCCCCGGCGG 
                 5-10-5 
                 79 
               
               
                   
               
               
                 395156 
                  14 
                   620 
                 NM_174936.2 
                 ATGGAAGACATGCAGGATCT 
                 5-10-5 
                 75 
               
               
                   
               
               
                 395157 
                  15 
                   646 
                 NM_174936.2 
                 TTCACCAGGAAGCCAGGAAG 
                 5-10-5 
                 72 
               
               
                   
               
               
                 395158 
                  17 
                   705 
                 NM_174936.2 
                 CCTCGATGTAGTCGACATGG 
                 5-10-5 
                 61 
               
               
                   
               
               
                 395159 
                  18 
                   785 
                 NM_174936.2 
                 GTATTCATCCGCCCGGTACC 
                 5-10-5 
                 35 
               
               
                   
               
               
                 395160 
                  19 
                   835 
                 NM_174936.2 
                 CTGGTGTCTAGGAGATACAC 
                 5-10-5 
                 47 
               
               
                   
               
               
                 395161 
                  21 
                   860 
                 NM_174936.2 
                 GATTTCCCGGTGGTCACTCT 
                 5-10-5 
                 70 
               
               
                   
               
               
                 395162 
                  24 
                   890 
                 NM_174936.2 
                 CTCGAAGTCGGTGACCATGA 
                 5-10-5 
                 52 
               
               
                   
               
               
                 395163 
                  25 
                   923 
                 NM_174936.2 
                 GTGGAAGCGGGTCCCGTCCT 
                 5-10-5 
                 73 
               
               
                   
               
               
                 395164 
                  26 
                   970 
                 NM_174936.2 
                 ACCCCTGCCAGGTGGGTGCC 
                 5-10-5 
                 69 
               
               
                   
               
               
                 395165 
                  28 
                  1004 
                 NM_174936.2 
                 ACCCTTGGCCACGCCGGCAT 
                 5-10-5 
                 81 
               
               
                   
               
               
                 395166 
                  29 
                  1040 
                 NM_174936.2 
                 TTGGCAGTTGAGCACGCGCA 
                 5-10-5 
                 65 
               
               
                   
               
               
                 395167 
                  31 
                  1077 
                 NM_174936.2 
                 CCAGGCCTATGAGGGTGCCG 
                 5-10-5 
                 34 
               
               
                   
               
               
                 395168 
                  32 
                  1098 
                 NM_174936.2 
                 GCTGGCTTTTCCGAATAAAC 
                 5-10-5 
                 69 
               
               
                   
               
               
                 395169 
                  33 
                  1210 
                 NM_174936.2 
                 GTGACCAGCACGACCCCAGC 
                 5-10-5 
                 61 
               
               
                   
               
               
                 395171 
                  34 
                  1326 
                 NM_174936.2 
                 CCAAAGTCCCCAGGGTCACC 
                 5-10-5 
                 38 
               
               
                   
               
               
                 395173 
                  36 
                  1340 
                 NM_174936.2 
                 GCCAAAGTTGGTCCCCAAAG 
                 5-10-5 
                 64 
               
               
                   
               
               
                 395174 
                  38 
                  1361 
                 NM_174936.2 
                 GGCAAAGAGGTCCACACAGC 
                 5-10-5 
                 72 
               
               
                   
               
               
                 395175 
                  39 
                  1389 
                 NM_174936.2 
                 TGGAGGCACCAATGATGTCC 
                 5-10-5 
                 41 
               
               
                   
               
               
                 395177 
                  45 
                  1534 
                 NM_174936.2 
                 TTGGCAGAGAAGTGGATCAG 
                 5-10-5 
                 41 
               
               
                   
               
               
                 395178 
                  50 
                  1569 
                 NM_174936.2 
                 GGTCCTCAGGGAACCAGGCC 
                 5-10-5 
                 67 
               
               
                   
               
               
                 395181 
                  52 
                  1640 
                 NM_174936.2 
                 AAACAGCTGCCAACCTGCCC 
                 5-10-5 
                 37 
               
               
                   
               
               
                 395182 
                  54 
                  1675 
                 NM_174936.2 
                 GTAGGCCCCGAGTGTGCTGA 
                 5-10-5 
                 51 
               
               
                   
               
               
                 395183 
                  57 
                  1812 
                 NM_174936.2 
                 CGTTGTGGGCCCGGCAGACC 
                 5-10-5 
                 74 
               
               
                   
               
               
                 395184 
                  58 
                  1858 
                 NM_174936.2 
                 AGCAGGCAGCACCTGGCAAT 
                 5-10-5 
                 61 
               
               
                   
               
               
                 395185 
                  59 
                  1920 
                 NM_174936.2 
                 CACGGGTCCCCATGCTGGCC 
                 5-10-5 
                 73 
               
               
                   
               
               
                 395186 
                  60 
                  2100 
                 NM_174936.2 
                 CTTTGCATTCCAGACCTGGG 
                 5-10-5 
                 83 
               
               
                   
               
               
                 395187 
                  62 
                  2310 
                 NM_174936.2 
                 GGCAGCAGATGGCAACGGCT 
                 5-10-5 
                 80 
               
               
                   
               
               
                 395189 
                  64 
                  2504 
                 NM_174936.2 
                 TCAAGGGCCAGGCCAGCAGC 
                 5-10-5 
                 65 
               
               
                   
               
               
                 395190 
                  66 
                  2597 
                 NM_174936.2 
                 ATGCCCCACAGTGAGGGAGG 
                 5-10-5 
                 60 
               
               
                   
               
               
                 395191 
                  67 
                  2606 
                 NM_174936.2 
                 AATGGTGAAATGCCCCACAG 
                 5-10-5 
                 76 
               
               
                   
               
               
                 395193 
                  68 
                  2750 
                 NM_174936.2 
                 CATGGGAAGAATCCTGCCTC 
                 5-10-5 
                 48 
               
               
                   
               
               
                 395194 
                  69 
                  2832 
                 NM_174936.2 
                 GGAGATGAGGGCCATCAGCA 
                 5-10-5 
                 64 
               
               
                   
               
               
                 395195 
                  70 
                  2900 
                 NM_174936.2 
                 TAGATGCCATCCAGAAAGCT 
                 5-10-5 
                 44 
               
               
                   
               
               
                 395196 
                  72 
                  2983 
                 NM_174936.2 
                 GGCATAGAGCAGAGTAAAGG 
                 5-10-5 
                 39 
               
               
                   
               
               
                 395198 
                  75 
                  3437 
                 NM_174936.2 
                 GCTCAAGGAGGGACAGTTGT 
                 5-10-5 
                 73 
               
               
                   
               
               
                 395199 
                  76 
                  3472 
                 NM_174936.2 
                 AAAGATAAATGTCTGCTTGC 
                 5-10-5 
                 83 
               
               
                   
               
               
                 395200 
                  78 
                  3543 
                 NM_174936.2 
                 TCTTCAAGTTACAAAAGCAA 
                 5-10-5 
                 40 
               
               
                   
               
               
                 395202 
                 129 
                 13816 
                 NT_032977.8 
                 GTGCCATCTGAACAGCACCT 
                 5-10-5 
                 36 
               
               
                   
               
               
                 395203 
                 110 
                 13926 
                 NT_032977.8 
                 CCTGGAACCCCTGCAGCCAG 
                 5-10-5 
                 64 
               
               
                   
               
               
                 395204 
                 152 
                 13977 
                 NT_032977.8 
                 TTCAGGCAGGTTGCTGCTAG 
                 5-10-5 
                 55 
               
               
                   
               
               
                 395206 
                 136 
                 14122 
                 NT_032977.8 
                 TAGGAGAAAGTAGGGAGAGC 
                 5-10-5 
                 45 
               
               
                   
               
               
                 395207 
                 132 
                 14179 
                 NT_032977.8 
                 TAAAAGCTGCAAGAGACTCA 
                 5-10-5 
                 49 
               
               
                   
               
               
                 395208 
                 139 
                 14267 
                 NT_032977.8 
                 TCAGAGAAAACAGTCACCGA 
                 5-10-5 
                 56 
               
               
                   
               
               
                 395209 
                 142 
                 14404 
                 NT_032977.8 
                 TCATTTTAGAGACAGGAAGC 
                 5-10-5 
                 73 
               
               
                   
               
               
                 395210 
                 113 
                 14441 
                 NT_032977.8 
                 GAATAACAGTGATGTCTGGC 
                 5-10-5 
                 82 
               
               
                   
               
               
                 395211 
                 138 
                 14494 
                 NT_032977.8 
                 TCACAGCTCACCGAGTCTGC 
                 5-10-5 
                 60 
               
               
                   
               
               
                 395212 
                  98 
                 14524 
                 NT_032977.8 
                 AGTGTAAAATAAAGCCCCTA 
                 5-10-5 
                 50 
               
               
                   
               
               
                 395213 
                  96 
                 14601 
                 NT_032977.8 
                 AGGACCCAAGTCATCCTGCT 
                 5-10-5 
                 57 
               
               
                   
               
               
                 395214 
                 124 
                 14631 
                 NT_032977.8 
                 GGCCATCAGCTGGCAATGCT 
                 5-10-5 
                 50 
               
               
                   
               
               
                 395215 
                 133 
                 14675 
                 NT_032977.8 
                 TAGACAAGGAAAGGGAGGCC 
                 5-10-5 
                 60 
               
               
                   
               
               
                 395216 
                 103 
                 14681 
                 NT_032977.8 
                 ATTTCATAGACAAGGAAAGG 
                 5-10-5 
                 51 
               
               
                   
               
               
                 395218 
                 146 
                  1315 
                 AK124635.1 
                 TGACATTTGTGGGAGAGGAG 
                 5-10-5 
                 35 
               
               
                   
               
               
                 395220 
                 104 
                  2085 
                 AK124635.1 
                 CACAGTCCTGCAAAACAGCT 
                 5-10-5 
                 54 
               
               
                   
               
               
                 395221 
                 102 
                  5590 
                 NT_032977.8 
                 ATGTGCAGAGATCAATCACA 
                 5-10-5 
                 69 
               
               
                   
               
               
                 395222 
                 127 
                 10633 
                 NT_032977.8 
                 GGTGGTAATTTGTCACAGCA 
                 5-10-5 
                 64 
               
               
                   
               
               
                 395223 
                  84 
                 11308 
                 NT_032977.8 
                 AAGGTCACACAGTTAAGAGT 
                 5-10-5 
                 55 
               
               
                   
               
               
                 395226 
                 147 
                 24858 
                 NT_032977.8 
                 TGAGTTCATTTAAGAGTGGA 
                 5-10-5 
                 42 
               
               
                   
               
               
                 399793 
                   8 
                   417 
                 NM_174936.2 
                 CCTCGGAACGCAAGGCTAGC 
                 5-10-5 
                 71 
               
               
                   
               
               
                 399794 
                  12 
                   606 
                 NM_174936.2 
                 GGATCTTGGTGAGGTATCCC 
                 5-10-5 
                 42 
               
               
                   
               
               
                 399795 
                  13 
                   615 
                 NM_174936.2 
                 AGACATGCAGGATCTTGGTG 
                 5-10-5 
                 54 
               
               
                   
               
               
                 399796 
                  16 
                   651 
                 NM_174936.2 
                 TCATCTTCACCAGGAAGCCA 
                 5-10-5 
                 50 
               
               
                   
               
               
                 399797 
                  20 
                   840 
                 NM_174936.2 
                 GTATGCTGGTGTCTAGGAGA 
                 5-10-5 
                 38 
               
               
                   
               
               
                 399798 
                  22 
                   866 
                 NM_174936.2 
                 GCCCTCGATTTCCCGGTGGT 
                 5-10-5 
                 54 
               
               
                   
               
               
                 399799 
                  23 
                   880 
                 NM_174936.2 
                 GTGACCATGACCCTGCCCTC 
                 5-10-5 
                 75 
               
               
                   
               
               
                 399800 
                  27 
                   975 
                 NM_174936.2 
                 TGACCACCCCTGCCAGGTGG 
                 5-10-5 
                 67 
               
               
                   
               
               
                 399801 
                  30 
                  1045 
                 NM_174936.2 
                 TTCCCTTGGCAGTTGAGCAC 
                 5-10-5 
                 79 
               
               
                   
               
               
                 399802 
                  35 
                  1335 
                 NM_174936.2 
                 AGTTGGTCCCCAAAGTCCCC 
                 5-10-5 
                 71 
               
               
                   
               
               
                 399803 
                  37 
                  1352 
                 NM_174936.2 
                 GTCCACACAGCGGCCAAAGT 
                 5-10-5 
                 63 
               
               
                   
               
               
                 399804 
                  40 
                  1400 
                 NM_174936.2 
                 GCTGCAGTCGCTGGAGGCAC 
                 5-10-5 
                 46 
               
               
                   
               
               
                 399805 
                  41 
                  1411 
                 NM_174936.2 
                 ACAAAGCAGGTGCTGCAGTC 
                 5-10-5 
                 46 
               
               
                   
               
               
                 399806 
                  42 
                  1470 
                 NM_174936.2 
                 GCATCATGGCTGCAATGCCA 
                 5-10-5 
                 85 
               
               
                   
               
               
                 399807 
                  43 
                  1478 
                 NM_174936.2 
                 GGCAGACAGCATCATGGCTG 
                 5-10-5 
                 71 
               
               
                   
               
               
                 399808 
                  44 
                  1526 
                 NM_174936.2 
                 GAAGTGGATCAGTCTCTGCC 
                 5-10-5 
                 38 
               
               
                   
               
               
                 399809 
                  46 
                  1539 
                 NM_174936.2 
                 CATCTTTGGCAGAGAAGTGG 
                 5-10-5 
                 53 
               
               
                   
               
               
                 399810 
                  47 
                  1545 
                 NM_174936.2 
                 TGATGACATCTTTGGCAGAG 
                 5-10-5 
                 63 
               
               
                   
               
               
                 399811 
                  48 
                  1552 
                 NM_174936.2 
                 GCCTCATTGATGACATCTTT 
                 5-10-5 
                 61 
               
               
                   
               
               
                 399812 
                  49 
                  1564 
                 NM_174936.2 
                 TCAGGGAACCAGGCCTCATT 
                 5-10-5 
                 46 
               
               
                   
               
               
                 399813 
                  51 
                  1583 
                 NM_174936.2 
                 GGTCAGTACCCGCTGGTCCT 
                 5-10-5 
                 72 
               
               
                   
               
               
                 399814 
                  53 
                  1645 
                 NM_174936.2 
                 CTGCAAAACAGCTGCCAACC 
                 5-10-5 
                 88 
               
               
                   
               
               
                 399815 
                  55 
                  1740 
                 NM_174936.2 
                 AGAAACTGGAGCAGCTCAGC 
                 5-10-5 
                 38 
               
               
                   
               
               
                 399816 
                  56 
                  1746 
                 NM_174936.2 
                 TCCTGGAGAAACTGGAGCAG 
                 5-10-5 
                 51 
               
               
                   
               
               
                 399817 
                  61 
                  2105 
                 NM_174936.2 
                 CTTGACTTTGCATTCCAGAC 
                 5-10-5 
                 84 
               
               
                   
               
               
                 399818 
                  63 
                  2415 
                 NM_174936.2 
                 AACCATTTTAAAGCTCAGCC 
                 5-10-5 
                 68 
               
               
                   
               
               
                 399819 
                  65 
                  2509 
                 NM_174936.2 
                 CCCACTCAAGGGCCAGGCCA 
                 5-10-5 
                 87 
               
               
                   
               
               
                 399821 
                  71 
                  2906 
                 NM_174936.2 
                 TCTGGCTAGATGCCATCCAG 
                 5-10-5 
                 83 
               
               
                   
               
               
                 399822 
                  73 
                  2988 
                 NM_174936.2 
                 AGCCTGGCATAGAGCAGAGT 
                 5-10-5 
                 70 
               
               
                   
               
               
                 399824 
                  74 
                  3233 
                 NM_174936.2 
                 AAGTAAGAAGAGGCTTGGCT 
                 5-10-5 
                 43 
               
               
                   
               
               
                 399825 
                  77 
                  3477 
                 NM_174936.2 
                 ACCCAAAAGATAAATGTCTG 
                 5-10-5 
                 61 
               
               
                   
               
               
                 399827 
                 100 
                 13746 
                 NT_032977.8 
                 ATCTCAGGACAGGTGAGCAA 
                 5-10-5 
                 81 
               
               
                   
               
               
                 399828 
                 116 
                 13760 
                 NT_032977.8 
                 GAGTAGAGATTCTCATCTCA 
                 5-10-5 
                 73 
               
               
                   
               
               
                 399829 
                 117 
                 13828 
                 NT_032977.8 
                 GAGTCTTCTGAAGTGCCATC 
                 5-10-5 
                 65 
               
               
                   
               
               
                 399831 
                  83 
                 13986 
                 NT_032977.8 
                 AAGGAAGACTTCAGGCAGGT 
                 5-10-5 
                 52 
               
               
                   
               
               
                 399833 
                  92 
                 14397 
                 NT_032977.8 
                 AGAGACAGGAAGCTGCAGCT 
                 5-10-5 
                 54 
               
               
                   
               
               
                 399834 
                  82 
                 14670 
                 NT_032977.8 
                 AAGGAAAGGGAGGCCTAGAG 
                 5-10-5 
                 44 
               
               
                   
               
               
                 399836 
                 130 
                  2095 
                 AK124635.1 
                 GTGCTGACCACACAGTCCTG 
                 5-10-5 
                 96 
               
               
                   
               
               
                 399837 
                 107 
                  3056 
                 NT_032977.8 
                 CCCACTATAATGGCAAGCCC 
                 5-10-5 
                 83 
               
               
                   
               
               
                 399838 
                  80 
                  4306 
                 NT_032977.8 
                 AACCCAGTTCTAATGCACCT 
                 5-10-5 
                 81 
               
               
                   
               
               
                 399839 
                 106 
                  5140 
                 NT_032977.8 
                 CCAGTCAGAGTAGAACAGAG 
                 5-10-5 
                 68 
               
               
                   
               
               
                 399840 
                 121 
                  5599 
                 NT_032977.8 
                 GGAGCCTACATGTGCAGAGA 
                 5-10-5 
                 46 
               
               
                   
               
               
                 399841 
                  94 
                  5667 
                 NT_032977.8 
                 AGCATGGCACCAGCATCTGC 
                 5-10-5 
                 59 
               
               
                   
               
               
                 399842 
                 108 
                  6652 
                 NT_032977.8 
                 CCCAGCCCTATCAGGAAGTG 
                 5-10-5 
                 67 
               
               
                   
               
               
                 399843 
                 144 
                  7099 
                 NT_032977.8 
                 TGACATCCAGGAGGGAGGAG 
                 5-10-5 
                 33 
               
               
                   
               
               
                 399844 
                  91 
                  7556 
                 NT_032977.8 
                 AGACTGATGGAAGGCATTGA 
                 5-10-5 
                 56 
               
               
                   
               
               
                 399845 
                 131 
                  7565 
                 NT_032977.8 
                 GTGTTGAGCAGACTGATGGA 
                 5-10-5 
                 48 
               
               
                   
               
               
                 399846 
                 145 
                  8836 
                 NT_032977.8 
                 TGACATCTTGTCTGGGAGCC 
                 5-10-5 
                 58 
               
               
                   
               
               
                 399847 
                  90 
                  8948 
                 NT_032977.8 
                 AGACTAGGAGCCTGAGTTTT 
                 5-10-5 
                 38 
               
               
                   
               
               
                 399849 
                 148 
                 10252 
                 NT_032977.8 
                 TGGCAGCAACTCAGACATAT 
                 5-10-5 
                 74 
               
               
                   
               
               
                 399851 
                  88 
                 12715 
                 NT_032977.8 
                 ACTGGATACATTGGCAGACA 
                 5-10-5 
                 62 
               
               
                   
               
               
                 399852 
                 111 
                 12928 
                 NT_032977.8 
                 CTAGAGGAACCACTAGATAT 
                 5-10-5 
                 66 
               
               
                   
               
               
                 399854 
                  97 
                 16134 
                 NT_032977.8 
                 AGTCAAGCTGCTGCCCAGAG 
                 5-10-5 
                 82 
               
               
                   
               
               
                 399855 
                 120 
                 16668 
                 NT_032977.8 
                 GCTAGTTATTAAGCACCTGC 
                 5-10-5 
                 71 
               
               
                   
               
               
                 399856 
                 150 
                 17267 
                 NT_032977.8 
                 TGTGAGCTCTGGCCCAGTGG 
                 5-10-5 
                 64 
               
               
                   
               
               
                 399857 
                 115 
                 18377 
                 NT_032977.8 
                 GAGTAAGGCAGGTTACTCTC 
                 5-10-5 
                 79 
               
               
                   
               
               
                 399858 
                 134 
                 18408 
                 NT_032977.8 
                 TAGATGTGACTAACATTTAA 
                 5-10-5 
                 57 
               
               
                   
               
               
                 399859 
                 105 
                 19203 
                 NT_032977.8 
                 CACATTAGCCTTGCTCAAGT 
                 5-10-5 
                 75 
               
               
                   
               
               
                 399860 
                 151 
                 19913 
                 NT_032977.8 
                 TGTGATGACCTGGAAAGGTG 
                 5-10-5 
                 36 
               
               
                   
               
               
                 399862 
                 109 
                 20188 
                 NT_032977.8 
                 CCCCTGCACAGAGCCTGGCA 
                 5-10-5 
                 59 
               
               
                   
               
               
                 399863 
                 141 
                 20624 
                 NT_032977.8 
                 TCATGGCTGCAATGCCTGGT 
                 5-10-5 
                 46 
               
               
                   
               
               
                 399864 
                  93 
                 20995 
                 NT_032977.8 
                 AGAGAGGAGGGCTTAAAGAA 
                 5-10-5 
                 30 
               
               
                   
               
               
                 399865 
                  95 
                 21082 
                 NT_032977.8 
                 AGCTGCCAACCTGCAAAAAG 
                 5-10-5 
                 75 
               
               
                   
               
               
                 399866 
                 143 
                 21481 
                 NT_032977.8 
                 TGAAAATCCATCCAGCACTG 
                 5-10-5 
                 74 
               
               
                   
               
               
                 399867 
                  89 
                 21589 
                 NT_032977.8 
                 AGAACCATGGAGCACCTGAG 
                 5-10-5 
                 84 
               
               
                   
               
               
                 399868 
                 123 
                 21696 
                 NT_032977.8 
                 GGCACTGCCCTTCCACCAAA 
                 5-10-5 
                 53 
               
               
                   
               
               
                 399869 
                 118 
                 24907 
                 NT_032977.8 
                 GCACCATCCAGACCAGAATC 
                 5-10-5 
                 49 
               
               
                   
               
               
                 399870 
                 114 
                 25413 
                 NT_032977.8 
                 GAGAGGTTCAGATCCAGGCC 
                 5-10-5 
                 66 
               
               
                   
               
               
                 399871 
                   4 
                   135 
                 NM_174936.2 
                 GCGCGGAATCCTGGCTGGGA 
                 3-14-3 
                 40 
               
               
                   
               
               
                 399872 
                   5 
                   242 
                 NM_174936.2 
                 GAGGAGACCTAGAGGCCGTG 
                 3-14-3 
                 64 
               
               
                   
               
               
                 399873 
                   6 
                   300 
                 NM_174936.2 
                 AGGACCGCCTGGAGCTGACG 
                 3-14-3 
                 65 
               
               
                   
               
               
                 399874 
                   7 
                   410 
                 NM_174936.2 
                 ACGCAAGGCTAGCACCAGCT 
                 3-14-3 
                 80 
               
               
                   
               
               
                 399875 
                   9 
                   480 
                 NM_174936.2 
                 CCTTGGCGCAGCGGTGGAAG 
                 3-14-3 
                 67 
               
               
                   
               
               
                 399876 
                  10 
                   561 
                 NM_174936.2 
                 GGCGGGCAGTGCGCTCTGAC 
                 3-14-3 
                 62 
               
               
                   
               
               
                 399877 
                  11 
                   600 
                 NM_174936.2 
                 TGGTGAGGTATCCCCGGCGG 
                 3-14-3 
                 73 
               
               
                   
               
               
                 399878 
                  14 
                   620 
                 NM_174936.2 
                 ATGGAAGACATGCAGGATCT 
                 3-14-3 
                 54 
               
               
                   
               
               
                 399879 
                  15 
                   646 
                 NM_174936.2 
                 TTCACCAGGAAGCCAGGAAG 
                 3-14-3 
                 75 
               
               
                   
               
               
                 399880 
                  17 
                   705 
                 NM_174936.2 
                 CCTCGATGTAGTCGACATGG 
                 3-14-3 
                 80 
               
               
                   
               
               
                 399881 
                  18 
                   785 
                 NM_174936.2 
                 GTATTCATCCGCCCGGTACC 
                 3-14-3 
                 63 
               
               
                   
               
               
                 399882 
                  19 
                   835 
                 NM_174936.2 
                 CTGGTGTCTAGGAGATACAC 
                 3-14-3 
                 66 
               
               
                   
               
               
                 399883 
                  21 
                   860 
                 NM_174936.2 
                 GATTTCCCGGTGGTCACTCT 
                 3-14-3 
                 59 
               
               
                   
               
               
                 399884 
                  24 
                   890 
                 NM_174936.2 
                 CTCGAAGTCGGTGACCATGA 
                 3-14-3 
                 71 
               
               
                   
               
               
                 399885 
                  25  
                   923 
                 NM_174936.2 
                 GTGGAAGCGGGTCCCGTCCT 
                 3-14-3 
                 73 
               
               
                   
               
               
                 399886 
                  26  
                   970 
                 NM_174936.2 
                 ACCCCTGCCAGGTGGGTGCC 
                 3-14-3 
                 76 
               
               
                   
               
               
                 399887 
                  28 
                  1004 
                 NM_174936.2 
                 ACCCTTGGCCACGCCGGCAT 
                 3-14-3 
                 54 
               
               
                   
               
               
                 399888 
                  29 
                  1040 
                 NM_174936.2 
                 TTGGCAGTTGAGCACGCGCA 
                 3-14-3 
                 75 
               
               
                   
               
               
                 399889 
                  31 
                  1077 
                 NM_174936.2 
                 CCAGGCCTATGAGGGTGCCG 
                 3-14-3 
                 84 
               
               
                   
               
               
                 399890 
                  32 
                  1098 
                 NM_174936.2 
                 GCTGGCTTTTCCGAATAAAC 
                 3-14-3 
                 73 
               
               
                   
               
               
                 399891 
                  33 
                  1210 
                 NM_174936.2 
                 GTGACCAGCACGACCCCAGC 
                 3-14-3 
                 99 
               
               
                   
               
               
                 399892 
                 149 
                  1297 
                 NM_174936.2 
                 TGGGCATTGGTGGCCCCAAC 
                 3-14-3 
                 61 
               
               
                   
               
               
                 399893 
                  34 
                  1326 
                 NM_174936.2 
                 CCAAAGTCCCCAGGGTCACC 
                 3-14-3 
                 54 
               
               
                   
               
               
                 399894 
                 128 
                  1330 
                 NM_174936.2 
                 GTCCCCAAAGTCCCCAGGGT 
                 3-14-3 
                 80 
               
               
                   
               
               
                 399895 
                  36 
                  1340 
                 NM_174936.2 
                 GCCAAAGTTGGTCCCCAAAG 
                 3-14-3 
                 82 
               
               
                   
               
               
                 399896 
                  38 
                  1361 
                 NM_174936.2 
                 GGCAAAGAGGTCCACACAGC 
                 3-14-3 
                 83 
               
               
                   
               
               
                 399897 
                  39 
                  1389 
                 NM_174936.2 
                 TGGAGGCACCAATGATGTCC 
                 3-14-3 
                 70 
               
               
                   
               
               
                 399898 
                 101 
                  1465 
                 NM_174936.2 
                 ATGGCTGCAATGCCAGCCAC 
                 3-14-3 
                 37 
               
               
                   
               
               
                 399899 
                  45 
                  1534 
                 NM_174936.2 
                 TTGGCAGAGAAGTGGATCAG 
                 3-14-3 
                 64 
               
               
                   
               
               
                 399900 
                  50 
                  1569 
                 NM_174936.2 
                 GGTCCTCAGGGAACCAGGCC 
                 3-14-3 
                 82 
               
               
                   
               
               
                 399901 
                  87 
                  1576 
                 NM_174936.2 
                 ACCCGCTGGTCCTCAGGGAA 
                 3-14-3 
                 76 
               
               
                   
               
               
                 399902 
                 119 
                  1605 
                 NM_174936.2 
                 GCAGGGCGGCCACCAGGTTG 
                 3-14-3 
                 39 
               
               
                   
               
               
                 399903 
                  52 
                  1640 
                 NM_174936.2 
                 AAACAGCTGCCAACCTGCCC 
                 3-14-3 
                 73 
               
               
                   
               
               
                 399904 
                  54 
                  1675 
                 NM_174936.2 
                 GTAGGCCCCGAGTGTGCTGA 
                 3-14-3 
                 81 
               
               
                   
               
               
                 399905 
                  57 
                  1812 
                 NM_174936.2 
                 CGTTGTGGGCCCGGCAGACC 
                 3-14-3 
                 80 
               
               
                   
               
               
                 399906 
                  58 
                  1858 
                 NM_174936.2 
                 AGCAGGCAGCACCTGGCAAT 
                 3-14-3 
                 92 
               
               
                   
               
               
                 399907 
                  59 
                  1920 
                 NM_174936.2 
                 CACGGGTCCCCATGCTGGCC 
                 3-14-3 
                 95 
               
               
                   
               
               
                 399908 
                  60 
                  2100 
                 NM_174936.2 
                 CTTTGCATTCCAGACCTGGG 
                 3-14-3 
                 84 
               
               
                   
               
               
                 399909 
                  62 
                  2310 
                 NM_174936.2 
                 GGCAGCAGATGGCAACGGCT 
                 3-14-3 
                 73 
               
               
                   
               
               
                 399910 
                 154 
                  2410 
                 NM_174936.2 
                 TTTTAAAGCTCAGCCCCAGC 
                 3-14-3 
                 57 
               
               
                   
               
               
                 399911 
                  64 
                  2504 
                 NM_174936.2 
                 TCAAGGGCCAGGCCAGCAGC 
                 3-14-3 
                 82 
               
               
                   
               
               
                 399912 
                  66 
                  2597 
                 NM_174936.2 
                 ATGCCCCACAGTGAGGGAGG 
                 3-14-3 
                 68 
               
               
                   
               
               
                 399913 
                  67 
                  2606 
                 NM_174936.2 
                 AATGGTGAAATGCCCCACAG 
                 3-14-3 
                 92 
               
               
                   
               
               
                 399914 
                 153 
                  2649 
                 NM_174936.2 
                 TTGGGAGCAGCTGGCAGCAC 
                 3-14-3 
                 59 
               
               
                   
               
               
                 399915 
                  68 
                  2750 
                 NM_174936.2 
                 CATGGGAAGAATCCTGCCTC 
                 3-14-3 
                 78 
               
               
                   
               
               
                 399916 
                  69 
                  2832 
                 NM_174936.2 
                 GGAGATGAGGGCCATCAGCA 
                 3-14-3 
                 71 
               
               
                   
               
               
                 399917 
                  70 
                  2900 
                 NM_174936.2 
                 TAGATGCCATCCAGAAAGCT 
                 3-14-3 
                 81 
               
               
                   
               
               
                 399918 
                  72 
                  2983 
                 NM_174936.2 
                 GGCATAGAGCAGAGTAAAGG 
                 3-14-3 
                 82 
               
               
                   
               
               
                 399919 
                 112 
                  3227 
                 NM_174936.2 
                 GAAGAGGCTTGGCTTCAGAG 
                 3-14-3 
                 57 
               
               
                   
               
               
                 399920 
                  75 
                  3437 
                 NM_174936.2 
                 GCTCAAGGAGGGACAGTTGT 
                 3-14-3 
                 84 
               
               
                   
               
               
                 399921 
                  76 
                  3472 
                 NM_174936.2 
                 AAAGATAAATGTCTGCTTGC 
                 3-14-3 
                 78 
               
               
                   
               
               
                 399922 
                  78 
                  3543 
                 NM_174936.2 
                 TCTTCAAGTTACAAAAGCAA 
                 3-14-3 
                 61 
               
               
                   
               
               
                 399923 
                  85 
                 13681 
                 NT_032977.8 
                 ACAAATTCCCAGACTCAGCA 
                 3-14-3 
                 82 
               
               
                   
               
               
                 399924 
                 129 
                 13816 
                 NT_032977.8 
                 GTGCCATCTGAACAGCACCT 
                 3-14-3 
                 84 
               
               
                   
               
               
                 399925 
                 110 
                 13926 
                 NT_032977.8 
                 CCTGGAACCCCTGCAGCCAG 
                 3-14-3 
                 73 
               
               
                   
               
               
                 399926 
                 152 
                 13977 
                 NT_032977.8 
                 TTCAGGCAGGTTGCTGCTAG 
                 3-14-3 
                 47 
               
               
                   
               
               
                 399927 
                 140 
                 13998 
                 NT_032977.8 
                 TCAGCCAGGCCAAAGGAAGA 
                 3-14-3 
                 78 
               
               
                   
               
               
                 399928 
                 136 
                 14122 
                 NT_032977.8 
                 TAGGAGAAAGTAGGGAGAGC 
                 3-14-3 
                 47 
               
               
                   
               
               
                 399929 
                 132 
                 14179 
                 NT_032977.8 
                 TAAAAGCTGCAAGAGACTCA 
                 3-14-3 
                 69 
               
               
                   
               
               
                 399930 
                 139 
                 14267 
                 NT_032977.8 
                 TCAGAGAAAACAGTCACCGA 
                 3-14-3 
                 82 
               
               
                   
               
               
                 399931 
                 142 
                 14404 
                 NT_032977.8 
                 TCATTTTAGAGACAGGAAGC 
                 3-14-3 
                 79 
               
               
                   
               
               
                 399932 
                 113 
                 14441 
                 NT_032977.8 
                 GAATAACAGTGATGTCTGGC 
                 3-14-3 
                 83 
               
               
                   
               
               
                 399933 
                 138 
                 14494 
                 NT_032977.8 
                 TCACAGCTCACCGAGTCTGC 
                 3-14-3 
                 78 
               
               
                   
               
               
                 399934 
                  98 
                 14524 
                 NT_032977.8 
                 AGTGTAAAATAAAGCCCCTA 
                 3-14-3 
                 79 
               
               
                   
               
               
                 399935 
                  96 
                 14601 
                 NT_032977.8 
                 AGGACCCAAGTCATCCTGCT 
                 3-14-3 
                 89 
               
               
                   
               
               
                 399936 
                 124 
                 14631 
                 NT_032977.8 
                 GGCCATCAGCTGGCAATGCT 
                 3-14-3 
                 70 
               
               
                   
               
               
                 399937 
                 133 
                 14675 
                 NT_032977.8 
                 TAGACAAGGAAAGGGAGGCC 
                 3-14-3 
                 78 
               
               
                   
               
               
                 399938 
                 103 
                 14681 
                 NT_032977.8 
                 ATTTCATAGACAAGGAAAGG 
                 3-14-3 
                 67 
               
               
                   
               
               
                 399940 
                 146 
                  1315 
                 AK124635.1 
                 TGACATTTGTGGGAGAGGAG 
                 3-14-3 
                 35 
               
               
                   
               
               
                 399942 
                 104 
                  2085 
                 AK124635.1 
                 CACAGTCCTGCAAAACAGCT 
                 3-14-3 
                 75 
               
               
                   
               
               
                 399943 
                 102 
                  5590 
                 NT_032977.8 
                 ATGTGCAGAGATCAATCACA 
                 3-14-3 
                 64 
               
               
                   
               
               
                 399944 
                 127 
                 10633 
                 NT_032977.8 
                 GGTGGTAATTTGTCACAGCA 
                 3-14-3 
                 73 
               
               
                   
               
               
                 399945 
                  84 
                 11308 
                 NT_032977.8 
                 AAGGTCACACAGTTAAGAGT 
                 3-14-3 
                 89 
               
               
                   
               
               
                 399947 
                 126 
                 22292 
                 NT_032977.8 
                 GGTGCATAAGGAGAAAGAGA 
                 3-14-3 
                 70 
               
               
                   
               
               
                 399948 
                 147 
                 24858 
                 NT_032977.8 
                 TGAGTTCATTTAAGAGTGGA 
                 3-14-3 
                 46 
               
               
                   
               
               
                 399949 
                   8 
                   417 
                 NM_174936.2 
                 CCTCGGAACGCAAGGCTAGC 
                 3-14-3 
                 74 
               
               
                   
               
               
                 399950 
                  12 
                   606 
                 NM_174936.2 
                 GGATCTTGGTGAGGTATCCC 
                 3-14-3 
                 68 
               
               
                   
               
               
                 399951 
                  13 
                   615 
                 NM_174936.2 
                 AGACATGCAGGATCTTGGTG 
                 3-14-3 
                 67 
               
               
                   
               
               
                 399952 
                  16 
                   651 
                 NM_174936.2 
                 TCATCTTCACCAGGAAGCCA 
                 3-14-3 
                 74 
               
               
                   
               
               
                 399953 
                  20 
                   840 
                 NM_174936.2 
                 GTATGCTGGTGTCTAGGAGA 
                 3-14-3 
                 59 
               
               
                   
               
               
                 399954 
                  22 
                   866 
                 NM_174936.2 
                 GCCCTCGATTTCCCGGTGGT 
                 3-14-3 
                 83 
               
               
                   
               
               
                 399955 
                  23 
                   880 
                 NM_174936.2 
                 GTGACCATGACCCTGCCCTC 
                 3-14-3 
                 62 
               
               
                   
               
               
                 399956 
                  27 
                   975 
                 NM_174936.2 
                 TGACCACCCCTGCCAGGTGG 
                 3-14-3 
                 78 
               
               
                   
               
               
                 399957 
                  30 
                  1045 
                 NM_174936.2 
                 TTCCCTTGGCAGTTGAGCAC 
                 3-14-3 
                 82 
               
               
                   
               
               
                 399958 
                  35 
                  1335 
                 NM_174936.2 
                 AGTTGGTCCCCAAAGTCCCC 
                 3-14-3 
                 78 
               
               
                   
               
               
                 399959 
                  37 
                  1352 
                 NM_174936.2 
                 GTCCACACAGCGGCCAAAGT 
                 3-14-3 
                 89 
               
               
                   
               
               
                 399960 
                  40 
                  1400 
                 NM_174936.2 
                 GCTGCAGTCGCTGGAGGCAC 
                 3-14-3 
                 64 
               
               
                   
               
               
                 399961 
                  41 
                  1411 
                 NM_174936.2 
                 ACAAAGCAGGTGCTGCAGTC 
                 3-14-3 
                 63 
               
               
                   
               
               
                 399962 
                  42 
                  1470 
                 NM_174936.2 
                 GCATCATGGCTGCAATGCCA 
                 3-14-3 
                 68 
               
               
                   
               
               
                 399963 
                  43 
                  1478 
                 NM_174936.2 
                 GGCAGACAGCATCATGGCTG 
                 3-14-3 
                 70 
               
               
                   
               
               
                 399964 
                  44 
                  1526 
                 NM_174936.2 
                 GAAGTGGATCAGTCTCTGCC 
                 3-14-3 
                 70 
               
               
                   
               
               
                 399965 
                  46 
                  1539 
                 NM_174936.2 
                 CATCTTTGGCAGAGAAGTGG 
                 3-14-3 
                 49 
               
               
                   
               
               
                 399966 
                  47 
                  1545 
                 NM_174936.2 
                 TGATGACATCTTTGGCAGAG 
                 3-14-3 
                 78 
               
               
                   
               
               
                 399967 
                  48 
                  1552 
                 NM_174936.2 
                 GCCTCATTGATGACATCTTT 
                 3-14-3 
                 82 
               
               
                   
               
               
                 399968 
                  49 
                  1564 
                 NM_174936.2 
                 TCAGGGAACCAGGCCTCATT 
                 3-14-3 
                 71 
               
               
                   
               
               
                 399969 
                  51 
                  1583 
                 NM_174936.2 
                 GGTCAGTACCCGCTGGTCCT 
                 3-14-3 
                 82 
               
               
                   
               
               
                 399970 
                  53 
                  1645 
                 NM_174936.2 
                 CTGCAAAACAGCTGCCAACC 
                 3-14-3 
                 74 
               
               
                   
               
               
                 399971 
                  55 
                  1740 
                 NM_174936.2 
                 AGAAACTGGAGCAGCTCAGC 
                 3-14-3 
                 48 
               
               
                   
               
               
                 399972 
                  56 
                  1746 
                 NM_174936.2 
                 TCCTGGAGAAACTGGAGCAG 
                 3-14-3 
                 63 
               
               
                   
               
               
                 399973 
                  61 
                  2105 
                 NM_174936.2 
                 CTTGACTTTGCATTCCAGAC 
                 3-14-3 
                 74 
               
               
                   
               
               
                 399974 
                  63 
                  2415 
                 NM_174936.2 
                 AACCATTTTAAAGCTCAGCC 
                 3-14-3 
                 71 
               
               
                   
               
               
                 399975 
                  65 
                  2509 
                 NM_174936.2 
                 CCCACTCAAGGGCCAGGCCA 
                 3-14-3 
                 91 
               
               
                   
               
               
                 399976 
                 122 
                  2582 
                 NM_174936.2 
                 GGAGGGAGCTTCCTGGCACC 
                 3-14-3 
                 67 
               
               
                   
               
               
                 399977 
                  71 
                  2906 
                 NM_174936.2 
                 TCTGGCTAGATGCCATCCAG 
                 3-14-3 
                 89 
               
               
                   
               
               
                 399978 
                  73 
                  2988 
                 NM_174936.2 
                 AGCCTGGCATAGAGCAGAGT 
                 3-14-3 
                 80 
               
               
                   
               
               
                 399979 
                 135 
                  2994 
                 NM_174936.2 
                 TAGCACAGCCTGGCATAGAG 
                 3-14-3 
                 83 
               
               
                   
               
               
                 399980 
                  74 
                  3233 
                 NM_174936.2 
                 AAGTAAGAAGAGGCTTGGCT 
                 3-14-3 
                 50 
               
               
                   
               
               
                 399981 
                  77 
                  3477 
                 NM_174936.2 
                 ACCCAAAAGATAAATGTCTG 
                 3-14-3 
                 55 
               
               
                   
               
               
                 399982 
                  99 
                  3550 
                 NM_174936.2 
                 ATAAATATCTTCAAGTTACA 
                 3-14-3 
                 36 
               
               
                   
               
               
                 399983 
                 100 
                 13746 
                 NT_032977.8 
                 ATCTCAGGACAGGTGAGCAA 
                 3-14-3 
                 96 
               
               
                   
               
               
                 399984 
                 116 
                 13760 
                 NT_032977.8 
                 GAGTAGAGATTCTCATCTCA 
                 3-14-3 
                 71 
               
               
                   
               
               
                 399985 
                 117 
                 13828 
                 NT_032977.8 
                 GAGTCTTCTGAAGTGCCATC 
                 3-14-3 
                 76 
               
               
                   
               
               
                 399986 
                  81 
                 13903 
                 NT_032977.8 
                 AAGCAGGGCCTCAGGTGGAA 
                 3-14-3 
                 68 
               
               
                   
               
               
                 399987 
                  83 
                 13986 
                 NT_032977.8 
                 AAGGAAGACTTCAGGCAGGT 
                 3-14-3 
                 59 
               
               
                   
               
               
                 399988 
                 137 
                 14112 
                 NT_032977.8 
                 TAGGGAGAGCTCACAGATGC 
                 3-14-3 
                 31 
               
               
                   
               
               
                 399989 
                  92 
                 14397 
                 NT_032977.8 
                 AGAGACAGGAAGCTGCAGCT 
                 3-14-3 
                 65 
               
               
                   
               
               
                 399990 
                  82 
                 14670 
                 NT_032977.8 
                 AAGGAAAGGGAGGCCTAGAG 
                 3-14-3 
                 59 
               
               
                   
               
               
                 399992 
                 130 
                  2095 
                 AK124635.1 
                 GTGCTGACCACACAGTCCTG 
                 3-14-3 
                 94 
               
               
                   
               
               
                 399993 
                 107 
                  3056 
                 NT_032977.8 
                 CCCACTATAATGGCAAGCCC 
                 3-14-3 
                 76 
               
               
                   
               
               
                 399994 
                  80 
                  4306 
                 NT_032977.8 
                 AACCCAGTTCTAATGCACCT 
                 3-14-3 
                 82 
               
               
                   
               
               
                 399995 
                 106 
                  5140 
                 NT_032977.8 
                 CCAGTCAGAGTAGAACAGAG 
                 3-14-3 
                 74 
               
               
                   
               
               
                 399996 
                 121 
                  5599 
                 NT_032977.8 
                 GGAGCCTACATGTGCAGAGA 
                 3-14-3 
                 65 
               
               
                   
               
               
                 399997 
                  94 
                  5667 
                 NT_032977.8 
                 AGCATGGCACCAGCATCTGC 
                 3-14-3 
                 77 
               
               
                   
               
               
                 399998 
                 108 
                  6652 
                 NT_032977.8 
                 CCCAGCCCTATCAGGAAGTG 
                 3-14-3 
                 78 
               
               
                   
               
               
                 399999 
                 144 
                  7099 
                 NT_032977.8 
                 TGACATCCAGGAGGGAGGAG 
                 3-14-3 
                 43 
               
               
                   
               
               
                 400000 
                  91 
                  7556 
                 NT_032977.8 
                 AGACTGATGGAAGGCATTGA 
                 3-14-3 
                 84 
               
               
                   
               
               
                 400001 
                 131 
                  7565 
                 NT_032977.8 
                 GTGTTGAGCAGACTGATGGA 
                 3-14-3 
                 73 
               
               
                   
               
               
                 400002 
                 145 
                  8836 
                 NT_032977.8 
                 TGACATCTTGTCTGGGAGCC 
                 3-14-3 
                 82 
               
               
                   
               
               
                 400003 
                  90 
                  8948 
                 NT_032977.8 
                 AGACTAGGAGCCTGAGTTTT 
                 3-14-3 
                 48 
               
               
                   
               
               
                 400004 
                 125 
                  9099 
                 NT_032977.8 
                 GGCCTGCAGAAGCCAGAGAG 
                 3-14-3 
                 45 
               
               
                   
               
               
                 400005 
                 148 
                 10252 
                 NT_032977.8 
                 TGGCAGCAACTCAGACATAT 
                 3-14-3 
                 73 
               
               
                   
               
               
                 400006 
                  79 
                 11472 
                 NT_032977.8 
                 AAATGCAGGGCTAAAATCAC 
                 3-14-3 
                 78 
               
               
                   
               
               
                 400007 
                  88 
                 12715 
                 NT_032977.8 
                 ACTGGATACATTGGCAGACA 
                 3-14-3 
                 77 
               
               
                   
               
               
                 400008 
                 111 
                 12928 
                 NT_032977.8 
                 CTAGAGGAACCACTAGATAT 
                 3-14-3 
                 78 
               
               
                   
               
               
                 400009 
                  86 
                 15471 
                 NT_032977.8 
                 ACAGCATTCTTGGTTAGGAG 
                 3-14-3 
                 73 
               
               
                   
               
               
                 400010 
                  97 
                 16134 
                 NT_032977.8 
                 AGTCAAGCTGCTGCCCAGAG 
                 3-14-3 
                 74 
               
               
                   
               
               
                 400011 
                 120 
                 16668 
                 NT_032977.8 
                 GCTAGTTATTAAGCACCTGC 
                 3-14-3 
                 75 
               
               
                   
               
               
                 400012 
                 150 
                 17267 
                 NT_032977.8 
                 TGTGAGCTCTGGCCCAGTGG 
                 3-14-3 
                 64 
               
               
                   
               
               
                 400013 
                 115 
                 18377 
                 NT_032977.8 
                 GAGTAAGGCAGGTTACTCTC 
                 3-14-3 
                 88 
               
               
                   
               
               
                 400014 
                 134 
                 18408 
                 NT_032977.8 
                 TAGATGTGACTAACATTTAA 
                 3-14-3 
                 58 
               
               
                   
               
               
                 400015 
                 105 
                 19203 
                 NT_032977.8 
                 CACATTAGCCTTGCTCAAGT 
                 3-14-3 
                 89 
               
               
                   
               
               
                 400018 
                 109 
                 20188 
                 NT_032977.8 
                 CCCCTGCACAGAGCCTGGCA 
                 3-14-3 
                 62 
               
               
                   
               
               
                 400019 
                 141 
                 20624 
                 NT_032977.8 
                 TCATGGCTGCAATGCCTGGT 
                 3-14-3 
                 47 
               
               
                   
               
               
                 400020 
                  93 
                 20995 
                 NT_032977.8 
                 AGAGAGGAGGGCTTAAAGAA 
                 3-14-3 
                 66 
               
               
                   
               
               
                 400021 
                  95 
                 21082 
                 NT_032977.8 
                 AGCTGCCAACCTGCAAAAAG 
                 3-14-3 
                 61 
               
               
                   
               
               
                 400022 
                 143 
                 21481 
                 NT_032977.8 
                 TGAAAATCCATCCAGCACTG 
                 3-14-3 
                 90 
               
               
                   
               
               
                 400023 
                 89 
                 21589 
                 NT_032977.8 
                 AGAACCATGGAGCACCTGAG 
                 3-14-3 
                 83 
               
               
                   
               
               
                 400024 
                 123 
                 21696 
                 NT_032977.8 
                 GGCACTGCCCTTCCACCAAA 
                 3-14-3 
                 79 
               
               
                   
               
               
                 400025 
                 118 
                 24907 
                 NT_032977.8 
                 GCACCATCCAGACCAGAATC 
                 3-14-3 
                 78 
               
               
                   
               
               
                 400026 
                 114 
                 25413 
                 NT_032977.8 
                 GAGAGGTTCAGATCCAGGCC 
                 3-14-3 
                 81 
               
               
                   
               
            
           
         
       
     
     Antisense oligonucleotides with the following ISIS Nos exhibited at least 80% inhibition of PCSK9 mRNA levels: 399806, 399814, 399817, 399819, 399821, 399827, 399836, 399837, 399854, 399867, 399889, 399891, 399906, 399907, 399908, 399913, 399920, 399924, 399935, 399945, 399959, 399975, 399977, 399983, 399992, 400000, 400013, 400015, 400022, and 400023. The target segments to which these antisense oligonucleotides are targeted are active target segments. The target regions to which these antisense oligonucleotides are targeted are active target regions. 
     ISIS Nos 399814, 399819, 399836, 399891, 399906, 399907, 399913, 399935, 399945, 399959, 399975, 399977, 399983, 399992, 400013, 400015, and 400022 each exhibited at least 85% inhibition of PCSK9 mRNA levels. 
     ISIS Nos 399836, 399891, 399906, 399907, 399913, 399975, 399983, 399992, and 400022 each exhibited at least 90% inhibition of PCSK9 mRNA levels. 
     Example 2: Antisense Inhibition of Human PCSK9 in HepG2 Cells 
     Antisense oligonucleotides were tested for their ability to inhibit the expression of PCSK9 mRNA in cultured HepG2 cells. HepG2 cells at a density of 10000 cells per well in a 96-well plate were treated with 1500 nM of antisense oligonucleotide. After a treatment period of approximately 24 hours, RNA was isolated from the cells and PCSK9 mRNA levels were measured by quantitative real-time PCR, as described herein. PCSK9 mRNA levels were adjusted according to total RNA content as measured by RIBOGREEN®. Results are presented as percent inhibition of PCSK9, relative to untreated control cells. 
     Isis Nos. 399819, 395149, 395150, 395151, 395152, 395153, 395154, 395155, 395156, 395157, 395158, 395161, 395162, 395163, 395164, 395165, 395166, 395167, 395168, 395172, 395173, 395174, 395178, 395179, 395182, 395183, 395185, 395186, 395187, 395189, 395190, 395191, 395193, 395194, 395195, 395198, 395199, 395203, 395207, 395210, 395211, 395213, 395214, 395221, 395222, 399793, 399794, 399795, 399798, 399801, 399803, 399804, 399806, 399807, 399812, 399813, 399814, 399816, 399817, 399820, 399821, 399822, 399823, 399827, 399828, 399829, 399833, 399834, 399836, 399837, 399841, 399844, 399846, 399848, 399849, 399851, 399852, 399854, 399855, 399856, 399857, 399862, 399865, 399867, 399868, 399872, 399873, 399874, 399875, 399876, 399877, 399879, 399880, 399883, 399884, 399885, 399886, 399887, 399888, 399889, 399890, 399891, 399892, 399894, 399895, 399896, 399900, 399901, 399902, 399904, 399905, 399906, 399907, 399908, 399909, 399911, 399912, 399913, 399915, 399916, 399918, 399920, 399921, 399924, 399925, 399929, 399931, 399935, 399936, 399937, 399943, 399944, 399945, 399949, 399950, 399954, 399957, 399959, 399960, 399962, 399963, 399966, 399967, 399968, 399969, 399970, 399972, 399973, 399975, 399976, 399977, 399978, 399979, 399983, 399984, 399985, 399986, 399989, 399990, 399992, 399996, 399997, 399998, 400000, 400001, 400002, 400004, 400005, 400007, 400008, 400009, 400010, 400012, 400013, 400015, 400018, 400021, 400023, 400024, 400025, and 400026 each inhibited PCSK9 by at least 70% in this experiment. The target segments to which these antisense oligonucleotides are targeted are active target segments. The target regions to which these antisense oligonucleotides are targeted are active target regions. 
     Isis Nos 399819, 395150, 395152, 395153, 395154, 395155, 395156, 395158, 395163, 395164, 395165, 395166, 395167, 395168, 395173, 395178, 395183, 395185, 395186, 395187, 395189, 395190, 395193, 395194, 395199, 395203, 395210, 395213, 395214, 399793, 399798, 399801, 399804, 399806, 399813, 399816, 399820, 399821, 399822, 399836, 399849, 399856, 399857, 399862, 399868, 399875, 399877, 399880, 399885, 399886, 399887, 399888, 399889, 399890, 399894, 399896, 399900, 399901, 399904, 399905, 399906, 399907, 399911, 399912, 399916, 399920, 399925, 399935, 399936, 399937, 399945, 399954, 399957, 399959, 399960, 399962, 399968, 399969, 399973, 399976, 399977, 399978, 399989, 399992, 400002, 400004, 400007, 400012, 400013, 400023, and 400024 each inhibited PCSK9 by at least 80% in this experiment. 
     Isis Nos 399819, 395152, 395153, 395155, 395156, 395158, 395163, 395164, 395165, 395166, 395168, 395178, 395183, 395185, 395187, 395189, 395190, 395194, 395199, 395203, 395214, 399793, 399804, 399813, 399821, 399822, 399836, 399856, 399868, 399877, 399887, 399888, 399890, 399900, 399904, 399905, 399907, 399911, 399912, 399916, 399925, 399936, 399954, 399960, 399962, 399969, 399976, 399977, 399978, 399989, 399992, 400012, 400013, 400023, and 400024 each inhibited PCSK9 by at least 85% in this experiment. 
     Isis Nos 399819, 395165, 395183, 395185, 399868, 399900, 399907, 399911, 399912, 399916, 399936, 399969, and 400024 each inhibited PCSK9 by at least 90% in this experiment. 
     Example 3: Antisense Inhibition of Human PCSK9 (Hep3B Cells) 
     Antisense oligonucleotides targeted to a PCSK9 nucleic acid were tested for their effects on PCSK9 mRNA in vitro. Cultured Hep3B cells at a density of 4000 cells per well in a 96-well plate were treated with 75 nM of antisense oligonucleotide. After a treatment period of approximately 24 hours, RNA was isolated from the cells and PCSK9 mRNA levels were measured by quantitative real-time PCR, as described herein. PCSK9 mRNA levels were adjusted according to total RNA content as measured by RIBOGREEN®. Results are presented as percent inhibition of PCSK9, relative to untreated control cells. Antisense oligonucleotides that exhibited at least 30% inhibition of PCSK9 expression are shown in Tables 17, 18, and 19. 
     The motif column indicates the wing-gap-wing motif of each antisense oligonucleotide. Antisense oligonucleotides were designed as 5-10-5 gapmers, or alternatively as 3-14-3 gapmers, or alternatively as 2-13-5 gapmers where the gap segment comprises 2′-deoxynucleotides and each wing segment comprises 2′-MOE nucleotides. As illustrated in Table 17, 18 and 19, a single nucleobase sequence may be represented by a 5-10-5 motif as well as a 3-14-3 motif as well as a 2-13-5 motif. “5′ target site” indicates the 5′-most nucleotide which the antisense oligonucleotide is targeted on the indicated GENBANK Accession No. 
     
       
         
           
               
             
               
                 TABLE 17 
               
             
            
               
                   
               
               
                 Antisense inhibition of PCSK9 in human cells (Hep3B) targeting SEQ ID NO: 1 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                 5′ Target 
                 3′ Target 
                   
                   
                   
                   
               
               
                   
                 Site to 
                 Site to 
                   
                   
                   
                 SEQ 
               
               
                   
                 SEQ ID 
                 SEQ ID 
                   
                   
                 % 
                 ID 
               
               
                 Isis No. 
                 NO: 1 
                 NO: 1 
                 Sequence 5′-3′ 
                 Motif 
                 inhibition 
                 NO 
               
               
                   
               
               
                 410742 
                  294 
                   313 
                 GCCTGGAGCTGACGGTGCCC 
                 5-10-5 
                 75.1 
                 159 
               
               
                   
               
               
                 405999 
                  298 
                   317 
                 GACCGCCTGGAGCTGACGGT 
                 5-10-5 
                 70.3 
                 160 
               
               
                   
               
               
                 395151 
                  300 
                  319 
                 AGGACCGCCTGGAGCTGACG 
                 5-10-5 
                 57.3 
                   6 
               
               
                   
               
               
                 405861 
                  406 
                  425 
                 AAGGCTAGCACCAGCTCCTC 
                 5-10-5 
                 90.5 
                 162 
               
               
                   
               
               
                 405862 
                  407 
                  426 
                 CAAGGCTAGCACCAGCTCCT 
                 5-10-5 
                 92.3 
                 163 
               
               
                   
               
               
                 405863 
                  408 
                  427 
                 GCAAGGCTAGCACCAGCTCC 
                 5-10-5 
                 82.6 
                 164 
               
               
                   
               
               
                 405864 
                  409 
                  428 
                 CGCAAGGCTAGCACCAGCTC 
                 5-10-5 
                 91.8 
                 165 
               
               
                   
               
               
                 395152 
                  410 
                  429 
                 ACGCAAGGCTAGCACCAGCT 
                 5-10-5 
                 93.3 
                   7 
               
               
                   
               
               
                 405865 
                  411 
                  430 
                 AACGCAAGGCTAGCACCAGC 
                 5-10-5 
                 84.6 
                 166 
               
               
                   
               
               
                 405866 
                  412 
                  431 
                 GAACGCAAGGCTAGCACCAG 
                 5-10-5 
                 81.8 
                 167 
               
               
                   
               
               
                 405867 
                  413 
                  432 
                 GGAACGCAAGGCTAGCACCA 
                 5-10-5 
                 74.0 
                 168 
               
               
                   
               
               
                 405868 
                  414 
                  433 
                 CGGAACGCAAGGCTAGCACC 
                 5-10-5 
                 76.8 
                 169 
               
               
                   
               
               
                 399793 
                  417 
                  436 
                 CCTCGGAACGCAAGGCTAGC 
                 5-10-5 
                 77.9 
                   8 
               
               
                   
               
               
                 410743 
                  421 
                  440 
                 TCCTCCTCGGAACGCAAGGC 
                 5-10-5 
                 76.7 
                 170 
               
               
                   
               
               
                 410744 
                  446 
                  465 
                 GTGCTCGGGTGCTTCGGCCA 
                 5-10-5 
                 76.9 
                 171 
               
               
                   
               
               
                 410745 
                  466 
                  485 
                 TGGAAGGTGGCTGTGGTTCC 
                 5-10-5 
                 41.7 
                 172 
               
               
                   
               
               
                 395153 
                  480 
                  499 
                 CCTTGGCGCAGCGGTGGAAG 
                 5-10-5 
                 81.1 
                   9 
               
               
                   
               
               
                 406000 
                  482 
                  501 
                 ATCCTTGGCGCAGCGGTGGA 
                 5-10-5 
                 79.1 
                 173 
               
               
                   
               
               
                 406001 
                  484 
                  503 
                 GGATCCTTGGCGCAGCGGTG 
                 5-10-5 
                 63.1 
                 174 
               
               
                   
               
               
                 406002 
                  488 
                  507 
                 CCACGGATCCTTGGCGCAGC 
                 5-10-5 
                 80.8 
                 175 
               
               
                   
               
               
                 410746 
                  507 
                  526 
                 CGTAGGTGCCAGGCAACCTC 
                 5-10-5 
                 44.8 
                 176 
               
               
                   
               
               
                 410747 
                  545 
                  564 
                 TGACTGCGAGAGGTGGGTCT 
                 5-10-5 
                 NA 
                 177 
               
               
                   
               
               
                 406003 
                  555 
                  574 
                 CAGTGCGCTCTGACTGCGAG 
                 5-10-5 
                 84.2 
                 178 
               
               
                   
               
               
                 406004 
                  557 
                  576 
                 GGCAGTGCGCTCTGACTGCG 
                 5-10-5 
                 56.4 
                 179 
               
               
                   
               
               
                 406005 
                  559 
                  578 
                 CGGGCAGTGCGCTCTGACTG 
                 5-10-5 
                 83.4 
                 180 
               
               
                   
               
               
                 406006 
                  562 
                  581 
                 CGGCGGGCAGTGCGCTCTGA 
                 5-10-5 
                 71.0 
                 181 
               
               
                   
               
               
                 410748 
                  591 
                  610 
                 ATCCCCGGCGGGCAGCCTGG 
                 5-10-5 
                 56.0 
                 182 
               
               
                   
               
               
                 406007 
                  595 
                  614 
                 AGGTATCCCCGGCGGGCAGC 
                 5-10-5 
                 76.3 
                 183 
               
               
                   
               
               
                 410574 
                  597 
                  616 
                 TGAGGTATCCCCGGCGGGCA 
                 3-14-3 
                 69.1 
                 184 
               
               
                   
               
               
                 410529 
                  597 
                  616 
                 TGAGGTATCCCCGGCGGGCA 
                 5-10-5 
                 77.4 
                 184 
               
               
                   
               
               
                 410647 
                  597 
                  616 
                 TGAGGTATCCCCGGCGGGCA 
                 2-13-5 
                 90.7 
                 184 
               
               
                   
               
               
                 410575 
                  598 
                  617 
                 GTGAGGTATCCCCGGCGGGC 
                 3-14-3 
                 71.5 
                 185 
               
               
                   
               
               
                 410648 
                  598 
                  617 
                 GTGAGGTATCCCCGGCGGGC 
                 2-13-5 
                 82.8 
                 185 
               
               
                   
               
               
                 410530 
                  598 
                  617 
                 GTGAGGTATCCCCGGCGGGC 
                 5-10-5 
                 83.2 
                 185 
               
               
                   
               
               
                 410649 
                  599 
                  618 
                 GGTGAGGTATCCCCGGCGGG 
                 2-13-5 
                 53.5 
                 186 
               
               
                   
               
               
                 410576 
                  599 
                  618 
                 GGTGAGGTATCCCCGGCGGG 
                 3-14-3 
                 56.2 
                 186 
               
               
                   
               
               
                 410531 
                  599 
                  618 
                 GGTGAGGTATCCCCGGCGGG 
                 5-10-5 
                 63.6 
                 186 
               
               
                   
               
               
                 410650 
                  600 
                  619 
                 TGGTGAGGTATCCCCGGCGG 
                 2-13-5 
                 86.1 
                  11 
               
               
                   
               
               
                 399877 
                  600 
                  619 
                 TGGTGAGGTATCCCCGGCGG 
                 3-14-3 
                 92.6 
                  11 
               
               
                   
               
               
                 395155 
                  600 
                  619 
                 TGGTGAGGTATCCCCGGCGG 
                 5-10-5 
                 92.7 
                  11 
               
               
                   
               
               
                 410577 
                  601 
                  620 
                 TTGGTGAGGTATCCCCGGCG 
                 3-14-3 
                 62.4 
                 187 
               
               
                   
               
               
                 410532 
                  601 
                  620 
                 TTGGTGAGGTATCCCCGGCG 
                 5-10-5 
                 63.5 
                 187 
               
               
                   
               
               
                 410651 
                  601 
                  620 
                 TTGGTGAGGTATCCCCGGCG 
                 2-13-5 
                 75.5 
                 187 
               
               
                   
               
               
                 410652 
                  602 
                  621 
                 CTTGGTGAGGTATCCCCGGC 
                 2-13-5 
                 81.2 
                 188 
               
               
                   
               
               
                 410578 
                  602 
                  621 
                 CTTGGTGAGGTATCCCCGGC 
                 3-14-3 
                 83.3 
                 188 
               
               
                   
               
               
                 406008 
                  602 
                  621 
                 CTTGGTGAGGTATCCCCGGC 
                 5-10-5 
                 95.2 
                 188 
               
               
                   
               
               
                 410653 
                  603 
                  622 
                 TCTTGGTGAGGTATCCCCGG 
                 2-13-5 
                 68.9 
                 189 
               
               
                   
               
               
                 410579 
                  603 
                  622 
                 TCTTGGTGAGGTATCCCCGG 
                 3-14-3 
                 74.0 
                 189 
               
               
                   
               
               
                 410533 
                  603 
                  622 
                 TCTTGGTGAGGTATCCCCGG 
                 5-10-5 
                 79.0 
                 189 
               
               
                   
               
               
                 410580 
                  604 
                  623 
                 ATCTTGGTGAGGTATCCCCG 
                 3-14-3 
                 62.3 
                 190 
               
               
                   
               
               
                 410654 
                  604 
                  623 
                 ATCTTGGTGAGGTATCCCCG 
                 2-13-5 
                 65.2 
                 190 
               
               
                   
               
               
                 406009 
                  604 
                  623 
                 ATCTTGGTGAGGTATCCCCG 
                 5-10-5 
                 90.7 
                 190 
               
               
                   
               
               
                 410534 
                  605 
                  624 
                 GATCTTGGTGAGGTATCCCC 
                 5-10-5 
                 59.8 
                 191 
               
               
                   
               
               
                 410581 
                  605 
                  624 
                 GATCTTGGTGAGGTATCCCC 
                 3-14-3 
                 72.9 
                 191 
               
               
                   
               
               
                 410655 
                  605 
                  624 
                 GATCTTGGTGAGGTATCCCC 
                 2-13-5 
                 77.4 
                 191 
               
               
                   
               
               
                 399794 
                  606 
                  625 
                 GGATCTTGGTGAGGTATCCC 
                 5-10-5 
                 56.5 
                  12 
               
               
                   
               
               
                 410656 
                  606 
                  625 
                 GGATCTTGGTGAGGTATCCC 
                 2-13-5 
                 68.0 
                  12 
               
               
                   
               
               
                 399950 
                  606 
                  625 
                 GGATCTTGGTGAGGTATCCC 
                 3-14-3 
                 74.4 
                  12 
               
               
                   
               
               
                 410535 
                  607 
                  626 
                 AGGATCTTGGTGAGGTATCC 
                 5-10-5 
                 65.7 
                 192 
               
               
                   
               
               
                 410582 
                  607 
                  626 
                 AGGATCTTGGTGAGGTATCC 
                 3-14-3 
                 69.5 
                 192 
               
               
                   
               
               
                 410657 
                  607 
                  626 
                 AGGATCTTGGTGAGGTATCC 
                 2-13-5 
                 73.1 
                 192 
               
               
                   
               
               
                 406010 
                  609 
                  628 
                 GCAGGATCTTGGTGAGGTAT 
                 5-10-5 
                 56.9 
                 193 
               
               
                   
               
               
                 406011 
                  611 
                  630 
                 ATGCAGGATCTTGGTGAGGT 
                 5-10-5 
                 70.7 
                 194 
               
               
                   
               
               
                 406012 
                  613 
                  632 
                 ACATGCAGGATCTTGGTGAG 
                 5-10-5 
                 69.1 
                 195 
               
               
                   
               
               
                 406013 
                  617 
                  636 
                 GAAGACATGCAGGATCTTGG 
                 5-10-5 
                 77.4 
                 196 
               
               
                   
               
               
                 395156 
                  620 
                  639 
                 ATGGAAGACATGCAGGATCT 
                 5-10-5 
                 76.7 
                  14 
               
               
                   
               
               
                 410749 
                  628 
                  647 
                 AGAAGGCCATGGAAGACATG 
                 5-10-5 
                 59.4 
                 197 
               
               
                   
               
               
                 410750 
                  638 
                  657 
                 GAAGCCAGGAAGAAGGCCAT 
                 5-10-5 
                 57.5 
                 198 
               
               
                   
               
               
                 399879 
                  646 
                  665 
                 TTCACCAGGAAGCCAGGAAG 
                 3-14-3 
                 91.9 
                  15 
               
               
                   
               
               
                 406014 
                  648 
                  667 
                 TCTTCACCAGGAAGCCAGGA 
                 5-10-5 
                 94.0 
                 199 
               
               
                   
               
               
                 406015 
                  653 
                  672 
                 ACTCATCTTCACCAGGAAGC 
                 5-10-5 
                 78.8 
                 200 
               
               
                   
               
               
                 406016 
                  655 
                  674 
                 CCACTCATCTTCACCAGGAA 
                 5-10-5 
                 87.2 
                 201 
               
               
                   
               
               
                 410730 
                  657 
                  676 
                 CGCCACTCATCTTCACCAGG 
                 5-10-5 
                 85.4 
                 202 
               
               
                   
               
               
                 406017 
                  659 
                  678 
                 GTCGCCACTCATCTTCACCA 
                 5-10-5 
                 76.3 
                 203 
               
               
                   
               
               
                 406018 
                  661 
                  680 
                 AGGTCGCCACTCATCTTCAC 
                 5-10-5 
                 63.2 
                 204 
               
               
                   
               
               
                 406019 
                  663 
                  682 
                 GCAGGTCGCCACTCATCTTC 
                 5-10-5 
                 68.1 
                 205 
               
               
                   
               
               
                 406020 
                  665 
                  684 
                 CAGCAGGTCGCCACTCATCT 
                 5-10-5 
                 83.7 
                 206 
               
               
                   
               
               
                 410731 
                  667 
                  686 
                 TCCAGCAGGTCGCCACTCAT 
                 5-10-5 
                 72.9 
                 207 
               
               
                   
               
               
                 410751 
                  685 
                  704 
                 GGCAACTTCAAGGCCAGCTC 
                 5-10-5 
                 84.6 
                 208 
               
               
                   
               
               
                 395158 
                  705 
                  724 
                 CCTCGATGTAGTCGACATGG 
                 5-10-5 
                 93.9 
                  17 
               
               
                   
               
               
                 410752 
                  724 
                  743 
                 GCAAAGACAGAGGAGTCCTC 
                 5-10-5 
                 76.3 
                 209 
               
               
                   
               
               
                 406021 
                  782 
                  801 
                 TTCATCCGCCCGGTACCGTG 
                 5-10-5 
                 79.6 
                 210 
               
               
                   
               
               
                 406022 
                  784 
                  803 
                 TATTCATCCGCCCGGTACCG 
                 5-10-5 
                 78.7 
                 211 
               
               
                   
               
               
                 406023 
                  787 
                  806 
                 TGGTATTCATCCGCCCGGTA 
                 5-10-5 
                 92.5 
                 212 
               
               
                   
               
               
                 406024 
                  789 
                  808 
                 GCTGGTATTCATCCGCCCGG 
                 5-10-5 
                 69.7 
                 213 
               
               
                   
               
               
                 410732 
                  791 
                  810 
                 GGGCTGGTATTCATCCGCCC 
                 5-10-5 
                 30.4 
                 214 
               
               
                   
               
               
                 410753 
                  821 
                  840 
                 ATACACCTCCACCAGGCTGC 
                 5-10-5 
                 72.8 
                 215 
               
               
                   
               
               
                 406025 
                  832 
                  851 
                 GTGTCTAGGAGATACACCTC 
                 5-10-5 
                 74.2 
                 216 
               
               
                   
               
               
                 406026 
                  837 
                  856 
                 TGCTGGTGTCTAGGAGATAC 
                 5-10-5 
                 80.5 
                 217 
               
               
                   
               
               
                 405869 
                  862 
                  881 
                 TCGATTTCCCGGTGGTCACT 
                 5-10-5 
                 87.6 
                 218 
               
               
                   
               
               
                 405870 
                  863 
                  882 
                 CTCGATTTCCCGGTGGTCAC 
                 5-10-5 
                 83.3 
                 219 
               
               
                   
               
               
                 405871 
                  864 
                  883 
                 CCTCGATTTCCCGGTGGTCA 
                 5-10-5 
                 87.0 
                 220 
               
               
                   
               
               
                 405872 
                  865 
                  884 
                 CCCTCGATTTCCCGGTGGTC 
                 5-10-5 
                 88.2 
                 221 
               
               
                   
               
               
                 399798 
                  866 
                  885 
                 GCCCTCGATTTCCCGGTGGT 
                 5-10-5 
                 84.3 
                  22 
               
               
                   
               
               
                 399954 
                  866 
                  885 
                 GCCCTCGATTTCCCGGTGGT 
                 3-14-3 
                 90.3 
                  22 
               
               
                   
               
               
                 405873 
                  867 
                  886 
                 TGCCCTCGATTTCCCGGTGG 
                 5-10-5 
                 90.0 
                 222 
               
               
                   
               
               
                 405874 
                  868 
                  887 
                 CTGCCCTCGATTTCCCGGTG 
                 5-10-5 
                 91.4 
                 223 
               
               
                   
               
               
                 405875 
                  869 
                  888 
                 CCTGCCCTCGATTTCCCGGT 
                 5-10-5 
                 93.5 
                 224 
               
               
                   
               
               
                 405876 
                  870 
                  889 
                 CCCTGCCCTCGATTTCCCGG 
                 5-10-5 
                 90.1 
                 225 
               
               
                   
               
               
                 406027 
                  874 
                  893 
                 ATGACCCTGCCCTCGATTTC 
                 5-10-5 
                 73.9 
                 226 
               
               
                   
               
               
                 406028 
                  876 
                  895 
                 CCATGACCCTGCCCTCGATT 
                 5-10-5 
                 92.3 
                 227 
               
               
                   
               
               
                 406029 
                  878 
                  897 
                 GACCATGACCCTGCCCTCGA 
                 5-10-5 
                 91.4 
                 228 
               
               
                   
               
               
                 406030 
                  882 
                  901 
                 CGGTGACCATGACCCTGCCC 
                 5-10-5 
                 95.6 
                 229 
               
               
                   
               
               
                 406031 
                  884 
                  903 
                 GTCGGTGACCATGACCCTGC 
                 5-10-5 
                 89.6 
                 230 
               
               
                   
               
               
                 410733 
                  886 
                  905 
                 AAGTCGGTGACCATGACCCT 
                 5-10-5 
                 65.7 
                 231 
               
               
                   
               
               
                 406032 
                  888 
                  907 
                 CGAAGTCGGTGACCATGACC 
                 5-10-5 
                 88.5 
                 232 
               
               
                   
               
               
                 410754 
                  898 
                  917 
                 GGCACATTCTCGAAGTCGGT 
                 5-10-5 
                 80.1 
                 233 
               
               
                   
               
               
                 395163 
                  923 
                  942 
                 GTGGAAGCGGGTCCCGTCCT 
                 5-10-5 
                 83.9 
                  25 
               
               
                   
               
               
                 410755 
                  933 
                  952 
                 TGGCCTGTCTGTGGAAGCGG 
                 5-10-5 
                 NA 
                 234 
               
               
                   
               
               
                 410756 
                  960 
                  979 
                 GGTGGGTGCCATGACTGTCA 
                 5-10-5 
                 67.1 
                 235 
               
               
                   
               
               
                 406033 
                  967 
                  986 
                 CCTGCCAGGTGGGTGCCATG 
                 5-10-5 
                 91.2 
                 237 
               
               
                   
               
               
                 406034 
                  972 
                  991 
                 CCACCCCTGCCAGGTGGGTG 
                 5-10-5 
                 59.3 
                 238 
               
               
                   
               
               
                 406035 
                  977 
                  996 
                 GCTGACCACCCCTGCCAGGT 
                 5-10-5 
                 91.7 
                 239 
               
               
                   
               
               
                 410757 
                  985 
                 1004 
                 TCCCGGCCGCTGACCACCCC 
                 5-10-5 
                 88.9 
                 240 
               
               
                   
               
               
                 406036 
                  989 
                 1008 
                 GGCATCCCGGCCGCTGACCA 
                 5-10-5 
                 84.0 
                 241 
               
               
                   
               
               
                 406037 
                  992 
                 1011 
                 GCCGGCATCCCGGCCGCTGA 
                 5-10-5 
                 55.9 
                 242 
               
               
                   
               
               
                 410536 
                  997 
                 1016 
                 GCCACGCCGGCATCCCGGCC 
                 5-10-5 
                 63.7 
                 243 
               
               
                   
               
               
                 410658 
                  997 
                 1016 
                 GCCACGCCGGCATCCCGGCC 
                 2-13-5 
                 82.0 
                 243 
               
               
                   
               
               
                 410583 
                  997 
                 1016 
                 GCCACGCCGGCATCCCGGCC 
                 3-14-3 
                 87.3 
                 243 
               
               
                   
               
               
                 410537 
                  998 
                 1017 
                 GGCCACGCCGGCATCCCGGC 
                 5-10-5 
                 58.5 
                 244 
               
               
                   
               
               
                 410659 
                  998 
                 1017 
                 GGCCACGCCGGCATCCCGGC 
                 2-13-5 
                 73.7 
                 244 
               
               
                   
               
               
                 410584 
                  998 
                 1017 
                 GGCCACGCCGGCATCCCGGC 
                 3-14-3 
                 79.5 
                 244 
               
               
                   
               
               
                 410660 
                  999 
                 1018 
                 TGGCCACGCCGGCATCCCGG 
                 2-13-5 
                 63.0 
                 245 
               
               
                   
               
               
                 410585 
                  999 
                 1018 
                 TGGCCACGCCGGCATCCCGG 
                 3-14-3 
                 73.2 
                 245 
               
               
                   
               
               
                 406038 
                  999 
                 1018 
                 TGGCCACGCCGGCATCCCGG 
                 5-10-5 
                 86.3 
                 245 
               
               
                   
               
               
                 410661 
                 1000 
                 1019 
                 TTGGCCACGCCGGCATCCCG 
                 2-13-5 
                 53.3 
                 246 
               
               
                   
               
               
                 410586 
                 1000 
                 1019 
                 TTGGCCACGCCGGCATCCCG 
                 3-14-3 
                 60.3 
                 246 
               
               
                   
               
               
                 405877 
                 1000 
                 1019 
                 TTGGCCACGCCGGCATCCCG 
                 5-10-5 
                 83.2 
                 246 
               
               
                   
               
               
                 410587 
                 1001 
                 1020 
                 CTTGGCCACGCCGGCATCCC 
                 3-14-3 
                 63.2 
                 247 
               
               
                   
               
               
                 410662 
                 1001 
                 1020 
                 CTTGGCCACGCCGGCATCCC 
                 2-13-5 
                 67.3 
                 247 
               
               
                   
               
               
                 405878 
                 1001 
                 1020 
                 CTTGGCCACGCCGGCATCCC 
                 5-10-5 
                 91.4 
                 247 
               
               
                   
               
               
                 410588 
                 1002 
                 1021 
                 CCTTGGCCACGCCGGCATCC 
                 3-14-3 
                 65.3 
                 248 
               
               
                   
               
               
                 410663 
                 1002 
                 1021 
                 CCTTGGCCACGCCGGCATCC 
                 2-13-5 
                 67.9 
                 248 
               
               
                   
               
               
                 405879 
                 1002 
                 1021 
                 CCTTGGCCACGCCGGCATCC 
                 5-10-5 
                 94.1 
                 248 
               
               
                   
               
               
                 410589 
                 1003 
                 1022 
                 CCCTTGGCCACGCCGGCATC 
                 3-14-3 
                 80.1 
                 249 
               
               
                   
               
               
                 410664 
                 1003 
                 1022 
                 CCCTTGGCCACGCCGGCATC 
                 2-13-5 
                 81.9 
                 249 
               
               
                   
               
               
                 405880 
                 1003 
                 1022 
                 CCCTTGGCCACGCCGGCATC 
                 5-10-5 
                 93.5 
                 249 
               
               
                   
               
               
                 410665 
                 1004 
                 1023 
                 ACCCTTGGCCACGCCGGCAT 
                 2-13-5 
                 78.7 
                  28 
               
               
                   
               
               
                 399887 
                 1004 
                 1023 
                 ACCCTTGGCCACGCCGGCAT 
                 3-14-3 
                 91.9 
                  28 
               
               
                   
               
               
                 395165 
                 1004 
                 1023 
                 ACCCTTGGCCACGCCGGCAT 
                 5-10-5 
                 96.7 
                  28 
               
               
                   
               
               
                 410590 
                 1005 
                 1024 
                 CACCCTTGGCCACGCCGGCA 
                 3-14-3 
                 82.2 
                 250 
               
               
                   
               
               
                 410666 
                 1005 
                 1024 
                 CACCCTTGGCCACGCCGGCA 
                 2-13-5 
                 82.7 
                 250 
               
               
                   
               
               
                 405881 
                 1005 
                 1024 
                 CACCCTTGGCCACGCCGGCA 
                 5-10-5 
                 98.3 
                 250 
               
               
                   
               
               
                 410667 
                 1006 
                 1025 
                 GCACCCTTGGCCACGCCGGC 
                 2-13-5 
                 84.7 
                 251 
               
               
                   
               
               
                 410591 
                 1006 
                 1025 
                 GCACCCTTGGCCACGCCGGC 
                 3-14-3 
                 86.3 
                 251 
               
               
                   
               
               
                 405882 
                 1006 
                 1025 
                 GCACCCTTGGCCACGCCGGC 
                 5-10-5 
                 91.6 
                 251 
               
               
                   
               
               
                 410668 
                 1007 
                 1026 
                 GGCACCCTTGGCCACGCCGG 
                 2-13-5 
                 91.4 
                 252 
               
               
                   
               
               
                 405883 
                 1007 
                 1026 
                 GGCACCCTTGGCCACGCCGG 
                 5-10-5 
                 92.5 
                 252 
               
               
                   
               
               
                 410592 
                 1007 
                 1026 
                 GGCACCCTTGGCCACGCCGG 
                 3-14-3 
                 93.4 
                 252 
               
               
                   
               
               
                 410669 
                 1008 
                 1027 
                 TGGCACCCTTGGCCACGCCG 
                 2-13-5 
                 69.0 
                 253 
               
               
                   
               
               
                 410593 
                 1008 
                 1027 
                 TGGCACCCTTGGCCACGCCG 
                 3-14-3 
                 88.8 
                 253 
               
               
                   
               
               
                 405884 
                 1008 
                 1027 
                 TGGCACCCTTGGCCACGCCG 
                 5-10-5 
                 90.8 
                 253 
               
               
                   
               
               
                 410670 
                 1009 
                 1028 
                 CTGGCACCCTTGGCCACGCC 
                 2-13-5 
                 74.9 
                 254 
               
               
                   
               
               
                 410594 
                 1009 
                 1028 
                 CTGGCACCCTTGGCCACGCC 
                 3-14-3 
                 75.2 
                 254 
               
               
                   
               
               
                 410538 
                 1009 
                 1028 
                 CTGGCACCCTTGGCCACGCC 
                 5-10-5 
                 78.2 
                 254 
               
               
                   
               
               
                 410539 
                 1010 
                 1029 
                 GCTGGCACCCTTGGCCACGC 
                 5-10-5 
                 61.9 
                 255 
               
               
                   
               
               
                 410595 
                 1010 
                 1029 
                 GCTGGCACCCTTGGCCACGC 
                 3-14-3 
                 83.1 
                 255 
               
               
                   
               
               
                 410671 
                 1010 
                 1029 
                 GCTGGCACCCTTGGCCACGC 
                 2-13-5 
                 83.3 
                 255 
               
               
                   
               
               
                 410758 
                 1015 
                 1034 
                 CGCATGCTGGCACCCTTGGC 
                 5-10-5 
                 73.6 
                 256 
               
               
                   
               
               
                 406039 
                 1036 
                 1055 
                 CAGTTGAGCACGCGCAGGCT 
                 5-10-5 
                 91.2 
                 257 
               
               
                   
               
               
                 406040 
                 1038 
                 1057 
                 GGCAGTTGAGCACGCGCAGG 
                 5-10-5 
                 96.5 
                 258 
               
               
                   
               
               
                 399888 
                 1040 
                 1059 
                 TTGGCAGTTGAGCACGCGCA 
                 3-14-3 
                 90.9 
                  29 
               
               
                   
               
               
                 395166 
                 1040 
                 1059 
                 TTGGCAGTTGAGCACGCGCA 
                 5-10-5 
                 96.2 
                  29 
               
               
                   
               
               
                 406041 
                 1042 
                 1061 
                 CCTTGGCAGTTGAGCACGCG 
                 5-10-5 
                 96.6 
                 259 
               
               
                   
               
               
                 399801 
                 1045 
                 1064 
                 TTCCCTTGGCAGTTGAGCAC 
                 5-10-5 
                 95.6 
                  30 
               
               
                   
               
               
                 406042 
                 1047 
                 1066 
                 CCTTCCCTTGGCAGTTGAGC 
                 5-10-5 
                 92.0 
                 260 
               
               
                   
               
               
                 406043 
                 1051 
                 1070 
                 GTGCCCTTCCCTTGGCAGTT 
                 5-10-5 
                 91.9 
                 261 
               
               
                   
               
               
                 406044 
                 1053 
                 1072 
                 CCGTGCCCTTCCCTTGGCAG 
                 5-10-5 
                 95.4 
                 262 
               
               
                   
               
               
                 410759 
                 1064 
                 1083 
                 GGTGCCGCTAACCGTGCCCT 
                 5-10-5 
                 83.7 
                 263 
               
               
                   
               
               
                 410760 
                 1088 
                 1107 
                 CCGAATAAACTCCAGGCCTA 
                 5-10-5 
                 96.7 
                 265 
               
               
                   
               
               
                 406045 
                 1096 
                 1115 
                 TGGCTTTTCCGAATAAACTC 
                 5-10-5 
                 88.4 
                 266 
               
               
                   
               
               
                 395168 
                 1098 
                 1117 
                 GCTGGCTTTTCCGAATAAAC 
                 5-10-5 
                 91.9 
                  32 
               
               
                   
               
               
                 405909 
                 1100 
                 1119 
                 CAGCTGGCTTTTCCGAATAA 
                 5-10-5 
                 80.3 
                 267 
               
               
                   
               
               
                 405910 
                 1102 
                 1121 
                 ACCAGCTGGCTTTTCCGAAT 
                 5-10-5 
                 90.9 
                 268 
               
               
                   
               
               
                 405911 
                 1104 
                 1123 
                 GGACCAGCTGGCTTTTCCGA 
                 5-10-5 
                 88.0 
                 269 
               
               
                   
               
               
                 405912 
                 1108 
                 1127 
                 GGCTGGACCAGCTGGCTTTT 
                 5-10-5 
                 78.2 
                 270 
               
               
                   
               
               
                 410761 
                 1119 
                 1138 
                 GTGGCCCCACAGGCTGGACC 
                 5-10-5 
                 53.7 
                 271 
               
               
                   
               
               
                 410762 
                 1132 
                 1151 
                 AGCAGCACCACCAGTGGCCC 
                 5-10-5 
                 57.6 
                 272 
               
               
                   
               
               
                 410763 
                 1154 
                 1173 
                 GCTGTACCCACCCGCCAGGG 
                 5-10-5 
                 68.8 
                 273 
               
               
                   
               
               
                 410764 
                 1200 
                 1219 
                 CGACCCCAGCCCTCGCCAGG 
                 5-10-5 
                 66.3 
                 274 
               
               
                   
               
               
                 399891 
                 1210 
                 1229 
                 GTGACCAGCACGACCCCAGC 
                 3-14-3 
                 91.1 
                  33 
               
               
                   
               
               
                 405913 
                 1212 
                 1231 
                 CGGTGACCAGCACGACCCCA 
                 5-10-5 
                 93.8 
                 275 
               
               
                   
               
               
                 405914 
                 1214 
                 1233 
                 AGCGGTGACCAGCACGACCC 
                 5-10-5 
                 90.4 
                 276 
               
               
                   
               
               
                 405915 
                 1216 
                 1235 
                 GCAGCGGTGACCAGCACGAC 
                 5-10-5 
                 86.8 
                 277 
               
               
                   
               
               
                 405916 
                 1218 
                 1237 
                 CGGCAGCGGTGACCAGCACG 
                 5-10-5 
                 91.3 
                 278 
               
               
                   
               
               
                 410734 
                 1219 
                 1238 
                 CCGGCAGCGGTGACCAGCAC 
                 5-10-5 
                 65.8 
                 279 
               
               
                   
               
               
                 405917 
                 1222 
                 1241 
                 TTGCCGGCAGCGGTGACCAG 
                 5-10-5 
                 62.0 
                 280 
               
               
                   
               
               
                 405918 
                 1224 
                 1243 
                 AGTTGCCGGCAGCGGTGACC 
                 5-10-5 
                 33.5 
                 281 
               
               
                   
               
               
                 405919 
                 1226 
                 1245 
                 GAAGTTGCCGGCAGCGGTGA 
                 5-10-5 
                 68.2 
                 282 
               
               
                   
               
               
                 405920 
                 1228 
                 1247 
                 CGGAAGTTGCCGGCAGCGGT 
                 5-10-5 
                 86.2 
                 283 
               
               
                   
               
               
                 405921 
                 1230 
                 1249 
                 CCCGGAAGTTGCCGGCAGCG 
                 5-10-5 
                 85.5 
                 284 
               
               
                   
               
               
                 405922 
                 1232 
                 1251 
                 GTCCCGGAAGTTGCCGGCAG 
                 5-10-5 
                 86.0 
                 285 
               
               
                   
               
               
                 410765 
                 1273 
                 1292 
                 ATGACCTCGGGAGCTGAGGC 
                 5-10-5 
                 50.4 
                 286 
               
               
                   
               
               
                 410766 
                 1283 
                 1302 
                 CCCAACTGTGATGACCTCGG 
                 5-10-5 
                 70.6 
                 287 
               
               
                   
               
               
                 405923 
                 1295 
                 1314 
                 GGCATTGGTGGCCCCAACTG 
                 5-10-5 
                 94.3 
                 288 
               
               
                   
               
               
                 410767 
                 1305 
                 1324 
                 GCTGGTCTTGGGCATTGGTG 
                 5-10-5 
                 65.1 
                 289 
               
               
                   
               
               
                 405924 
                 1318 
                 1337 
                 CCCAGGGTCACCGGCTGGTC 
                 5-10-5 
                 93.1 
                 290 
               
               
                   
               
               
                 410735 
                 1320 
                 1339 
                 TCCCCAGGGTCACCGGCTGG 
                 5-10-5 
                 78.1 
                 291 
               
               
                   
               
               
                 405925 
                 1322 
                 1341 
                 AGTCCCCAGGGTCACCGGCT 
                 5-10-5 
                 93.5 
                 292 
               
               
                   
               
               
                 405926 
                 1324 
                 1343 
                 AAAGTCCCCAGGGTCACCGG 
                 5-10-5 
                 94.6 
                 293 
               
               
                   
               
               
                 405927 
                 1328 
                 1347 
                 CCCCAAAGTCCCCAGGGTCA 
                 5-10-5 
                 94.5 
                 294 
               
               
                   
               
               
                 405928 
                 1333 
                 1352 
                 TTGGTCCCCAAAGTCCCCAG 
                 5-10-5 
                 90.0 
                 295 
               
               
                   
               
               
                 405929 
                 1337 
                 1356 
                 AAAGTTGGTCCCCAAAGTCC 
                 5-10-5 
                 85.5 
                 296 
               
               
                   
               
               
                 399895 
                 1340 
                 1359 
                 GCCAAAGTTGGTCCCCAAAG 
                 3-14-3 
                 84.6 
                  36 
               
               
                   
               
               
                 395173 
                 1340 
                 1359 
                 GCCAAAGTTGGTCCCCAAAG 
                 5-10-5 
                 94.8 
                  36 
               
               
                   
               
               
                 405930 
                 1342 
                 1361 
                 CGGCCAAAGTTGGTCCCCAA 
                 5-10-5 
                 92.9 
                 297 
               
               
                   
               
               
                 405931 
                 1344 
                 1363 
                 AGCGGCCAAAGTTGGTCCCC 
                 5-10-5 
                 88.8 
                 298 
               
               
                   
               
               
                 405932 
                 1346 
                 1365 
                 ACAGCGGCCAAAGTTGGTCC 
                 5-10-5 
                 90.6 
                 299 
               
               
                   
               
               
                 405933 
                 1348 
                 1367 
                 ACACAGCGGCCAAAGTTGGT 
                 5-10-5 
                 NA 
                 300 
               
               
                   
               
               
                 405934 
                 1350 
                 1369 
                 CCACACAGCGGCCAAAGTTG 
                 5-10-5 
                 92.7 
                 301 
               
               
                   
               
               
                 405935 
                 1354 
                 1373 
                 AGGTCCACACAGCGGCCAAA 
                 5-10-5 
                 86.0 
                 302 
               
               
                   
               
               
                 410736 
                 1356 
                 1375 
                 AGAGGTCCACACAGCGGCCA 
                 5-10-5 
                 73.8 
                 303 
               
               
                   
               
               
                 405936 
                 1358 
                 1377 
                 AAAGAGGTCCACACAGCGGC 
                 5-10-5 
                 93.9 
                 304 
               
               
                   
               
               
                 410768 
                 1380 
                 1399 
                 CAATGATGTCCTCCCCTGGG 
                 5-10-5 
                 79.7 
                 305 
               
               
                   
               
               
                 405937 
                 1387 
                 1406 
                 GAGGCACCAATGATGTCCTC 
                 5-10-5 
                 77.7 
                 306 
               
               
                   
               
               
                 405938 
                 1391 
                 1410 
                 GCTGGAGGCACCAATGATGT 
                 5-10-5 
                 75.5 
                 307 
               
               
                   
               
               
                 405939 
                 1393 
                 1412 
                 TCGCTGGAGGCACCAATGAT 
                 5-10-5 
                 70.6 
                 308 
               
               
                   
               
               
                 405940 
                 1395 
                 1414 
                 AGTCGCTGGAGGCACCAATG 
                 5-10-5 
                 84.4 
                 309 
               
               
                   
               
               
                 405941 
                 1397 
                 1416 
                 GCAGTCGCTGGAGGCACCAA 
                 5-10-5 
                 90.1 
                 310 
               
               
                   
               
               
                 399804 
                 1400 
                 1419 
                 GCTGCAGTCGCTGGAGGCAC 
                 5-10-5 
                 80.8 
                  40 
               
               
                   
               
               
                 399960 
                 1400 
                 1419 
                 GCTGCAGTCGCTGGAGGCAC 
                 3-14-3 
                 82.4 
                  40 
               
               
                   
               
               
                 405942 
                 1402 
                 1421 
                 GTGCTGCAGTCGCTGGAGGC 
                 5-10-5 
                 69.8 
                 311 
               
               
                   
               
               
                 405943 
                 1404 
                 1423 
                 AGGTGCTGCAGTCGCTGGAG 
                 5-10-5 
                 83.6 
                 312 
               
               
                   
               
               
                 410737 
                 1406 
                 1425 
                 GCAGGTGCTGCAGTCGCTGG 
                 5-10-5 
                 49.8 
                 313 
               
               
                   
               
               
                 405944 
                 1407 
                 1426 
                 AGCAGGTGCTGCAGTCGCTG 
                 5-10-5 
                 80.7 
                 314 
               
               
                   
               
               
                 405945 
                 1409 
                 1428 
                 AAAGCAGGTGCTGCAGTCGC 
                 5-10-5 
                 41.1 
                 315 
               
               
                   
               
               
                 405946 
                 1413 
                 1432 
                 ACACAAAGCAGGTGCTGCAG 
                 5-10-5 
                 70.4 
                 316 
               
               
                   
               
               
                 405947 
                 1415 
                 1434 
                 TGACACAAAGCAGGTGCTGC 
                 5-10-5 
                 72.5 
                 317 
               
               
                   
               
               
                 410769 
                 1425 
                 1444 
                 TCCCACTCTGTGACACAAAG 
                 5-10-5 
                 84.9 
                 318 
               
               
                   
               
               
                 405948 
                 1467 
                 1486 
                 TCATGGCTGCAATGCCAGCC 
                 5-10-5 
                 45.9 
                 319 
               
               
                   
               
               
                 399806 
                 1470 
                 1489 
                 GCATCATGGCTGCAATGCCA 
                 5-10-5 
                 82.8 
                  42 
               
               
                   
               
               
                 399962 
                 1470 
                 1489 
                 GCATCATGGCTGCAATGCCA 
                 3-14-3 
                 86.1 
                  42 
               
               
                   
               
               
                 405949 
                 1472 
                 1491 
                 CAGCATCATGGCTGCAATGC 
                 5-10-5 
                 84.9 
                 320 
               
               
                   
               
               
                 405950 
                 1474 
                 1493 
                 GACAGCATCATGGCTGCAAT 
                 5-10-5 
                 76.9 
                 321 
               
               
                   
               
               
                 405951 
                 1476 
                 1495 
                 CAGACAGCATCATGGCTGCA 
                 5-10-5 
                 75.4 
                 322 
               
               
                   
               
               
                 405952 
                 1480 
                 1499 
                 TCGGCAGACAGCATCATGGC 
                 5-10-5 
                 85.1 
                 323 
               
               
                   
               
               
                 410738 
                 1482 
                 1501 
                 GCTCGGCAGACAGCATCATG 
                 5-10-5 
                 68.4 
                 324 
               
               
                   
               
               
                 405953 
                 1484 
                 1503 
                 CGGCTCGGCAGACAGCATCA 
                 5-10-5 
                 93.6 
                 325 
               
               
                   
               
               
                 405954 
                 1486 
                 1505 
                 TCCGGCTCGGCAGACAGCAT 
                 5-10-5 
                 87.5 
                 326 
               
               
                   
               
               
                 410770 
                 1500 
                 1519 
                 CGGCCAGGGTGAGCTCCGGC 
                 5-10-5 
                 68.5 
                 327 
               
               
                   
               
               
                 405955 
                 1513 
                 1532 
                 CTCTGCCTCAACTCGGCCAG 
                 5-10-5 
                 94.2 
                 328 
               
               
                   
               
               
                 405956 
                 1515 
                 1534 
                 GTCTCTGCCTCAACTCGGCC 
                 5-10-5 
                 94.3 
                 329 
               
               
                   
               
               
                 405958 
                 1519 
                 1538 
                 ATCAGTCTCTGCCTCAACTC 
                 5-10-5 
                 80.3 
                 331 
               
               
                   
               
               
                 405959 
                 1521 
                 1540 
                 GGATCAGTCTCTGCCTCAAC 
                 5-10-5 
                 95.4 
                 332 
               
               
                   
               
               
                 405960 
                 1523 
                 1542 
                 GTGGATCAGTCTCTGCCTCA 
                 5-10-5 
                 90.1 
                 333 
               
               
                   
               
               
                 405961 
                 1525 
                 1544 
                 AAGTGGATCAGTCTCTGCCT 
                 5-10-5 
                 88.8 
                 334 
               
               
                   
               
               
                 405962 
                 1528 
                 1547 
                 GAGAAGTGGATCAGTCTCTG 
                 5-10-5 
                 56.1 
                 335 
               
               
                   
               
               
                 410739 
                 1530 
                 1549 
                 CAGAGAAGTGGATCAGTCTC 
                 5-10-5 
                 NA 
                 336 
               
               
                   
               
               
                 405963 
                 1532 
                 1551 
                 GGCAGAGAAGTGGATCAGTC 
                 5-10-5 
                 59.7 
                 337 
               
               
                   
               
               
                 405964 
                 1536 
                 1555 
                 CTTTGGCAGAGAAGTGGATC 
                 5-10-5 
                 45.3 
                 338 
               
               
                   
               
               
                 405965 
                 1541 
                 1560 
                 GACATCTTTGGCAGAGAAGT 
                 5-10-5 
                 55.9 
                 339 
               
               
                   
               
               
                 405966 
                 1543 
                 1562 
                 ATGACATCTTTGGCAGAGAA 
                 5-10-5 
                 51.3 
                 340 
               
               
                   
               
               
                 405967 
                 1547 
                 1566 
                 ATTGATGACATCTTTGGCAG 
                 5-10-5 
                 64.4 
                 341 
               
               
                   
               
               
                 405968 
                 1549 
                 1568 
                 TCATTGATGACATCTTTGGC 
                 5-10-5 
                 74.6 
                 342 
               
               
                   
               
               
                 399967 
                 1552 
                 1571 
                 GCCTCATTGATGACATCTTT 
                 3-14-3 
                 80.1 
                  48 
               
               
                   
               
               
                 405969 
                 1554 
                 1573 
                 AGGCCTCATTGATGACATCT 
                 5-10-5 
                 63.0 
                 343 
               
               
                   
               
               
                 405970 
                 1556 
                 1575 
                 CCAGGCCTCATTGATGACAT 
                 5-10-5 
                 66.8 
                 344 
               
               
                   
               
               
                 410740 
                 1558 
                 1577 
                 AACCAGGCCTCATTGATGAC 
                 5-10-5 
                 46.8 
                 345 
               
               
                   
               
               
                 405885 
                 1560 
                 1579 
                 GGAACCAGGCCTCATTGATG 
                 5-10-5 
                 73.4 
                 346 
               
               
                   
               
               
                 410596 
                 1562 
                 1581 
                 AGGGAACCAGGCCTCATTGA 
                 3-14-3 
                 NA 
                 348 
               
               
                   
               
               
                 410672 
                 1562 
                 1581 
                 AGGGAACCAGGCCTCATTGA 
                 2-13-5 
                 NA 
                 348 
               
               
                   
               
               
                 405887 
                 1562 
                 1581 
                 AGGGAACCAGGCCTCATTGA 
                 5-10-5 
                 NA 
                 348 
               
               
                   
               
               
                 410597 
                 1563 
                 1582 
                 CAGGGAACCAGGCCTCATTG 
                 3-14-3 
                 NA 
                 349 
               
               
                   
               
               
                 405888 
                 1563 
                 1582 
                 CAGGGAACCAGGCCTCATTG 
                 5-10-5 
                 NA 
                 349 
               
               
                   
               
               
                 410673 
                 1563 
                 1582 
                 CAGGGAACCAGGCCTCATTG 
                 2-13-5 
                 NA 
                 349 
               
               
                   
               
               
                 410674 
                 1564 
                 1583 
                 TCAGGGAACCAGGCCTCATT 
                 2-13-5 
                 60.7 
                  49 
               
               
                   
               
               
                 399812 
                 1564 
                 1583 
                 TCAGGGAACCAGGCCTCATT 
                 5-10-5 
                 68.7 
                  49 
               
               
                   
               
               
                 399968 
                 1564 
                 1583 
                 TCAGGGAACCAGGCCTCATT 
                 3-14-3 
                 84.5 
                  49 
               
               
                   
               
               
                 410598 
                 1565 
                 1584 
                 CTCAGGGAACCAGGCCTCAT 
                 3-14-3 
                 74.5 
                 350 
               
               
                   
               
               
                 410675 
                 1565 
                 1584 
                 CTCAGGGAACCAGGCCTCAT 
                 2-13-5 
                 76.9 
                 350 
               
               
                   
               
               
                 405889 
                 1565 
                 1584 
                 CTCAGGGAACCAGGCCTCAT 
                 5-10-5 
                 80.2 
                 350 
               
               
                   
               
               
                 410599 
                 1566 
                 1585 
                 CCTCAGGGAACCAGGCCTCA 
                 3-14-3 
                 70.6 
                 351 
               
               
                   
               
               
                 410676 
                 1566 
                 1585 
                 CCTCAGGGAACCAGGCCTCA 
                 2-13-5 
                 77.8 
                 351 
               
               
                   
               
               
                 405890 
                 1566 
                 1585 
                 CCTCAGGGAACCAGGCCTCA 
                 5-10-5 
                 87.7 
                 351 
               
               
                   
               
               
                 410600 
                 1567 
                 1586 
                 TCCTCAGGGAACCAGGCCTC 
                 3-14-3 
                 76.5 
                 352 
               
               
                   
               
               
                 410677 
                 1567 
                 1586 
                 TCCTCAGGGAACCAGGCCTC 
                 2-13-5 
                 88.4 
                 352 
               
               
                   
               
               
                 405891 
                 1567 
                 1586 
                 TCCTCAGGGAACCAGGCCTC 
                 5-10-5 
                 96.1 
                 352 
               
               
                   
               
               
                 405892 
                 1568 
                 1587 
                 GTCCTCAGGGAACCAGGCCT 
                 5-10-5 
                 71.4 
                 353 
               
               
                   
               
               
                 410601 
                 1568 
                 1587 
                 GTCCTCAGGGAACCAGGCCT 
                 3-14-3 
                 72.7 
                 353 
               
               
                   
               
               
                 410678 
                 1568 
                 1587 
                 GTCCTCAGGGAACCAGGCCT 
                 2-13-5 
                 75.0 
                 353 
               
               
                   
               
               
                 395178 
                 1569 
                 1588 
                 GGTCCTCAGGGAACCAGGCC 
                 5-10-5 
                 76.7 
                  50 
               
               
                   
               
               
                 410679 
                 1569 
                 1588 
                 GGTCCTCAGGGAACCAGGCC 
                 2-13-5 
                 77.6 
                  50 
               
               
                   
               
               
                 399900 
                 1569 
                 1588 
                 GGTCCTCAGGGAACCAGGCC 
                 3-14-3 
                 92.0 
                  50 
               
               
                   
               
               
                 408653 
                 1570 
                 1589 
                 TGGTCCTCAGGGAACCAGGC 
                 5-10-5 
                 42.5 
                 354 
               
               
                   
               
               
                 410602 
                 1570 
                 1589 
                 TGGTCCTCAGGGAACCAGGC 
                 3-14-3 
                 66.5 
                 354 
               
               
                   
               
               
                 410680 
                 1570 
                 1589 
                 TGGTCCTCAGGGAACCAGGC 
                 2-13-5 
                 71.6 
                 354 
               
               
                   
               
               
                 410603 
                 1571 
                 1590 
                 CTGGTCCTCAGGGAACCAGG 
                 3-14-3 
                 40.8 
                 355 
               
               
                   
               
               
                 410681 
                 1571 
                 1590 
                 CTGGTCCTCAGGGAACCAGG 
                 2-13-5 
                 44.4 
                 355 
               
               
                   
               
               
                 405971 
                 1571 
                 1590 
                 CTGGTCCTCAGGGAACCAGG 
                 5-10-5 
                 65.5 
                 355 
               
               
                   
               
               
                 410540 
                 1572 
                 1591 
                 GCTGGTCCTCAGGGAACCAG 
                 5-10-5 
                 50.9 
                 356 
               
               
                   
               
               
                 410682 
                 1572 
                 1591 
                 GCTGGTCCTCAGGGAACCAG 
                 2-13-5 
                 54.1 
                 356 
               
               
                   
               
               
                 410604 
                 1572 
                 1591 
                 GCTGGTCCTCAGGGAACCAG 
                 3-14-3 
                 62.5 
                 356 
               
               
                   
               
               
                 405972 
                 1573 
                 1592 
                 CGCTGGTCCTCAGGGAACCA 
                 5-10-5 
                 77.6 
                 357 
               
               
                   
               
               
                 405973 
                 1578 
                 1597 
                 GTACCCGCTGGTCCTCAGGG 
                 5-10-5 
                 83.8 
                 358 
               
               
                   
               
               
                 405974 
                 1580 
                 1599 
                 CAGTACCCGCTGGTCCTCAG 
                 5-10-5 
                 89.0 
                 359 
               
               
                   
               
               
                 399813 
                 1583 
                 1602 
                 GGTCAGTACCCGCTGGTCCT 
                 5-10-5 
                 72.4 
                  51 
               
               
                   
               
               
                 399969 
                 1583 
                 1602 
                 GGTCAGTACCCGCTGGTCCT 
                 3-14-3 
                 93.4 
                  51 
               
               
                   
               
               
                 410771 
                 1628 
                 1647 
                 ACCTGCCCCATGGGTGCTGG 
                 5-10-5 
                 NA 
                 360 
               
               
                   
               
               
                 395181 
                 1640 
                 1659 
                 AAACAGCTGCCAACCTGCCC 
                 5-10-5 
                 87.5 
                  52 
               
               
                   
               
               
                 405975 
                 1642 
                 1661 
                 CAAAACAGCTGCCAACCTGC 
                 5-10-5 
                 77.4 
                 361 
               
               
                   
               
               
                 405976 
                 1647 
                 1666 
                 TCCTGCAAAACAGCTGCCAA 
                 5-10-5 
                 81.2 
                 362 
               
               
                   
               
               
                 405977 
                 1649 
                 1668 
                 AGTCCTGCAAAACAGCTGCC 
                 5-10-5 
                 89.5 
                 363 
               
               
                   
               
               
                 410772 
                 1660 
                 1679 
                 GCTGACCATACAGTCCTGCA 
                 5-10-5 
                 91.2 
                 364 
               
               
                   
               
               
                 405978 
                 1672 
                 1691 
                 GGCCCCGAGTGTGCTGACCA 
                 5-10-5 
                 95.3 
                 365 
               
               
                   
               
               
                 399904 
                 1675 
                 1694 
                 GTAGGCCCCGAGTGTGCTGA 
                 3-14-3 
                 92.6 
                  54 
               
               
                   
               
               
                 405979 
                 1677 
                 1696 
                 GTGTAGGCCCCGAGTGTGCT 
                 5-10-5 
                 85.5 
                 366 
               
               
                   
               
               
                 405980 
                 1679 
                 1698 
                 CCGTGTAGGCCCCGAGTGTG 
                 5-10-5 
                 86.5 
                 367 
               
               
                   
               
               
                 405981 
                 1681 
                 1700 
                 ATCCGTGTAGGCCCCGAGTG 
                 5-10-5 
                 77.8 
                 368 
               
               
                   
               
               
                 410741 
                 1683 
                 1702 
                 CCATCCGTGTAGGCCCCGAG 
                 5-10-5 
                 78.4 
                 369 
               
               
                   
               
               
                 405982 
                 1685 
                 1704 
                 GGCCATCCGTGTAGGCCCCG 
                 5-10-5 
                 86.7 
                 370 
               
               
                   
               
               
                 405983 
                 1687 
                 1706 
                 GTGGCCATCCGTGTAGGCCC 
                 5-10-5 
                 73.1 
                 371 
               
               
                   
               
               
                 405984 
                 1735 
                 1754 
                 CTGGAGCAGCTCAGCAGCTC 
                 5-10-5 
                 83.4 
                 372 
               
               
                   
               
               
                 405985 
                 1737 
                 1756 
                 AACTGGAGCAGCTCAGCAGC 
                 5-10-5 
                 50.7 
                 373 
               
               
                   
               
               
                 405986 
                 1742 
                 1761 
                 GGAGAAACTGGAGCAGCTCA 
                 5-10-5 
                 75.6 
                 374 
               
               
                   
               
               
                 405987 
                 1744 
                 1763 
                 CTGGAGAAACTGGAGCAGCT 
                 5-10-5 
                 88.0 
                 375 
               
               
                   
               
               
                 399905 
                 1812 
                 1831 
                 CGTTGTGGGCCCGGCAGACC 
                 3-14-3 
                 91.2 
                  57 
               
               
                   
               
               
                 395183 
                 1812 
                 1831 
                 CGTTGTGGGCCCGGCAGACC 
                 5-10-5 
                 93.1 
                  57 
               
               
                   
               
               
                 410541 
                 1849 
                 1868 
                 CACCTGGCAATGGCGTAGAC 
                 5-10-5 
                 46.1 
                 376 
               
               
                   
               
               
                 410605 
                 1849 
                 1868 
                 CACCTGGCAATGGCGTAGAC 
                 3-14-3 
                 67.4 
                 376 
               
               
                   
               
               
                 410683 
                 1849 
                 1868 
                 CACCTGGCAATGGCGTAGAC 
                 2-13-5 
                 71.8 
                 376 
               
               
                   
               
               
                 410606 
                 1850 
                 1869 
                 GCACCTGGCAATGGCGTAGA 
                 3-14-3 
                 74.3 
                 377 
               
               
                   
               
               
                 410542 
                 1850 
                 1869 
                 GCACCTGGCAATGGCGTAGA 
                 5-10-5 
                 75.5 
                 377 
               
               
                   
               
               
                 410684 
                 1850 
                 1869 
                 GCACCTGGCAATGGCGTAGA 
                 2-13-5 
                 78.7 
                 377 
               
               
                   
               
               
                 410543 
                 1851 
                 1870 
                 AGCACCTGGCAATGGCGTAG 
                 5-10-5 
                 76.4 
                 378 
               
               
                   
               
               
                 410685 
                 1851 
                 1870 
                 AGCACCTGGCAATGGCGTAG 
                 2-13-5 
                 76.9 
                 378 
               
               
                   
               
               
                 410607 
                 1851 
                 1870 
                 AGCACCTGGCAATGGCGTAG 
                 3-14-3 
                 77.1 
                 378 
               
               
                   
               
               
                 410544 
                 1852 
                 1871 
                 CAGCACCTGGCAATGGCGTA 
                 5-10-5 
                 62.7 
                 379 
               
               
                   
               
               
                 410608 
                 1852 
                 1871 
                 CAGCACCTGGCAATGGCGTA 
                 3-14-3 
                 69.6 
                 379 
               
               
                   
               
               
                 410686 
                 1852 
                 1871 
                 CAGCACCTGGCAATGGCGTA 
                 2-13-5 
                 81.0 
                 379 
               
               
                   
               
               
                 410545 
                 1853 
                 1872 
                 GCAGCACCTGGCAATGGCGT 
                 5-10-5 
                 75.5 
                 380 
               
               
                   
               
               
                 410687 
                 1853 
                 1872 
                 GCAGCACCTGGCAATGGCGT 
                 2-13-5 
                 79.2 
                 380 
               
               
                   
               
               
                 410609 
                 1853 
                 1872 
                 GCAGCACCTGGCAATGGCGT 
                 3-14-3 
                 83.2 
                 380 
               
               
                   
               
               
                 410610 
                 1854 
                 1873 
                 GGCAGCACCTGGCAATGGCG 
                 3-14-3 
                 67.5 
                 381 
               
               
                   
               
               
                 410688 
                 1854 
                 1873 
                 GGCAGCACCTGGCAATGGCG 
                 2-13-5 
                 89.3 
                 381 
               
               
                   
               
               
                 405988 
                 1854 
                 1873 
                 GGCAGCACCTGGCAATGGCG 
                 5-10-5 
                 95.9 
                 381 
               
               
                   
               
               
                 410546 
                 1855 
                 1874 
                 AGGCAGCACCTGGCAATGGC 
                 5-10-5 
                 74.8 
                 382 
               
               
                   
               
               
                 410689 
                 1855 
                 1874 
                 AGGCAGCACCTGGCAATGGC 
                 2-13-5 
                 83.9 
                 382 
               
               
                   
               
               
                 410611 
                 1855 
                 1874 
                 AGGCAGCACCTGGCAATGGC 
                 3-14-3 
                 88.2 
                 382 
               
               
                   
               
               
                 410612 
                 1856 
                 1875 
                 CAGGCAGCACCTGGCAATGG 
                 3-14-3 
                 72.8 
                 383 
               
               
                   
               
               
                 410690 
                 1856 
                 1875 
                 CAGGCAGCACCTGGCAATGG 
                 2-13-5 
                 74.8 
                 383 
               
               
                   
               
               
                 405989 
                 1856 
                 1875 
                 CAGGCAGCACCTGGCAATGG 
                 5-10-5 
                 88.1 
                 383 
               
               
                   
               
               
                 410547 
                 1857 
                 1876 
                 GCAGGCAGCACCTGGCAATG 
                 5-10-5 
                 63.0 
                 384 
               
               
                   
               
               
                 410691 
                 1857 
                 1876 
                 GCAGGCAGCACCTGGCAATG 
                 2-13-5 
                 70.2 
                 384 
               
               
                   
               
               
                 410613 
                 1857 
                 1876 
                 GCAGGCAGCACCTGGCAATG 
                 3-14-3 
                 76.7 
                 384 
               
               
                   
               
               
                 395184 
                 1858 
                 1877 
                 AGCAGGCAGCACCTGGCAAT 
                 5-10-5 
                 68.5 
                  58 
               
               
                   
               
               
                 410692 
                 1858 
                 1877 
                 AGCAGGCAGCACCTGGCAAT 
                 2-13-5 
                 69.1 
                  58 
               
               
                   
               
               
                 399906 
                 1858 
                 1877 
                 AGCAGGCAGCACCTGGCAAT 
                 3-14-3 
                 94.2 
                  58 
               
               
                   
               
               
                 410614 
                 1859 
                 1878 
                 TAGCAGGCAGCACCTGGCAA 
                 3-14-3 
                 36.6 
                 385 
               
               
                   
               
               
                 410548 
                 1859 
                 1878 
                 TAGCAGGCAGCACCTGGCAA 
                 5-10-5 
                 75.0 
                 385 
               
               
                   
               
               
                 410693 
                 1859 
                 1878 
                 TAGCAGGCAGCACCTGGCAA 
                 2-13-5 
                 82.0 
                 385 
               
               
                   
               
               
                 405990 
                 1860 
                 1879 
                 GTAGCAGGCAGCACCTGGCA 
                 5-10-5 
                 96.8 
                 386 
               
               
                   
               
               
                 410773 
                 1905 
                 1924 
                 TGGCCTCAGCTGGTGGAGCT 
                 5-10-5 
                 61.3 
                 387 
               
               
                   
               
               
                 410549 
                 1915 
                 1934 
                 GTCCCCATGCTGGCCTCAGC 
                 5-10-5 
                 63.0 
                 388 
               
               
                   
               
               
                 410615 
                 1915 
                 1934 
                 GTCCCCATGCTGGCCTCAGC 
                 3-14-3 
                 72.5 
                 388 
               
               
                   
               
               
                 410694 
                 1915 
                 1934 
                 GTCCCCATGCTGGCCTCAGC 
                 2-13-5 
                 74.8 
                 388 
               
               
                   
               
               
                 410550 
                 1916 
                 1935 
                 GGTCCCCATGCTGGCCTCAG 
                 5-10-5 
                 69.4 
                 389 
               
               
                   
               
               
                 410616 
                 1916 
                 1935 
                 GGTCCCCATGCTGGCCTCAG 
                 3-14-3 
                 80.7 
                 389 
               
               
                   
               
               
                 410695 
                 1916 
                 1935 
                 GGTCCCCATGCTGGCCTCAG 
                 2-13-5 
                 85.5 
                 389 
               
               
                   
               
               
                 410551 
                 1917 
                 1936 
                 GGGTCCCCATGCTGGCCTCA 
                 5-10-5 
                 68.7 
                 390 
               
               
                   
               
               
                 410696 
                 1917 
                 1936 
                 GGGTCCCCATGCTGGCCTCA 
                 2-13-5 
                 86.3 
                 390 
               
               
                   
               
               
                 410617 
                 1917 
                 1936 
                 GGGTCCCCATGCTGGCCTCA 
                 3-14-3 
                 86.5 
                 390 
               
               
                   
               
               
                 410552 
                 1918 
                 1937 
                 CGGGTCCCCATGCTGGCCTC 
                 5-10-5 
                 77.9 
                 391 
               
               
                   
               
               
                 410618 
                 1918 
                 1937 
                 CGGGTCCCCATGCTGGCCTC 
                 3-14-3 
                 86.7 
                 391 
               
               
                   
               
               
                 410697 
                 1918 
                 1937 
                 CGGGTCCCCATGCTGGCCTC 
                 2-13-5 
                 87.0 
                 391 
               
               
                   
               
               
                 410553 
                 1919 
                 1938 
                 ACGGGTCCCCATGCTGGCCT 
                 5-10-5 
                 72.8 
                 392 
               
               
                   
               
               
                 410619 
                 1919 
                 1938 
                 ACGGGTCCCCATGCTGGCCT 
                 3-14-3 
                 84.1 
                 392 
               
               
                   
               
               
                 410698 
                 1919 
                 1938 
                 ACGGGTCCCCATGCTGGCCT 
                 2-13-5 
                 87.0 
                 392 
               
               
                   
               
               
                 410699 
                 1920 
                 1939 
                 CACGGGTCCCCATGCTGGCC 
                 2-13-5 
                 79.5 
                  59 
               
               
                   
               
               
                 395185 
                 1920 
                 1939 
                 CACGGGTCCCCATGCTGGCC 
                 5-10-5 
                 92.7 
                  59 
               
               
                   
               
               
                 399907 
                 1920 
                 1939 
                 CACGGGTCCCCATGCTGGCC 
                 3-14-3 
                 93.7 
                  59 
               
               
                   
               
               
                 410620 
                 1921 
                 1940 
                 ACACGGGTCCCCATGCTGGC 
                 3-14-3 
                 74.4 
                 393 
               
               
                   
               
               
                 410554 
                 1921 
                 1940 
                 ACACGGGTCCCCATGCTGGC 
                 5-10-5 
                 79.7 
                 393 
               
               
                   
               
               
                 410700 
                 1921 
                 1940 
                 ACACGGGTCCCCATGCTGGC 
                 2-13-5 
                 84.4 
                 393 
               
               
                   
               
               
                 410621 
                 1922 
                 1941 
                 GACACGGGTCCCCATGCTGG 
                 3-14-3 
                 76.0 
                 394 
               
               
                   
               
               
                 410701 
                 1922 
                 1941 
                 GACACGGGTCCCCATGCTGG 
                 2-13-5 
                 83.4 
                 394 
               
               
                   
               
               
                 405991 
                 1922 
                 1941 
                 GACACGGGTCCCCATGCTGG 
                 5-10-5 
                 91.9 
                 394 
               
               
                   
               
               
                 410555 
                 1923 
                 1942 
                 GGACACGGGTCCCCATGCTG 
                 5-10-5 
                 77.0 
                 395 
               
               
                   
               
               
                 410622 
                 1923 
                 1942 
                 GGACACGGGTCCCCATGCTG 
                 3-14-3 
                 79.8 
                 395 
               
               
                   
               
               
                 410702 
                 1923 
                 1942 
                 GGACACGGGTCCCCATGCTG 
                 2-13-5 
                 85.0 
                 395 
               
               
                   
               
               
                 410703 
                 1924 
                 1943 
                 TGGACACGGGTCCCCATGCT 
                 2-13-5 
                 70.4 
                 396 
               
               
                   
               
               
                 410623 
                 1924 
                 1943 
                 TGGACACGGGTCCCCATGCT 
                 3-14-3 
                 78.9 
                 396 
               
               
                   
               
               
                 405992 
                 1924 
                 1943 
                 TGGACACGGGTCCCCATGCT 
                 5-10-5 
                 89.3 
                 396 
               
               
                   
               
               
                 410704 
                 1925 
                 1944 
                 GTGGACACGGGTCCCCATGC 
                 2-13-5 
                 78.6 
                 397 
               
               
                   
               
               
                 410556 
                 1925 
                 1944 
                 GTGGACACGGGTCCCCATGC 
                 5-10-5 
                 81.4 
                 397 
               
               
                   
               
               
                 410624 
                 1925 
                 1944 
                 GTGGACACGGGTCCCCATGC 
                 3-14-3 
                 82.8 
                 397 
               
               
                   
               
               
                 410625 
                 1926 
                 1945 
                 AGTGGACACGGGTCCCCATG 
                 3-14-3 
                 64.4 
                 398 
               
               
                   
               
               
                 410705 
                 1926 
                 1945 
                 AGTGGACACGGGTCCCCATG 
                 2-13-5 
                 74.7 
                 398 
               
               
                   
               
               
                 405993 
                 1926 
                 1945 
                 AGTGGACACGGGTCCCCATG 
                 5-10-5 
                 85.5 
                 398 
               
               
                   
               
               
                 410706 
                 1927 
                 1946 
                 CAGTGGACACGGGTCCCCAT 
                 2-13-5 
                 70.8 
                 399 
               
               
                   
               
               
                 410557 
                 1927 
                 1946 
                 CAGTGGACACGGGTCCCCAT 
                 5-10-5 
                 74.2 
                 399 
               
               
                   
               
               
                 410626 
                 1927 
                 1946 
                 CAGTGGACACGGGTCCCCAT 
                 3-14-3 
                 76.8 
                 399 
               
               
                   
               
               
                 410627 
                 1928 
                 1947 
                 GCAGTGGACACGGGTCCCCA 
                 3-14-3 
                 71.4 
                 400 
               
               
                   
               
               
                 410707 
                 1928 
                 1947 
                 GCAGTGGACACGGGTCCCCA 
                 2-13-5 
                 72.8 
                 400 
               
               
                   
               
               
                 405994 
                 1928 
                 1947 
                 GCAGTGGACACGGGTCCCCA 
                 5-10-5 
                 95.2 
                 400 
               
               
                   
               
               
                 410708 
                 1929 
                 1948 
                 GGCAGTGGACACGGGTCCCC 
                 2-13-5 
                 79.0 
                 401 
               
               
                   
               
               
                 410628 
                 1929 
                 1948 
                 GGCAGTGGACACGGGTCCCC 
                 3-14-3 
                 88.1 
                 401 
               
               
                   
               
               
                 410558 
                 1929 
                 1948 
                 GGCAGTGGACACGGGTCCCC 
                 5-10-5 
                 88.9 
                 401 
               
               
                   
               
               
                 410629 
                 1930 
                 1949 
                 TGGCAGTGGACACGGGTCCC 
                 3-14-3 
                 66.5 
                 402 
               
               
                   
               
               
                 410709 
                 1930 
                 1949 
                 TGGCAGTGGACACGGGTCCC 
                 2-13-5 
                 66.9 
                 402 
               
               
                   
               
               
                 405995 
                 1930 
                 1949 
                 TGGCAGTGGACACGGGTCCC 
                 5-10-5 
                 92.4 
                 402 
               
               
                   
               
               
                 410630 
                 1931 
                 1950 
                 GTGGCAGTGGACACGGGTCC 
                 3-14-3 
                 54.1 
                 403 
               
               
                   
               
               
                 410710 
                 1931 
                 1950 
                 GTGGCAGTGGACACGGGTCC 
                 2-13-5 
                 61.4 
                 403 
               
               
                   
               
               
                 410559 
                 1931 
                 1950 
                 GTGGCAGTGGACACGGGTCC 
                 5-10-5 
                 77.5 
                 403 
               
               
                   
               
               
                 410711 
                 1932 
                 1951 
                 GGTGGCAGTGGACACGGGTC 
                 2-13-5 
                 NA 
                 404 
               
               
                   
               
               
                 410631 
                 1932 
                 1951 
                 GGTGGCAGTGGACACGGGTC 
                 3-14-3 
                 NA 
                 404 
               
               
                   
               
               
                 410560 
                 1932 
                 1951 
                 GGTGGCAGTGGACACGGGTC 
                 5-10-5 
                 42.5 
                 404 
               
               
                   
               
               
                 410712 
                 1933 
                 1952 
                 TGGTGGCAGTGGACACGGGT 
                 2-13-5 
                 NA 
                 405 
               
               
                   
               
               
                 410632 
                 1933 
                 1952 
                 TGGTGGCAGTGGACACGGGT 
                 3-14-3 
                 NA 
                 405 
               
               
                   
               
               
                 410561 
                 1933 
                 1952 
                 TGGTGGCAGTGGACACGGGT 
                 5-10-5 
                 NA 
                 405 
               
               
                   
               
               
                 410774 
                 1936 
                 1955 
                 TGTTGGTGGCAGTGGACACG 
                 5-10-5 
                 47.8 
                 406 
               
               
                   
               
               
                 410775 
                 1962 
                 1981 
                 AGCTGCAGCCTGTGAGGACG 
                 5-10-5 
                 36.3 
                 407 
               
               
                   
               
               
                 410776 
                 1990 
                 2009 
                 GTGCCAAGGTCCTCCACCTC 
                 5-10-5 
                 77.3 
                 408 
               
               
                   
               
               
                 410777 
                 2010 
                 2029 
                 TCAGCACAGGCGGCTTGTGG 
                 5-10-5 
                 40.0 
                 409 
               
               
                   
               
               
                 410778 
                 2040 
                 2059 
                 CCACGCACTGGTTGGGCTGA 
                 5-10-5 
                 52.7 
                 410 
               
               
                   
               
               
                 399908 
                 2100 
                 2119 
                 CTTTGCATTCCAGACCTGGG 
                 3-14-3 
                 74.9 
                  60 
               
               
                   
               
               
                 410713 
                 2100 
                 2119 
                 CTTTGCATTCCAGACCTGGG 
                 2-13-5 
                 84.9 
                  60 
               
               
                   
               
               
                 395186 
                 2100 
                 2119 
                 CTTTGCATTCCAGACCTGGG 
                 5-10-5 
                 93.7 
                  60 
               
               
                   
               
               
                 410714 
                 2101 
                 2120 
                 ACTTTGCATTCCAGACCTGG 
                 2-13-5 
                 82.4 
                 411 
               
               
                   
               
               
                 410633 
                 2101 
                 2120 
                 ACTTTGCATTCCAGACCTGG 
                 3-14-3 
                 83.8 
                 411 
               
               
                   
               
               
                 410562 
                 2101 
                 2120 
                 ACTTTGCATTCCAGACCTGG 
                 5-10-5 
                 87.3 
                 411 
               
               
                   
               
               
                 410715 
                 2102 
                 2121 
                 GACTTTGCATTCCAGACCTG 
                 2-13-5 
                 80.5 
                 412 
               
               
                   
               
               
                 410634 
                 2102 
                 2121 
                 GACTTTGCATTCCAGACCTG 
                 3-14-3 
                 81.8 
                 412 
               
               
                   
               
               
                 405996 
                 2102 
                 2121 
                 GACTTTGCATTCCAGACCTG 
                 5-10-5 
                 91.0 
                 412 
               
               
                   
               
               
                 410563 
                 2103 
                 2122 
                 TGACTTTGCATTCCAGACCT 
                 5-10-5 
                 75.4 
                 413 
               
               
                   
               
               
                 410635 
                 2103 
                 2122 
                 TGACTTTGCATTCCAGACCT 
                 3-14-3 
                 75.9 
                 413 
               
               
                   
               
               
                 410716 
                 2103 
                 2122 
                 TGACTTTGCATTCCAGACCT 
                 2-13-5 
                 88.3 
                 413 
               
               
                   
               
               
                 410636 
                 2104 
                 2123 
                 TTGACTTTGCATTCCAGACC 
                 3-14-3 
                 61.3 
                 414 
               
               
                   
               
               
                 410564 
                 2104 
                 2123 
                 TTGACTTTGCATTCCAGACC 
                 5-10-5 
                 71.3 
                 414 
               
               
                   
               
               
                 410717 
                 2104 
                 2123 
                 TTGACTTTGCATTCCAGACC 
                 2-13-5 
                 76.7 
                 414 
               
               
                   
               
               
                 410718 
                 2105 
                 2124 
                 CTTGACTTTGCATTCCAGAC 
                 2-13-5 
                 55.8 
                  61 
               
               
                   
               
               
                 399973 
                 2105 
                 2124 
                 CTTGACTTTGCATTCCAGAC 
                 3-14-3 
                 82.1 
                  61 
               
               
                   
               
               
                 399817 
                 2105 
                 2124 
                 CTTGACTTTGCATTCCAGAC 
                 5-10-5 
                 93.6 
                  61 
               
               
                   
               
               
                 405997 
                 2107 
                 2126 
                 TCCTTGACTTTGCATTCCAG 
                 5-10-5 
                 95.6 
                 415 
               
               
                   
               
               
                 410779 
                 2120 
                 2139 
                 CGGGATTCCATGCTCCTTGA 
                 5-10-5 
                 79.7 
                 416 
               
               
                   
               
               
                 410780 
                 2150 
                 2169 
                 GCAGGCCACGGTCACCTGCT 
                 5-10-5 
                 60.9 
                 417 
               
               
                   
               
               
                 410781 
                 2187 
                 2206 
                 GGAGGGCACTGCAGCCAGTC 
                 5-10-5 
                 66.0 
                 418 
               
               
                   
               
               
                 410719 
                 2305 
                 2324 
                 CAGATGGCAACGGCTGTCAC 
                 2-13-5 
                 61.0 
                 419 
               
               
                   
               
               
                 410637 
                 2305 
                 2324 
                 CAGATGGCAACGGCTGTCAC 
                 3-14-3 
                 66.0 
                 419 
               
               
                   
               
               
                 410565 
                 2305 
                 2324 
                 CAGATGGCAACGGCTGTCAC 
                 5-10-5 
                 71.6 
                 419 
               
               
                   
               
               
                 410638 
                 2306 
                 2325 
                 GCAGATGGCAACGGCTGTCA 
                 3-14-3 
                 71.9 
                 420 
               
               
                   
               
               
                 410720 
                 2306 
                 2325 
                 GCAGATGGCAACGGCTGTCA 
                 2-13-5 
                 75.1 
                 420 
               
               
                   
               
               
                 410566 
                 2306 
                 2325 
                 GCAGATGGCAACGGCTGTCA 
                 5-10-5 
                 77.7 
                 420 
               
               
                   
               
               
                 410639 
                 2307 
                 2326 
                 AGCAGATGGCAACGGCTGTC 
                 3-14-3 
                 67.7 
                 421 
               
               
                   
               
               
                 410721 
                 2307 
                 2326 
                 AGCAGATGGCAACGGCTGTC 
                 2-13-5 
                 68.8 
                 421 
               
               
                   
               
               
                 410567 
                 2307 
                 2326 
                 AGCAGATGGCAACGGCTGTC 
                 5-10-5 
                 72.1 
                 421 
               
               
                   
               
               
                 410568 
                 2308 
                 2327 
                 CAGCAGATGGCAACGGCTGT 
                 5-10-5 
                 54.2 
                 422 
               
               
                   
               
               
                 410640 
                 2308 
                 2327 
                 CAGCAGATGGCAACGGCTGT 
                 3-14-3 
                 57.7 
                 422 
               
               
                   
               
               
                 410722 
                 2308 
                 2327 
                 CAGCAGATGGCAACGGCTGT 
                 2-13-5 
                 59.2 
                 422 
               
               
                   
               
               
                 410569 
                 2309 
                 2328 
                 GCAGCAGATGGCAACGGCTG 
                 5-10-5 
                 57.7 
                 423 
               
               
                   
               
               
                 410641 
                 2309 
                 2328 
                 GCAGCAGATGGCAACGGCTG 
                 3-14-3 
                 66.1 
                 423 
               
               
                   
               
               
                 410723 
                 2309 
                 2328 
                 GCAGCAGATGGCAACGGCTG 
                 2-13-5 
                 81.1 
                 423 
               
               
                   
               
               
                 399909 
                 2310 
                 2329 
                 GGCAGCAGATGGCAACGGCT 
                 3-14-3 
                 69.9 
                  62 
               
               
                   
               
               
                 410724 
                 2310 
                 2329 
                 GGCAGCAGATGGCAACGGCT 
                 2-13-5 
                 87.4 
                  62 
               
               
                   
               
               
                 395187 
                 2310 
                 2329 
                 GGCAGCAGATGGCAACGGCT 
                 5-10-5 
                 92.7 
                  62 
               
               
                   
               
               
                 410642 
                 2311 
                 2330 
                 CGGCAGCAGATGGCAACGGC 
                 3-14-3 
                 70.4 
                 424 
               
               
                   
               
               
                 410725 
                 2311 
                 2330 
                 CGGCAGCAGATGGCAACGGC 
                 2-13-5 
                 75.6 
                 424 
               
               
                   
               
               
                 410570 
                 2311 
                 2330 
                 CGGCAGCAGATGGCAACGGC 
                 5-10-5 
                 78.3 
                 424 
               
               
                   
               
               
                 410571 
                 2312 
                 2331 
                 CCGGCAGCAGATGGCAACGG 
                 5-10-5 
                 52.8 
                 425 
               
               
                   
               
               
                 410643 
                 2312 
                 2331 
                 CCGGCAGCAGATGGCAACGG 
                 3-14-3 
                 59.8 
                 425 
               
               
                   
               
               
                 410726 
                 2312 
                 2331 
                 CCGGCAGCAGATGGCAACGG 
                 2-13-5 
                 69.8 
                 425 
               
               
                   
               
               
                 410644 
                 2313 
                 2332 
                 TCCGGCAGCAGATGGCAACG 
                 3-14-3 
                 59.0 
                 426 
               
               
                   
               
               
                 410727 
                 2313 
                 2332 
                 TCCGGCAGCAGATGGCAACG 
                 2-13-5 
                 68.3 
                 426 
               
               
                   
               
               
                 405998 
                 2313 
                 2332 
                 TCCGGCAGCAGATGGCAACG 
                 5-10-5 
                 75.6 
                 426 
               
               
                   
               
               
                 410572 
                 2314 
                 2333 
                 CTCCGGCAGCAGATGGCAAC 
                 5-10-5 
                 40.9 
                 427 
               
               
                   
               
               
                 410728 
                 2314 
                 2333 
                 CTCCGGCAGCAGATGGCAAC 
                 2-13-5 
                 56.4 
                 427 
               
               
                   
               
               
                 410645 
                 2314 
                 2333 
                 CTCCGGCAGCAGATGGCAAC 
                 3-14-3 
                 70.2 
                 427 
               
               
                   
               
               
                 410729 
                 2315 
                 2334 
                 GCTCCGGCAGCAGATGGCAA 
                 2-13-5 
                 67.7 
                 428 
               
               
                   
               
               
                 410573 
                 2315 
                 2334 
                 GCTCCGGCAGCAGATGGCAA 
                 5-10-5 
                 71.8 
                 428 
               
               
                   
               
               
                 410646 
                 2315 
                 2334 
                 GCTCCGGCAGCAGATGGCAA 
                 3-14-3 
                 72.8 
                 428 
               
               
                   
               
               
                 410782 
                 2325 
                 2344 
                 CCAGGTGCCGGCTCCGGCAG 
                 5-10-5 
                 43.2 
                 429 
               
               
                   
               
               
                 410783 
                 2335 
                 2354 
                 GAGGCCTGCGCCAGGTGCCG 
                 5-10-5 
                 63.7 
                 430 
               
               
                   
               
               
                 399819 
                 2509 
                 2528 
                 CCCACTCAAGGGCCAGGCCA 
                 5-10-5 
                 93.4 
                  65 
               
               
                   
               
               
                 399912 
                 2597 
                 2616 
                 ATGCCCCACAGTGAGGGAGG 
                 3-14-3 
                 84.3 
                  66 
               
               
                   
               
               
                 405893 
                 2828 
                 2847 
                 ATGAGGGCCATCAGCACCTT 
                 5-10-5 
                 93.9 
                 431 
               
               
                   
               
               
                 405894 
                 2829 
                 2848 
                 GATGAGGGCCATCAGCACCT 
                 5-10-5 
                 93.9 
                 432 
               
               
                   
               
               
                 405895 
                 2830 
                 2849 
                 AGATGAGGGCCATCAGCACC 
                 5-10-5 
                 91.8 
                 433 
               
               
                   
               
               
                 405896 
                 2831 
                 2850 
                 GAGATGAGGGCCATCAGCAC 
                 5-10-5 
                 88.5 
                 434 
               
               
                   
               
               
                 395194 
                 2832 
                 2851 
                 GGAGATGAGGGCCATCAGCA 
                 5-10-5 
                 90.0 
                  69 
               
               
                   
               
               
                 399916 
                 2832 
                 2851 
                 GGAGATGAGGGCCATCAGCA 
                 3-14-3 
                 94.5 
                  69 
               
               
                   
               
               
                 405897 
                 2833 
                 2852 
                 TGGAGATGAGGGCCATCAGC 
                 5-10-5 
                 85.1 
                 435 
               
               
                   
               
               
                 405898 
                 2834 
                 2853 
                 CTGGAGATGAGGGCCATCAG 
                 5-10-5 
                 86.9 
                 436 
               
               
                   
               
               
                 405899 
                 2835 
                 2854 
                 GCTGGAGATGAGGGCCATCA 
                 5-10-5 
                 91.5 
                 437 
               
               
                   
               
               
                 405900 
                 2836 
                 2855 
                 AGCTGGAGATGAGGGCCATC 
                 5-10-5 
                 83.7 
                 438 
               
               
                   
               
               
                 405901 
                 2902 
                 2921 
                 GCTAGATGCCATCCAGAAAG 
                 5-10-5 
                 88.4 
                 439 
               
               
                   
               
               
                 405902 
                 2903 
                 2922 
                 GGCTAGATGCCATCCAGAAA 
                 5-10-5 
                 89.3 
                 440 
               
               
                   
               
               
                 405903 
                 2904 
                 2923 
                 TGGCTAGATGCCATCCAGAA 
                 5-10-5 
                 92.6 
                 441 
               
               
                   
               
               
                 405904 
                 2905 
                 2924 
                 CTGGCTAGATGCCATCCAGA 
                 5-10-5 
                 90.4 
                 442 
               
               
                   
               
               
                 399821 
                 2906 
                 2925 
                 TCTGGCTAGATGCCATCCAG 
                 5-10-5 
                 91.7 
                  71 
               
               
                   
               
               
                 405905 
                 2907 
                 2926 
                 CTCTGGCTAGATGCCATCCA 
                 5-10-5 
                 90.7 
                 443 
               
               
                   
               
               
                 405906 
                 2908 
                 2927 
                 CCTCTGGCTAGATGCCATCC 
                 5-10-5 
                 93.3 
                 444 
               
               
                   
               
               
                 405907 
                 2909 
                 2928 
                 GCCTCTGGCTAGATGCCATC 
                 5-10-5 
                 90.2 
                 445 
               
               
                   
               
               
                 405908 
                 2910 
                 2929 
                 AGCCTCTGGCTAGATGCCAT 
                 5-10-5 
                 83.3 
                 446 
               
               
                   
               
               
                 399978 
                 2988 
                 3007 
                 AGCCTGGCATAGAGCAGAGT 
                 3-14-3 
                 96.4 
                  73 
               
               
                   
               
            
           
         
       
     
     Antisense oligonucleotides that exhibited less than 30% inhibition of PCSK9 mRNA levels were marked with “NA”. 
     Antisense oligonucleotides with the following ISIS Nos exhibited at least 80% inhibition of PCSK9 mRNA levels: 395152, 395153, 395155, 395158, 395163, 395165, 395166, 395168, 395173, 395181, 395183, 395185, 395186, 395187, 395194, 399798, 399801, 399804, 399806, 399817, 399819, 399821, 399877, 399879, 399887, 399888, 399891, 399895, 399900, 399904, 399905, 399906, 399907, 399912, 399916, 399954, 399960, 399962, 399967, 399968, 399969, 399973, 399978, 405861, 405862, 405863, 405864, 405865, 405866, 405869, 405870, 405871, 405872, 405873, 405874, 405875, 405876, 405877, 405878, 405879, 405880, 405881, 405882, 405883, 405884, 405889, 405890, 405891, 405893, 405894, 405895, 405896, 405897, 405898, 405899, 405900, 405901, 405902, 405903, 405904, 405905, 405906, 405907, 405908, 405909, 405910, 405911, 405913, 405914, 405915, 405916, 405920, 405921, 405922, 405923, 405924, 405925, 405926, 405927, 405928, 405929, 405930, 405931, 405932, 405934, 405935, 405936, 405940, 405941, 405943, 405944, 405949, 405952, 405953, 405954, 405955, 405956, 405958, 405959, 405960, 405961, 405973, 405974, 405976, 405977, 405978, 405979, 405980, 405982, 405984, 405987, 405988, 405989, 405990, 405991, 405992, 405993, 405994, 405995, 405996, 405997, 406002, 406003, 406005, 406008, 406009, 406014, 406016, 406020, 406023, 406026, 406028, 406029, 406030, 406031, 406032, 406033, 406035, 406036, 406038, 406039, 406040, 406041, 406042, 406043, 406044, 406045, 410530, 410556, 410558, 410562, 410578, 410583, 410589, 410590, 410591, 410592, 410593, 410595, 410609, 410611, 410616, 410617, 410618, 410619, 410624, 410628, 410633, 410634, 410647, 410648, 410650, 410652, 410658, 410664, 410666, 410667, 410668, 410671, 410677, 410686, 410688, 410689, 410693, 410695, 410696, 410697, 410698, 410700, 410701, 410702, 410713, 410714, 410715, 410716, 410723, 410724, 410730, 410751, 410754, 410757, 410759, 410760, 410769, and 410772. The target segments to which these antisense oligonucleotides are targeted are active target segments. The target regions to which these antisense oligonucleotides are targeted are active target regions. 
     ISIS Nos 395152, 395155, 395158, 395165, 395166, 395168, 395173, 395181, 395183, 395185, 395186, 395187, 395194, 399801, 399817, 399819, 399821, 399877, 399879, 399887, 399888, 399891, 399900, 399904, 399905, 399906, 399907, 399916, 399954, 399962, 399969, 399978, 405861, 405862, 405864, 405869, 405871, 405872, 405873, 405874, 405875, 405876, 405878, 405879, 405880, 405881, 405882, 405883, 405884, 405890, 405891, 405893, 405894, 405895, 405896, 405897, 405898, 405899, 405901, 405902, 405903, 405904, 405905, 405906, 405907, 405910, 405911, 405913, 405914, 405915, 405916, 405920, 405921, 405922, 405923, 405924, 405925, 405926, 405927, 405928, 405929, 405930, 405931, 405932, 405934, 405935, 405936, 405941, 405952, 405953, 405954, 405955, 405956, 405959, 405960, 405961, 405974, 405977, 405978, 405979, 405980, 405982, 405987, 405988, 405989, 405990, 405991, 405992, 405993, 405994, 405995, 405996, 405997, 406008, 406009, 406014, 406016, 406023, 406028, 406029, 406030, 406031, 406032, 406033, 406035, 406038, 406039, 406040, 406041, 406042, 406043, 406044, 406045, 410558, 410562, 410583, 410591, 410592, 410593, 410611, 410617, 410618, 410628, 410647, 410650, 410668, 410677, 410688, 410695, 410696, 410697, 410698, 410702, 410716, 410724, 410730, 410757, 410760, and 410772 each exhibited at least 85% inhibition of PCSK9 mRNA levels. 
     ISIS Nos 395152, 395155, 395158, 395165, 395166, 395168, 395173, 395183, 395185, 395186, 395187, 395194, 399801, 399817, 399819, 399821, 399877, 399879, 399887, 399888, 399891, 399900, 399904, 399905, 399906, 399907, 399916, 399954, 399969, 399978, 405861, 405862, 405864, 405873, 405874, 405875, 405876, 405878, 405879, 405880, 405881, 405882, 405883, 405884, 405891, 405893, 405894, 405895, 405899, 405903, 405904, 405905, 405906, 405907, 405910, 405913, 405914, 405916, 405923, 405924, 405925, 405926, 405927, 405928, 405930, 405932, 405934, 405936, 405941, 405953, 405955, 405956, 405959, 405960, 405978, 405988, 405990, 405991, 405994, 405995, 405996, 405997, 406008, 406009, 406014, 406023, 406028, 406029, 406030, 406033, 406035, 406039, 406040, 406041, 406042, 406043, 406044, 410592, 410647, 410668, 410760, and 410772 each exhibited at least 90% inhibition of PCSK9 mRNA levels. 
     ISIS Nos 395165, 395166, 399801, 399978, 405881, 405891, 405959, 405978, 405988, 405990, 405994, 405997, 406008, 406030, 406040, 406041, 406044, and 410760 each exhibited at least 95% inhibition of PCSK9 mRNA levels. 
     
       
         
           
               
             
               
                 TABLE 18 
               
             
            
               
                   
               
               
                 Antisense inhibition of PCSK9 in human cells (Hep3B) 
               
               
                 targeting SEQ ID NO: 2 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                 5′ Target 
                 3′ Target 
                   
                   
                   
                   
               
               
                   
                 Site to 
                 Site to 
                   
                   
                   
                 SEQ 
               
               
                 Isis 
                 SEQ ID 
                 SEQ ID 
                   
                   
                 % 
                 ID 
               
               
                 No. 
                 NO: 2 
                 NO: 2 
                 Sequence 5′-3′ 
                 Motif 
                 inhibition 
                 NO: 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                 410742 
                 2433 
                 2452 
                 GCCTGGAGCTGACGGTGCCC 
                 5-10-5 
                 75.1 
                 159 
               
               
                   
               
               
                 405999 
                 2437 
                 2456 
                 GACCGCCTGGAGCTGACGGT 
                 5-10-5 
                 70.3 
                 160 
               
               
                   
               
               
                 395151 
                 2439 
                 2458 
                 AGGACCGCCTGGAGCTGACG 
                 5-10-5 
                 57.3 
                 6 
               
               
                   
               
               
                 405861 
                 2545 
                 2564 
                 AAGGCTAGCACCAGCTCCTC 
                 5-10-5 
                 90.5 
                 162 
               
               
                   
               
               
                 405862 
                 2546 
                 2565 
                 CAAGGCTAGCACCAGCTCCT 
                 5-10-5 
                 92.3 
                 163 
               
               
                   
               
               
                 405863 
                 2547 
                 2566 
                 GCAAGGCTAGCACCAGCTCC 
                 5-10-5 
                 82.6 
                 164 
               
               
                   
               
               
                 405864 
                 2548 
                 2567 
                 CGCAAGGCTAGCACCAGCTC 
                 5-10-5 
                 91.8 
                 165 
               
               
                   
               
               
                 395152 
                 2549 
                 2568 
                 ACGCAAGGCTAGCACCAGCT 
                 5-10-5 
                 93.3 
                 7 
               
               
                   
               
               
                 405865 
                 2550 
                 2569 
                 AACGCAAGGCTAGCACCAGC 
                 5-10-5 
                 84.6 
                 166 
               
               
                   
               
               
                 405866 
                 2551 
                 2570 
                 GAACGCAAGGCTAGCACCAG 
                 5-10-5 
                 81.8 
                 167 
               
               
                   
               
               
                 405867 
                 2552 
                 2571 
                 GGAACGCAAGGCTAGCACCA 
                 5-10-5 
                 74.0 
                 168 
               
               
                   
               
               
                 405868 
                 2553 
                 2572 
                 CGGAACGCAAGGCTAGCACC 
                 5-10-5 
                 76.8 
                 169 
               
               
                   
               
               
                 399793 
                 2556 
                 2575 
                 CCTCGGAACGCAAGGCTAGC 
                 5-10-5 
                 77.9 
                 8 
               
               
                   
               
               
                 410743 
                 2560 
                 2579 
                 TCCTCCTCGGAACGCAAGGC 
                 5-10-5 
                 76.7 
                 170 
               
               
                   
               
               
                 410744 
                 2585 
                 2604 
                 GTGCTCGGGTGCTTCGGCCA 
                 5-10-5 
                 76.9 
                 171 
               
               
                   
               
               
                 410745 
                 2605 
                 2624 
                 TGGAAGGTGGCTGTGGTTCC 
                 5-10-5 
                 41.7 
                 172 
               
               
                   
               
               
                 395153 
                 2619 
                 2638 
                 CCTTGGCGCAGCGGTGGAAG 
                 5-10-5 
                 81.1 
                 9 
               
               
                   
               
               
                 410746 
                 6444 
                 6463 
                 CGTAGGTGCCAGGCAACCTC 
                 5-10-5 
                 44.8 
                 176 
               
               
                   
               
               
                 410747 
                 6482 
                 6501 
                 TGACTGCGAGAGGTGGGTCT 
                 5-10-5 
                 NA 
                 177 
               
               
                   
               
               
                 406003 
                 6492 
                 6511 
                 CAGTGCGCTCTGACTGCGAG 
                 5-10-5 
                 84.2 
                 178 
               
               
                   
               
               
                 406004 
                 6494 
                 6513 
                 GGCAGTGCGCTCTGACTGCG 
                 5-10-5 
                 56.4 
                 179 
               
               
                   
               
               
                 406005 
                 6496 
                 6515 
                 CGGGCAGTGCGCTCTGACTG 
                 5-10-5 
                 83.4 
                 180 
               
               
                   
               
               
                 406006 
                 6499 
                 6518 
                 CGGCGGGCAGTGCGCTCTGA 
                 5-10-5 
                 71.0 
                 181 
               
               
                   
               
               
                 410748 
                 6528 
                 6547 
                 ATCCCCGGCGGGCAGCCTGG 
                 5-10-5 
                 56.0 
                 182 
               
               
                   
               
               
                 406007 
                 6532 
                 6551 
                 AGGTATCCCCGGCGGGCAGC 
                 5-10-5 
                 76.3 
                 183 
               
               
                   
               
               
                 410574 
                 6534 
                 6553 
                 TGAGGTATCCCCGGCGGGCA 
                 3-14-3 
                 69.1 
                 184 
               
               
                   
               
               
                 410529 
                 6534 
                 6553 
                 TGAGGTATCCCCGGCGGGCA 
                 5-10-5 
                 77.4 
                 184 
               
               
                   
               
               
                 410647 
                 6534 
                 6553 
                 TGAGGTATCCCCGGCGGGCA 
                 2-13-5 
                 90.7 
                 184 
               
               
                   
               
               
                 410575 
                 6535 
                 6554 
                 GTGAGGTATCCCCGGCGGGC 
                 3-14-3 
                 71.5 
                 185 
               
               
                   
               
               
                 410648 
                 6535 
                 6554 
                 GTGAGGTATCCCCGGCGGGC 
                 2-13-5 
                 82.8 
                 185 
               
               
                   
               
               
                 410530 
                 6535 
                 6554 
                 GTGAGGTATCCCCGGCGGGC 
                 5-10-5 
                 83.2 
                 185 
               
               
                   
               
               
                 410649 
                 6536 
                 6555 
                 GGTGAGGTATCCCCGGCGGG 
                 2-13-5 
                 53.5 
                 186 
               
               
                   
               
               
                 410576 
                 6536 
                 6555 
                 GGTGAGGTATCCCCGGCGGG 
                 3-14-3 
                 56.2 
                 186 
               
               
                   
               
               
                 410531 
                 6536 
                 6555 
                 GGTGAGGTATCCCCGGCGGG 
                 5-10-5 
                 63.6 
                 186 
               
               
                   
               
               
                 410650 
                 6537 
                 6556 
                 TGGTGAGGTATCCCCGGCGG 
                 2-13-5 
                 86.1 
                 11 
               
               
                   
               
               
                 399877 
                 6537 
                 6556 
                 TGGTGAGGTATCCCCGGCGG 
                 3-14-3 
                 92.6 
                 11 
               
               
                   
               
               
                 395155 
                 6537 
                 6556 
                 TGGTGAGGTATCCCCGGCGG 
                 5-10-5 
                 92.7 
                 11 
               
               
                   
               
               
                 410577 
                 6538 
                 6557 
                 TTGGTGAGGTATCCCCGGCG 
                 3-14-3 
                 62.4 
                 187 
               
               
                   
               
               
                 410532 
                 6538 
                 6557 
                 TTGGTGAGGTATCCCCGGCG 
                 5-10-5 
                 63.5 
                 187 
               
               
                   
               
               
                 410651 
                 6538 
                 6557 
                 TTGGTGAGGTATCCCCGGCG 
                 2-13-5 
                 75.5 
                 187 
               
               
                   
               
               
                 410652 
                 6539 
                 6558 
                 CTTGGTGAGGTATCCCCGGC 
                 2-13-5 
                 81.2 
                 188 
               
               
                   
               
               
                 410578 
                 6539 
                 6558 
                 CTTGGTGAGGTATCCCCGGC 
                 3-14-3 
                 83.3 
                 188 
               
               
                   
               
               
                 406008 
                 6539 
                 6558 
                 CTTGGTGAGGTATCCCCGGC 
                 5-10-5 
                 95.2 
                 188 
               
               
                   
               
               
                 410653 
                 6540 
                 6559 
                 TCTTGGTGAGGTATCCCCGG 
                 2-13-5 
                 68.9 
                 189 
               
               
                   
               
               
                 410579 
                 6540 
                 6559 
                 TCTTGGTGAGGTATCCCCGG 
                 3-14-3 
                 74.0 
                 189 
               
               
                   
               
               
                 410533 
                 6540 
                 6559 
                 TCTTGGTGAGGTATCCCCGG 
                 5-10-5 
                 79.0 
                 189 
               
               
                   
               
               
                 410580 
                 6541 
                 6560 
                 ATCTTGGTGAGGTATCCCCG 
                 3-14-3 
                 62.3 
                 190 
               
               
                   
               
               
                 410654 
                 6541 
                 6560 
                 ATCTTGGTGAGGTATCCCCG 
                 2-13-5 
                 65.2 
                 190 
               
               
                   
               
               
                 406009 
                 6541 
                 6560 
                 ATCTTGGTGAGGTATCCCCG 
                 5-10-5 
                 90.7 
                 190 
               
               
                   
               
               
                 410534 
                 6542 
                 6561 
                 GATCTTGGTGAGGTATCCCC 
                 5-10-5 
                 59.8 
                 191 
               
               
                   
               
               
                 410581 
                 6542 
                 6561 
                 GATCTTGGTGAGGTATCCCC 
                 3-14-3 
                 72.9 
                 191 
               
               
                   
               
               
                 410655 
                 6542 
                 6561 
                 GATCTTGGTGAGGTATCCCC 
                 2-13-5 
                 77.4 
                 191 
               
               
                   
               
               
                 399794 
                 6543 
                 6562 
                 GGATCTTGGTGAGGTATCCC 
                 5-10-5 
                 56.5 
                 12 
               
               
                   
               
               
                 410656 
                 6543 
                 6562 
                 GGATCTTGGTGAGGTATCCC 
                 2-13-5 
                 68.0 
                 12 
               
               
                   
               
               
                 399950 
                 6543 
                 6562 
                 GGATCTTGGTGAGGTATCCC 
                 3-14-3 
                 74.4 
                 12 
               
               
                   
               
               
                 410535 
                 6544 
                 6563 
                 AGGATCTTGGTGAGGTATCC 
                 5-10-5 
                 65.7 
                 192 
               
               
                   
               
               
                 410582 
                 6544 
                 6563 
                 AGGATCTTGGTGAGGTATCC 
                 3-14-3 
                 69.5 
                 192 
               
               
                   
               
               
                 410657 
                 6544 
                 6563 
                 AGGATCTTGGTGAGGTATCC 
                 2-13-5 
                 73.1 
                 192 
               
               
                   
               
               
                 406010 
                 6546 
                 6565 
                 GCAGGATCTTGGTGAGGTAT 
                 5-10-5 
                 56.9 
                 193 
               
               
                   
               
               
                 406011 
                 6548 
                 6567 
                 ATGCAGGATCTTGGTGAGGT 
                 5-10-5 
                 70.7 
                 194 
               
               
                   
               
               
                 406012 
                 6550 
                 6569 
                 ACATGCAGGATCTTGGTGAG 
                 5-10-5 
                 69.1 
                 195 
               
               
                   
               
               
                 406013 
                 6554 
                 6573 
                 GAAGACATGCAGGATCTTGG 
                 5-10-5 
                 77.4 
                 196 
               
               
                   
               
               
                 395156 
                 6557 
                 6576 
                 ATGGAAGACATGCAGGATCT 
                 5-10-5 
                 76.7 
                 14 
               
               
                   
               
               
                 410749 
                 6565 
                 6584 
                 AGAAGGCCATGGAAGACATG 
                 5-10-5 
                 59.4 
                 197 
               
               
                   
               
               
                 410750 
                 6575 
                 6594 
                 GAAGCCAGGAAGAAGGCCAT 
                 5-10-5 
                 57.5 
                 198 
               
               
                   
               
               
                 399879 
                 6583 
                 6602 
                 TTCACCAGGAAGCCAGGAAG 
                 3-14-3 
                 91.9 
                 15 
               
               
                   
               
               
                 406014 
                 6585 
                 6604 
                 TCTTCACCAGGAAGCCAGGA 
                 5-10-5 
                 94.0 
                 199 
               
               
                   
               
               
                 406015 
                 6590 
                 6609 
                 ACTCATCTTCACCAGGAAGC 
                 5-10-5 
                 78.8 
                 200 
               
               
                   
               
               
                 406016 
                 6592 
                 6611 
                 CCACTCATCTTCACCAGGAA 
                 5-10-5 
                 87.2 
                 201 
               
               
                   
               
               
                 410730 
                 6594 
                 6613 
                 CGCCACTCATCTTCACCAGG 
                 5-10-5 
                 85.4 
                 202 
               
               
                   
               
               
                 406017 
                 6596 
                 6615 
                 GTCGCCACTCATCTTCACCA 
                 5-10-5 
                 76.3 
                 203 
               
               
                   
               
               
                 406018 
                 6598 
                 6617 
                 AGGTCGCCACTCATCTTCAC 
                 5-10-5 
                 63.2 
                 204 
               
               
                   
               
               
                 406019 
                 6600 
                 6619 
                 GCAGGTCGCCACTCATCTTC 
                 5-10-5 
                 68.1 
                 205 
               
               
                   
               
               
                 406020 
                 6602 
                 6621 
                 CAGCAGGTCGCCACTCATCT 
                 5-10-5 
                 83.7 
                 206 
               
               
                   
               
               
                 410731 
                 6604 
                 6623 
                 TCCAGCAGGTCGCCACTCAT 
                 5-10-5 
                 72.9 
                 207 
               
               
                   
               
               
                 395158 
                 9130 
                 9149 
                 CCTCGATGTAGTCGACATGG 
                 5-10-5 
                 93.9 
                 17 
               
               
                   
               
               
                 410752 
                 9149 
                 9168 
                 GCAAAGACAGAGGAGTCCTC 
                 5-10-5 
                 76.3 
                 209 
               
               
                   
               
               
                 406021 
                 9207 
                 9226 
                 TTCATCCGCCCGGTACCGTG 
                 5-10-5 
                 79.6 
                 210 
               
               
                   
               
               
                 406022 
                 9209 
                 9228 
                 TATTCATCCGCCCGGTACCG 
                 5-10-5 
                 78.7 
                 211 
               
               
                   
               
               
                 406023 
                 9212 
                 9231 
                 TGGTATTCATCCGCCCGGTA 
                 5-10-5 
                 92.5 
                 212 
               
               
                   
               
               
                 406024 
                 9214 
                 9233 
                 GCTGGTATTCATCCGCCCGG 
                 5-10-5 
                 69.7 
                 213 
               
               
                   
               
               
                 410732 
                 9216 
                 9235 
                 GGGCTGGTATTCATCCGCCC 
                 5-10-5 
                 30.4 
                 214 
               
               
                   
               
               
                 399935 
                 14601 
                 14620 
                 AGGACCCAAGTCATCCTGCT 
                 3-14-3 
                 81.1 
                 96 
               
               
                   
               
               
                 399936 
                 14631 
                 14650 
                 GGCCATCAGCTGGCAATGCT 
                 3-14-3 
                 89.0 
                 124 
               
               
                   
               
               
                 410753 
                 14877 
                 14896 
                 ATACACCTCCACCAGGCTGC 
                 5-10-5 
                 72.8 
                 315 
               
               
                   
               
               
                 406025 
                 14888 
                 14907 
                 GTGTCTAGGAGATACACCTC 
                 5-10-5 
                 74.2 
                 216 
               
               
                   
               
               
                 406026 
                 14893 
                 14912 
                 TGCTGGTGTCTAGGAGATAC 
                 5-10-5 
                 80.5 
                 217 
               
               
                   
               
               
                 405869 
                 14918 
                 14937 
                 TCGATTTCCCGGTGGTCACT 
                 5-10-5 
                 87.6 
                 218 
               
               
                   
               
               
                 405870 
                 14919 
                 14938 
                 CTCGATTTCCCGGTGGTCAC 
                 5-10-5 
                 83.3 
                 219 
               
               
                   
               
               
                 405871 
                 14920 
                 14939 
                 CCTCGATTTCCCGGTGGTCA 
                 5-10-5 
                 87.0 
                 220 
               
               
                   
               
               
                 405872 
                 14921 
                 14940 
                 CCCTCGATTTCCCGGTGGTC 
                 5-10-5 
                 88.2 
                 221 
               
               
                   
               
               
                 399798 
                 14922 
                 14941 
                 GCCCTCGATTTCCCGGTGGT 
                 5-10-5 
                 84.3 
                 22 
               
               
                   
               
               
                 399954 
                 14922 
                 14941 
                 GCCCTCGATTTCCCGGTGGT 
                 3-14-3 
                 90.3 
                 22 
               
               
                   
               
               
                 405873 
                 14923 
                 14942 
                 TGCCCTCGATTTCCCGGTGG 
                 5-10-5 
                 90.0 
                 222 
               
               
                   
               
               
                 405874 
                 14924 
                 14943 
                 CTGCCCTCGATTTCCCGGTG 
                 5-10-5 
                 91.4 
                 223 
               
               
                   
               
               
                 405875 
                 14925 
                 14944 
                 CCTGCCCTCGATTTCCCGGT 
                 5-10-5 
                 93.5 
                 224 
               
               
                   
               
               
                 405876 
                 14926 
                 14945 
                 CCCTGCCCTCGATTTCCCGG 
                 5-10-5 
                 90.1 
                 225 
               
               
                   
               
               
                 406027 
                 14930 
                 14949 
                 ATGACCCTGCCCTCGATTTC 
                 5-10-5 
                 73.9 
                 226 
               
               
                   
               
               
                 406028 
                 14932 
                 14951 
                 CCATGACCCTGCCCTCGATT 
                 5-10-5 
                 92.3 
                 227 
               
               
                   
               
               
                 406029 
                 14934 
                 14953 
                 GACCATGACCCTGCCCTCGA 
                 5-10-5 
                 91.4 
                 228 
               
               
                   
               
               
                 406030 
                 14938 
                 14957 
                 CGGTGACCATGACCCTGCCC 
                 5-10-5 
                 95.6 
                 229 
               
               
                   
               
               
                 406031 
                 14940 
                 14959 
                 GTCGGTGACCATGACCCTGC 
                 5-10-5 
                 89.6 
                 230 
               
               
                   
               
               
                 410733 
                 14942 
                 14961 
                 AAGTCGGTGACCATGACCCT 
                 5-10-5 
                 65.7 
                 231 
               
               
                   
               
               
                 406032 
                 14944 
                 14963 
                 CGAAGTCGGTGACCATGACC 
                 5-10-5 
                 88.5 
                 232 
               
               
                   
               
               
                 410754 
                 14954 
                 14973 
                 GGCACATTCTCGAAGTCGGT 
                 5-10-5 
                 80.1 
                 233 
               
               
                   
               
               
                 395163 
                 14979 
                 14998 
                 GTGGAAGCGGGTCCCGTCCT 
                 5-10-5 
                 83.9 
                 25 
               
               
                   
               
               
                 410756 
                 15254 
                 15273 
                 GGTGGGTGCCATGACTGTCA 
                 5-10-5 
                 67.1 
                 235 
               
               
                   
               
               
                 406033 
                 15261 
                 15280 
                 CCTGCCAGGTGGGTGCCATG 
                 5-10-5 
                 91.2 
                 237 
               
               
                   
               
               
                 406034 
                 15266 
                 15285 
                 CCACCCCTGCCAGGTGGGTG 
                 5-10-5 
                 59.3 
                 238 
               
               
                   
               
               
                 406035 
                 15271 
                 15290 
                 GCTGACCACCCCTGCCAGGT 
                 5-10-5 
                 91.7 
                 239 
               
               
                   
               
               
                 410757 
                 15279 
                 15298 
                 TCCCGGCCGCTGACCACCCC 
                 5-10-5 
                 88.9 
                 240 
               
               
                   
               
               
                 406036 
                 15283 
                 15302 
                 GGCATCCCGGCCGCTGACCA 
                 5-10-5 
                 84.0 
                 241 
               
               
                   
               
               
                 406037 
                 15286 
                 15305 
                 GCCGGCATCCCGGCCGCTGA 
                 5-10-5 
                 55.9 
                 242 
               
               
                   
               
               
                 410536 
                 15291 
                 15310 
                 GCCACGCCGGCATCCCGGCC 
                 5-10-5 
                 63.7 
                 243 
               
               
                   
               
               
                 410658 
                 15291 
                 15310 
                 GCCACGCCGGCATCCCGGCC 
                 2-13-5 
                 82.0 
                 243 
               
               
                   
               
               
                 410583 
                 15291 
                 15310 
                 GCCACGCCGGCATCCCGGCC 
                 3-14-3 
                 87.3 
                 243 
               
               
                   
               
               
                 410537 
                 15292 
                 15311 
                 GGCCACGCCGGCATCCCGGC 
                 5-10-5 
                 58.5 
                 244 
               
               
                   
               
               
                 410659 
                 15292 
                 15311 
                 GGCCACGCCGGCATCCCGGC 
                 2-13-5 
                 73.7 
                 244 
               
               
                   
               
               
                 410584 
                 15292 
                 15311 
                 GGCCACGCCGGCATCCCGGC 
                 3-14-3 
                 79.5 
                 244 
               
               
                   
               
               
                 410660 
                 15293 
                 15312 
                 TGGCCACGCCGGCATCCCGG 
                 2-13-5 
                 63.0 
                 245 
               
               
                   
               
               
                 410585 
                 15293 
                 15312 
                 TGGCCACGCCGGCATCCCGG 
                 3-14-3 
                 73.2 
                 245 
               
               
                   
               
               
                 406038 
                 15293 
                 15312 
                 TGGCCACGCCGGCATCCCGG 
                 5-10-5 
                 86.3 
                 245 
               
               
                   
               
               
                 410661 
                 15294 
                 15313 
                 TTGGCCACGCCGGCATCCCG 
                 2-13-5 
                 53.3 
                 246 
               
               
                   
               
               
                 410586 
                 15294 
                 15313 
                 TTGGCCACGCCGGCATCCCG 
                 3-14-3 
                 60.3 
                 246 
               
               
                   
               
               
                 405877 
                 15294 
                 15313 
                 TTGGCCACGCCGGCATCCCG 
                 5-10-5 
                 83.2 
                 246 
               
               
                   
               
               
                 410587 
                 15295 
                 15314 
                 CTTGGCCACGCCGGCATCCC 
                 3-14-3 
                 63.2 
                 247 
               
               
                   
               
               
                 410662 
                 15295 
                 15314 
                 CTTGGCCACGCCGGCATCCC 
                 2-13-5 
                 67.3 
                 247 
               
               
                   
               
               
                 405878 
                 15295 
                 15314 
                 CTTGGCCACGCCGGCATCCC 
                 5-10-5 
                 91.4 
                 247 
               
               
                   
               
               
                 410588 
                 15296 
                 15315 
                 CCTTGGCCACGCCGGCATCC 
                 3-14-3 
                 65.3 
                 248 
               
               
                   
               
               
                 410663 
                 15296 
                 15315 
                 CCTTGGCCACGCCGGCATCC 
                 2-13-5 
                 67.9 
                 248 
               
               
                   
               
               
                 405879 
                 15296 
                 15315 
                 CCTTGGCCACGCCGGCATCC 
                 5-10-5 
                 94.1 
                 248 
               
               
                   
               
               
                 410589 
                 15297 
                 15316 
                 CCCTTGGCCACGCCGGCATC 
                 3-14-3 
                 80.1 
                 249 
               
               
                   
               
               
                 410664 
                 15297 
                 15316 
                 CCCTTGGCCACGCCGGCATC 
                 2-13-5 
                 81.9 
                 249 
               
               
                   
               
               
                 405880 
                 15297 
                 15316 
                 CCCTTGGCCACGCCGGCATC 
                 5-10-5 
                 93.5 
                 249 
               
               
                   
               
               
                 410665 
                 15298 
                 15317 
                 ACCCTTGGCCACGCCGGCAT 
                 2-13-5 
                 78.7 
                 28 
               
               
                   
               
               
                 399887 
                 15298 
                 15317 
                 ACCCTTGGCCACGCCGGCAT 
                 3-14-3 
                 91.9 
                 28 
               
               
                   
               
               
                 395165 
                 15298 
                 15317 
                 ACCCTTGGCCACGCCGGCAT 
                 5-10-5 
                 96.7 
                 28 
               
               
                   
               
               
                 410590 
                 15299 
                 15318 
                 CACCCTTGGCCACGCCGGCA 
                 3-14-3 
                 82.2 
                 250 
               
               
                   
               
               
                 410666 
                 15299 
                 15318 
                 CACCCTTGGCCACGCCGGCA 
                 2-13-5 
                 82.7 
                 250 
               
               
                   
               
               
                 405881 
                 15299 
                 15318 
                 CACCCTTGGCCACGCCGGCA 
                 5-10-5 
                 98.3 
                 250 
               
               
                   
               
               
                 410667 
                 15300 
                 15319 
                 GCACCCTTGGCCACGCCGGC 
                 2-13-5 
                 84.7 
                 251 
               
               
                   
               
               
                 410591 
                 15300 
                 15319 
                 GCACCCTTGGCCACGCCGGC 
                 3-14-3 
                 86.3 
                 251 
               
               
                   
               
               
                 405882 
                 15300 
                 15319 
                 GCACCCTTGGCCACGCCGGC 
                 5-10-5 
                 91.6 
                 251 
               
               
                   
               
               
                 410668 
                 15301 
                 15320 
                 GGCACCCTTGGCCACGCCGG 
                 2-13-5 
                 91.4 
                 252 
               
               
                   
               
               
                 405883 
                 15301 
                 15320 
                 GGCACCCTTGGCCACGCCGG 
                 5-10-5 
                 92.5 
                 252 
               
               
                   
               
               
                 410592 
                 15301 
                 15320 
                 GGCACCCTTGGCCACGCCGG 
                 3-14-3 
                 93.4 
                 252 
               
               
                   
               
               
                 410669 
                 15302 
                 15321 
                 TGGCACCCTTGGCCACGCCG 
                 2-13-5 
                 69.0 
                 253 
               
               
                   
               
               
                 410593 
                 15302 
                 15321 
                 TGGCACCCTTGGCCACGCCG 
                 3-14-3 
                 88.8 
                 253 
               
               
                   
               
               
                 405884 
                 15302 
                 15321 
                 TGGCACCCTTGGCCACGCCG 
                 5-10-5 
                 90.8 
                 253 
               
               
                   
               
               
                 410670 
                 15303 
                 15322 
                 CTGGCACCCTTGGCCACGCC 
                 2-13-5 
                 74.9 
                 254 
               
               
                   
               
               
                 410594 
                 15303 
                 15322 
                 CTGGCACCCTTGGCCACGCC 
                 3-14-3 
                 75.2 
                 254 
               
               
                   
               
               
                 410538 
                 15303 
                 15322 
                 CTGGCACCCTTGGCCACGCC 
                 5-10-5 
                 78.2 
                 254 
               
               
                   
               
               
                 410539 
                 15304 
                 15323 
                 GCTGGCACCCTTGGCCACGC 
                 5-10-5 
                 61.9 
                 255 
               
               
                   
               
               
                 410595 
                 15304 
                 15323 
                 GCTGGCACCCTTGGCCACGC 
                 3-14-3 
                 83.1 
                 255 
               
               
                   
               
               
                 410671 
                 15304 
                 15323 
                 GCTGGCACCCTTGGCCACGC 
                 2-13-5 
                 83.3 
                 255 
               
               
                   
               
               
                 410758 
                 15309 
                 15328 
                 CGCATGCTGGCACCCTTGGC 
                 5-10-5 
                 73.6 
                 256 
               
               
                   
               
               
                 406039 
                 15330 
                 15349 
                 CAGTTGAGCACGCGCAGGCT 
                 5-10-5 
                 91.2 
                 257 
               
               
                   
               
               
                 406040 
                 15332 
                 15351 
                 GGCAGTTGAGCACGCGCAGG 
                 5-10-5 
                 96.5 
                 258 
               
               
                   
               
               
                 399888 
                 15334 
                 15353 
                 TTGGCAGTTGAGCACGCGCA 
                 3-14-3 
                 90.9 
                 29 
               
               
                   
               
               
                 395166 
                 15334 
                 15353 
                 TTGGCAGTTGAGCACGCGCA 
                 5-10-5 
                 96.2 
                 29 
               
               
                   
               
               
                 406041 
                 15336 
                 15355 
                 CCTTGGCAGTTGAGCACGCG 
                 5-10-5 
                 96.6 
                 259 
               
               
                   
               
               
                 399801 
                 15339 
                 15358 
                 TTCCCTTGGCAGTTGAGCAC 
                 5-10-5 
                 95.6 
                 30 
               
               
                   
               
               
                 406042 
                 15341 
                 15360 
                 CCTTCCCTTGGCAGTTGAGC 
                 5-10-5 
                 92.0 
                 260 
               
               
                   
               
               
                 406043 
                 15345 
                 15364 
                 GTGCCCTTCCCTTGGCAGTT 
                 5-10-5 
                 91.9 
                 261 
               
               
                   
               
               
                 406044 
                 15347 
                 15366 
                 CCGTGCCCTTCCCTTGGCAG 
                 5-10-5 
                 95.4 
                 262 
               
               
                   
               
               
                 410759 
                 15358 
                 15377 
                 GGTGCCGCTAACCGTGCCCT 
                 5-10-5 
                 83.7 
                 263 
               
               
                   
               
               
                 406045 
                 18591 
                 18610 
                 TGGCTTTTCCGAATAAACTC 
                 5-10-5 
                 88.4 
                 266 
               
               
                   
               
               
                 395168 
                 18593 
                 18612 
                 GCTGGCTTTTCCGAATAAAC 
                 5-10-5 
                 91.9 
                 32 
               
               
                   
               
               
                 405909 
                 18595 
                 18614 
                 CAGCTGGCTTTTCCGAATAA 
                 5-10-5 
                 80.3 
                 267 
               
               
                   
               
               
                 405910 
                 18597 
                 18616 
                 ACCAGCTGGCTTTTCCGAAT 
                 5-10-5 
                 90.9 
                 268 
               
               
                   
               
               
                 405911 
                 18599 
                 18618 
                 GGACCAGCTGGCTTTTCCGA 
                 5-10-5 
                 88.0 
                 269 
               
               
                   
               
               
                 405912 
                 18603 
                 18622 
                 GGCTGGACCAGCTGGCTTTT 
                 5-10-5 
                 78.2 
                 270 
               
               
                   
               
               
                 410761 
                 18614 
                 18633 
                 GTGGCCCCACAGGCTGGACC 
                 5-10-5 
                 53.7 
                 271 
               
               
                   
               
               
                 410762 
                 18627 
                 18646 
                 AGCAGCACCACCAGTGGCCC 
                 5-10-5 
                 57.6 
                 272 
               
               
                   
               
               
                 410763 
                 18649 
                 18668 
                 GCTGTACCCACCCGCCAGGG 
                 5-10-5 
                 68.8 
                 273 
               
               
                   
               
               
                 410764 
                 18695 
                 18714 
                 CGACCCCAGCCCTCGCCAGG 
                 5-10-5 
                 66.3 
                 274 
               
               
                   
               
               
                 399891 
                 18705 
                 18724 
                 GTGACCAGCACGACCCCAGC 
                 3-14-3 
                 91.1 
                 33 
               
               
                   
               
               
                 405913 
                 18707 
                 18726 
                 CGGTGACCAGCACGACCCCA 
                 5-10-5 
                 93.8 
                 275 
               
               
                   
               
               
                 405914 
                 18709 
                 18728 
                 AGCGGTGACCAGCACGACCC 
                 5-10-5 
                 90.4 
                 276 
               
               
                   
               
               
                 405915 
                 18711 
                 18730 
                 GCAGCGGTGACCAGCACGAC 
                 5-10-5 
                 86.8 
                 277 
               
               
                   
               
               
                 405916 
                 18713 
                 18732 
                 CGGCAGCGGTGACCAGCACG 
                 5-10-5 
                 91.3 
                 278 
               
               
                   
               
               
                 410734 
                 18714 
                 18733 
                 CCGGCAGCGGTGACCAGCAC 
                 5-10-5 
                 65.8 
                 279 
               
               
                   
               
               
                 405917 
                 18717 
                 18736 
                 TTGCCGGCAGCGGTGACCAG 
                 5-10-5 
                 62.0 
                 280 
               
               
                   
               
               
                 405918 
                 18719 
                 18738 
                 AGTTGCCGGCAGCGGTGACC 
                 5-10-5 
                 33.5 
                 281 
               
               
                   
               
               
                 405919 
                 18721 
                 18740 
                 GAAGTTGCCGGCAGCGGTGA 
                 5-10-5 
                 68.2 
                 282 
               
               
                   
               
               
                 405920 
                 18723 
                 18742 
                 CGGAAGTTGCCGGCAGCGGT 
                 5-10-5 
                 86.2 
                 283 
               
               
                   
               
               
                 405921 
                 18725 
                 18744 
                 CCCGGAAGTTGCCGGCAGCG 
                 5-10-5 
                 85.5 
                 284 
               
               
                   
               
               
                 405922 
                 18727 
                 18746 
                 GTCCCGGAAGTTGCCGGCAG 
                 5-10-5 
                 86.0 
                 285 
               
               
                   
               
               
                 405923 
                 19931 
                 19950 
                 GGCATTGGTGGCCCCAACTG 
                 5-10-5 
                 94.3 
                 288 
               
               
                   
               
               
                 410767 
                 19941 
                 19960 
                 GCTGGTCTTGGGCATTGGTG 
                 5-10-5 
                 65.1 
                 289 
               
               
                   
               
               
                 405924 
                 19954 
                 19973 
                 CCCAGGGTCACCGGCTGGTC 
                 5-10-5 
                 93.1 
                 290 
               
               
                   
               
               
                 410735 
                 19956 
                 19975 
                 TCCCCAGGGTCACCGGCTGG 
                 5-10-5 
                 78.1 
                 291 
               
               
                   
               
               
                 405925 
                 19958 
                 19977 
                 AGTCCCCAGGGTCACCGGCT 
                 5-10-5 
                 93.5 
                 292 
               
               
                   
               
               
                 405926 
                 19960 
                 19979 
                 AAAGTCCCCAGGGTCACCGG 
                 5-10-5 
                 94.6 
                 293 
               
               
                   
               
               
                 405927 
                 19964 
                 19983 
                 CCCCAAAGTCCCCAGGGTCA 
                 5-10-5 
                 94.5 
                 294 
               
               
                   
               
               
                 405928 
                 19969 
                 19988 
                 TTGGTCCCCAAAGTCCCCAG 
                 5-10-5 
                 90.0 
                 295 
               
               
                   
               
               
                 405929 
                 19973 
                 19992 
                 AAAGTTGGTCCCCAAAGTCC 
                 5-10-5 
                 85.5 
                 296 
               
               
                   
               
               
                 399895 
                 19976 
                 19995 
                 GCCAAAGTTGGTCCCCAAAG 
                 3-14-3 
                 84.6 
                 36 
               
               
                   
               
               
                 395173 
                 19976 
                 19995 
                 GCCAAAGTTGGTCCCCAAAG 
                 5-10-5 
                 94.8 
                 36 
               
               
                   
               
               
                 405930 
                 19978 
                 19997 
                 CGGCCAAAGTTGGTCCCCAA 
                 5-10-5 
                 92.9 
                 297 
               
               
                   
               
               
                 405931 
                 19980 
                 19999 
                 AGCGGCCAAAGTTGGTCCCC 
                 5-10-5 
                 88.8 
                 298 
               
               
                   
               
               
                 405932 
                 19982 
                 20001 
                 ACAGCGGCCAAAGTTGGTCC 
                 5-10-5 
                 90.6 
                 299 
               
               
                   
               
               
                 405933 
                 19984 
                 20003 
                 ACACAGCGGCCAAAGTTGGT 
                 5-10-5 
                 NA 
                 300 
               
               
                   
               
               
                 405934 
                 19986 
                 20005 
                 CCACACAGCGGCCAAAGTTG 
                 5-10-5 
                 92.7 
                 301 
               
               
                   
               
               
                 405935 
                 19990 
                 20009 
                 AGGTCCACACAGCGGCCAAA 
                 5-10-5 
                 86.0 
                 302 
               
               
                   
               
               
                 410736 
                 19992 
                 20011 
                 AGAGGTCCACACAGCGGCCA 
                 5-10-5 
                 73.8 
                 303 
               
               
                   
               
               
                 405936 
                 19994 
                 20013 
                 AAAGAGGTCCACACAGCGGC 
                 5-10-5 
                 93.9 
                 304 
               
               
                   
               
               
                 410768 
                 20016 
                 20035 
                 CAATGATGTCCTCCCCTGGG 
                 5-10-5 
                 79.7 
                 305 
               
               
                   
               
               
                 405937 
                 20023 
                 20042 
                 GAGGCACCAATGATGTCCTC 
                 5-10-5 
                 77.7 
                 306 
               
               
                   
               
               
                 405938 
                 20027 
                 20046 
                 GCTGGAGGCACCAATGATGT 
                 5-10-5 
                 75.5 
                 307 
               
               
                   
               
               
                 405939 
                 20029 
                 20048 
                 TCGCTGGAGGCACCAATGAT 
                 5-10-5 
                 70.6 
                 308 
               
               
                   
               
               
                 405940 
                 20031 
                 20050 
                 AGTCGCTGGAGGCACCAATG 
                 5-10-5 
                 84.4 
                 309 
               
               
                   
               
               
                 405941 
                 20033 
                 20052 
                 GCAGTCGCTGGAGGCACCAA 
                 5-10-5 
                 90.1 
                 310 
               
               
                   
               
               
                 399804 
                 20036 
                 20055 
                 GCTGCAGTCGCTGGAGGCAC 
                 5-10-5 
                 80.8 
                 40 
               
               
                   
               
               
                 399960 
                 20036 
                 20055 
                 GCTGCAGTCGCTGGAGGCAC 
                 3-14-3 
                 82.4 
                 40 
               
               
                   
               
               
                 405942 
                 20038 
                 20057 
                 GTGCTGCAGTCGCTGGAGGC 
                 5-10-5 
                 69.8 
                 311 
               
               
                   
               
               
                 405943 
                 20040 
                 20059 
                 AGGTGCTGCAGTCGCTGGAG 
                 5-10-5 
                 83.6 
                 312 
               
               
                   
               
               
                 410737 
                 20042 
                 20061 
                 GCAGGTGCTGCAGTCGCTGG 
                 5-10-5 
                 49.8 
                 313 
               
               
                   
               
               
                 405944 
                 20043 
                 20062 
                 AGCAGGTGCTGCAGTCGCTG 
                 5-10-5 
                 80.7 
                 314 
               
               
                   
               
               
                 405945 
                 20045 
                 20064 
                 AAAGCAGGTGCTGCAGTCGC 
                 5-10-5 
                 41.1 
                 315 
               
               
                   
               
               
                 405946 
                 20049 
                 20068 
                 ACACAAAGCAGGTGCTGCAG 
                 5-10-5 
                 70.4 
                 316 
               
               
                   
               
               
                 405947 
                 20051 
                 20070 
                 TGACACAAAGCAGGTGCTGC 
                 5-10-5 
                 72.5 
                 317 
               
               
                   
               
               
                 410769 
                 20061 
                 20080 
                 TCCCACTCTGTGACACAAAG 
                 5-10-5 
                 84.9 
                 318 
               
               
                   
               
               
                 405949 
                 20629 
                 20648 
                 CAGCATCATGGCTGCAATGC 
                 5-10-5 
                 84.9 
                 320 
               
               
                   
               
               
                 405950 
                 20631 
                 20650 
                 GACAGCATCATGGCTGCAAT 
                 5-10-5 
                 76.9 
                 321 
               
               
                   
               
               
                 405951 
                 20633 
                 20652 
                 CAGACAGCATCATGGCTGCA 
                 5-10-5 
                 75.4 
                 322 
               
               
                   
               
               
                 405952 
                 20637 
                 20656 
                 TCGGCAGACAGCATCATGGC 
                 5-10-5 
                 85.1 
                 323 
               
               
                   
               
               
                 410738 
                 20639 
                 20658 
                 GCTCGGCAGACAGCATCATG 
                 5-10-5 
                 68.4 
                 324 
               
               
                   
               
               
                 405953 
                 20641 
                 20660 
                 CGGCTCGGCAGACAGCATCA 
                 5-10-5 
                 93.6 
                 325 
               
               
                   
               
               
                 405954 
                 20643 
                 20662 
                 TCCGGCTCGGCAGACAGCAT 
                 5-10-5 
                 87.5 
                 326 
               
               
                   
               
               
                 410770 
                 20657 
                 20676 
                 CGGCCAGGGTGAGCTCCGGC 
                 5-10-5 
                 68.5 
                 327 
               
               
                   
               
               
                 405955 
                 20670 
                 20689 
                 CTCTGCCTCAACTCGGCCAG 
                 5-10-5 
                 94.2 
                 328 
               
               
                   
               
               
                 405956 
                 20672 
                 20691 
                 GTCTCTGCCTCAACTCGGCC 
                 5-10-5 
                 94.3 
                 329 
               
               
                   
               
               
                 405958 
                 20676 
                 20695 
                 ATCAGTCTCTGCCTCAACTC 
                 5-10-5 
                 80.3 
                 331 
               
               
                   
               
               
                 405959 
                 20678 
                 20697 
                 GGATCAGTCTCTGCCTCAAC 
                 5-10-5 
                 95.4 
                 332 
               
               
                   
               
               
                 405960 
                 20680 
                 20699 
                 GTGGATCAGTCTCTGCCTCA 
                 5-10-5 
                 90.1 
                 333 
               
               
                   
               
               
                 405961 
                 20682 
                 20701 
                 AAGTGGATCAGTCTCTGCCT 
                 5-10-5 
                 88.8 
                 334 
               
               
                   
               
               
                 405962 
                 20685 
                 20704 
                 GAGAAGTGGATCAGTCTCTG 
                 5-10-5 
                 56.1 
                 335 
               
               
                   
               
               
                 410739 
                 20687 
                 20706 
                 CAGAGAAGTGGATCAGTCTC 
                 5-10-5 
                 NA 
                 336 
               
               
                   
               
               
                 405963 
                 20689 
                 20708 
                 GGCAGAGAAGTGGATCAGTC 
                 5-10-5 
                 59.7 
                 337 
               
               
                   
               
               
                 405964 
                 20693 
                 20712 
                 CTTTGGCAGAGAAGTGGATC 
                 5-10-5 
                 45.3 
                 338 
               
               
                   
               
               
                 405965 
                 20698 
                 20717 
                 GACATCTTTGGCAGAGAAGT 
                 5-10-5 
                 55.9 
                 339 
               
               
                   
               
               
                 405966 
                 20700 
                 20719 
                 ATGACATCTTTGGCAGAGAA 
                 5-10-5 
                 51.3 
                 340 
               
               
                   
               
               
                 405967 
                 20704 
                 20723 
                 ATTGATGACATCTTTGGCAG 
                 5-10-5 
                 64.4 
                 341 
               
               
                   
               
               
                 405968 
                 20706 
                 20725 
                 TCATTGATGACATCTTTGGC 
                 5-10-5 
                 74.6 
                 342 
               
               
                   
               
               
                 399967 
                 20709 
                 20728 
                 GCCTCATTGATGACATCTTT 
                 3-14-3 
                 80.1 
                 48 
               
               
                   
               
               
                 405969 
                 20711 
                 20730 
                 AGGCCTCATTGATGACATCT 
                 5-10-5 
                 63.0 
                 343 
               
               
                   
               
               
                 405970 
                 20713 
                 20732 
                 CCAGGCCTCATTGATGACAT 
                 5-10-5 
                 66.8 
                 344 
               
               
                   
               
               
                 410740 
                 20715 
                 20734 
                 AACCAGGCCTCATTGATGAC 
                 5-10-5 
                 46.8 
                 345 
               
               
                   
               
               
                 405885 
                 20717 
                 20736 
                 GGAACCAGGCCTCATTGATG 
                 5-10-5 
                 73.4 
                 346 
               
               
                   
               
               
                 410596 
                 20719 
                 20738 
                 AGGGAACCAGGCCTCATTGA 
                 3-14-3 
                 NA 
                 348 
               
               
                   
               
               
                 410672 
                 20719 
                 20738 
                 AGGGAACCAGGCCTCATTGA 
                 2-13-5 
                 NA 
                 348 
               
               
                   
               
               
                 405887 
                 20719 
                 20738 
                 AGGGAACCAGGCCTCATTGA 
                 5-10-5 
                 NA 
                 348 
               
               
                   
               
               
                 410597 
                 20720 
                 20739 
                 CAGGGAACCAGGCCTCATTG 
                 3-14-3 
                 NA 
                 349 
               
               
                   
               
               
                 405888 
                 20720 
                 20739 
                 CAGGGAACCAGGCCTCATTG 
                 5-10-5 
                 NA 
                 349 
               
               
                   
               
               
                 410673 
                 20720 
                 20739 
                 CAGGGAACCAGGCCTCATTG 
                 2-13-5 
                 NA 
                 349 
               
               
                   
               
               
                 410674 
                 20721 
                 20740 
                 TCAGGGAACCAGGCCTCATT 
                 2-13-5 
                 60.7 
                 49 
               
               
                   
               
               
                 399812 
                 20721 
                 20740 
                 TCAGGGAACCAGGCCTCATT 
                 5-10-5 
                 68.7 
                 49 
               
               
                   
               
               
                 399968 
                 20721 
                 20740 
                 TCAGGGAACCAGGCCTCATT 
                 3-14-3 
                 84.5 
                 49 
               
               
                   
               
               
                 410598 
                 20722 
                 20741 
                 CTCAGGGAACCAGGCCTCAT 
                 3-14-3 
                 74.5 
                 350 
               
               
                   
               
               
                 410675 
                 20722 
                 20741 
                 CTCAGGGAACCAGGCCTCAT 
                 2-13-5 
                 76.9 
                 350 
               
               
                   
               
               
                 405889 
                 20722 
                 20741 
                 CTCAGGGAACCAGGCCTCAT 
                 5-10-5 
                 80.2 
                 350 
               
               
                   
               
               
                 410599 
                 20723 
                 20742 
                 CCTCAGGGAACCAGGCCTCA 
                 3-14-3 
                 70.6 
                 351 
               
               
                   
               
               
                 410676 
                 20723 
                 20742 
                 CCTCAGGGAACCAGGCCTCA 
                 2-13-5 
                 77.8 
                 351 
               
               
                   
               
               
                 405890 
                 20723 
                 20742 
                 CCTCAGGGAACCAGGCCTCA 
                 5-10-5 
                 87.7 
                 351 
               
               
                   
               
               
                 410600 
                 20724 
                 20743 
                 TCCTCAGGGAACCAGGCCTC 
                 3-14-3 
                 76.5 
                 352 
               
               
                   
               
               
                 410677 
                 20724 
                 20743 
                 TCCTCAGGGAACCAGGCCTC 
                 2-13-5 
                 88.4 
                 352 
               
               
                   
               
               
                 405891 
                 20724 
                 20743 
                 TCCTCAGGGAACCAGGCCTC 
                 5-10-5 
                 96.1 
                 352 
               
               
                   
               
               
                 405892 
                 20725 
                 20744 
                 GTCCTCAGGGAACCAGGCCT 
                 5-10-5 
                 71.4 
                 353 
               
               
                   
               
               
                 410601 
                 20725 
                 20744 
                 GTCCTCAGGGAACCAGGCCT 
                 3-14-3 
                 72.7 
                 353 
               
               
                   
               
               
                 410678 
                 20725 
                 20744 
                 GTCCTCAGGGAACCAGGCCT 
                 2-13-5 
                 75.0 
                 353 
               
               
                   
               
               
                 395178 
                 20726 
                 20745 
                 GGTCCTCAGGGAACCAGGCC 
                 5-10-5 
                 76.7 
                 50 
               
               
                   
               
               
                 410679 
                 20726 
                 20745 
                 GGTCCTCAGGGAACCAGGCC 
                 2-13-5 
                 77.6 
                 50 
               
               
                   
               
               
                 399900 
                 20726 
                 20745 
                 GGTCCTCAGGGAACCAGGCC 
                 3-14-3 
                 92.0 
                 50 
               
               
                   
               
               
                 408653 
                 20727 
                 20746 
                 TGGTCCTCAGGGAACCAGGC 
                 5-10-5 
                 42.5 
                 354 
               
               
                   
               
               
                 410602 
                 20727 
                 20746 
                 TGGTCCTCAGGGAACCAGGC 
                 3-14-3 
                 66.5 
                 354 
               
               
                   
               
               
                 410680 
                 20727 
                 20746 
                 TGGTCCTCAGGGAACCAGGC 
                 2-13-5 
                 71.6 
                 354 
               
               
                   
               
               
                 410603 
                 20728 
                 20747 
                 CTGGTCCTCAGGGAACCAGG 
                 3-14-3 
                 40.8 
                 355 
               
               
                   
               
               
                 410681 
                 20728 
                 20747 
                 CTGGTCCTCAGGGAACCAGG 
                 2-13-5 
                 44.4 
                 355 
               
               
                   
               
               
                 405971 
                 20728 
                 20747 
                 CTGGTCCTCAGGGAACCAGG 
                 5-10-5 
                 65.5 
                 355 
               
               
                   
               
               
                 410540 
                 20729 
                 20748 
                 GCTGGTCCTCAGGGAACCAG 
                 5-10-5 
                 50.9 
                 356 
               
               
                   
               
               
                 410682 
                 20729 
                 20748 
                 GCTGGTCCTCAGGGAACCAG 
                 2-13-5 
                 54.1 
                 356 
               
               
                   
               
               
                 410604 
                 20729 
                 20748 
                 GCTGGTCCTCAGGGAACCAG 
                 3-14-3 
                 62.5 
                 356 
               
               
                   
               
               
                 405972 
                 20730 
                 20749 
                 CGCTGGTCCTCAGGGAACCA 
                 5-10-5 
                 77.6 
                 357 
               
               
                   
               
               
                 405973 
                 20735 
                 20754 
                 GTACCCGCTGGTCCTCAGGG 
                 5-10-5 
                 83.8 
                 358 
               
               
                   
               
               
                 405974 
                 20737 
                 20756 
                 CAGTACCCGCTGGTCCTCAG 
                 5-10-5 
                 89.0 
                 359 
               
               
                   
               
               
                 399813 
                 20740 
                 20759 
                 GGTCAGTACCCGCTGGTCCT 
                 5-10-5 
                 72.4 
                 51 
               
               
                   
               
               
                 399969 
                 20740 
                 20759 
                 GGTCAGTACCCGCTGGTCCT 
                 3-14-3 
                 93.4 
                 51 
               
               
                   
               
               
                 410771 
                 20785 
                 20804 
                 ACCTGCCCCATGGGTGCTGG 
                 5-10-5 
                 NA 
                 360 
               
               
                   
               
               
                 405975 
                 21088 
                 21107 
                 CAAAACAGCTGCCAACCTGC 
                 5-10-5 
                 77.4 
                 361 
               
               
                   
               
               
                 405976 
                 21093 
                 21112 
                 TCCTGCAAAACAGCTGCCAA 
                 5-10-5 
                 81.2 
                 362 
               
               
                   
               
               
                 405977 
                 21095 
                 21114 
                 AGTCCTGCAAAACAGCTGCC 
                 5-10-5 
                 89.5 
                 363 
               
               
                   
               
               
                 410772 
                 21106 
                 21125 
                 GCTGACCATACAGTCCTGCA 
                 5-10-5 
                 91.2 
                 264 
               
               
                   
               
               
                 405978 
                 21118 
                 21137 
                 GGCCCCGAGTGTGCTGACCA 
                 5-10-5 
                 95.3 
                 365 
               
               
                   
               
               
                 399904 
                 21121 
                 21140 
                 GTAGGCCCCGAGTGTGCTGA 
                 3-14-3 
                 92.6 
                 54 
               
               
                   
               
               
                 405979 
                 21123 
                 21142 
                 GTGTAGGCCCCGAGTGTGCT 
                 5-10-5 
                 85.5 
                 366 
               
               
                   
               
               
                 405980 
                 21125 
                 21144 
                 CCGTGTAGGCCCCGAGTGTG 
                 5-10-5 
                 86.5 
                 367 
               
               
                   
               
               
                 405981 
                 21127 
                 21146 
                 ATCCGTGTAGGCCCCGAGTG 
                 5-10-5 
                 77.8 
                 368 
               
               
                   
               
               
                 410741 
                 21129 
                 21148 
                 CCATCCGTGTAGGCCCCGAG 
                 5-10-5 
                 78.4 
                 369 
               
               
                   
               
               
                 405982 
                 21131 
                 21150 
                 GGCCATCCGTGTAGGCCCCG 
                 5-10-5 
                 86.7 
                 370 
               
               
                   
               
               
                 405983 
                 21133 
                 21152 
                 GTGGCCATCCGTGTAGGCCC 
                 5-10-5 
                 73.1 
                 371 
               
               
                   
               
               
                 405984 
                 21181 
                 21200 
                 CTGGAGCAGCTCAGCAGCTC 
                 5-10-5 
                 83.4 
                 372 
               
               
                   
               
               
                 405985 
                 21183 
                 21202 
                 AACTGGAGCAGCTCAGCAGC 
                 5-10-5 
                 50.7 
                 373 
               
               
                   
               
               
                 405986 
                 21188 
                 21207 
                 GGAGAAACTGGAGCAGCTCA 
                 5-10-5 
                 75.6 
                 374 
               
               
                   
               
               
                 405987 
                 21190 
                 21209 
                 CTGGAGAAACTGGAGCAGCT 
                 5-10-5 
                 88.0 
                 375 
               
               
                   
               
               
                 399868 
                 21696 
                 21715 
                 GGCACTGCCCTTCCACCAAA 
                 5-10-5 
                 85.8 
                 123 
               
               
                   
               
               
                 399905 
                 22096 
                 22115 
                 CGTTGTGGGCCCGGCAGACC 
                 3-14-3 
                 91.2 
                 57 
               
               
                   
               
               
                 395183 
                 22096 
                 22115 
                 CGTTGTGGGCCCGGCAGACC 
                 5-10-5 
                 93.1 
                 57 
               
               
                   
               
               
                 410541 
                 22133 
                 22152 
                 CACCTGGCAATGGCGTAGAC 
                 5-10-5 
                 46.1 
                 376 
               
               
                   
               
               
                 410605 
                 22133 
                 22152 
                 CACCTGGCAATGGCGTAGAC 
                 3-14-3 
                 67.4 
                 376 
               
               
                   
               
               
                 410683 
                 22133 
                 22152 
                 CACCTGGCAATGGCGTAGAC 
                 2-13-5 
                 71.8 
                 376 
               
               
                   
               
               
                 410606 
                 22134 
                 22153 
                 GCACCTGGCAATGGCGTAGA 
                 3-14-3 
                 74.3 
                 377 
               
               
                   
               
               
                 410542 
                 22134 
                 22153 
                 GCACCTGGCAATGGCGTAGA 
                 5-10-5 
                 75.5 
                 377 
               
               
                   
               
               
                 410684 
                 22134 
                 22153 
                 GCACCTGGCAATGGCGTAGA 
                 2-13-5 
                 78.7 
                 377 
               
               
                   
               
               
                 410543 
                 22135 
                 22154 
                 AGCACCTGGCAATGGCGTAG 
                 5-10-5 
                 76.4 
                 378 
               
               
                   
               
               
                 410685 
                 22135 
                 22154 
                 AGCACCTGGCAATGGCGTAG 
                 2-13-5 
                 76.9 
                 378 
               
               
                   
               
               
                 410607 
                 22135 
                 22154 
                 AGCACCTGGCAATGGCGTAG 
                 3-14-3 
                 77.1 
                 378 
               
               
                   
               
               
                 410544 
                 22136 
                 22155 
                 CAGCACCTGGCAATGGCGTA 
                 5-10-5 
                 62.7 
                 379 
               
               
                   
               
               
                 410608 
                 22136 
                 22155 
                 CAGCACCTGGCAATGGCGTA 
                 3-14-3 
                 69.6 
                 379 
               
               
                   
               
               
                 410686 
                 22136 
                 22155 
                 CAGCACCTGGCAATGGCGTA 
                 2-13-5 
                 81.0 
                 379 
               
               
                   
               
               
                 410545 
                 22137 
                 22156 
                 GCAGCACCTGGCAATGGCGT 
                 5-10-5 
                 75.5 
                 380 
               
               
                   
               
               
                 410687 
                 22137 
                 22156 
                 GCAGCACCTGGCAATGGCGT 
                 2-13-5 
                 79.2 
                 380 
               
               
                   
               
               
                 410609 
                 22137 
                 22156 
                 GCAGCACCTGGCAATGGCGT 
                 3-14-3 
                 83.2 
                 380 
               
               
                   
               
               
                 410610 
                 22138 
                 22157 
                 GGCAGCACCTGGCAATGGCG 
                 3-14-3 
                 67.5 
                 381 
               
               
                   
               
               
                 410688 
                 22138 
                 22157 
                 GGCAGCACCTGGCAATGGCG 
                 2-13-5 
                 89.3 
                 381 
               
               
                   
               
               
                 405988 
                 22138 
                 22157 
                 GGCAGCACCTGGCAATGGCG 
                 5-10-5 
                 95.9 
                 381 
               
               
                   
               
               
                 410546 
                 22139 
                 22158 
                 AGGCAGCACCTGGCAATGGC 
                 5-10-5 
                 74.8 
                 382 
               
               
                   
               
               
                 410689 
                 22139 
                 22158 
                 AGGCAGCACCTGGCAATGGC 
                 2-13-5 
                 83.9 
                 382 
               
               
                   
               
               
                 410611 
                 22139 
                 22158 
                 AGGCAGCACCTGGCAATGGC 
                 3-14-3 
                 88.2 
                 382 
               
               
                   
               
               
                 410612 
                 22140 
                 22159 
                 CAGGCAGCACCTGGCAATGG 
                 3-14-3 
                 72.8 
                 383 
               
               
                   
               
               
                 410690 
                 22140 
                 22159 
                 CAGGCAGCACCTGGCAATGG 
                 2-13-5 
                 74.8 
                 383 
               
               
                   
               
               
                 405989 
                 22140 
                 22159 
                 CAGGCAGCACCTGGCAATGG 
                 5-10-5 
                 88.1 
                 383 
               
               
                   
               
               
                 410547 
                 22141 
                 22160 
                 GCAGGCAGCACCTGGCAATG 
                 5-10-5 
                 63.0 
                 384 
               
               
                   
               
               
                 410691 
                 22141 
                 22160 
                 GCAGGCAGCACCTGGCAATG 
                 2-13-5 
                 70.2 
                 384 
               
               
                   
               
               
                 410613 
                 22141 
                 22160 
                 GCAGGCAGCACCTGGCAATG 
                 3-14-3 
                 76.7 
                 384 
               
               
                   
               
               
                 395184 
                 22142 
                 22161 
                 AGCAGGCAGCACCTGGCAAT 
                 5-10-5 
                 68.5 
                 58 
               
               
                   
               
               
                 410692 
                 22142 
                 22161 
                 AGCAGGCAGCACCTGGCAAT 
                 2-13-5 
                 69.1 
                 58 
               
               
                   
               
               
                 399906 
                 22142 
                 22161 
                 AGCAGGCAGCACCTGGCAAT 
                 3-14-3 
                 94.2 
                 58 
               
               
                   
               
               
                 410614 
                 22143 
                 22162 
                 TAGCAGGCAGCACCTGGCAA 
                 3-14-3 
                 36.6 
                 385 
               
               
                   
               
               
                 410548 
                 22143 
                 22162 
                 TAGCAGGCAGCACCTGGCAA 
                 5-10-5 
                 75.0 
                 385 
               
               
                   
               
               
                 410693 
                 22143 
                 22162 
                 TAGCAGGCAGCACCTGGCAA 
                 2-13-5 
                 82.0 
                 385 
               
               
                   
               
               
                 405990 
                 22144 
                 22163 
                 GTAGCAGGCAGCACCTGGCA 
                 5-10-5 
                 96.8 
                 386 
               
               
                   
               
               
                 410773 
                 22189 
                 22208 
                 TGGCCTCAGCTGGTGGAGCT 
                 5-10-5 
                 61.3 
                 387 
               
               
                   
               
               
                 410549 
                 22199 
                 22218 
                 GTCCCCATGCTGGCCTCAGC 
                 5-10-5 
                 63.0 
                 388 
               
               
                   
               
               
                 410615 
                 22199 
                 22218 
                 GTCCCCATGCTGGCCTCAGC 
                 3-14-3 
                 72.5 
                 388 
               
               
                   
               
               
                 410694 
                 22199 
                 22218 
                 GTCCCCATGCTGGCCTCAGC 
                 2-13-5 
                 74.8 
                 388 
               
               
                   
               
               
                 410550 
                 22200 
                 22219 
                 GGTCCCCATGCTGGCCTCAG 
                 5-10-5 
                 69.4 
                 389 
               
               
                   
               
               
                 410616 
                 22200 
                 22219 
                 GGTCCCCATGCTGGCCTCAG 
                 3-14-3 
                 80.7 
                 389 
               
               
                   
               
               
                 410695 
                 22200 
                 22219 
                 GGTCCCCATGCTGGCCTCAG 
                 2-13-5 
                 85.5 
                 389 
               
               
                   
               
               
                 410551 
                 22201 
                 22220 
                 GGGTCCCCATGCTGGCCTCA 
                 5-10-5 
                 68.7 
                 390 
               
               
                   
               
               
                 410696 
                 22201 
                 22220 
                 GGGTCCCCATGCTGGCCTCA 
                 2-13-5 
                 86.3 
                 390 
               
               
                   
               
               
                 410617 
                 22201 
                 22220 
                 GGGTCCCCATGCTGGCCTCA 
                 3-14-3 
                 86.5 
                 390 
               
               
                   
               
               
                 410552 
                 22202 
                 22221 
                 CGGGTCCCCATGCTGGCCTC 
                 5-10-5 
                 77.9 
                 391 
               
               
                   
               
               
                 410618 
                 22202 
                 22221 
                 CGGGTCCCCATGCTGGCCTC 
                 3-14-3 
                 86.7 
                 391 
               
               
                   
               
               
                 410697 
                 22202 
                 22221 
                 CGGGTCCCCATGCTGGCCTC 
                 2-13-5 
                 87.0 
                 391 
               
               
                   
               
               
                 410553 
                 22203 
                 22222 
                 ACGGGTCCCCATGCTGGCCT 
                 5-10-5 
                 72.8 
                 392 
               
               
                   
               
               
                 410619 
                 22203 
                 22222 
                 ACGGGTCCCCATGCTGGCCT 
                 3-14-3 
                 84.1 
                 392 
               
               
                   
               
               
                 410698 
                 22203 
                 22222 
                 ACGGGTCCCCATGCTGGCCT 
                 2-13-5 
                 87.0 
                 392 
               
               
                   
               
               
                 410699 
                 22204 
                 22223 
                 CACGGGTCCCCATGCTGGCC 
                 2-13-5 
                 79.5 
                 59 
               
               
                   
               
               
                 395185 
                 22204 
                 22223 
                 CACGGGTCCCCATGCTGGCC 
                 5-10-5 
                 92.7 
                 59 
               
               
                   
               
               
                 399907 
                 22204 
                 22223 
                 CACGGGTCCCCATGCTGGCC 
                 3-14-3 
                 93.7 
                 59 
               
               
                   
               
               
                 410620 
                 22205 
                 22224 
                 ACACGGGTCCCCATGCTGGC 
                 3-14-3 
                 74.4 
                 393 
               
               
                   
               
               
                 410554 
                 22205 
                 22224 
                 ACACGGGTCCCCATGCTGGC 
                 5-10-5 
                 79.7 
                 393 
               
               
                   
               
               
                 410700 
                 22205 
                 22224 
                 ACACGGGTCCCCATGCTGGC 
                 2-13-5 
                 84.4 
                 393 
               
               
                   
               
               
                 410621 
                 22206 
                 22225 
                 GACACGGGTCCCCATGCTGG 
                 3-14-3 
                 76.0 
                 394 
               
               
                   
               
               
                 410701 
                 22206 
                 22225 
                 GACACGGGTCCCCATGCTGG 
                 2-13-5 
                 83.4 
                 394 
               
               
                   
               
               
                 405991 
                 22206 
                 22225 
                 GACACGGGTCCCCATGCTGG 
                 5-10-5 
                 91.9 
                 394 
               
               
                   
               
               
                 410555 
                 22207 
                 22226 
                 GGACACGGGTCCCCATGCTG 
                 5-10-5 
                 77.0 
                 395 
               
               
                   
               
               
                 410622 
                 22207 
                 22226 
                 GGACACGGGTCCCCATGCTG 
                 3-14-3 
                 79.8 
                 395 
               
               
                   
               
               
                 410702 
                 22207 
                 22226 
                 GGACACGGGTCCCCATGCTG 
                 2-13-5 
                 85.0 
                 395 
               
               
                   
               
               
                 410703 
                 22208 
                 22227 
                 TGGACACGGGTCCCCATGCT 
                 2-13-5 
                 70.4 
                 396 
               
               
                   
               
               
                 410623 
                 22208 
                 22227 
                 TGGACACGGGTCCCCATGCT 
                 3-14-3 
                 78.9 
                 396 
               
               
                   
               
               
                 405992 
                 22208 
                 22227 
                 TGGACACGGGTCCCCATGCT 
                 5-10-5 
                 89.3 
                 396 
               
               
                   
               
               
                 410704 
                 22209 
                 22228 
                 GTGGACACGGGTCCCCATGC 
                 2-13-5 
                 78.6 
                 397 
               
               
                   
               
               
                 410556 
                 22209 
                 22228 
                 GTGGACACGGGTCCCCATGC 
                 5-10-5 
                 81.4 
                 397 
               
               
                   
               
               
                 410624 
                 22209 
                 22228 
                 GTGGACACGGGTCCCCATGC 
                 3-14-3 
                 82.8 
                 397 
               
               
                   
               
               
                 410625 
                 22210 
                 22229 
                 AGTGGACACGGGTCCCCATG 
                 3-14-3 
                 64.4 
                 398 
               
               
                   
               
               
                 410705 
                 22210 
                 22229 
                 AGTGGACACGGGTCCCCATG 
                 2-13-5 
                 74.7 
                 398 
               
               
                   
               
               
                 405993 
                 22210 
                 22229 
                 AGTGGACACGGGTCCCCATG 
                 5-10-5 
                 85.5 
                 398 
               
               
                   
               
               
                 410706 
                 22211 
                 22230 
                 CAGTGGACACGGGTCCCCAT 
                 2-13-5 
                 70.8 
                 399 
               
               
                   
               
               
                 410557 
                 22211 
                 22230 
                 CAGTGGACACGGGTCCCCAT 
                 5-10-5 
                 74.2 
                 399 
               
               
                   
               
               
                 410626 
                 22211 
                 22230 
                 CAGTGGACACGGGTCCCCAT 
                 3-14-3 
                 76.8 
                 399 
               
               
                   
               
               
                 410627 
                 22212 
                 22231 
                 GCAGTGGACACGGGTCCCCA 
                 3-14-3 
                 71.4 
                 400 
               
               
                   
               
               
                 410707 
                 22212 
                 22231 
                 GCAGTGGACACGGGTCCCCA 
                 2-13-5 
                 72.8 
                 400 
               
               
                   
               
               
                 405994 
                 22212 
                 22231 
                 GCAGTGGACACGGGTCCCCA 
                 5-10-5 
                 95.2 
                 400 
               
               
                   
               
               
                 410708 
                 22213 
                 22232 
                 GGCAGTGGACACGGGTCCCC 
                 2-13-5 
                 79.0 
                 401 
               
               
                   
               
               
                 410628 
                 22213 
                 22232 
                 GGCAGTGGACACGGGTCCCC 
                 3-14-3 
                 88.1 
                 401 
               
               
                   
               
               
                 410558 
                 22213 
                 22232 
                 GGCAGTGGACACGGGTCCCC 
                 5-10-5 
                 88.9 
                 401 
               
               
                   
               
               
                 410629 
                 22214 
                 22233 
                 TGGCAGTGGACACGGGTCCC 
                 3-14-3 
                 66.5 
                 402 
               
               
                   
               
               
                 410709 
                 22214 
                 22233 
                 TGGCAGTGGACACGGGTCCC 
                 2-13-5 
                 66.9 
                 402 
               
               
                   
               
               
                 405995 
                 22214 
                 22233 
                 TGGCAGTGGACACGGGTCCC 
                 5-10-5 
                 92.4 
                 402 
               
               
                   
               
               
                 410630 
                 22215 
                 22234 
                 GTGGCAGTGGACACGGGTCC 
                 3-14-3 
                 54.1 
                 403 
               
               
                   
               
               
                 410710 
                 22215 
                 22234 
                 GTGGCAGTGGACACGGGTCC 
                 2-13-5 
                 61.4 
                 403 
               
               
                   
               
               
                 410559 
                 22215 
                 22234 
                 GTGGCAGTGGACACGGGTCC 
                 5-10-5 
                 77.5 
                 403 
               
               
                   
               
               
                 410711 
                 22216 
                 22235 
                 GGTGGCAGTGGACACGGGTC 
                 2-13-5 
                 NA 
                 404 
               
               
                   
               
               
                 410631 
                 22216 
                 22235 
                 GGTGGCAGTGGACACGGGTC 
                 3-14-3 
                 NA 
                 404 
               
               
                   
               
               
                 410560 
                 22216 
                 22235 
                 GGTGGCAGTGGACACGGGTC 
                 5-10-5 
                 42.5 
                 404 
               
               
                   
               
               
                 410712 
                 22217 
                 22236 
                 TGGTGGCAGTGGACACGGGT 
                 2-13-5 
                 NA 
                 405 
               
               
                   
               
               
                 410632 
                 22217 
                 22236 
                 TGGTGGCAGTGGACACGGGT 
                 3-14-3 
                 NA 
                 405 
               
               
                   
               
               
                 410561 
                 22217 
                 22236 
                 TGGTGGCAGTGGACACGGGT 
                 5-10-5 
                 NA 
                 405 
               
               
                   
               
               
                 410774 
                 22220 
                 22239 
                 TGTTGGTGGCAGTGGACACG 
                 5-10-5 
                 47.8 
                 406 
               
               
                   
               
               
                 410776 
                 23985 
                 24004 
                 GTGCCAAGGTCCTCCACCTC 
                 5-10-5 
                 77.3 
                 408 
               
               
                   
               
               
                 410777 
                 24005 
                 24024 
                 TCAGCACAGGCGGCTTGTGG 
                 5-10-5 
                 40.0 
                 409 
               
               
                   
               
               
                 410778 
                 24035 
                 24054 
                 CCACGCACTGGTTGGGCTGA 
                 5-10-5 
                 52.7 
                 410 
               
               
                   
               
               
                 399908 
                 24095 
                 24114 
                 CTTTGCATTCCAGACCTGGG 
                 3-14-3 
                 74.9 
                 60 
               
               
                   
               
               
                 410713 
                 24095 
                 24114 
                 CTTTGCATTCCAGACCTGGG 
                 2-13-5 
                 84.9 
                 60 
               
               
                   
               
               
                 395186 
                 24095 
                 24114 
                 CTTTGCATTCCAGACCTGGG 
                 5-10-5 
                 93.7 
                 60 
               
               
                   
               
               
                 410714 
                 24096 
                 24115 
                 ACTTTGCATTCCAGACCTGG 
                 2-13-5 
                 82.4 
                 411 
               
               
                   
               
               
                 410633 
                 24096 
                 24115 
                 ACTTTGCATTCCAGACCTGG 
                 3-14-3 
                 83.8 
                 411 
               
               
                   
               
               
                 410562 
                 24096 
                 24115 
                 ACTTTGCATTCCAGACCTGG 
                 5-10-5 
                 87.3 
                 411 
               
               
                   
               
               
                 410715 
                 24097 
                 24116 
                 GACTTTGCATTCCAGACCTG 
                 2-13-5 
                 80.5 
                 412 
               
               
                   
               
               
                 410634 
                 24097 
                 24116 
                 GACTTTGCATTCCAGACCTG 
                 3-14-3 
                 81.8 
                 412 
               
               
                   
               
               
                 405996 
                 24097 
                 24116 
                 GACTTTGCATTCCAGACCTG 
                 5-10-5 
                 91.0 
                 412 
               
               
                   
               
               
                 410563 
                 24098 
                 24117 
                 TGACTTTGCATTCCAGACCT 
                 5-10-5 
                 75.4 
                 413 
               
               
                   
               
               
                 410635 
                 24098 
                 24117 
                 TGACTTTGCATTCCAGACCT 
                 3-14-3 
                 75.9 
                 413 
               
               
                   
               
               
                 410716 
                 24098 
                 24117 
                 TGACTTTGCATTCCAGACCT 
                 2-13-5 
                 88.3 
                 413 
               
               
                   
               
               
                 410636 
                 24099 
                 24118 
                 TTGACTTTGCATTCCAGACC 
                 3-14-3 
                 61.3 
                 414 
               
               
                   
               
               
                 410564 
                 24099 
                 24118 
                 TTGACTTTGCATTCCAGACC 
                 5-10-5 
                 71.3 
                 414 
               
               
                   
               
               
                 410717 
                 24099 
                 24118 
                 TTGACTTTGCATTCCAGACC 
                 2-13-5 
                 76.7 
                 414 
               
               
                   
               
               
                 410718 
                 24100 
                 24119 
                 CTTGACTTTGCATTCCAGAC 
                 2-13-5 
                 55.8 
                 61 
               
               
                   
               
               
                 399973 
                 24100 
                 24119 
                 CTTGACTTTGCATTCCAGAC 
                 3-14-3 
                 82.1 
                 61 
               
               
                   
               
               
                 399817 
                 24100 
                 24119 
                 CTTGACTTTGCATTCCAGAC 
                 5-10-5 
                 93.6 
                 61 
               
               
                   
               
               
                 405997 
                 24102 
                 24121 
                 TCCTTGACTTTGCATTCCAG 
                 5-10-5 
                 95.6 
                 415 
               
               
                   
               
               
                 410779 
                 24115 
                 24134 
                 CGGGATTCCATGCTCCTTGA 
                 5-10-5 
                 79.7 
                 416 
               
               
                   
               
               
                 410781 
                 25994 
                 26013 
                 GGAGGGCACTGCAGCCAGTC 
                 5-10-5 
                 66.0 
                 418 
               
               
                   
               
               
                 410719 
                 26112 
                 26131 
                 CAGATGGCAACGGCTGTCAC 
                 2-13-5 
                 61.0 
                 419 
               
               
                   
               
               
                 410637 
                 26112 
                 26131 
                 CAGATGGCAACGGCTGTCAC 
                 3-14-3 
                 66.0 
                 419 
               
               
                   
               
               
                 410565 
                 26112 
                 26131 
                 CAGATGGCAACGGCTGTCAC 
                 5-10-5 
                 71.6 
                 419 
               
               
                   
               
               
                 410638 
                 26113 
                 26132 
                 GCAGATGGCAACGGCTGTCA 
                 3-14-3 
                 71.9 
                 420 
               
               
                   
               
               
                 410720 
                 26113 
                 26132 
                 GCAGATGGCAACGGCTGTCA 
                 2-13-5 
                 75.1 
                 420 
               
               
                   
               
               
                 410566 
                 26113 
                 26132 
                 GCAGATGGCAACGGCTGTCA 
                 5-10-5 
                 77.7 
                 420 
               
               
                   
               
               
                 410639 
                 26114 
                 26133 
                 AGCAGATGGCAACGGCTGTC 
                 3-14-3 
                 67.7 
                 421 
               
               
                   
               
               
                 410721 
                 26114 
                 26133 
                 AGCAGATGGCAACGGCTGTC 
                 2-13-5 
                 68.8 
                 421 
               
               
                   
               
               
                 410567 
                 26114 
                 26133 
                 AGCAGATGGCAACGGCTGTC 
                 5-10-5 
                 72.1 
                 421 
               
               
                   
               
               
                 410568 
                 26115 
                 26134 
                 CAGCAGATGGCAACGGCTGT 
                 5-10-5 
                 54.2 
                 422 
               
               
                   
               
               
                 410640 
                 26115 
                 26134 
                 CAGCAGATGGCAACGGCTGT 
                 3-14-3 
                 57.7 
                 422 
               
               
                   
               
               
                 410722 
                 26115 
                 26134 
                 CAGCAGATGGCAACGGCTGT 
                 2-13-5 
                 59.2 
                 422 
               
               
                   
               
               
                 410569 
                 26116 
                 26135 
                 GCAGCAGATGGCAACGGCTG 
                 5-10-5 
                 57.7 
                 423 
               
               
                   
               
               
                 410641 
                 26116 
                 26135 
                 GCAGCAGATGGCAACGGCTG 
                 3-14-3 
                 66.1 
                 423 
               
               
                   
               
               
                 410723 
                 26116 
                 26135 
                 GCAGCAGATGGCAACGGCTG 
                 2-13-5 
                 81.1 
                 423 
               
               
                   
               
               
                 399909 
                 26117 
                 26136 
                 GGCAGCAGATGGCAACGGCT 
                 3-14-3 
                 69.9 
                 62 
               
               
                   
               
               
                 410724 
                 26117 
                 26136 
                 GGCAGCAGATGGCAACGGCT 
                 2-13-5 
                 87.4 
                 62 
               
               
                   
               
               
                 395187 
                 26117 
                 26136 
                 GGCAGCAGATGGCAACGGCT 
                 5-10-5 
                 92.7 
                 62 
               
               
                   
               
               
                 410642 
                 26118 
                 26137 
                 CGGCAGCAGATGGCAACGGC 
                 3-14-3 
                 70.4 
                 424 
               
               
                   
               
               
                 410725 
                 26118 
                 26137 
                 CGGCAGCAGATGGCAACGGC 
                 2-13-5 
                 75.6 
                 424 
               
               
                   
               
               
                 410570 
                 26118 
                 26137 
                 CGGCAGCAGATGGCAACGGC 
                 5-10-5 
                 78.3 
                 424 
               
               
                   
               
               
                 410571 
                 26119 
                 26138 
                 CCGGCAGCAGATGGCAACGG 
                 5-10-5 
                 52.8 
                 425 
               
               
                   
               
               
                 410643 
                 26119 
                 26138 
                 CCGGCAGCAGATGGCAACGG 
                 3-14-3 
                 59.8 
                 425 
               
               
                   
               
               
                 410726 
                 26119 
                 26138 
                 CCGGCAGCAGATGGCAACGG 
                 2-13-5 
                 69.8 
                 425 
               
               
                   
               
               
                 410644 
                 26120 
                 26139 
                 TCCGGCAGCAGATGGCAACG 
                 3-14-3 
                 59.0 
                 426 
               
               
                   
               
               
                 410727 
                 26120 
                 26139 
                 TCCGGCAGCAGATGGCAACG 
                 2-13-5 
                 68.3 
                 426 
               
               
                   
               
               
                 405998 
                 26120 
                 26139 
                 TCCGGCAGCAGATGGCAACG 
                 5-10-5 
                 75.6 
                 426 
               
               
                   
               
               
                 410572 
                 26121 
                 26140 
                 CTCCGGCAGCAGATGGCAAC 
                 5-10-5 
                 40.9 
                 427 
               
               
                   
               
               
                 410728 
                 26121 
                 26140 
                 CTCCGGCAGCAGATGGCAAC 
                 2-13-5 
                 56.4 
                 427 
               
               
                   
               
               
                 410645 
                 26121 
                 26140 
                 CTCCGGCAGCAGATGGCAAC 
                 3-14-3 
                 70.2 
                 427 
               
               
                   
               
               
                 410729 
                 26122 
                 26141 
                 GCTCCGGCAGCAGATGGCAA 
                 2-13-5 
                 67.7 
                 428 
               
               
                   
               
               
                 410573 
                 26122 
                 26141 
                 GCTCCGGCAGCAGATGGCAA 
                 5-10-5 
                 71.8 
                 428 
               
               
                   
               
               
                 410646 
                 26122 
                 26141 
                 GCTCCGGCAGCAGATGGCAA 
                 3-14-3 
                 72.8 
                 428 
               
               
                   
               
               
                 410782 
                 26132 
                 26151 
                 CCAGGTGCCGGCTCCGGCAG 
                 5-10-5 
                 43.2 
                 429 
               
               
                   
               
               
                 410783 
                 26142 
                 26161 
                 GAGGCCTGCGCCAGGTGCCG 
                 5-10-5 
                 63.7 
                 430 
               
               
                   
               
               
                 399819 
                 26316 
                 26335 
                 CCCACTCAAGGGCCAGGCCA 
                 5-10-5 
                 93.4 
                 65 
               
               
                   
               
               
                 399912 
                 26404 
                 26423 
                 ATGCCCCACAGTGAGGGAGG 
                 3-14-3 
                 84.3 
                 66 
               
               
                   
               
               
                 405893 
                 26635 
                 26654 
                 ATGAGGGCCATCAGCACCTT 
                 5-10-5 
                 93.9 
                 431 
               
               
                   
               
               
                 405894 
                 26636 
                 26655 
                 GATGAGGGCCATCAGCACCT 
                 5-10-5 
                 93.9 
                 432 
               
               
                   
               
               
                 405895 
                 26637 
                 26656 
                 AGATGAGGGCCATCAGCACC 
                 5-10-5 
                 91.8 
                 433 
               
               
                   
               
               
                 405896 
                 26638 
                 26657 
                 GAGATGAGGGCCATCAGCAC 
                 5-10-5 
                 88.5 
                 434 
               
               
                   
               
               
                 395194 
                 26639 
                 26658 
                 GGAGATGAGGGCCATCAGCA 
                 5-10-5 
                 90.0 
                 69 
               
               
                   
               
               
                 399916 
                 26639 
                 26658 
                 GGAGATGAGGGCCATCAGCA 
                 3-14-3 
                 94.5 
                 69 
               
               
                   
               
               
                 405897 
                 26640 
                 26659 
                 TGGAGATGAGGGCCATCAGC 
                 5-10-5 
                 85.1 
                 435 
               
               
                   
               
               
                 405898 
                 26641 
                 26660 
                 CTGGAGATGAGGGCCATCAG 
                 5-10-5 
                 86.9 
                 436 
               
               
                   
               
               
                 405899 
                 26642 
                 26661 
                 GCTGGAGATGAGGGCCATCA 
                 5-10-5 
                 91.5 
                 437 
               
               
                   
               
               
                 405900 
                 26643 
                 26662 
                 AGCTGGAGATGAGGGCCATC 
                 5-10-5 
                 83.7 
                 438 
               
               
                   
               
               
                 405901 
                 26709 
                 26728 
                 GCTAGATGCCATCCAGAAAG 
                 5-10-5 
                 88.4 
                 439 
               
               
                   
               
               
                 405902 
                 26710 
                 26729 
                 GGCTAGATGCCATCCAGAAA 
                 5-10-5 
                 89.3 
                 440 
               
               
                   
               
               
                 405903 
                 26711 
                 26730 
                 TGGCTAGATGCCATCCAGAA 
                 5-10-5 
                 92.6 
                 441 
               
               
                   
               
               
                 405904 
                 26712 
                 26731 
                 CTGGCTAGATGCCATCCAGA 
                 5-10-5 
                 90.4 
                 442 
               
               
                   
               
               
                 399821 
                 26713 
                 26732 
                 TCTGGCTAGATGCCATCCAG 
                 5-10-5 
                 91.7 
                 71 
               
               
                   
               
               
                 405905 
                 26714 
                 26733 
                 CTCTGGCTAGATGCCATCCA 
                 5-10-5 
                 90.7 
                 443 
               
               
                   
               
               
                 405906 
                 26715 
                 26734 
                 CCTCTGGCTAGATGCCATCC 
                 5-10-5 
                 93.3 
                 444 
               
               
                   
               
               
                 405907 
                 26716 
                 26735 
                 GCCTCTGGCTAGATGCCATC 
                 5-10-5 
                 90.2 
                 445 
               
               
                   
               
               
                 405908 
                 26717 
                 26736 
                 AGCCTCTGGCTAGATGCCAT 
                 5-10-5 
                 83.3 
                 446 
               
               
                   
               
               
                 399978 
                 26795 
                 26814 
                 AGCCTGGCATAGAGCAGAGT 
                 3-14-3 
                 96.4 
                 73 
               
               
                   
               
            
           
         
       
     
     Antisense oligonucleotides that exhibited less than 30% inhibition of PCSK9 mRNA levels were marked with “NA”. 
     Antisense oligonucleotides with the following ISIS Nos exhibited at least 80% inhibition of PCSK9 mRNA levels: 395152, 395153, 395155, 395158, 395163, 395165, 395166, 395168, 395173, 395183, 395185, 395186, 395187, 395194, 399798, 399801, 399804, 399817, 399819, 399821, 399868, 399877, 399879, 399887, 399888, 399891, 399895, 399900, 399904, 399905, 399906, 399907, 399912, 399916, 399935, 399936, 399954, 399960, 399967, 399968, 399969, 399973, 399978, 405861, 405862, 405863, 405864, 405865, 405866, 405869, 405870, 405871, 405872, 405873, 405874, 405875, 405876, 405877, 405878, 405879, 405880, 405881, 405882, 405883, 405884, 405889, 405890, 405891, 405893, 405894, 405895, 405896, 405897, 405898, 405899, 405900, 405901, 405902, 405903, 405904, 405905, 405906, 405907, 405908, 405909, 405910, 405911, 405913, 405914, 405915, 405916, 405920, 405921, 405922, 405923, 405924, 405925, 405926, 405927, 405928, 405929, 405930, 405931, 405932, 405934, 405935, 405936, 405940, 405941, 405943, 405944, 405949, 405952, 405953, 405954, 405955, 405956, 405958, 405959, 405960, 405961, 405973, 405974, 405976, 405977, 405978, 405979, 405980, 405982, 405984, 405987, 405988, 405989, 405990, 405991, 405992, 405993, 405994, 405995, 405996, 405997, 406003, 406005, 406008, 406009, 406014, 406016, 406020, 406023, 406026, 406028, 406029, 406030, 406031, 406032, 406033, 406035, 406036, 406038, 406039, 406040, 406041, 406042, 406043, 406044, 406045, 410530, 410556, 410558, 410562, 410578, 410583, 410589, 410590, 410591, 410592, 410593, 410595, 410609, 410611, 410616, 410617, 410618, 410619, 410624, 410628, 410633, 410634, 410647, 410648, 410650, 410652, 410658, 410664, 410666, 410667, 410668, 410671, 410677, 410686, 410688, 410689, 410693, 410695, 410696, 410697, 410698, 410700, 410701, 410702, 410713, 410714, 410715, 410716, 410723, 410724, 410730, 410754, 410757, 410759, 410769, and 410772. The target segments to which these antisense oligonucleotides are targeted are active target segments. The target regions to which these antisense oligonucleotides are targeted are active target regions. 
     ISIS Nos 395152, 395155, 395158, 395165, 395166, 395168, 395173, 395183, 395185, 395186, 395187, 395194, 399801, 399817, 399819, 399821, 399868, 399877, 399879, 399887, 399888, 399891, 399900, 399904, 399905, 399906, 399907, 399916, 399936, 399954, 399969, 399978, 405861, 405862, 405864, 405869, 405871, 405872, 405873, 405874, 405875, 405876, 405878, 405879, 405880, 405881, 405882, 405883, 405884, 405890, 405891, 405893, 405894, 405895, 405896, 405897, 405898, 405899, 405901, 405902, 405903, 405904, 405905, 405906, 405907, 405910, 405911, 405913, 405914, 405915, 405916, 405920, 405921, 405922, 405923, 405924, 405925, 405926, 405927, 405928, 405929, 405930, 405931, 405932, 405934, 405935, 405936, 405941, 405952, 405953, 405954, 405955, 405956, 405959, 405960, 405961, 405974, 405977, 405978, 405979, 405980, 405982, 405987, 405988, 405989, 405990, 405991, 405992, 405993, 405994, 405995, 405996, 405997, 406008, 406009, 406014, 406016, 406023, 406028, 406029, 406030, 406031, 406032, 406033, 406035, 406038, 406039, 406040, 406041, 406042, 406043, 406044, 406045, 410558, 410562, 410583, 410591, 410592, 410593, 410611, 410617, 410618, 410628, 410647, 410650, 410668, 410677, 410688, 410695, 410696, 410697, 410698, 410702, 410716, 410724, 410730, 410757, and 410772 each exhibited at least 85% inhibition of PCSK9 mRNA levels. 
     ISIS Nos 395152, 395155, 395158, 395165, 395166, 395168, 395173, 395183, 395185, 395186, 395187, 399801, 399817, 399819, 399821, 399877, 399879, 399887, 399888, 399891, 399900, 399904, 399905, 399906, 399907, 399916, 399969, 399978, 405862, 405864, 405874, 405875, 405878, 405879, 405880, 405881, 405882, 405883, 405884, 405891, 405893, 405894, 405895, 405899, 405903, 405906, 405910, 405913, 405916, 405923, 405924, 405925, 405926, 405927, 405930, 405934, 405936, 405953, 405955, 405956, 405959, 405978, 405988, 405990, 405991, 405994, 405995, 405996, 405997, 406008, 406014, 406023, 406028, 406029, 406030, 406033, 406035, 406039, 406040, 406041, 406042, 406043, 406044, 410592, 410647, 410668, and 410772 each exhibited at least 90% inhibition of PCSK9 mRNA levels. 
     ISIS Nos 395165, 395166, 399801, 399978, 405881, 405891, 405959, 405978, 405988, 405990, 405994, 405997, 406008, 406030, 406040, 406041, and 406044 each exhibited at least 95% inhibition of PCSK9 mRNA levels. 
     
       
         
           
               
             
               
                 TABLE 19 
               
             
            
               
                   
               
               
                 Antisense inhibition of PCSK9 in human cells (Hep3B) 
               
               
                 targeting SEQ ID NO: 3 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                 5′ Target 
                 3′ Target 
                   
                   
                   
                   
               
               
                   
                 Site to 
                 Site to 
                   
                   
                   
                 SEQ 
               
               
                 Isis 
                 SEQ ID 
                 SEQ ID 
                   
                   
                 % 
                 ID 
               
               
                 No. 
                 NO: 3 
                 NO: 3 
                 Sequence 5′-3′ 
                 Motif 
                 inhibition 
                 NO: 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                 399935 
                 1075 
                 1094 
                 AGGACCCAAGTCATCCTGCT 
                 3-14-3 
                 81.1 
                 96 
               
               
                   
               
               
                 399936 
                 1105 
                 1124 
                 GGCCATCAGCTGGCAATGCT 
                 3-14-3 
                 89.0 
                 124 
               
               
                   
               
               
                 410753 
                 1351 
                 1370 
                 ATACACCTCCACCAGGCTGC 
                 5-10-5 
                 72.8 
                 215 
               
               
                   
               
               
                 406025 
                 1362 
                 1381 
                 GTGTCTAGGAGATACACCTC 
                 5-10-5 
                 74.2 
                 216 
               
               
                   
               
               
                 406026 
                 1367 
                 1386 
                 TGCTGGTGTCTAGGAGATAC 
                 5-10-5 
                 80.5 
                 217 
               
               
                   
               
               
                 405869 
                 1392 
                 1411 
                 TCGATTTCCCGGTGGTCACT 
                 5-10-5 
                 87.6 
                 218 
               
               
                   
               
               
                 405870 
                 1393 
                 1412 
                 CTCGATTTCCCGGTGGTCAC 
                 5-10-5 
                 83.3 
                 219 
               
               
                   
               
               
                 405871 
                 1394 
                 1413 
                 CCTCGATTTCCCGGTGGTCA 
                 5-10-5 
                 87.0 
                 220 
               
               
                   
               
               
                 405872 
                 1395 
                 1414 
                 CCCTCGATTTCCCGGTGGTC 
                 5-10-5 
                 88.2 
                 221 
               
               
                   
               
               
                 399798 
                 1396 
                 1415 
                 GCCCTCGATTTCCCGGTGGT 
                 5-10-5 
                 84.3 
                 22 
               
               
                   
               
               
                 399954 
                 1396 
                 1415 
                 GCCCTCGATTTCCCGGTGGT 
                 3-14-3 
                 90.3 
                 22 
               
               
                   
               
               
                 405873 
                 1397 
                 1416 
                 TGCCCTCGATTTCCCGGTGG 
                 5-10-5 
                 90.0 
                 222 
               
               
                   
               
               
                 405874 
                 1398 
                 1417 
                 CTGCCCTCGATTTCCCGGTG 
                 5-10-5 
                 91.4 
                 223 
               
               
                   
               
               
                 405875 
                 1399 
                 1418 
                 CCTGCCCTCGATTTCCCGGT 
                 5-10-5 
                 93.5 
                 224 
               
               
                   
               
               
                 405876 
                 1400 
                 1419 
                 CCCTGCCCTCGATTTCCCGG 
                 5-10-5 
                 90.1 
                 225 
               
               
                   
               
               
                 406027 
                 1404 
                 1423 
                 ATGACCCTGCCCTCGATTTC 
                 5-10-5 
                 73.9 
                 226 
               
               
                   
               
               
                 406028 
                 1406 
                 1425 
                 CCATGACCCTGCCCTCGATT 
                 5-10-5 
                 92.3 
                 227 
               
               
                   
               
               
                 406029 
                 1408 
                 1427 
                 GACCATGACCCTGCCCTCGA 
                 5-10-5 
                 91.4 
                 228 
               
               
                   
               
               
                 406030 
                 1412 
                 1431 
                 CGGTGACCATGACCCTGCCC 
                 5-10-5 
                 95.6 
                 229 
               
               
                   
               
               
                 406031 
                 1414 
                 1433 
                 GTCGGTGACCATGACCCTGC 
                 5-10-5 
                 89.6 
                 230 
               
               
                   
               
               
                 410733 
                 1416 
                 1435 
                 AAGTCGGTGACCATGACCCT 
                 5-10-5 
                 65.7 
                 231 
               
               
                   
               
               
                 406032 
                 1418 
                 1437 
                 CGAAGTCGGTGACCATGACC 
                 5-10-5 
                 88.5 
                 232 
               
               
                   
               
               
                 410754 
                 1428 
                 1447 
                 GGCACATTCTCGAAGTCGGT 
                 5-10-5 
                 80.1 
                 233 
               
               
                   
               
               
                 395163 
                 1453 
                 1472 
                 GTGGAAGCGGGTCCCGTCCT 
                 5-10-5 
                 83.9 
                 25 
               
               
                   
               
               
                 410755 
                 1463 
                 1482 
                 TGGCCTGTCTGTGGAAGCGG 
                 5-10-5 
                 NA 
                 234 
               
               
                   
               
               
                 410756 
                 1490 
                 1509 
                 GGTGGGTGCCATGACTGTCA 
                 5-10-5 
                 67.1 
                 235 
               
               
                   
               
               
                 406033 
                 1497 
                 1516 
                 CCTGCCAGGTGGGTGCCATG 
                 5-10-5 
                 91.2 
                 237 
               
               
                   
               
               
                 406034 
                 1502 
                 1521 
                 CCACCCCTGCCAGGTGGGTG 
                 5-10-5 
                 59.3 
                 238 
               
               
                   
               
               
                 406035 
                 1507 
                 1526 
                 GCTGACCACCCCTGCCAGGT 
                 5-10-5 
                 91.7 
                 239 
               
               
                   
               
               
                 410757 
                 1515 
                 1534 
                 TCCCGGCCGCTGACCACCCC 
                 5-10-5 
                 88.9 
                 240 
               
               
                   
               
               
                 406036 
                 1519 
                 1538 
                 GGCATCCCGGCCGCTGACCA 
                 5-10-5 
                 84.0 
                 241 
               
               
                   
               
               
                 406037 
                 1522 
                 1541 
                 GCCGGCATCCCGGCCGCTGA 
                 5-10-5 
                 55.9 
                 242 
               
               
                   
               
               
                 410536 
                 1527 
                 1546 
                 GCCACGCCGGCATCCCGGCC 
                 5-10-5 
                 63.7 
                 243 
               
               
                   
               
               
                 410658 
                 1527 
                 1546 
                 GCCACGCCGGCATCCCGGCC 
                 2-13-5 
                 82.0 
                 243 
               
               
                   
               
               
                 410583 
                 1527 
                 1546 
                 GCCACGCCGGCATCCCGGCC 
                 3-14-3 
                 87.3 
                 243 
               
               
                   
               
               
                 410537 
                 1528 
                 1547 
                 GGCCACGCCGGCATCCCGGC 
                 5-10-5 
                 58.5 
                 244 
               
               
                   
               
               
                 410659 
                 1528 
                 1547 
                 GGCCACGCCGGCATCCCGGC 
                 2-13-5 
                 73.7 
                 244 
               
               
                   
               
               
                 410584 
                 1528 
                 1547 
                 GGCCACGCCGGCATCCCGGC 
                 3-14-3 
                 79.5 
                 244 
               
               
                   
               
               
                 410660 
                 1529 
                 1548 
                 TGGCCACGCCGGCATCCCGG 
                 2-13-5 
                 63.0 
                 245 
               
               
                   
               
               
                 410585 
                 1529 
                 1548 
                 TGGCCACGCCGGCATCCCGG 
                 3-14-3 
                 73.2 
                 245 
               
               
                   
               
               
                 406038 
                 1529 
                 1548 
                 TGGCCACGCCGGCATCCCGG 
                 5-10-5 
                 86.3 
                 245 
               
               
                   
               
               
                 410661 
                 1530 
                 1549 
                 TTGGCCACGCCGGCATCCCG 
                 2-13-5 
                 53.3 
                 246 
               
               
                   
               
               
                 410586 
                 1530 
                 1549 
                 TTGGCCACGCCGGCATCCCG 
                 3-14-3 
                 60.3 
                 246 
               
               
                   
               
               
                 405877 
                 1530 
                 1549 
                 TTGGCCACGCCGGCATCCCG 
                 5-10-5 
                 83.2 
                 246 
               
               
                   
               
               
                 410587 
                 1531 
                 1550 
                 CTTGGCCACGCCGGCATCCC 
                 3-14-3 
                 63.2 
                 247 
               
               
                   
               
               
                 410662 
                 1531 
                 1550 
                 CTTGGCCACGCCGGCATCCC 
                 2-13-5 
                 67.3 
                 247 
               
               
                   
               
               
                 405878 
                 1531 
                 1550 
                 CTTGGCCACGCCGGCATCCC 
                 5-10-5 
                 91.4 
                 247 
               
               
                   
               
               
                 410588 
                 1532 
                 1551 
                 CCTTGGCCACGCCGGCATCC 
                 3-14-3 
                 65.3 
                 248 
               
               
                   
               
               
                 410663 
                 1532 
                 1551 
                 CCTTGGCCACGCCGGCATCC 
                 2-13-5 
                 67.9 
                 248 
               
               
                   
               
               
                 405879 
                 1532 
                 1551 
                 CCTTGGCCACGCCGGCATCC 
                 5-10-5 
                 94.1 
                 248 
               
               
                   
               
               
                 410589 
                 1533 
                 1552 
                 CCCTTGGCCACGCCGGCATC 
                 3-14-3 
                 80.1 
                 249 
               
               
                   
               
               
                 410664 
                 1533 
                 1552 
                 CCCTTGGCCACGCCGGCATC 
                 2-13-5 
                 81.9 
                 249 
               
               
                   
               
               
                 405880 
                 1533 
                 1552 
                 CCCTTGGCCACGCCGGCATC 
                 5-10-5 
                 93.5 
                 249 
               
               
                   
               
               
                 410665 
                 1534 
                 1553 
                 ACCCTTGGCCACGCCGGCAT 
                 2-13-5 
                 78.7 
                 28 
               
               
                   
               
               
                 399887 
                 1534 
                 1553 
                 ACCCTTGGCCACGCCGGCAT 
                 3-14-3 
                 91.9 
                 28 
               
               
                   
               
               
                 395165 
                 1534 
                 1553 
                 ACCCTTGGCCACGCCGGCAT 
                 5-10-5 
                 96.7 
                 28 
               
               
                   
               
               
                 410590 
                 1535 
                 1554 
                 CACCCTTGGCCACGCCGGCA 
                 3-14-3 
                 82.2 
                 250 
               
               
                   
               
               
                 410666 
                 1535 
                 1554 
                 CACCCTTGGCCACGCCGGCA 
                 2-13-5 
                 82.7 
                 250 
               
               
                   
               
               
                 405881 
                 1535 
                 1554 
                 CACCCTTGGCCACGCCGGCA 
                 5-10-5 
                 98.3 
                 250 
               
               
                   
               
               
                 410667 
                 1536 
                 1555 
                 GCACCCTTGGCCACGCCGGC 
                 2-13-5 
                 84.7 
                 251 
               
               
                   
               
               
                 410591 
                 1536 
                 1555 
                 GCACCCTTGGCCACGCCGGC 
                 3-14-3 
                 86.3 
                 251 
               
               
                   
               
               
                 405882 
                 1536 
                 1555 
                 GCACCCTTGGCCACGCCGGC 
                 5-10-5 
                 91.6 
                 251 
               
               
                   
               
               
                 410668 
                 1537 
                 1556 
                 GGCACCCTTGGCCACGCCGG 
                 2-13-5 
                 91.4 
                 252 
               
               
                   
               
               
                 405883 
                 1537 
                 1556 
                 GGCACCCTTGGCCACGCCGG 
                 5-10-5 
                 92.5 
                 252 
               
               
                   
               
               
                 410592 
                 1537 
                 1556 
                 GGCACCCTTGGCCACGCCGG 
                 3-14-3 
                 93.4 
                 252 
               
               
                   
               
               
                 410669 
                 1538 
                 1557 
                 TGGCACCCTTGGCCACGCCG 
                 2-13-5 
                 69.0 
                 253 
               
               
                   
               
               
                 410593 
                 1538 
                 1557 
                 TGGCACCCTTGGCCACGCCG 
                 3-14-3 
                 88.8 
                 253 
               
               
                   
               
               
                 405884 
                 1538 
                 1557 
                 TGGCACCCTTGGCCACGCCG 
                 5-10-5 
                 90.8 
                 253 
               
               
                   
               
               
                 410670 
                 1539 
                 1558 
                 CTGGCACCCTTGGCCACGCC 
                 2-13-5 
                 74.9 
                 254 
               
               
                   
               
               
                 410594 
                 1539 
                 1558 
                 CTGGCACCCTTGGCCACGCC 
                 3-14-3 
                 75.2 
                 254 
               
               
                   
               
               
                 410538 
                 1539 
                 1558 
                 CTGGCACCCTTGGCCACGCC 
                 5-10-5 
                 78.2 
                 254 
               
               
                   
               
               
                 410539 
                 1540 
                 1559 
                 GCTGGCACCCTTGGCCACGC 
                 5-10-5 
                 61.9 
                 255 
               
               
                   
               
               
                 410595 
                 1540 
                 1559 
                 GCTGGCACCCTTGGCCACGC 
                 3-14-3 
                 83.1 
                 255 
               
               
                   
               
               
                 410671 
                 1540 
                 1559 
                 GCTGGCACCCTTGGCCACGC 
                 2-13-5 
                 83.3 
                 255 
               
               
                   
               
               
                 410758 
                 1545 
                 1564 
                 CGCATGCTGGCACCCTTGGC 
                 5-10-5 
                 73.6 
                 256 
               
               
                   
               
               
                 406039 
                 1566 
                 1585 
                 CAGTTGAGCACGCGCAGGCT 
                 5-10-5 
                 91.2 
                 257 
               
               
                   
               
               
                 406040 
                 1568 
                 1587 
                 GGCAGTTGAGCACGCGCAGG 
                 5-10-5 
                 96.5 
                 258 
               
               
                   
               
               
                 399888 
                 1570 
                 1589 
                 TTGGCAGTTGAGCACGCGCA 
                 3-14-3 
                 90.9 
                 29 
               
               
                   
               
               
                 395166 
                 1570 
                 1589 
                 TTGGCAGTTGAGCACGCGCA 
                 5-10-5 
                 96.2 
                 29 
               
               
                   
               
               
                 406041 
                 1572 
                 1591 
                 CCTTGGCAGTTGAGCACGCG 
                 5-10-5 
                 96.6 
                 259 
               
               
                   
               
               
                 399801 
                 1575 
                 1594 
                 TTCCCTTGGCAGTTGAGCAC 
                 5-10-5 
                 95.6 
                 30 
               
               
                   
               
               
                 406042 
                 1577 
                 1596 
                 CCTTCCCTTGGCAGTTGAGC 
                 5-10-5 
                 92.0 
                 260 
               
               
                   
               
               
                 406043 
                 1581 
                 1600 
                 GTGCCCTTCCCTTGGCAGTT 
                 5-10-5 
                 91.9 
                 261 
               
               
                   
               
               
                 406044 
                 1583 
                 1602 
                 CCGTGCCCTTCCCTTGGCAG 
                 5-10-5 
                 95.4 
                 262 
               
               
                   
               
               
                 410759 
                 1594 
                 1613 
                 GGTGCCGCTAACCGTGCCCT 
                 5-10-5 
                 83.7 
                 263 
               
               
                   
               
               
                 410760 
                 1618 
                 1637 
                 CCGAATAAACTCCAGGCCTA 
                 5-10-5 
                 96.7 
                 265 
               
               
                   
               
               
                 406045 
                 1626 
                 1645 
                 TGGCTTTTCCGAATAAACTC 
                 5-10-5 
                 88.4 
                 266 
               
               
                   
               
               
                 395168 
                 1628 
                 1647 
                 GCTGGCTTTTCCGAATAAAC 
                 5-10-5 
                 91.9 
                 32 
               
               
                   
               
               
                 405909 
                 1630 
                 1649 
                 CAGCTGGCTTTTCCGAATAA 
                 5-10-5 
                 80.3 
                 267 
               
               
                   
               
               
                 405910 
                 1632 
                 1651 
                 ACCAGCTGGCTTTTCCGAAT 
                 5-10-5 
                 90.9 
                 268 
               
               
                   
               
               
                 405911 
                 1634 
                 1653 
                 GGACCAGCTGGCTTTTCCGA 
                 5-10-5 
                 88.0 
                 269 
               
               
                   
               
               
                 405912 
                 1638 
                 1657 
                 GGCTGGACCAGCTGGCTTTT 
                 5-10-5 
                 78.2 
                 270 
               
               
                   
               
               
                 410761 
                 1649 
                 1668 
                 GTGGCCCCACAGGCTGGACC 
                 5-10-5 
                 53.7 
                 271 
               
               
                   
               
               
                 410762 
                 1662 
                 1681 
                 AGCAGCACCACCAGTGGCCC 
                 5-10-5 
                 57.6 
                 272 
               
               
                   
               
               
                 410763 
                 1684 
                 1703 
                 GCTGTACCCACCCGCCAGGG 
                 5-10-5 
                 68.8 
                 273 
               
               
                   
               
               
                 410764 
                 1730 
                 1749 
                 CGACCCCAGCCCTCGCCAGG 
                 5-10-5 
                 66.3 
                 274 
               
               
                   
               
               
                 399891 
                 1740 
                 1759 
                 GTGACCAGCACGACCCCAGC 
                 3-14-3 
                 91.1 
                 33 
               
               
                   
               
               
                 405913 
                 1742 
                 1761 
                 CGGTGACCAGCACGACCCCA 
                 5-10-5 
                 93.8 
                 275 
               
               
                   
               
               
                 405914 
                 1744 
                 1763 
                 AGCGGTGACCAGCACGACCC 
                 5-10-5 
                 90.4 
                 276 
               
               
                   
               
               
                 405915 
                 1746 
                 1765 
                 GCAGCGGTGACCAGCACGAC 
                 5-10-5 
                 86.8 
                 277 
               
               
                   
               
               
                 405916 
                 1748 
                 1767 
                 CGGCAGCGGTGACCAGCACG 
                 5-10-5 
                 91.3 
                 278 
               
               
                   
               
               
                 410734 
                 1749 
                 1768 
                 CCGGCAGCGGTGACCAGCAC 
                 5-10-5 
                 65.8 
                 249 
               
               
                   
               
               
                 405917 
                 1752 
                 1771 
                 TTGCCGGCAGCGGTGACCAG 
                 5-10-5 
                 62.0 
                 280 
               
               
                   
               
               
                 405918 
                 1754 
                 1773 
                 AGTTGCCGGCAGCGGTGACC 
                 5-10-5 
                 33.5 
                 281 
               
               
                   
               
               
                 405919 
                 1756 
                 1775 
                 GAAGTTGCCGGCAGCGGTGA 
                 5-10-5 
                 68.2 
                 282 
               
               
                   
               
               
                 405920 
                 1758 
                 1777 
                 CGGAAGTTGCCGGCAGCGGT 
                 5-10-5 
                 86.2 
                 283 
               
               
                   
               
               
                 405921 
                 1760 
                 1779 
                 CCCGGAAGTTGCCGGCAGCG 
                 5-10-5 
                 85.5 
                 284 
               
               
                   
               
               
                 405922 
                 1762 
                 1781 
                 GTCCCGGAAGTTGCCGGCAG 
                 5-10-5 
                 86.0 
                 285 
               
               
                   
               
               
                 405937 
                 1820 
                 1839 
                 GAGGCACCAATGATGTCCTC 
                 5-10-5 
                 77.7 
                 306 
               
               
                   
               
               
                 405938 
                 1824 
                 1843 
                 GCTGGAGGCACCAATGATGT 
                 5-10-5 
                 75.5 
                 307 
               
               
                   
               
               
                 405939 
                 1826 
                 1845 
                 TCGCTGGAGGCACCAATGAT 
                 5-10-5 
                 70.6 
                 308 
               
               
                   
               
               
                 405940 
                 1828 
                 1847 
                 AGTCGCTGGAGGCACCAATG 
                 5-10-5 
                 84.4 
                 309 
               
               
                   
               
               
                 405941 
                 1830 
                 1849 
                 GCAGTCGCTGGAGGCACCAA 
                 5-10-5 
                 90.1 
                 310 
               
               
                   
               
               
                 399804 
                 1833 
                 1852 
                 GCTGCAGTCGCTGGAGGCAC 
                 5-10-5 
                 80.8 
                 40 
               
               
                   
               
               
                 399960 
                 1833 
                 1852 
                 GCTGCAGTCGCTGGAGGCAC 
                 3-14-3 
                 82.4 
                 40 
               
               
                   
               
               
                 405942 
                 1835 
                 1854 
                 GTGCTGCAGTCGCTGGAGGC 
                 5-10-5 
                 69.8 
                 311 
               
               
                   
               
               
                 405943 
                 1837 
                 1856 
                 AGGTGCTGCAGTCGCTGGAG 
                 5-10-5 
                 83.6 
                 312 
               
               
                   
               
               
                 410737 
                 1839 
                 1858 
                 GCAGGTGCTGCAGTCGCTGG 
                 5-10-5 
                 49.8 
                 313 
               
               
                   
               
               
                 405944 
                 1840 
                 1859 
                 AGCAGGTGCTGCAGTCGCTG 
                 5-10-5 
                 80.7 
                 314 
               
               
                   
               
               
                 405945 
                 1842 
                 1861 
                 AAAGCAGGTGCTGCAGTCGC 
                 5-10-5 
                 41.1 
                 315 
               
               
                   
               
               
                 405946 
                 1846 
                 1865 
                 ACACAAAGCAGGTGCTGCAG 
                 5-10-5 
                 70.4 
                 316 
               
               
                   
               
               
                 405947 
                 1848 
                 1867 
                 TGACACAAAGCAGGTGCTGC 
                 5-10-5 
                 72.5 
                 317 
               
               
                   
               
               
                 410769 
                 1858 
                 1877 
                 TCCCACTCTGTGACACAAAG 
                 5-10-5 
                 84.9 
                 318 
               
               
                   
               
               
                 405948 
                 1900 
                 1919 
                 TCATGGCTGCAATGCCAGCC 
                 5-10-5 
                 45.9 
                 319 
               
               
                   
               
               
                 399806 
                 1903 
                 1922 
                 GCATCATGGCTGCAATGCCA 
                 5-10-5 
                 82.8 
                 42 
               
               
                   
               
               
                 399962 
                 1903 
                 1922 
                 GCATCATGGCTGCAATGCCA 
                 3-14-3 
                 86.1 
                 42 
               
               
                   
               
               
                 405949 
                 1905 
                 1924 
                 CAGCATCATGGCTGCAATGC 
                 5-10-5 
                 84.9 
                 320 
               
               
                   
               
               
                 405950 
                 1907 
                 1926 
                 GACAGCATCATGGCTGCAAT 
                 5-10-5 
                 76.9 
                 321 
               
               
                   
               
               
                 405951 
                 1909 
                 1928 
                 CAGACAGCATCATGGCTGCA 
                 5-10-5 
                 75.4 
                 322 
               
               
                   
               
               
                 405952 
                 1913 
                 1932 
                 TCGGCAGACAGCATCATGGC 
                 5-10-5 
                 85.1 
                 323 
               
               
                   
               
               
                 410738 
                 1915 
                 1934 
                 GCTCGGCAGACAGCATCATG 
                 5-10-5 
                 68.4 
                 324 
               
               
                   
               
               
                 405953 
                 1917 
                 1936 
                 CGGCTCGGCAGACAGCATCA 
                 5-10-5 
                 93.6 
                 325 
               
               
                   
               
               
                 405954 
                 1919 
                 1938 
                 TCCGGCTCGGCAGACAGCAT 
                 5-10-5 
                 87.5 
                 326 
               
               
                   
               
               
                 410770 
                 1933 
                 1952 
                 CGGCCAGGGTGAGCTCCGGC 
                 5-10-5 
                 68.5 
                 327 
               
               
                   
               
               
                 405955 
                 1946 
                 1965 
                 CTCTGCCTCAACTCGGCCAG 
                 5-10-5 
                 94.2 
                 328 
               
               
                   
               
               
                 405956 
                 1948 
                 1967 
                 GTCTCTGCCTCAACTCGGCC 
                 5-10-5 
                 94.3 
                 329 
               
               
                   
               
               
                 405958 
                 1952 
                 1971 
                 ATCAGTCTCTGCCTCAACTC 
                 5-10-5 
                 80.3 
                 331 
               
               
                   
               
               
                 405959 
                 1954 
                 1973 
                 GGATCAGTCTCTGCCTCAAC 
                 5-10-5 
                 95.4 
                 332 
               
               
                   
               
               
                 405960 
                 1956 
                 1975 
                 GTGGATCAGTCTCTGCCTCA 
                 5-10-5 
                 90.1 
                 333 
               
               
                   
               
               
                 405961 
                 1958 
                 1977 
                 AAGTGGATCAGTCTCTGCCT 
                 5-10-5 
                 88.8 
                 334 
               
               
                   
               
               
                 405962 
                 1961 
                 1980 
                 GAGAAGTGGATCAGTCTCTG 
                 5-10-5 
                 56.1 
                 335 
               
               
                   
               
               
                 410739 
                 1963 
                 1982 
                 CAGAGAAGTGGATCAGTCTC 
                 5-10-5 
                 NA 
                 336 
               
               
                   
               
               
                 405963 
                 1965 
                 1984 
                 GGCAGAGAAGTGGATCAGTC 
                 5-10-5 
                 59.7 
                 337 
               
               
                   
               
               
                 405964 
                 1969 
                 1988 
                 CTTTGGCAGAGAAGTGGATC 
                 5-10-5 
                 45.3 
                 338 
               
               
                   
               
               
                 405965 
                 1974 
                 1993 
                 GACATCTTTGGCAGAGAAGT 
                 5-10-5 
                 55.9 
                 339 
               
               
                   
               
               
                 405966 
                 1976 
                 1995 
                 ATGACATCTTTGGCAGAGAA 
                 5-10-5 
                 51.3 
                 340 
               
               
                   
               
               
                 405967 
                 1980 
                 1999 
                 ATTGATGACATCTTTGGCAG 
                 5-10-5 
                 64.4 
                 341 
               
               
                   
               
               
                 405968 
                 1982 
                 2001 
                 TCATTGATGACATCTTTGGC 
                 5-10-5 
                 74.6 
                 342 
               
               
                   
               
               
                 399967 
                 1985 
                 2004 
                 GCCTCATTGATGACATCTTT 
                 3-14-3 
                 80.1 
                 48 
               
               
                   
               
               
                 405969 
                 1987 
                 2006 
                 AGGCCTCATTGATGACATCT 
                 5-10-5 
                 63.0 
                 343 
               
               
                   
               
               
                 405970 
                 1989 
                 2008 
                 CCAGGCCTCATTGATGACAT 
                 5-10-5 
                 66.8 
                 344 
               
               
                   
               
               
                 410740 
                 1991 
                 2010 
                 AACCAGGCCTCATTGATGAC 
                 5-10-5 
                 46.8 
                 345 
               
               
                   
               
               
                 405885 
                 1993 
                 2012 
                 GGAACCAGGCCTCATTGATG 
                 5-10-5 
                 73.4 
                 346 
               
               
                   
               
               
                 410596 
                 1995 
                 2014 
                 AGGGAACCAGGCCTCATTGA 
                 3-14-3 
                 NA 
                 348 
               
               
                   
               
               
                 410672 
                 1995 
                 2014 
                 AGGGAACCAGGCCTCATTGA 
                 2-13-5 
                 NA 
                 348 
               
               
                   
               
               
                 405887 
                 1995 
                 2014 
                 AGGGAACCAGGCCTCATTGA 
                 5-10-5 
                 NA 
                 348 
               
               
                   
               
               
                 410597 
                 1996 
                 2015 
                 CAGGGAACCAGGCCTCATTG 
                 3-14-3 
                 NA 
                 349 
               
               
                   
               
               
                 405888 
                 1996 
                 2015 
                 CAGGGAACCAGGCCTCATTG 
                 5-10-5 
                 NA 
                 349 
               
               
                   
               
               
                 410673 
                 1996 
                 2015 
                 CAGGGAACCAGGCCTCATTG 
                 2-13-5 
                 NA 
                 349 
               
               
                   
               
               
                 410674 
                 1997 
                 2016 
                 TCAGGGAACCAGGCCTCATT 
                 2-13-5 
                 60.7 
                 49 
               
               
                   
               
               
                 399812 
                 1997 
                 2016 
                 TCAGGGAACCAGGCCTCATT 
                 5-10-5 
                 68.7 
                 49 
               
               
                   
               
               
                 399968 
                 1997 
                 2016 
                 TCAGGGAACCAGGCCTCATT 
                 3-14-3 
                 84.5 
                 49 
               
               
                   
               
               
                 410598 
                 1998 
                 2017 
                 CTCAGGGAACCAGGCCTCAT 
                 3-14-3 
                 74.5 
                 350 
               
               
                   
               
               
                 410675 
                 1998 
                 2017 
                 CTCAGGGAACCAGGCCTCAT 
                 2-13-5 
                 76.9 
                 350 
               
               
                   
               
               
                 405889 
                 1998 
                 2017 
                 CTCAGGGAACCAGGCCTCAT 
                 5-10-5 
                 80.2 
                 350 
               
               
                   
               
               
                 410599 
                 1999 
                 2018 
                 CCTCAGGGAACCAGGCCTCA 
                 3-14-3 
                 70.6 
                 351 
               
               
                   
               
               
                 410676 
                 1999 
                 2018 
                 CCTCAGGGAACCAGGCCTCA 
                 2-13-5 
                 77.8 
                 351 
               
               
                   
               
               
                 405890 
                 1999 
                 2018 
                 CCTCAGGGAACCAGGCCTCA 
                 5-10-5 
                 87.7 
                 351 
               
               
                   
               
               
                 410600 
                 2000 
                 2019 
                 TCCTCAGGGAACCAGGCCTC 
                 3-14-3 
                 76.5 
                 352 
               
               
                   
               
               
                 410677 
                 2000 
                 2019 
                 TCCTCAGGGAACCAGGCCTC 
                 2-13-5 
                 88.4 
                 352 
               
               
                   
               
               
                 405891 
                 2000 
                 2019 
                 TCCTCAGGGAACCAGGCCTC 
                 5-10-5 
                 96.1 
                 352 
               
               
                   
               
               
                 405892 
                 2001 
                 2020 
                 GTCCTCAGGGAACCAGGCCT 
                 5-10-5 
                 71.4 
                 353 
               
               
                   
               
               
                 410601 
                 2001 
                 2020 
                 GTCCTCAGGGAACCAGGCCT 
                 3-14-3 
                 72.7 
                 353 
               
               
                   
               
               
                 410678 
                 2001 
                 2020 
                 GTCCTCAGGGAACCAGGCCT 
                 2-13-5 
                 75.0 
                 353 
               
               
                   
               
               
                 395178 
                 2002 
                 2021 
                 GGTCCTCAGGGAACCAGGCC 
                 5-10-5 
                 76.7 
                 50 
               
               
                   
               
               
                 410679 
                 2002 
                 2021 
                 GGTCCTCAGGGAACCAGGCC 
                 2-13-5 
                 77.6 
                 50 
               
               
                   
               
               
                 399900 
                 2002 
                 2021 
                 GGTCCTCAGGGAACCAGGCC 
                 3-14-3 
                 92.0 
                 50 
               
               
                   
               
               
                 408653 
                 2003 
                 2022 
                 TGGTCCTCAGGGAACCAGGC 
                 5-10-5 
                 42.5 
                 354 
               
               
                   
               
               
                 410602 
                 2003 
                 2022 
                 TGGTCCTCAGGGAACCAGGC 
                 3-14-3 
                 66.5 
                 354 
               
               
                   
               
               
                 410680 
                 2003 
                 2022 
                 TGGTCCTCAGGGAACCAGGC 
                 2-13-5 
                 71.6 
                 354 
               
               
                   
               
               
                 410603 
                 2004 
                 2023 
                 CTGGTCCTCAGGGAACCAGG 
                 3-14-3 
                 40.8 
                 355 
               
               
                   
               
               
                 410681 
                 2004 
                 2023 
                 CTGGTCCTCAGGGAACCAGG 
                 2-13-5 
                 44.4 
                 355 
               
               
                   
               
               
                 405971 
                 2004 
                 2023 
                 CTGGTCCTCAGGGAACCAGG 
                 5-10-5 
                 65.5 
                 355 
               
               
                   
               
               
                 410540 
                 2005 
                 2024 
                 GCTGGTCCTCAGGGAACCAG 
                 5-10-5 
                 50.9 
                 356 
               
               
                   
               
               
                 410682 
                 2005 
                 2024 
                 GCTGGTCCTCAGGGAACCAG 
                 2-13-5 
                 54.1 
                 356 
               
               
                   
               
               
                 410604 
                 2005 
                 2024 
                 GCTGGTCCTCAGGGAACCAG 
                 3-14-3 
                 62.5 
                 356 
               
               
                   
               
               
                 405972 
                 2006 
                 2025 
                 CGCTGGTCCTCAGGGAACCA 
                 5-10-5 
                 77.6 
                 357 
               
               
                   
               
               
                 405973 
                 2011 
                 2030 
                 GTACCCGCTGGTCCTCAGGG 
                 5-10-5 
                 83.8 
                 358 
               
               
                   
               
               
                 405974 
                 2013 
                 2032 
                 CAGTACCCGCTGGTCCTCAG 
                 5-10-5 
                 89.0 
                 359 
               
               
                   
               
               
                 399813 
                 2016 
                 2035 
                 GGTCAGTACCCGCTGGTCCT 
                 5-10-5 
                 72.4 
                 51 
               
               
                   
               
               
                 399969 
                 2016 
                 2035 
                 GGTCAGTACCCGCTGGTCCT 
                 3-14-3 
                 93.4 
                 51 
               
               
                   
               
               
                 410771 
                 2061 
                 2080 
                 ACCTGCCCCATGGGTGCTGG 
                 5-10-5 
                 NA 
                 360 
               
               
                   
               
               
                 395181 
                 2073 
                 2092 
                 AAACAGCTGCCAACCTGCCC 
                 5-10-5 
                 87.5 
                 52 
               
               
                   
               
               
                 405975 
                 2075 
                 2094 
                 CAAAACAGCTGCCAACCTGC 
                 5-10-5 
                 77.4 
                 361 
               
               
                   
               
               
                 405976 
                 2080 
                 2099 
                 TCCTGCAAAACAGCTGCCAA 
                 5-10-5 
                 81.2 
                 362 
               
               
                   
               
               
                 405977 
                 2082 
                 2101 
                 AGTCCTGCAAAACAGCTGCC 
                 5-10-5 
                 89.5 
                 363 
               
               
                   
               
               
                 399992 
                 2095 
                 2114 
                 GTGCTGACCACACAGTCCTG 
                 3-14-3 
                 92.6 
                 130 
               
               
                   
               
               
                 405978 
                 2105 
                 2124 
                 GGCCCCGAGTGTGCTGACCA 
                 5-10-5 
                 95.3 
                 365 
               
               
                   
               
               
                 399904 
                 2108 
                 2127 
                 GTAGGCCCCGAGTGTGCTGA 
                 3-14-3 
                 92.6 
                 54 
               
               
                   
               
               
                 405979 
                 2110 
                 2129 
                 GTGTAGGCCCCGAGTGTGCT 
                 5-10-5 
                 85.5 
                 366 
               
               
                   
               
               
                 405980 
                 2112 
                 2131 
                 CCGTGTAGGCCCCGAGTGTG 
                 5-10-5 
                 86.5 
                 367 
               
               
                   
               
               
                 405981 
                 2114 
                 2133 
                 ATCCGTGTAGGCCCCGAGTG 
                 5-10-5 
                 77.8 
                 368 
               
               
                   
               
               
                 410741 
                 2116 
                 2135 
                 CCATCCGTGTAGGCCCCGAG 
                 5-10-5 
                 78.4 
                 369 
               
               
                   
               
               
                 405982 
                 2118 
                 2137 
                 GGCCATCCGTGTAGGCCCCG 
                 5-10-5 
                 86.7 
                 370 
               
               
                   
               
               
                 405983 
                 2120 
                 2139 
                 GTGGCCATCCGTGTAGGCCC 
                 5-10-5 
                 73.1 
                 371 
               
               
                   
               
               
                 405984 
                 2168 
                 2187 
                 CTGGAGCAGCTCAGCAGCTC 
                 5-10-5 
                 83.4 
                 372 
               
               
                   
               
               
                 405985 
                 2170 
                 2189 
                 AACTGGAGCAGCTCAGCAGC 
                 5-10-5 
                 50.7 
                 373 
               
               
                   
               
               
                 405986 
                 2175 
                 2194 
                 GGAGAAACTGGAGCAGCTCA 
                 5-10-5 
                 75.6 
                 374 
               
               
                   
               
               
                 405987 
                 2177 
                 2196 
                 CTGGAGAAACTGGAGCAGCT 
                 5-10-5 
                 88.0 
                 375 
               
               
                   
               
               
                 410776 
                 2245 
                 2264 
                 GTGCCAAGGTCCTCCACCTC 
                 5-10-5 
                 77.3 
                 408 
               
               
                   
               
               
                 410777 
                 2265 
                 2284 
                 TCAGCACAGGCGGCTTGTGG 
                 5-10-5 
                 40.0 
                 409 
               
               
                   
               
               
                 410778 
                 2295 
                 2314 
                 CCACGCACTGGTTGGGCTGA 
                 5-10-5 
                 52.7 
                 410 
               
               
                   
               
               
                 399908 
                 2355 
                 2374 
                 CTTTGCATTCCAGACCTGGG 
                 3-14-3 
                 74.9 
                 60 
               
               
                   
               
               
                 410713 
                 2355 
                 2374 
                 CTTTGCATTCCAGACCTGGG 
                 2-13-5 
                 84.9 
                 60 
               
               
                   
               
               
                 395186 
                 2355 
                 2374 
                 CTTTGCATTCCAGACCTGGG 
                 5-10-5 
                 93.7 
                 60 
               
               
                   
               
               
                 410714 
                 2356 
                 2375 
                 ACTTTGCATTCCAGACCTGG 
                 2-13-5 
                 82.4 
                 411 
               
               
                   
               
               
                 410633 
                 2356 
                 2375 
                 ACTTTGCATTCCAGACCTGG 
                 3-14-3 
                 83.8 
                 411 
               
               
                   
               
               
                 410562 
                 2356 
                 2375 
                 ACTTTGCATTCCAGACCTGG 
                 5-10-5 
                 87.3 
                 411 
               
               
                   
               
               
                 410715 
                 2357 
                 2376 
                 GACTTTGCATTCCAGACCTG 
                 2-13-5 
                 80.5 
                 412 
               
               
                   
               
               
                 410634 
                 2357 
                 2376 
                 GACTTTGCATTCCAGACCTG 
                 3-14-3 
                 81.8 
                 412 
               
               
                   
               
               
                 405996 
                 2357 
                 2376 
                 GACTTTGCATTCCAGACCTG 
                 5-10-5 
                 91.0 
                 412 
               
               
                   
               
               
                 410563 
                 2358 
                 2377 
                 TGACTTTGCATTCCAGACCT 
                 5-10-5 
                 75.4 
                 413 
               
               
                   
               
               
                 410635 
                 2358 
                 2377 
                 TGACTTTGCATTCCAGACCT 
                 3-14-3 
                 75.9 
                 413 
               
               
                   
               
               
                 410716 
                 2358 
                 2377 
                 TGACTTTGCATTCCAGACCT 
                 2-13-5 
                 88.3 
                 413 
               
               
                   
               
               
                 410636 
                 2359 
                 2378 
                 TTGACTTTGCATTCCAGACC 
                 3-14-3 
                 61.3 
                 414 
               
               
                   
               
               
                 410564 
                 2359 
                 2378 
                 TTGACTTTGCATTCCAGACC 
                 5-10-5 
                 71.3 
                 414 
               
               
                   
               
               
                 410717 
                 2359 
                 2378 
                 TTGACTTTGCATTCCAGACC 
                 2-13-5 
                 76.7 
                 414 
               
               
                   
               
               
                 410718 
                 2360 
                 2379 
                 CTTGACTTTGCATTCCAGAC 
                 2-13-5 
                 55.8 
                 61 
               
               
                   
               
               
                 399973 
                 2360 
                 2379 
                 CTTGACTTTGCATTCCAGAC 
                 3-14-3 
                 82.1 
                 61 
               
               
                   
               
               
                 399817 
                 2360 
                 2379 
                 CTTGACTTTGCATTCCAGAC 
                 5-10-5 
                 93.6 
                 61 
               
               
                   
               
               
                 405997 
                 2362 
                 2381 
                 TCCTTGACTTTGCATTCCAG 
                 5-10-5 
                 95.6 
                 415 
               
               
                   
               
               
                 410779 
                 2375 
                 2394 
                 CGGGATTCCATGCTCCTTGA 
                 5-10-5 
                 79.7 
                 416 
               
               
                   
               
               
                 410780 
                 2405 
                 2424 
                 GCAGGCCACGGTCACCTGCT 
                 5-10-5 
                 60.9 
                 417 
               
               
                   
               
               
                 410781 
                 2442 
                 2461 
                 GGAGGGCACTGCAGCCAGTC 
                 5-10-5 
                 66.0 
                 418 
               
               
                   
               
               
                 410719 
                 2560 
                 2579 
                 CAGATGGCAACGGCTGTCAC 
                 2-13-5 
                 61.0 
                 419 
               
               
                   
               
               
                 410637 
                 2560 
                 2579 
                 CAGATGGCAACGGCTGTCAC 
                 3-14-3 
                 66.0 
                 419 
               
               
                   
               
               
                 410565 
                 2560 
                 2579 
                 CAGATGGCAACGGCTGTCAC 
                 5-10-5 
                 71.6 
                 419 
               
               
                   
               
               
                 410638 
                 2561 
                 2580 
                 GCAGATGGCAACGGCTGTCA 
                 3-14-3 
                 71.9 
                 420 
               
               
                   
               
               
                 410720 
                 2561 
                 2580 
                 GCAGATGGCAACGGCTGTCA 
                 2-13-5 
                 75.1 
                 420 
               
               
                   
               
               
                 410566 
                 2561 
                 2580 
                 GCAGATGGCAACGGCTGTCA 
                 5-10-5 
                 77.7 
                 420 
               
               
                   
               
               
                 410639 
                 2562 
                 2581 
                 AGCAGATGGCAACGGCTGTC 
                 3-14-3 
                 67.7 
                 421 
               
               
                   
               
               
                 410721 
                 2562 
                 2581 
                 AGCAGATGGCAACGGCTGTC 
                 2-13-5 
                 68.8 
                 421 
               
               
                   
               
               
                 410567 
                 2562 
                 2581 
                 AGCAGATGGCAACGGCTGTC 
                 5-10-5 
                 72.1 
                 421 
               
               
                   
               
               
                 410568 
                 2563 
                 2582 
                 CAGCAGATGGCAACGGCTGT 
                 5-10-5 
                 54.2 
                 422 
               
               
                   
               
               
                 410640 
                 2563 
                 2582 
                 CAGCAGATGGCAACGGCTGT 
                 3-14-3 
                 57.7 
                 422 
               
               
                   
               
               
                 410722 
                 2563 
                 2582 
                 CAGCAGATGGCAACGGCTGT 
                 2-13-5 
                 59.2 
                 422 
               
               
                   
               
               
                 410569 
                 2564 
                 2583 
                 GCAGCAGATGGCAACGGCTG 
                 5-10-5 
                 57.7 
                 423 
               
               
                   
               
               
                 410641 
                 2564 
                 2583 
                 GCAGCAGATGGCAACGGCTG 
                 3-14-3 
                 66.1 
                 423 
               
               
                   
               
               
                 410723 
                 2564 
                 2583 
                 GCAGCAGATGGCAACGGCTG 
                 2-13-5 
                 81.1 
                 423 
               
               
                   
               
               
                 399909 
                 2565 
                 2584 
                 GGCAGCAGATGGCAACGGCT 
                 3-14-3 
                 69.9 
                 62 
               
               
                   
               
               
                 410724 
                 2565 
                 2584 
                 GGCAGCAGATGGCAACGGCT 
                 2-13-5 
                 87.4 
                 62 
               
               
                   
               
               
                 395187 
                 2565 
                 2584 
                 GGCAGCAGATGGCAACGGCT 
                 5-10-5 
                 92.7 
                 62 
               
               
                   
               
               
                 410642 
                 2566 
                 2585 
                 CGGCAGCAGATGGCAACGGC 
                 3-14-3 
                 70.4 
                 424 
               
               
                   
               
               
                 410725 
                 2566 
                 2585 
                 CGGCAGCAGATGGCAACGGC 
                 2-13-5 
                 75.6 
                 424 
               
               
                   
               
               
                 410570 
                 2566 
                 2585 
                 CGGCAGCAGATGGCAACGGC 
                 5-10-5 
                 78.3 
                 424 
               
               
                   
               
               
                 410571 
                 2567 
                 2586 
                 CCGGCAGCAGATGGCAACGG 
                 5-10-5 
                 52.8 
                 425 
               
               
                   
               
               
                 410643 
                 2567 
                 2586 
                 CCGGCAGCAGATGGCAACGG 
                 3-14-3 
                 59.8 
                 425 
               
               
                   
               
               
                 410726 
                 2567 
                 2586 
                 CCGGCAGCAGATGGCAACGG 
                 2-13-5 
                 69.8 
                 425 
               
               
                   
               
               
                 410644 
                 2568 
                 2587 
                 TCCGGCAGCAGATGGCAACG 
                 3-14-3 
                 59.0 
                 426 
               
               
                   
               
               
                 410727 
                 2568 
                 2587 
                 TCCGGCAGCAGATGGCAACG 
                 2-13-5 
                 68.3 
                 426 
               
               
                   
               
               
                 405998 
                 2568 
                 2587 
                 TCCGGCAGCAGATGGCAACG 
                 5-10-5 
                 75.6 
                 426 
               
               
                   
               
               
                 405988 
                 2568 
                 2587 
                 TCCGGCAGCAGATGGCAACG 
                 5-10-5 
                 84.5 
                 426 
               
               
                   
               
               
                 410572 
                 2569 
                 2588 
                 CTCCGGCAGCAGATGGCAAC 
                 5-10-5 
                 40.9 
                 427 
               
               
                   
               
               
                 410728 
                 2569 
                 2588 
                 CTCCGGCAGCAGATGGCAAC 
                 2-13-5 
                 56.4 
                 427 
               
               
                   
               
               
                 410645 
                 2569 
                 2588 
                 CTCCGGCAGCAGATGGCAAC 
                 3-14-3 
                 70.2 
                 427 
               
               
                   
               
               
                 410729 
                 2570 
                 2589 
                 GCTCCGGCAGCAGATGGCAA 
                 2-13-5 
                 67.7 
                 428 
               
               
                   
               
               
                 410573 
                 2570 
                 2589 
                 GCTCCGGCAGCAGATGGCAA 
                 5-10-5 
                 71.8 
                 428 
               
               
                   
               
               
                 410646 
                 2570 
                 2589 
                 GCTCCGGCAGCAGATGGCAA 
                 3-14-3 
                 72.8 
                 428 
               
               
                   
               
               
                 410782 
                 2580 
                 2599 
                 CCAGGTGCCGGCTCCGGCAG 
                 5-10-5 
                 43.2 
                 429 
               
               
                   
               
               
                 410783 
                 2590 
                 2609 
                 GAGGCCTGCGCCAGGTGCCG 
                 5-10-5 
                 63.7 
                 430 
               
               
                   
               
               
                 399819 
                 2764 
                 2783 
                 CCCACTCAAGGGCCAGGCCA 
                 5-10-5 
                 93.4 
                 65 
               
               
                   
               
               
                 399912 
                 2852 
                 2871 
                 ATGCCCCACAGTGAGGGAGG 
                 3-14-3 
                 84.3 
                 66 
               
               
                   
               
               
                 405893 
                 3083 
                 3102 
                 ATGAGGGCCATCAGCACCTT 
                 5-10-5 
                 93.9 
                 431 
               
               
                   
               
               
                 405894 
                 3084 
                 3103 
                 GATGAGGGCCATCAGCACCT 
                 5-10-5 
                 93.9 
                 432 
               
               
                   
               
               
                 405895 
                 3085 
                 3104 
                 AGATGAGGGCCATCAGCACC 
                 5-10-5 
                 91.8 
                 433 
               
               
                   
               
               
                 405896 
                 3086 
                 3105 
                 GAGATGAGGGCCATCAGCAC 
                 5-10-5 
                 88.5 
                 434 
               
               
                   
               
               
                 395194 
                 3087 
                 3106 
                 GGAGATGAGGGCCATCAGCA 
                 5-10-5 
                 90.0 
                 69 
               
               
                   
               
               
                 399916 
                 3087 
                 3106 
                 GGAGATGAGGGCCATCAGCA 
                 3-14-3 
                 94.5 
                 69 
               
               
                   
               
               
                 405897 
                 3088 
                 3107 
                 TGGAGATGAGGGCCATCAGC 
                 5-10-5 
                 85.1 
                 435 
               
               
                   
               
               
                 405898 
                 3089 
                 3108 
                 CTGGAGATGAGGGCCATCAG 
                 5-10-5 
                 86.9 
                 436 
               
               
                   
               
               
                 405899 
                 3090 
                 3109 
                 GCTGGAGATGAGGGCCATCA 
                 5-10-5 
                 91.5 
                 437 
               
               
                   
               
               
                 405900 
                 3091 
                 3110 
                 AGCTGGAGATGAGGGCCATC 
                 5-10-5 
                 83.7 
                 438 
               
               
                   
               
               
                 405901 
                 3157 
                 3176 
                 GCTAGATGCCATCCAGAAAG 
                 5-10-5 
                 88.4 
                 439 
               
               
                   
               
               
                 405902 
                 3158 
                 3177 
                 GGCTAGATGCCATCCAGAAA 
                 5-10-5 
                 89.3 
                 440 
               
               
                   
               
               
                 405903 
                 3159 
                 3178 
                 TGGCTAGATGCCATCCAGAA 
                 5-10-5 
                 92.6 
                 441 
               
               
                   
               
               
                 405904 
                 3160 
                 3179 
                 CTGGCTAGATGCCATCCAGA 
                 5-10-5 
                 90.4 
                 442 
               
               
                   
               
               
                 399821 
                 3161 
                 3180 
                 TCTGGCTAGATGCCATCCAG 
                 5-10-5 
                 91.7 
                 71 
               
               
                   
               
               
                 405905 
                 3162 
                 3181 
                 CTCTGGCTAGATGCCATCCA 
                 5-10-5 
                 90.7 
                 443 
               
               
                   
               
               
                 405906 
                 3163 
                 3182 
                 CCTCTGGCTAGATGCCATCC 
                 5-10-5 
                 93.3 
                 444 
               
               
                   
               
               
                 405907 
                 3164 
                 3183 
                 GCCTCTGGCTAGATGCCATC 
                 5-10-5 
                 90.2 
                 445 
               
               
                   
               
               
                 405908 
                 3165 
                 3184 
                 AGCCTCTGGCTAGATGCCAT 
                 5-10-5 
                 83.3 
                 446 
               
               
                   
               
               
                 399978 
                 3243 
                 3262 
                 AGCCTGGCATAGAGCAGAGT 
                 3-14-3 
                 96.4 
                 73 
               
               
                   
               
            
           
         
       
     
     Antisense oligonucleotides that exhibited less than 30% inhibition of PCSK9 mRNA levels were marked with “NA”. 
     Antisense oligonucleotides with the following ISIS Nos exhibited at least 80% inhibition of PCSK9 mRNA levels: 395163, 395165, 395166, 395168, 395181, 395186, 395187, 395194, 399798, 399801, 399804, 399806, 399817, 399819, 399821, 399887, 399888, 399891, 399900, 399904, 399912, 399916, 399935, 399936, 399954, 399960, 399962, 399967, 399968, 399969, 399973, 399978, 399992, 405869, 405870, 405871, 405872, 405873, 405874, 405875, 405876, 405877, 405878, 405879, 405880, 405881, 405882, 405883, 405884, 405889, 405890, 405891, 405893, 405894, 405895, 405896, 405897, 405898, 405899, 405900, 405901, 405902, 405903, 405904, 405905, 405906, 405907, 405908, 405909, 405910, 405911, 405913, 405914, 405915, 405916, 405920, 405921, 405922, 405940, 405941, 405943, 405944, 405949, 405952, 405953, 405954, 405955, 405956, 405958, 405959, 405960, 405961, 405973, 405974, 405976, 405977, 405978, 405979, 405980, 405982, 405984, 405987, 405988, 405996, 405997, 406026, 406028, 406029, 406030, 406031, 406032, 406033, 406035, 406036, 406038, 406039, 406040, 406041, 406042, 406043, 406044, 406045, 410562, 410583, 410589, 410590, 410591, 410592, 410593, 410595, 410633, 410634, 410658, 410664, 410666, 410667, 410668, 410671, 410677, 410713, 410714, 410715, 410716, 410723, 410724, 410754, 410757, 410759, 410760, and 410769. The target segments to which these antisense oligonucleotides are targeted are active target segments. The target regions to which these antisense oligonucleotides are targeted are active target regions. 
     ISIS Nos 395165, 395166, 395168, 395181, 395186, 395187, 395194, 399801, 399817, 399819, 399821, 399887, 399888, 399891, 399900, 399904, 399916, 399936, 399954, 399962, 399969, 399978, 399992, 405869, 405871, 405872, 405873, 405874, 405875, 405876, 405878, 405879, 405880, 405881, 405882, 405883, 405884, 405890, 405891, 405893, 405894, 405895, 405896, 405897, 405898, 405899, 405901, 405902, 405903, 405904, 405905, 405906, 405907, 405910, 405911, 405913, 405914, 405915, 405916, 405920, 405921, 405922, 405941, 405952, 405953, 405954, 405955, 405956, 405959, 405960, 405961, 405974, 405977, 405978, 405979, 405980, 405982, 405987, 405996, 405997, 406028, 406029, 406030, 406031, 406032, 406033, 406035, 406038, 406039, 406040, 406041, 406042, 406043, 406044, 406045, 410562, 410583, 410591, 410592, 410593, 410668, 410677, 410716, 410724, 410757, and 410760 each exhibited at least 85% inhibition of PCSK9 mRNA levels. 
     ISIS Nos 395165, 395166, 395168, 395186, 395187, 395194, 399801, 399817, 399819, 399821, 399887, 399888, 399891, 399900, 399904, 399916, 399954, 399969, 399978, 399992, 405873, 405874, 405875, 405876, 405878, 405879, 405880, 405881, 405882, 405883, 405884, 405891, 405893, 405894, 405895, 405899, 405903, 405904, 405905, 405906, 405907, 405910, 405913, 405914, 405916, 405941, 405953, 405955, 405956, 405959, 405960, 405978, 405996, 405997, 406028, 406029, 406030, 406033, 406035, 406039, 406040, 406041, 406042, 406043, 406044, 410592, 410668, and 410760 each exhibited at least 90% inhibition of PCSK9 mRNA levels. 
     ISIS Nos 395165, 395166, 399801, 399978, 405881, 405891, 405959, 405978, 405997, 406030, 406040, 406041, 406044, and 410760 each exhibited at least 95% inhibition of PCSK9 mRNA levels. 
     Example 4: Antisense Reduction of Human PCSK9 mRNA in HepG2 Cells: Dose Response Experiment 
     Antisense oligonucleotides targeted to PCSK9 were tested at various doses in HepG2 cells. Cells were plated at densities of 10,000 cells per well and treated with nM concentrations of antisense oligonucleotide as indicated in Tables 20 and 21. After a treatment period of approximately 24 hours, RNA was isolated from the cells and PCSK9 mRNA levels were measured by quantitative real-time PCR, as described herein. Two different human PCSK9 primer probe sets were used to measure mRNA levels. Results with Primer Probe Set 2740 are shown in Table 20, and mRNA levels measured using primer probe set 2823 are shown in Table 21. Results are presented as percent PCSK9 mRNA levels relative to a control, as adjusted according to total RNA content measured by RIBOGREEN®. As illustrated in Tables 20 and 21, PCSK9 mRNA levels were reduced in a dose-dependent manner. 
     
       
         
           
               
             
               
                 TABLE 20 
               
             
            
               
                   
               
               
                 Antisense Reduction of PCSK9 mRNA in 
               
               
                 HepG2 cells, Primer Probe Set 2740 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                 6.25 
                 12.5 
                 25.0 
                 50.0 
                 100.0 
                 200.0 
               
               
                 Isis No 
                 nM 
                 nM 
                 nM 
                 nM 
                 nM 
                 nM 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                 399819 
                 93 
                 113 
                 84 
                 71 
                 26 
                 12 
               
               
                 395185 
                 81 
                 64 
                 50 
                 35 
                 24 
                 13 
               
               
                 399916 
                 65 
                 56 
                 41 
                 18 
                 20 
                 25 
               
               
                 399907 
                 68 
                 66 
                 42 
                 26 
                 30 
                 25 
               
               
                 399954 
                 71 
                 63 
                 38 
                 22 
                 16 
                 15 
               
               
                 395165 
                 71 
                 67 
                 47 
                 29 
                 21 
                 10 
               
               
                 399936 
                 65 
                 51 
                 31 
                 20 
                 30 
                 28 
               
               
                 399793 
                 61 
                 57 
                 44 
                 31 
                 39 
                 15 
               
               
                 399969 
                 57 
                 54 
                 40 
                 27 
                 25 
                 19 
               
               
                 395152 
                 75 
                 58 
                 58 
                 49 
                 24 
                 28 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 21 
               
             
            
               
                   
               
               
                 Antisense Reduction of PCSK9 mRNA in 
               
               
                 HepG2 cells, Primer Probe Set 2823 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                 6.25 
                 12.5 
                 25.0 
                 50.0 
                 100.0 
                 200.0 
               
               
                 Isis No 
                 nM 
                 nM 
                 nM 
                 nM 
                 nM 
                 nM 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                 399819 
                 80 
                 264 
                 87 
                 85 
                 34 
                 15 
               
               
                 395185 
                 86 
                 66 
                 57 
                 45 
                 29 
                 22 
               
               
                 399916 
                 75 
                 47 
                 45 
                 20 
                 30 
                 45 
               
               
                 399907 
                 67 
                 72 
                 47 
                 29 
                 31 
                 32 
               
               
                 399954 
                 59 
                 50 
                 35 
                 17 
                 22 
                 27 
               
               
                 395165 
                 74 
                 54 
                 41 
                 37 
                 26 
                 22 
               
               
                 399936 
                 62 
                 41 
                 33 
                 32 
                 28 
                 42 
               
               
                 399793 
                 62 
                 51 
                 38 
                 36 
                 44 
                 27 
               
               
                 399969 
                 73 
                 40 
                 58 
                 28 
                 29 
                 35 
               
               
                 395152 
                 78 
                 53 
                 64 
                 49 
                 22 
                 35 
               
               
                   
               
            
           
         
       
     
     Example 5: Antisense Reduction of Human PCSK9 mRNA in Hep3B Cells: Dose Response Experiment 
     Antisense oligonucleotides targeted to PCSK9 were tested at various doses in Hep3B cells. Cells were plated at densities of 4,500 cells per well and treated with nM concentrations of antisense oligonucleotide as indicated in Table 22. ISIS 141923 is not complementary to any known gene sequence and is used in this and the following experiments as a negative control. After a treatment period of approximately 24 hours, RNA was isolated from the cells and PCSK9 mRNA levels were measured by quantitative real-time PCR, as described herein. Two different human PCSK9 primer probe sets were used to measure mRNA levels. Results with Primer Probe Set 2740 are shown in Table 22. Results are presented as percent PCSK9 mRNA levels relative to a control, as adjusted according to total RNA content measured by RIBOGREEN®. As illustrated in Table 22, PCSK9 mRNA levels were reduced in a dose-dependent manner. 
     
       
         
           
               
             
               
                 TABLE 22 
               
             
            
               
                   
               
               
                 Antisense Reduction of PCSK9 mRNA in 
               
               
                 Hep3B cells, Primer Probe Set 2740 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                 Isis No. 
                 2.78 nM 
                 8.33 nM 
                 25.0 nM 
                 75.0 nM 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
               
            
               
                   
                 399819 
                 127.5 
                 85.0 
                 36.1 
                 21.9 
               
               
                   
                 405891 
                 133.7 
                 111.4 
                 40.2 
                 27.2 
               
               
                   
                 406008 
                 144.6 
                 108.3 
                 49.9 
                 17.7 
               
               
                   
                 395186 
                 124.4 
                 106.4 
                 42.2 
                 30.7 
               
               
                   
                 395185 
                 150.7 
                 106.6 
                 53.6 
                 38.1 
               
               
                   
                 405994 
                 141.9 
                 101.2 
                 49.3 
                 30.8 
               
               
                   
                 405988 
                 148.1 
                 117.4 
                 47.8 
                 25.2 
               
               
                   
                 406033 
                 138.1 
                 109.9 
                 62.4 
                 35.3 
               
               
                   
                 395187 
                 133.0 
                 115.6 
                 59.9 
                 31.6 
               
               
                   
                 405995 
                 124.1 
                 109.2 
                 57.8 
                 42.9 
               
               
                   
                 406023 
                 130.0 
                 103.5 
                 67.1 
                 28.0 
               
               
                   
                 399900 
                 131.2 
                 95.7 
                 81.1 
                 30.9 
               
               
                   
                 301012 
                 121.2 
                 100.1 
                 63.8 
                 49.6 
               
               
                   
                 395165 
                 113.2 
                 86.9 
                 41.6 
                 13.3 
               
               
                   
                 405879 
                 124.6 
                 88.8 
                 44.1 
                 13.1 
               
               
                   
                 405991 
                 100.6 
                 101.4 
                 95.9 
                 41.0 
               
               
                   
                 405923 
                 130.4 
                 115.0 
                 68.9 
                 35.1 
               
               
                   
                 395152 
                 143.8 
                 98.6 
                 61.3 
                 59.0 
               
               
                   
                 405881 
                 100.7 
                 77.4 
                 50.2 
                 4.5 
               
               
                   
                 141923 
                 131.4 
                 131.9 
                 144.0 
                 167.3 
               
               
                   
                   
               
            
           
         
       
     
     Example 6: Antisense Reduction of Human PCSK9 mRNA in HeLa Cells: Dose Response Experiment 
     Antisense oligonucleotides targeted to PCSK9 were tested at various doses in HeLa cells. Cells were plated at densities of 5,000 cells per well and treated with nM concentrations of antisense oligonucleotide as indicated in Table 23. After a treatment period of approximately 24 hours, RNA was isolated from the cells and PCSK9 mRNA levels were measured by quantitative real-time PCR, as described herein. Two different human PCSK9 primer probe sets were used to measure mRNA levels. Results with Primer Probe Set 2740 are shown in Table 23. Results are presented as percent PCSK9 mRNA levels relative to a control, as adjusted according to total RNA content measured by RIBOGREEN®. As illustrated in Table 23, PCSK9 mRNA levels were reduced in a dose-dependent manner. 
     
       
         
           
               
             
               
                 TABLE 23 
               
             
            
               
                   
               
               
                 Antisense Reduction of PCSK9 mRNA in 
               
               
                 HeLa cells, Primer Probe Set 2740 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                 Isis No. 
                 2.963 nM 
                 8.8889 nM 
                 26.6667 nM 
                 80.0 nM 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
               
            
               
                   
                 399819 
                 57 
                 32 
                 16 
                 14 
               
               
                   
                 405891 
                 57 
                 46 
                 17 
                 18 
               
               
                   
                 406008 
                 45 
                 27 
                 11 
                 5.3 
               
               
                   
                 395186 
                 40 
                 28 
                 11 
                 6.6 
               
               
                   
                 395185 
                 53 
                 32 
                 21 
                 17 
               
               
                   
                 405994 
                 48 
                 34 
                 20 
                 13 
               
               
                   
                 405988 
                 44 
                 32 
                 12 
                 7.3 
               
               
                   
                 406033 
                 61 
                 42 
                 25 
                 12 
               
               
                   
                 395187 
                 42 
                 35 
                 12 
                 6.6 
               
               
                   
                 405995 
                 54 
                 39 
                 21 
                 15 
               
               
                   
                 406023 
                 76 
                 46 
                 25 
                 6.2 
               
               
                   
                 399900 
                 85 
                 48 
                 23 
                 6.4 
               
               
                   
                 301012 
                 121 
                 109 
                 76 
                 65 
               
               
                   
                 395165 
                 61 
                 30 
                 10 
                 2 
               
               
                   
                 405879 
                 64 
                 32 
                 9.7 
                 1 
               
               
                   
                 405991 
                 64 
                 35 
                 24 
                 10 
               
               
                   
                 405923 
                 71 
                 45 
                 22 
                 5 
               
               
                   
                 395152 
                 73 
                 34 
                 13 
                 3.1 
               
               
                   
                 405881 
                 58 
                 33 
                 19 
                 2.8 
               
               
                   
                 141923 
                 122 
                 118 
                 131 
                 140 
               
               
                   
                   
               
            
           
         
       
     
     Example 7: Antisense Reduction of Human PCSK9 mRNA in Primary Hepatocytes 
     Antisense oligonucleotides targeted to PCSK9 were tested for antisense inhibition of PCSK9 in human primary hepatocytes. Human primary hepatocytes were purchased from a commercial supplier, and cultured according to routine culture procedures. Cells were treated with 10, 25, 50, 150, or 300 nM of antisense oligonucleotide for a period of 24 hours, after which RNA was isolated and PCSK9 mRNA was measured by real-time PCR as described herein. 
     The antisense oligonucleotides tested in human primary hepatocytes were Isis 395152, 395155, 395165, 395185, 399819, 399821, 399916, 399954, 399978, and 399992. The antisense oligonucleotides inhibited PCSK9 in a dose-dependent manner in human primary hepatocytes. 
     Monkey primary hepatocytes were similarly treated with 10, 25, 50, 150, or 300 nM concentrations of antisense oligonucleotide targeted to PCSK9. The antisense oligonucleotides tested in monkey primary hepatocytes were Isis 395152, 395155, 395165, 395185, 399819, 399821, 399916, 399954, 399978, and 399992. Each of these antisense oligonucleotides is fully complementary to a monkey PCSK9 nucleic acid. The antisense oligonucleotides inhibited PCSK9 in a dose-dependent manner in monkey primary hepatocytes. 
     Example 8: Additional Antisense Reduction of Human PCSK9 mRNA in Primary Hepatocytes 
     Antisense oligonucleotides targeted to PCSK9 were tested for antisense inhibition of PCSK9 in human primary hepatocytes. Human primary hepatocytes were purchased from a commercial supplier, and cultured according to routine culture procedures. Cells were treated with 10, 25, 50, 150, or 300 nM of antisense oligonucleotide for a period of 24 hours, after which RNA was isolated and PCSK9 mRNA was measured by real-time PCR as described herein. 
     The antisense oligonucleotides tested in human primary hepatocytes were Isis 395165, 395185, 395186, 395187, 405879, 405881, 405891, 405988, 405994, and 406008. The antisense oligonucleotides inhibited PCSK9 in a dose-dependent manner in human primary hepatocytes as shown in Table 24. 
     
       
         
           
               
             
               
                 TABLE 24 
               
             
            
               
                   
               
               
                 Dose-dependent Reduction in Human PCSK9 mRNA 
               
               
                 Expression in Human Primary Hepatocytes 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                 ISIS No. 
                 10 nM 
                 25 nM 
                 50 nM 
                 150 nM 
                 300 nM 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                 395165 
                 76 
                 48.7 
                 22.5 
                 20.2 
                 16.2 
               
               
                   
                 395185 
                 74.5 
                 42.9 
                 52.6 
                 25.5 
                 15.7 
               
               
                   
                 395186 
                 123.8 
                 58.3 
                 34.4 
                 21 
                 19.9 
               
               
                   
                 395187 
                 98.7 
                 43.5 
                 29.7 
                 17.4 
                 21.1 
               
               
                   
                 405879 
                 119.2 
                 176.6 
                 64.9 
                 48.4 
                 47.7 
               
               
                   
                 405881 
                 222.4 
                 115.3 
                 49.5 
                 22.3 
                 79.3 
               
               
                   
                 405891 
                 169.9 
                 138.7 
                 73.9 
                 86.9 
                 48.7 
               
               
                   
                 405988 
                 85.2 
                 105.4 
                 67.8 
                 43.9 
                 43.8 
               
               
                   
                 405994 
                 95.7 
                 83.3 
                 43.5 
                 24.6 
                 10.5 
               
               
                   
                 406008 
                 155 
                 101.7 
                 116 
                 41.7 
                 32.4 
               
               
                   
                   
               
            
           
         
       
     
     Example 9: Antisense Reduction of PCSK9 mRNA in Cyno Primary Hepatocytes 
     Antisense oligonucleotides targeted to PCSK9 were tested for antisense inhibition of PCSK9 in cyno primary hepatocytes. Cyno primary hepatocytes were purchased from a commercial supplier, and cultured according to routine culture procedures. Cells were treated with 10, 25, 50, 150, or 300 nM of antisense oligonucleotide for a period of 24 hours, after which RNA was isolated and PCSK9 mRNA was measured by real-time PCR as described herein. 
     The antisense oligonucleotides tested in cyno primary hepatocytes were Isis 395165, 395185, 395186, 395187, 405879, 405881, 405891, 405988, 405994, and 406008. The antisense oligonucleotides inhibited PCSK9 in a dose-dependent manner in cyno primary hepatocytes as shown in Table 25. 
     
       
         
           
               
             
               
                 TABLE 25 
               
             
            
               
                   
               
               
                 Dose-dependent PCSK9 mRNA Inhibition 
               
               
                 in Cyno Primary Hepatocytes 
               
            
           
           
               
               
               
               
               
               
            
               
                 ISIS No. 
                 10 nM 
                 25 nM 
                 50 nM 
                 150 nM 
                 300 nM 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 395165 
                 36.3 
                 29.9 
                 14.9 
                 8.6 
                 3.2 
               
               
                 395185 
                 65.0 
                 31.9 
                 35.1 
                 16.6 
                 12.0 
               
               
                 395186 
                 65.8 
                 42.3 
                 21.6 
                 23.3 
                 16.7 
               
               
                 395187 
                 61.3 
                 32.9 
                 13.2 
                 7.7 
                 9.02 
               
               
                 405879 
                 24.3 
                 21.9 
                 7.7 
                 7.1 
                 3.0 
               
               
                 405881 
                 75.0 
                 33.5 
                 26.5 
                 11.2 
                 4.9 
               
               
                 405891 
                 52.4 
                 24.8 
                 11.2 
                 10.8 
                 6.7 
               
               
                 405988 
                 59.4 
                 23.7 
                 22.5 
                 10.7 
                 8.2 
               
               
                 405994 
                 64.8 
                 52.7 
                 22.2 
                 7.9 
                 6.5 
               
               
                 406008 
                 56.3 
                 28.2 
                 26.5 
                 13.4 
                 13.3 
               
               
                   
               
            
           
         
       
     
     Example 10: Antisense Reduction of Mouse PCSK9 mRNA In Vitro 
     Antisense oligonucleotides were designed to target murine PCSK9, and were evaluated for their ability to reduce PCSK9 mRNA in primary mouse hepatocytes. 
     Primary mouse hepatocytes were treated with antisense oligonucleotides at doses of 50, 150, or 300 nM, for a period of 24 hours. RNA was isolated using QIAGEN® RNeasy isolation kits and subjected to quantitative real-time PCR using commercially available reagents (Invitrogen, Carlsbad, Calif.). PCSK9 mRNA levels were measured using a mouse PCSK9 primer probe set, and normalized to G3PDH mRNA levels and/or RIBOGREEN® levels. 
     ISIS 394814 (GAGCAACTTCGGAGGCAGC, SEQ ID NO: 456) was identified as a potent inhibitor of mouse PCSK9. PCSK9 mRNA levels ISIS 394814 yielded a 50% reduction in PCSK9 mRNA at a concentration of 25 nM (i.e., an IC50 of 25 nM) after a 24 hour incubation with primary mouse hepatocytes. No effect on cultured cell viability was observed. 
     Example 11: Antisense Reduction of PCSK9 mRNA in an Animal Model of Hyperlipidemia: High Fat Fed Mice 
     Treatment 
     C57BL/6 mice fed a high-fat diet are routinely employed as an animal model of hyperlipidemia, as well as an animal model of atherosclerosis. Accordingly, to evaluate the effects of PCSK9 antisense inhibition on serum lipid levels in vivo, ISIS 394814 was evaluated in C57BL/6 mice fed a high-fat diet. C57BL/6 mice 4-5 weeks of age were obtained from the Jackson Laboratory and maintained on a diet consisting of 60% fat. Treatment groups of 5 mice each were as follows: a group treated with ISIS 394814; a control group treated with saline; and control group treated with an oligonucleotide not complementary to any known gene sequence (ISIS 141923). Oligonucleotide or saline was administered intraperitoneally twice weekly, for a period of 6 weeks; oligonucleotide doses were 50 mg/kg. After the treatment period, whole blood was collected for analysis of serum parameters, and whole liver was collected for RNA analysis, protein analysis, and histological evaluation. Statistical analyses included a nonparametric, two-tailed t-test comparison of experimental samples (ISIS 394814) to control samples (saline or control oligonucleotide). 
     RNA Analysis 
     Liver RNA was isolated for real-time PCR analysis of PCSK9, LDL-receptor and apolipoprotein B mRNA levels. Treatment with ISIS 394814 resulted in a 92% reduction in PCSK9 mRNA levels, while no significant reduction in PCSK9 mRNA levels was observed in ISIS 141923-treated or saline-treated mice. Antisense inhibition of PCSK9 expression did not significantly affect liver LDL-receptor or liver apolipoprotein B mRNA levels. 
     Protein Analysis 
     Immunoblotting was performed to assess the effects of PCSK9 antisense inhibition on LDL-receptor protein and apolipoprotein B levels. Protein isolated from mouse liver was subjected to electrophoresis, transferred to a polyvinylidene-fluoride membrane, and subsequently probed with an anti-mouse LDL-receptor antibody and a scavenger receptor B1 (SR-B1) antibody. Mouse plasma was similarly subjected to electrophoresis and immunoblotting using an anti-mouse apolipoprotein B antibody. Secondary antibodies conjugated to peroxidase were used to detect primary antibodies. Protein bands were visualized using the ECL plus Western blot detection kit (Amersham Biosciences, UK) and quantified using ImageQuant™ analysis software (MolecularDynamics, Santa Clara, Calif.). 
     While LDL-receptor mRNA levels were not significantly affected, antisense inhibition of PCSK9 resulted in an approximate 2-fold increase in the level of hepatic LDL-receptor protein relative to 141923-treated controls. No changes in SR-B1 protein were observed. Furthermore, serum apoB-100 levels were significantly reduced by 50%, relative to 141923-treated controls. Serum apoB-48 levels were significantly increased by approximately 3-fold relative to 141923-treated controls. No significant changes in apoA-I protein were observed, relative to 141923-treated controls. 
     The mRNA levels of the RNA editing enzyme apobec-1 were also measured. Apobec-1 is responsible for the RNA editing that produces apoB-48 in murine liver and intestine. Human apobec-1 is expressed only in intestinal cells, thus these cells are the source of apoB-48 in humans. Antisense inhibition of PCSK9 resulted in an increase in murine hepatic apobec-1 mRNA levels by approximately 2.7 fold compared to saline-treated controls 
     Serum Lipid Analysis 
     Plasma concentrations of total cholesterol, LDL-C, HDL-C, free cholesterol, triglycerides, glucose, ketones, transaminases, and phospholipids were measured using an automated clinical chemistry analyzer (Hitachi Olympus AU400e, Melville, N.Y.). Serum lipoprotein and cholesterol profiling was performed as described by Crooke et al. (Lipid Res., 2005, 46, 872-884) using a Beckman System Gold 126 HPLC system, a 507e refrigerated autosampler, a 126 photodiode array detector (Beckman Instruments, Fullerton, Calif.), and a Superose 6 HR 10/30 column (Pfizer, Chicago, Ill.). HDL, LDL and VLDL fractions were measured at a wavelength of 505 nm and validated with a cholesterol calibration kit. (Sigma). 
     Administration of ISIS 394814 resulted in a 52% reduction in total cholesterol (saline, 183 mg/dL±18; ISIS 141923, 194 mg/dL±14; ISIS 394814, 87 mg/dL±19, p&lt;0.005) and a 36% reduction in LDL-C (saline 22 mg/dL±4; ISIS 141923, 25 mg/dL±2; ISIS 394814, 14 mg/dL±2, p&lt;0.005). Serum free cholesterol was reduced by 25% (saline 41 mg/dL±10; ISIS 141923, 58 mg/dL±3; ISIS 394814, 31 mg/dL±5, p&lt;0.005) and phospholipids were reduced 54% (saline, 354 mg/dL±29; ISIS 141923, 383 mg/dL±21; ISIS 394814, 169 mg/dL±35, p&lt;0.0001). HDL-C was also reduced by approximately 54% (saline, 183 mg/dL±18; ISIS 141923, 194 mg/dL±14; ISIS 394814, 87 mg/dL±19; p&lt;0.0001). HPLC profiling confirmed the reduction of LDL and HDL lipid classes. 
     Liver Triglyceride Analysis 
     Liver triglyceride content was measured according to routine experimental procedures, for example, per procedures described by Desai et al., Diabetes, 2001, 50:2287-2295. 
     Antisense inhibition of PCSK9 for 6 weeks reduced liver triglyceride content by approximately 65% (p=0.01) relative to saline controls. No statistically significant changes in liver triglyceride content following 141923 treatment were observed. 
     Accordingly, one embodiment is a method of lowering LDL-C levels through the administration of an antisense oligonucleotide targeted to a PCSK9 nucleic acid. An additional embodiment includes a method of lowering total cholesterol through the administration of an antisense oligonucleotide targeted to a PCSK9 nucleic acid. An addition embodiment is lowering liver triglycerides by administering an antisense oligonucleotide targeted to a PCSK9 target nucleic acid. 
     Example 12: Antisense Reduction of PCSK9 mRNA in LDL-R Deficient/apoB-100 Animals 
     LDL-receptor (LDL-R)-deficient/apoB-100 animals do not express the LDL-R gene, and express only the apoB-100 form of apoB. PCSK9 antisense oligonucleotide was administered to LDL-R deficient/apoB-100 mice, to evaluate the effects of antisense inhibition of PCSK9 in the absence of the LDL-R. Mice 4-5 weeks of age were maintained on a standard mouse diet. Treatment groups of 5 mice each were as follows: a group treated with ISIS 394814; a control group treated with saline; and control group treated with an oligonucleotide not complementary to any known gene sequence (ISIS 141923). Oligonucleotide or saline was administered intraperitoneally twice weekly, for a period of 6 weeks; oligonucleotide doses were 50 mg/kg (100 mg/kg/wk total). Real-time PCR of liver mRNA and serum analyses were performed as described for the C57Bl/6 study. 
     Antisense inhibition of PCSK9 reduced liver PCSK9 mRNA by approximately 90%, relative to saline controls. However, no reduction in serum cholesterol was observed. Liver triglyceride levels were unaffected by antisense inhibition of PCKS9 in these mice. An 80% increase in liver apobec1 mRNA levels was observed, relative to saline controls. These data suggest that a functioning LDL-R is required for cholesterol and liver triglyceride reduction via PCSK9 antisense inhibition. 
     Example 13: Antisense Reduction of PCSK9 mRNA in Mouse Primary Hepatocytes 
     Antisense oligonucleotides targeted to PCSK9 were tested for antisense inhibition of PCSK9 in mouse primary hepatocytes. Mouse primary hepatocytes were purchased from a commercial supplier, and cultured according to routine culture procedures. Cells were treated with 6.25, 12.5, 25, 50, 100, or 200 nM of antisense oligonucleotide for a period of 24 hours, after which RNA was isolated and PCSK9 mRNA was measured by real-time PCR as described herein. 
     The antisense oligonucleotides tested in human primary hepatocytes were Isis 395165, 395185, 395186, 395187, 405879, 405881, 405891, 405988, 405994, and 406008. The antisense oligonucleotides inhibited PCSK9 in a dose-dependent manner in human primary hepatocytes as shown in Table 26. 
     
       
         
           
               
             
               
                 TABLE 26 
               
             
            
               
                   
               
               
                 Dose-Dependent Reduction PCSK9 mRNA 
               
               
                 in Mouse Primary Hepatocytes 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                 6.25 
                 12.5 
                 25.0 
                 50.0 
                 100.0 
                 200.0 
               
               
                 ISIS No 
                 nM 
                 nM 
                 nM 
                 nM 
                 nM 
                 nM 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                 395165 
                 95.2 
                 94.9 
                 81.7 
                 66.3 
                 57.5 
                 29.9 
               
               
                 395185 
                 109.2 
                 100 
                 90.5 
                 81.2 
                 64.7 
                 35.8 
               
               
                 395186 
                 101.9 
                 91.5 
                 77.8 
                 59.1 
                 39.5 
                 13.7 
               
               
                 395187 
                 102.4 
                 96.1 
                 83.9 
                 66.4 
                 40 
                 15.3 
               
               
                 405879 
                 107.3 
                 97.5 
                 87.8 
                 76.6 
                 63 
                 43.1 
               
               
                 405881 
                 104.8 
                 102.1 
                 98.1 
                 84.9 
                 68.7 
                 48.9 
               
               
                 405891 
                 104.9 
                 103.3 
                 101.5 
                 88.9 
                 79.6 
                 49.5 
               
               
                 405988 
                 97.3 
                 101.1 
                 91.7 
                 82.3 
                 61.2 
                 34.8 
               
               
                 405994 
                 110.2 
                 101 
                 111.6 
                 94.4 
                 80.1 
                 57.7 
               
               
                 406008 
                 99.5 
                 91.3 
                 83.9 
                 73.7 
                 61.8 
                 39.4 
               
               
                 157700 
                 97.8 
                 98.3 
                 96.2 
                 94.3 
                 83.2 
                 76.4 
               
               
                 141923 
                 84.3 
                 80 
                 79.9 
                 77.3 
                 98.8 
                 64.2 
               
               
                   
               
            
           
         
       
     
     Example 14: Antisense Reduction of Human PCSK9 mRNA in Hep3B and HeLa Cells: Dose Response Experiment 
     A subset of the antisense oligonucleotides that inhibited PCSK9 expression at high levels in the cell culture systems described above was selected for further screening. The group of selected antisense compounds is shown in Table 27. Table 27 shows the Isis number, nucleotide sequence, and percent inhibition obtained in Hep3B cells using the protocol disclosed in Example 3 (see Table 17) for the various antisense compounds. 
     
       
         
           
               
               
               
               
               
             
               
                 TABLE 27 
               
               
                   
               
               
                   
                   
                   
                   
                 SEQ 
               
               
                 Isis 
                   
                   
                 % 
                 ID 
               
               
                 No. 
                 Sequence 5′-3′ 
                 Motif 
                 inhibition 
                 NO 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 405881 
                 CACCCTTGGCCACGCCGGCA 
                 5-10-5 
                 98.3 
                 250 
               
               
                   
               
               
                 399819 
                 CCCACTCAAGGGCCAGGCCA 
                 5-10-5 
                 93.4 
                 65 
               
               
                   
               
               
                 395165 
                 ACCCTTGGCCACGCCGGCAT 
                 5-10-5 
                 96.7 
                 28 
               
               
                   
               
               
                 405879 
                 CCTTGGCCACGCCGGCATCC 
                 5-10-5 
                 94.1 
                 248 
               
               
                   
               
               
                 406008 
                 CTTGGTGAGGTATCCCCGGC 
                 5-10-5 
                 95.2 
                 188 
               
               
                   
               
               
                 405891 
                 TCCTCAGGGAACCAGGCCTC 
                 5-10-5 
                 96.1 
                 352 
               
               
                   
               
               
                 395186 
                 CTTTGCATTCCAGACCTGGG 
                 5-10-5 
                 93.7 
                 60 
               
               
                   
               
               
                 405988 
                 GGCAGCACCTGGCAATGGCG 
                 5-10-5 
                 95.9 
                 381 
               
               
                   
               
               
                 405994 
                 GCAGTGGACACGGGTCCCCA 
                 5-10-5 
                 95.2 
                 400 
               
               
                   
               
               
                 406023 
                 TGGTATTCATCCGCCCGGTA 
                 5-10-5 
                 92.5 
                 212 
               
               
                   
               
               
                 395187 
                 GGCAGCAGATGGCAACGGCT 
                 5-10-5 
                 92.7 
                 62 
               
               
                   
               
               
                 395185 
                 CACGGGTCCCCATGCTGGCC 
                 5-10-5 
                 92.7 
                 59 
               
               
                   
               
               
                 406033 
                 CCTGCCAGGTGGGTGCCATG 
                 5-10-5 
                 91.2 
                 237 
               
               
                   
               
               
                 405923 
                 GGCATTGGTGGCCCCAACTG 
                 5-10-5 
                 94.3 
                 288 
               
               
                   
               
               
                 399900 
                 GGTCCTCAGGGAACCAGGCC 
                 3-14-3 
                 92.0 
                 50 
               
               
                   
               
               
                 405995 
                 TGGCAGTGGACACGGGTCCC 
                 5-10-5 
                 92.4 
                 402 
               
               
                   
               
               
                 405991 
                 GACACGGGTCCCCATGCTGG 
                 5-10-5 
                 91.9 
                 394 
               
               
                   
               
               
                 406005 
                 CGGGCAGTGCGCTCTGACTG 
                 5-10-5 
                 83.4 
                 180 
               
               
                   
               
               
                 399793 
                 CCTCGGAACGCAAGGCTAGC 
                 5-10-5 
                 77.9 
                 8 
               
               
                   
               
               
                 395152 
                 ACGCAAGGCTAGCACCAGCT 
                 5-10-5 
                 93.3 
                 7 
               
               
                   
               
            
           
         
       
     
     The IC 50  of the various antisense compounds was determined using different cell culture systems. Antisense oligonucleotides targeted to PCSK9 were tested at various doses in Hep3B or HeLa cells, for example. Cells were plated at densities of 4,500 cells or 5,000 per well, respectively, and treated with of antisense oligonucleotides at various concentrations. After a treatment period of approximately 24 hours, RNA was isolated from the cells and PCSK9 mRNA levels were measured by quantitative real-time PCR, as described herein, relative to untreated control cells. Two different human PCSK9 primer probe sets were used to measure mRNA levels. Results with Primer Probe Set 2740 are shown in Table 28. PCSK9 mRNA levels were adjusted according to total RNA content as measured by RIBOGREEN®. Table 28 shows IC 50  values (nM) obtained from two experiments with Hep3B cells and from one experiment with HeLa cells. 
     
       
         
           
               
             
               
                 TABLE 28 
               
             
            
               
                   
               
               
                 IC 50  values 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                 Hep3B 
                 Hep3B 
                 HeLa 
                   
                 SEQ 
               
               
                 ISIS 
                 IC 50   
                 IC 50   
                 IC 50   
                 PCSK9 Target 
                 ID 
               
               
                 # 
                 (nM) 
                 (nM) 
                 (nM) 
                 Sequence 
                 NO 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 405881 
                 21 
                 26 
                 13 
                 CACCCTTGGCCACGCCGGCA 
                 250 
               
               
                   
               
               
                 399819 
                 21 
                 28 
                 12 
                 CCCACTCAAGGGCCAGGCCA 
                 65 
               
               
                   
               
               
                 395165 
                 23 
                 28 
                 13 
                 ACCCTTGGCCACGCCGGCAT 
                 28 
               
               
                   
               
               
                 405879 
                 24 
                 28 
                 14 
                 CCTTGGCCACGCCGGCATCC 
                 248 
               
               
                   
               
               
                 406008 
                 31 
                 35 
                 8 
                 CTTGGTGAGGTATCCCCGGC 
                 188 
               
               
                   
               
               
                 405891 
                 32 
                 38 
                 14 
                 TCCTCAGGGAACCAGGCCTC 
                 352 
               
               
                   
               
               
                 395186 
                 33 
                 33 
                 7 
                 CTTTGCATTCCAGACCTGGG 
                 60 
               
               
                   
               
               
                 405988 
                 34 
                 42 
                 8 
                 GGCAGCACCTGGCAATGGCG 
                 381 
               
               
                   
               
               
                 405994 
                 35 
                 39 
                 9 
                 GCAGTGGACACGGGTCCCCA 
                 400 
               
               
                   
               
               
                 406023 
                 40 
                 50 
                 18 
                 TGGTATTCATCCGCCCGGTA 
                 212 
               
               
                   
               
               
                 395187 
                 41 
                 44 
                 8 
                 GGCAGCAGATGGCAACGGCT 
                 62 
               
               
                   
               
               
                 395185 
                 42 
                 43 
                 11 
                 CACGGGTCCCCATGCTGGCC 
                 59 
               
               
                   
               
               
                 406033 
                 44 
                 61 
                 15 
                 CCTGCCAGGTGGGTGCCATG 
                 237 
               
               
                   
               
               
                 405923 
                 47 
                 41 
                 20 
                 GGCATTGGTGGCCCCAACTG 
                 288 
               
               
                   
               
               
                 399900 
                 48 
                 44 
                 21 
                 GGTCCTCAGGGAACCAGGCC 
                 50 
               
               
                   
               
               
                 405995 
                 48 
                 63 
                 12 
                 TGGCAGTGGACACGGGTCCC 
                 402 
               
               
                   
               
               
                 405991 
                 63 
                 52 
                 15 
                 GACACGGGTCCCCATGCTGG 
                 394 
               
               
                   
               
               
                 406005 
                 63 
                   
                   
                 CGGGCAGTGCGCTCTGACTG 
                 180 
               
               
                   
               
               
                 399793 
                 &gt;75 
                   
                   
                 CCTCGGAACGCAAGGCTAGC 
                 8 
               
               
                   
               
               
                 395152 
                   
                 46 
                 16 
                 ACGCAAGGCTAGCACCAGCT 
                 7 
               
               
                   
               
            
           
         
       
     
     Several of the antisense compounds examined above were selected for further study. These antisense compounds exhibited at least about 93% inhibition of human PCSK9 mRNA expression in the Hep3B cell culture system, as shown in Tables 17-19, for example. As shown in Table 28, the selected antisense compounds also displayed IC 50  parameters of less than about 45 nM when tested with Hep3B cells and less than about 15 nM when tested with HeLa cells. The selected antisense compounds, listed in Table 29, are Isis 405881, Isis 395165, Isis 405879, Isis 406008, Isis 405891, Isis 395186, Isis 405988, Isis 405994, Isis 395187, and Isis 395185. Isis 405879, for example, showed superior results in both Hep3B and HeLa cells, with IC 50  values of about 26 nM and 14 nM, respectively. 
     Example 15: Dose-Dependent Antisense Reduction of PCSK9 mRNA in Human Primary Hepatocytes; Cynomolgus Monkey (“Cyno”) Primary Hepatocytes; and Human HEK-293 Cells 
     The selected antisense oligonucleotides were further tested for dose dependent antisense inhibition in human primary hepatocytes, cyno primary hepatocytes, and HEK-293 cells expressing human PCSK9. Cells were purchased from commercial suppliers and cultured according to routine culture procedures. Cells were treated with 10, 25, 50, 150, or 300 nM antisense oligonucleotide (i.e., a five-point dose response test) for a period of 24 hours, after which RNA was isolated. PCSK9 mRNA was measured by real-time PCR, as described herein. 
     Results of the five-point dose response tests using HEK-293 cells are shown in  FIG.  2   . Results of the five-point dose response tests using cyno primary hepatocytes are shown in  FIG.  3   . The IC 50  results, expressed in nM units, for the five-point dose response test using human primary hepatocytes, cyno primary hepatocytes, HEK-293 cells, Hep3B cells, and HeLa cells are summarized in Table 29. 
     
       
         
           
               
             
               
                 TABLE 29 
               
             
            
               
                   
               
               
                 IC 50  (nM) for Selected Antisense Compounds 
               
            
           
           
               
               
            
               
                   
                 Isis No. 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
            
               
                   
                 395165 
                 395185 
                 395186 
                 395187 
                 405879 
                 405881 
                 405891 
                 405988 
                 405994 
                 406008 
               
            
           
           
               
               
            
               
                   
                 SEQ ID NO: 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
            
               
                   
                 28 
                 59 
                 60 
                 62 
                 248 
                 250 
                 352 
                 381 
                 400 
                 188 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
            
               
                 Human Primary 
                 24 
                 33 
                 39 
                 30 
                 ND 
                 50 
                 297 
                 166 
                 56 
                 163 
               
               
                 Hepatocytes 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 Cyno Primary 
                 5 
                 17 
                 18 
                 14 
                 2 
                 19 
                 10 
                 12 
                 21 
                 11 
               
               
                 Hepatocytes 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 HEK-293 
                 40 
                 116 
                 6 
                 11 
                 35 
                 86 
                 21 
                 11 
                 17 
                 27 
               
               
                 Hep3B 
                 28 
                 43 
                 33 
                 44 
                 28 
                 26 
                 38 
                 42 
                 39 
                 35 
               
               
                 HeLa 
                 13 
                 11 
                 7 
                 8 
                 14 
                 13 
                 14 
                 8 
                 9 
                 8 
               
               
                   
               
            
           
         
       
     
     ISIS 405879 was tested at various doses in human primary hepatocytes. RNA was isolated from the cells and PCSK9 mRNA levels were measured by quantitative real-time PCR, as described herein. Human PCSK9 primer probe set 2740 was used to measure mRNA levels. Results are shown in Table 29.1. 
     
       
         
           
               
             
               
                 TABLE 29.1 
               
             
            
               
                   
               
               
                 Dose-dependent Reduction in Human PCSK9 mRNA 
               
               
                 Expression in Human Primary Hepatocytes 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                 300 
                 200 
                 150 
                 100 
                 50 
                 25 
                 10 
               
               
                 ISIS NO. 
                 nM 
                 nM 
                 nM 
                 nM 
                 nM 
                 nM 
                 nM 
               
               
                   
               
               
                 405879 
                 13 
                 18 
                 26 
                 30 
                 27 
                 54 
                 75 
               
               
                   
               
            
           
         
       
     
     Isis 405879 has an IC 50  value of 29 nM in human primary hepatocytes. Overall Isis 405879 displays superior activity, particularly in cyno primary hepatocytes. Isis 405879 was thus further tested in the various cell models, and the results of the additional testing are shown in Table 30. In these experiments, Isis 405879 was administered to the cells using lipofectin transfection reagents. PCSK9 mRNA was assayed by PCR following 24 hr incubation after transfection. These results confirm that Isis 405879 potently inhibits PCSK9 mRNA expression at low concentrations. 
     
       
         
           
               
             
               
                 TABLE 30 
               
             
            
               
                   
               
               
                 Isis 405879 activity in cell culture models 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                   
                   
                   
                 Hepatocyte 
                   
                   
                 Transgenic 
               
               
                   
                 Hep3B 
                 HepG2 
                 HeLa 
                 Transgenic 
                 Primary 
                 Primary 
                 HEK293 
               
               
                   
                 Cells 
                 Cells 
                 Cells 
                 Mouse 
                 Hepatocyte 
                 Hepatocyte 
                 cells 
               
               
                   
                 (human) 
                 (human) 
                 (human) 
                 (h-PCSK9) 
                 (human) 
                 (cyno) 
                 (h-PCSK9) 
               
               
                   
               
               
                 Mean 
                 17 
                 5 
                 14 
                 140 
                 22 
                 7.4 
                 18 
               
               
                 IC 50   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (nM) 
               
               
                   
               
            
           
         
       
     
     These experiments confirm that the presently disclosed antisense oligonucleotides are capable of potently inhibiting PCSK9 mRNA expression in a variety of cell model systems, including a human primary cell line. Exemplary antisense compounds inhibit PCSK9 mRNA expression with IC 50  values in the nM range. 
     The transgenic PCSK9 cDNA construct expressed in mouse hepatocytes is thought to be rapidly exported to the cytoplasm, because it does not require post-transcriptional editing. The antisense oligonucleotides provided herein act by recruiting the RNase H enzyme, which is restricted to the nucleus. Therefore, inhibition by antisense oligonucleotides in this cell type is significantly diminished. 
     Example 16: In Vivo Testing Procedures 
     16.1. High Fat (HF)-Fed Hyperlipidemic Mouse Model 
     Antisense compounds may be tested in a high fat-fed, hyperlipidemic mouse model to test efficacy of the antisense compounds in reducing PCSK9 mRNA expression, increasing LDL-R expression, reducing total cholesterol and LDL, and affecting other metrics of antisense compound efficacy. A representative hyperlipidemic mouse model is described in Graham et al.,  J. Lipid Res . (2007) 48: 763-767. 
     All animal experiments were conducted in accordance with Institutional American Association for the Accreditation of Laboratory Animal Care guidelines. C57BL/6 mice were obtained from Jackson Laboratory (http://www.jax.org). A majority of the mice were male, and studies were initiated when animals were 4-5 weeks of age. The mice were maintained on a 12 h light/12 h dark cycle and fed ad libitum. C57BL/6 mice were fed a diet consisting of 60% lard (Research Diets, New Brunswick, N.J.), whereas experimental Ldlr-deficient/apoB-100 mice were fed regular chow. 
     Antisense compounds were administered twice weekly (50 mg/kg) for 6 weeks by intraperitoneal injection (10 mg/mL dosing solution formulated in saline; saline control). After the treatment period, whole blood was collected for analysis of serum parameters, and whole liver was collected for RNA analysis, protein analysis, and histological evaluation. 
     16.2. H-ApoB/CETP Transgenic Mouse Model 
     A transgenic mouse model that expresses both human apolipoprotein (apo) B and human cholesteryl ester transfer protein (CETP) provides another useful animal model system to test the efficacy of the presently disclosed antisense compounds. The lipoprotein cholesterol distribution in the serum of a chow-fed h-apoB/CETP mouse resembles a human profile. Specifically, the percentages of total cholesterol within the HDL, LDL, and VLDL fractions of apoB/CETP animals are approximately 30%, 65%, and 5%, respectively, similar to the distribution of cholesterol in the plasma of normolipidemic humans. The h-apoB/CETP mouse model is described further in Grass et al.,  J. Lipid Res . (1995) 36: 1082-1091. 
     16.3. H-PCSK9 Transgenic Mouse Model 
     A transgenic mouse expressing human PCSK9 provides another useful animal model to study in vivo repression of PCSK9 mRNA by the present antisense compounds. H-PCSK9 transgenic mice overexpress human PCSK9 in liver and secrete large amounts of the protein into plasma, which increases plasma LDL-C concentrations to levels similar to those of LDLR-knockout mice. H-PCSK9 transgenic mice were constructed by inserting a cDNA encoding human PCSK9 into a pLiv-11 vector that contained the constitutive human apoE promoter and its hepatic control region, as described in Simonet et al.,  J. Biol. Chem . (1993) 268: 8221-8229. Transgenic mice were generated by injecting linearized pLiv-11-hPCSK9 into the fertilized eggs as described in Shimano et al.,  J. Clin. Invest . (1996) 98: 1575-1584. H-PCSK9 transgenic mice are further described in Lagace et al.,  J. Clin. Invest . (2006) 116: 2995-3005. 
     16.4. Mouse and Rat Models for In Vivo Tolerability, Half-Life and Tissue Distribution 
     Mouse (CD1) and rat (Sprague-Dawley) models were used to test the in vivo tolerability of various antisense compounds. In the mouse CD1 model, antisense compounds were overdosed at 100 mg/kg/wk for six weeks. Possible proinflammatory effects and hepatotoxcity were assayed following administration of the antisense compounds. Serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), blood urea nitrogen (BUN), creatinine, albumin, and bilirubin were assayed. Weights of livers, kidneys, and spleens of animals were determined. Histopathologic screening was conducted to detect hepatocellular swelling, multifocal apoptosis, inflammatory cell infiltrates in the liver or lungs, or follicular hyperplasia. Additional studies were conducted in the rat model to screen for renal toxicity or high renal accumulation and proinflammatroy effects. In these experiments, antisense compounds were administered at 60 or 100 mg/kg/wk for six weeks. In addition to the markers examined above, the urine protein/creatine ratio and proteinuria were assayed. 
     The half-life of administered antisense compounds also was examined in the target organ, i.e., liver, in the mouse model. For these experiments, antisense compounds were administered twice a week for two weeks at 50 mg/kg, and target organs were then harvested and assayed for the presence of the antisense compounds, as described below. 
     The distribution of administered antisense compounds in various organs also was examined in the rat model. Rats in these studies were administered 20 mg/kg antisense compounds twice weekly for three weeks. Livers and kidneys of test animals were then harvested and assayed for the presence of the antisense compounds, as described below. 
     16.5. Cynomolgus Monkey ( M. fascicularis ) Model 
     Potencies and pharmacodynamics of antisense compounds were compared in a cyno model to identify the compounds exhibiting the best combination of high potency and low renal accumulation, when given subcutaneously to animals for a 5-week period. In another study, dosing was conducted over a 13-week period. The cyno monkey is widely used in toxicity testing, and a substantial historic toxicology database is available for this model. 
     The PCSK9 target sequence for an antisense compound may differ in humans versus cyno monkey. As a result, an antisense compound for use in humans may not be fully complementary to a monkey PCSK9 nucleic acid. Antisense compounds having identical target sequences in the two species are preferred. Isis 405881 and Isis 395165 each have a one nucleotide mismatch compared to the cyno sequence, meaning that these antisense compounds are less preferred in the cyno model. 
     Cyno monkeys (Charles River BRF, Inc.) were approximately 26 to 32 months old and 2.5 to 4 kg in weight on the first day of dosing. Monkeys were offered water ad libitum and fed a daily ration of 12 biscuits approximately 2 hours post dose. Antisense compounds were administered subcutaneously at 3 doses every other day during the first week, then by weekly injections. A low dose of 15 mg/kg was used to assess the potency of the antisense compounds. A high dose of 8 subcutaneous injections of 30 mg/kg over 5 weeks or 13 weeks was used to assay renal accumulation and pharmacodynamics. Antisense compounds were administered at a concentration of 60 or 120 mg/mL, respectively, in a vehicle of sterile phosphate buffered saline. Plasma concentrations of antisense compounds were determined at each dose level to estimate systemic exposure in monkeys following subcutaneous administration and to assess whether systemic exposure was altered after repeat dosing. 
     To measure the host reaction to the administered antisense compounds, 2 mL blood samples were collected from the femoral vein of host individuals in tubes of appropriate size containing K 2 EDTA. Plasma was obtained by centrifugation and samples were stored frozen. The analysis of the plasma samples included a determination of the level of plasma PCSK9 protein. To measure an effect on pharmacodynamic end points, LDL, HDL, and apoB levels also were analyzed. To determine whether the host individuals suffered side effects, blood samples were further analyzed for an effect on the hematological parameters listed in Table 31 and the serum chemistry parameters listed in Table 32: 
     
       
         
           
               
             
               
                 TABLE 31 
               
               
                   
               
               
                 Hematology markers 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
            
               
                 erythrocyte count 
                 red cell distribution width 
               
               
                 hemoglobin 
                 platelet count 
               
               
                 hematocrit 
                 mean platelet volume 
               
               
                 mean corpuscular volume 
                 absolute total and differential 
               
               
                   
                 leukocyte counts 
               
               
                 mean corpuscular hemoglobin 
                 evaluation of cell morphology 
               
               
                 concentration 
                   
               
               
                 absolute reticulocyte count 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 32 
               
               
                   
               
               
                 Serum chemistry markers 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
            
               
                   
                 aspartate aminotransferase 
                 triglycerides 
               
               
                   
                 alanine aminotransferase 
                 glucose 
               
               
                   
                 gamma glutamyltransferase 
                 urea nitrogen 
               
               
                   
                 alkaline phosphatase 
                 creatinine 
               
               
                   
                 total bilirubin 
                 calcium 
               
               
                   
                 total cholesterol 
                 phosphorus 
               
               
                   
                 total protein 
                 sodium 
               
               
                   
                 albumin 
                 potassium 
               
               
                   
                 globulins 
                 chloride 
               
               
                   
                 albumin/globulin ratio 
               
               
                   
                   
               
            
           
         
       
     
     Possible additional side effects were determined by screening individuals administered antisense compounds for gross changes in organs or microscopic changes in tissues. A limited necropsy conducted on all test animals included gross examination of various organs and tissues. Terminal body weights were recorded, and kidneys and spleen were weighed for all test animals. For microscopic evaluation, liver, kidney, spleen and injection sites from all animals were fixed in 10% neutral buffered formalin and were processed, embedded in paraffin, sectioned, and stained with hematoxylin and eosin. 
     Representative tissue samples of liver and kidney cortex from each scheduled-necropsy monkey from the high-dose and control groups were collected for ultrastructural examination using electron microscopy. Thin slices (2-4 mm in thickness) of liver and kidney cortex were cut and transferred to a piece of dental wax containing a small volume of McDowell-Trump fixative. Thin slices were further minced into approximately 1×1-2 mm cubes in McDowell-Trump fixative and analyzed by electron microscopy. 
     To evaluate PCSK9 mRNA levels, samples from liver (approximately 1 g) were homogenized using a Polytron tissue disruptor in 10 mL of RLT solution (Qiagen) and snap-frozen and stored at −70° C. or colder. Additionally, samples (approximately 500 mg each) from kidney were collected and snap-frozen for mRNA analysis. 
     Tissue samples from liver and kidney cortex were also analyzed for the presence of the administered antisense compounds. Antisense compounds present in the tissues can be detected and quantified using capillary gel electrophoresis (CGE), as described in Leeds et al,  Drug Metab Dispos . (1998) 26: 670-675, for example. In this procedure, tissues are weighed, mixed with an internal standard (e.g., a 27-mer (T) oligonucleotide) in proteinase K digestion buffer (2.0 mg/ml proteinase K in 20 mM Tris-HCl, pH 8.0, 20 mM EDTA, 100 mM NaCl, 0.5% Nonidet P-40), and homogenized. Overnight incubation at 37° C. is followed by phenol/chloroform extraction. Tissue extracts are purified by sequential anion-exchange solid-phase extraction (SPE) followed by reverse-phase SPE, described in Leeds et al.,  Anal Biochem  (1996) 235: 36-43. Samples are further desalted by membrane dialysis before analysis using gel-filled capillaries, as described in Leeds et al. (1996). 
     Capillary gel electrophoresis separations can be performed as described by Leeds et al. (1998), using a Beckman P/ACE capillary electrophoresis instrument (model 5010) with a 27-cm column (effective length, 20 cm) containing 12% polyacrylamide, with 8.3 M urea in 100 mM Tris-borate, pH 8.5, as the running buffer. Separation is achieved at 50° C. and 550 V/cm. Oligomers eluting from the column are detected by UV absorption at 260 nm. Quantification of antisense oligonucleotides is based on the tissue weight extracted and the initial T27 concentration. 
     Example 17: In Vivo Testing Results 
     17.1. Reducing PCSK9 mRNA In Vivo Using a Murine Antisense Compound Correlates with In Vivo Plasma LDL-C and Liver TG Reduction 
     In vivo pharmacodynamic studies were performed with the murine antisense compound Isis 394816 to validate the pharmacodynamic endpoint of PCSK9 mRNA reduction. Isis 394816 has the sequence 5′ GGTAAGGTGCGGTAAGTCCT 3′ (SEQ ID NO: 462), which targets position 3100 (5′) of the coding sequence of murine PCSK9 mRNA (NCBI Accession No. NM_153565.1; SEQ ID NO: 463). Isis 394816 has a 3-14-3 motif. 
     Isis 394816 was administered by intraperitoneal injection to an h-apoB/CETP transgenic mouse for 6 weeks at a dosing regimen of 20 mg/kg/wk or 50 mg/kg/wk. See Example 16.2. As shown in  FIG.  4   , Isis 394816 administered at either dose caused an approximate 80% reduction in PCSK9 mRNA expression in livers of test animals, compared to control animals. As shown in  FIG.  5   , panel A, Isis 394816 produced a significant (p&lt;0.0001) decrease in the level of plasma LDL-C at the end of six weeks. Additionally, as shown in  FIG.  5   , panel B, Isis 394816 produced a significant (p&lt;0.02) decrease in the level of liver TG at the end of six weeks. 
     Additionally, Isis 394816 reduced PCSK9 mRNA expression, plasma LDL-C, and liver TG in a dose dependent manner, as shown in  FIG.  6   . The potency of Isis 394816 was much higher in a hyperlipidemic mouse model (see Example 16.1.) than in a lean mouse model (data not shown). The reduction of plasma LDL-C positively correlated with the inhibition of PCSK9 mRNA levels in liver, shown in  FIG.  7   . These studies demonstrate that the reduction of liver PCSK9 mRNA correlates with the desired endpoint of reducing plasma LDL-C and liver TG. Accordingly, the reduction of liver PCSK9 mRNA provides a valid pharmacodynamic endpoint. 
     17.2. Differences in the Half-Life (t 1/2 ) of Antisense Compounds in Liver 
     The half-lives of selected antisense compounds were assayed in mouse CD1 livers, according to the procedures set forth in Example 16.4. Half-lives varied among the tested antisense compounds, which again is attributable to differences in structural features of the antisense compounds, such as nucleotide sequences and/or motifs. For example, the half-life of Isis 405879 (t 1/2 2=27.7 days) was significantly higher than the half-life of Isis 395165 (20.4 days), although the target sequences of these two antisense compounds are shifted by only two nucleotides: 
                            Isis 405879:           (SEQ ID NO: 248)           CCTTGGCCACGCCGGCATCC                       Isis 395165:           (SEQ ID NO: 28)           ACCCTTGGCCACGCCGGCAT            
Half-life data for exemplary antisense compounds is summarized in Table 33. Isis 405879 displayed a particularly high half-life in liver.
 
     
       
         
           
               
             
               
                 TABLE 33 
               
             
            
               
                   
               
               
                 Liver t 1/2  (days) 
               
            
           
           
               
               
               
            
               
                   
                 Antisense Compound 
                 Liver t 1/2  (d) 
               
               
                   
                   
               
               
                   
                 395165 
                 20.4 
               
               
                   
                 395185 
                 20.2 
               
               
                   
                 395186 
                 19.9 
               
               
                   
                 395187 
                 13.7 
               
               
                   
                 405879 
                 27.7 
               
               
                   
                 405881 
                 14.1 
               
               
                   
                 405891 
                 17.1 
               
               
                   
                 405988 
                 14.6 
               
               
                   
                 405994 
                 20.2 
               
               
                   
                 406008 
                 19.7 
               
               
                   
                   
               
            
           
         
       
     
     17.3. Differences in the Liver and Kidney Distributions of Antisense Compounds 
     The antisense compounds listed in Table 29 were administered to rats to determine the distribution of antisense compounds in liver and kidney. Accumulation of high levels of antisense compounds in the kidneys may cause adverse side effects. Antisense compounds were dosed and administered as described in Example 16.2.  FIG.  8    shows the distribution of the antisense compounds shown in Table 29 in rat liver and kidneys. Isis 395185, Isis 395186, Isis 395187, Isis 405879, Isis 405881, Isis 405891, Isis 405988, and Isis 405994 show a particularly advantageous ratio of distribution between liver and kidney. 
     When tissue distribution was tested in a cyno model, further differences among antisense compounds were observed. Accumulation of Isis 395186, Isis 405879, and Isis 405891 in liver and kidney was examined after dosing each antisense compound at two concentrations. See Example 16.5. The results are shown in  FIG.  9   . Accumulation at each dosing concentration (15 mg/kg and 30 mg/kg) is shown for kidney (left side bar) and liver (right side bar). Isis 405879 advantageously accumulates at a high concentration in liver, even at a dose of 15 mg/kg, and accumulates at a low level in kidney. Specifically, Isis 405879 accumulated in kidneys at a concentration of 1300 μg/g (15 mg/kg dose) to 1800 μg/g (30 mg/kg dose). The average accumulation of antisense compounds in kidneys is 2500 μg/g (15 mg/kg dose) to 4000 μg/g (30 mg/kg dose). Variation in kidney and liver accumulation is attributable to structural differences, such as nucleotide sequences and/or motifs, between the antisense compounds. 
     17.4. Differences in Host Tolerance of Antisense Compounds 
     Rodent tolerability studies, conducted as described in Example 16.4, showed that antisense compounds were well tolerated. Following administration of the exemplary antisense compounds listing in Table 29, serum chemistry markers were normal, with some variably high ALT and AST levels observed for Isis 405988 and Isis 405994. Whole body weight and major organ weights in CD-1 mice also were not significantly affected by administration of the exemplary antisense compounds. Histological findings revealed differences between the various antisense compounds, but were consistent with the overall good tolerability for the antisense compounds. The results of the histological screens are shown in Table 34. 
     17.5. Results of the 5 wk Cyno Toxicology Study 
     The methods used to conduct the 5 wk cyno toxicology study are described in Example 16.5. Isis 405879 is referred to as BMS-844421 below and in the corresponding figures. The PCSK9 mRNA levels assayed by q-RT-PCR in the cyno liver tissue samples were decreased by BMS-844421 treatment by an average of 65% and 70% (average of males and females) versus saline controls at the low and high doses, respectively ( FIG.  25   ). The effect was seen in both females and male monkeys, despite relatively high variability of mRNA level between animals. No dose-dependency was seen between the 2 doses. The data are mean+/− for male and female animals combined. 
     The levels of BMS-844421 ASO were measured in liver at the end of the 5 wk study. As shown in  FIG.  26   , liver full-length BMS-844421 levels reached ˜1 mg/gram tissue in both dose groups. This level is consistent with values from previous experiences with other liver-targeting ASOs. Most of the compound was detected as intact full-length BMS-844421. No dose-dependency was seen in the ASO liver accumulation data, in agreement with the lack of dose-dependent effects on liver PCSK9 target mRNA. 
     Pharmacodynamic responses were assessed in serum lipid assays for the cyno 5 wk ASO study. As seen in  FIG.  27   , a modest trend (not statistically significant) toward lowering LDL-C was observed for BMS-844421 treated cyno monkeys at 2.5 and 5 wk of dosing. This trend at both time points for BMS-844421 relative to baseline was also seen in the scatterplot of individual animal data in  FIG.  28 A . HDL/LDL ratios were sometimes employed as a sensitive indicator of plasma lipid status. A chart of the average ratio of HDL/LDL in the cyno study showed a trend for increase in the ratio for BMS-844421 treated cynos at 2.5 and 5 wk ( FIG.  28 B ). 
     Gene expression profiling by Affymetrix microarray was conducted on the RNA samples from this study. The analysis included liver RNA from animals administered vehicle alone, BMS-844421 at 15 mg/kg and 30 mg/kg and BMS-844419 and BMS-844423 at 30 mg/kg only. By microarray, there were significant (p&lt;0.01) transcriptional changes in approximately 1 to 2% of genes with approximately 1% expected to change at this significance level by chance. For drug-dosed groups relative to control there were alterations in inflammation-, immune system-, and lipid homeostasis-related transcripts with statistically significant animal to animal variability. Other drug-related hepatic transcriptional changes common to multiple dose groups were associated with several or a few genes in various biological processes and are of unknown significance. 
     17.6. Results of the 13 wk Cyno Toxicology Study 
     An additional opportunity to monitor pharmacodynamic responses to BMS-844421 in monkeys was the 13 wk toxicology study, described in Example 16.5. Lean cyno monkeys with low LDL levels were again the subject for this study, as for the 5 wk cyno monkey study above. At 13 wks subcutaneous dosing at 4 different dose levels, BMS-844421 suppressed PCSK9 expression as measured by both liver PCSK9 mRNA and plasma PCSK9 protein levels. Despite the inter-animal variability in these values, it is apparent that BMS-844421 strongly suppressed both liver mRNA and plasma PCSK9 protein ( FIG.  29   ). 40 mg/kg suppressed PCSK9 protein levels very robustly with less variation between animals ( FIG.  29   ). No statistically significant differences were seen in plasma LDL-C or other lipid parameters in this study. 
     
       
         
           
               
             
               
                 TABLE 34 
               
             
            
               
                   
               
               
                 Histological Findings in CD-I Mice 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
            
               
                 Antisense 
                   
                   
                   
                   
                   
                 Lymph 
                   
                   
                   
                 Skeletal 
               
               
                 compound 
                 Liver 
                 Kidney 
                 Lung 
                 Heart 
                 Spleen 
                 node 
                 Intestine 
                 Thyroid 
                 Sternum 
                 Muscle 
               
               
                   
               
               
                 Saline 
                 − 
                 − 
                 − 
                 − 
                 − 
                 − 
                 − 
                 − 
                 − 
                 − 
               
               
                 ISIS 395165 
                 +/++ 
                 − 
                   
                   
                 −/+ 
                 −/+ 
                 − 
                 − 
                 − 
                 − 
               
               
                 ISIS 395185 
                 + 
                 − 
                 − 
                 − 
                 −/+ 
                 − 
                 − 
                 − 
                 − 
                 − 
               
               
                 ISIS 395186 
                 − 
                 − 
                 − 
                 − 
                 − 
                 − 
                 − 
                 − 
                 − 
                 − 
               
               
                 ISIS 395187 
                 − 
                 − 
                 − 
                 − 
                 −/+ 
                 − 
                 − 
                 − 
                 − 
                 − 
               
               
                 ISIS 405879 
                 − 
                 − 
                 − 
                 − 
                 − 
                 − 
                 − 
                 − 
                 − 
                 − 
               
               
                 ISIS 405881 
                 inflam 
                 − 
                 inflam 
                 − 
                 −/+ 
                 −/+ 
                 − 
                 − 
                 − 
                 − 
               
               
                 ISIS 405891 
                 − 
                 − 
                 − 
                 − 
                 −/+ 
                 −/+ 
                 − 
                 − 
                 − 
                 − 
               
               
                 ISIS 405988 
                 − 
                 − 
                 − 
                 − 
                 − 
                 − 
                 − 
                 − 
                 − 
                 − 
               
               
                 ISIS 405994 
                 ++ 
                 − 
                 − 
                 − 
                 −/+ 
                 − 
                 − 
                 − 
                 − 
                 − 
               
               
                 ISIS 406008 
                 +/++ 
                 − 
                 − 
                 − 
                 − 
                 − 
                 − 
                 − 
                 − 
                 − 
               
               
                   
               
               
                 Normal: − 
               
               
                 Minimal changes: −/+ 
               
               
                 Mild changes: + 
               
               
                 Moderate changes: ++ 
               
               
                 Severe changes: +++ 
               
            
           
         
       
     
     Microscopic evaluation of mouse organs from animals treated with 10 different human PCSK-9 antisense compounds revealed that all compounds generally were well tolerated, but that some antisense compounds were particularly well tolerated. The following results were seen in the various examined organs.
         Liver: Mild (+) to moderate (++) liver injuries (cytoplasmic swelling to multifocal apoptosis) were seen in Isis 395165 (+/++), Isis 395185 (+), Isis 405988 (+/++), Isis 405994 (++), and Isis 406008 (+/++) treated livers. Mild inflammatory changes were seen in Isis 405881 treated livers.   Lung: No significant abnormality was seen in treated animals except for mild histiocytosis noticed in Isis 405881 treated animals.   Spleen: Mild follicular hyperplasia was seen in Isis 395165, Isis 395185, Isis 395187, Isis 405881, Isis 405891, and Isis 405994 treated spleens.   Lymph node: Minimal histiocytosis was observed in Isis 395165, Isis 405881 and Isis 405891 treated animals.   Heart: Minimal levels of macrophage infiltration were seen in Isis 395165, Isis 395186, Isis 405879, Isis 405881, Isis 405891, Isis 405988, and Isis 406008 treated hearts.   Kidney, Thyroid, small intestine, skeletal muscle and sternum: No abnormality was visualized.       

     Differences in the histological findings were seen even between Isis 395165 and Isis 405879. As noted above, the target sequences of these two antisense compounds are only shifted by two nucleotide positions. Nevertheless, Isis 405879 advantageously displays no adverse reactions, whereas Isis 395165 elicits a mild inflammatory response in liver, spleen, and lymph nodes. In summary, Isis 405879, Isis 395186, and Isis 405988 display superior tolerance, compared to the other antisense compounds tested in this study. 
     17.7. Differences in Achieving Pharmacodynamic Endpoints in the Cyno Model. 
     Isis 395186 (“844419”), Isis 405879 (“844421”), and Isis 405891 (“844423”) were selected for further study in the cyno model, using the procedures described in Example 16.6. As set forth above, these antisense compounds displayed high activity in cell culture models, were well tolerated, and displayed advantageous tissue distribution and half-life properties. Further, none of these antisense compounds targeted a PCSK9 sequence known to have differences in monkeys and humans. In addition, the target sequences in human PCSK9 were known not to contain SNPs having a wide distribution in the population. 
     The antisense compounds were tested for their ability to reduce PCSK9 mRNA in cyno liver. See Example 16.6. The results of this experiment are shown in  FIG.  10   . Despite variability between the tested animals, Isis 405879 (labeled “844421”) displayed a superior ability to reduce PCSK9 mRNA levels significantly. When administered at a low dose (15 mg/kg, shown in the left side bar), Isis 405879 significantly (p&lt;0.023) reduced PCSK9 mRNA levels. When administered at a high dose (30 mg/kg, shown in the right side bar), Isis 405879 also significantly (p&lt;0.011) inhibited PCSK9 mRNA expression. The results obtained with Isis 405879 were superior to those obtained with Isis 395186 (labeled “844419”) and Isis 405891 (labeled “844423”). As shown in  FIG.  11   , Northern analysis of liver PCSK9 mRNA confirms that 15 mg/kg and 30 mg/kg Isis 405879 substantially reduces PCSK9 mRNA levels. 
     As described in Example 17.1, the reduction of PCSK9 mRNA is expected to correlate with a reduction in plasma LDL-C and liver TG. Consistent with this expectation, Isis 405879 produced a significant (p&lt;0.06) decrease in cyno serum LDL-C after five weeks of administration at 30 mg/kg, as shown in  FIG.  12   . Isis 405879 additionally produced a significant (p&lt;0.05) increase in the ratio of HDL to LDL following five weeks of administration at 30 mg/kg, as shown in  FIG.  13   . 
     Generally confirming earlier data obtained in rodents, Isis 405879 elicited no differences in serum chemistry, hematology, or organ weights, except for a slight increase in spleen weight. Histology revealed indicia of only mild inflammation. The advantageous distribution of Isis 405879 in liver and kidney in the cyno model is described above and shown in  FIG.  9   . 
     Example 18: Dose Response Study of Isis 405879 (“844421”) in a Human PCSK9 Transgenic Mouse Model 
     BMS-844421 is a human specific PCSK9 antisense oligonucleotide (ASO) designed to downregulate hepatic PCSK9 expression, increase LDL receptor activity, and promote clearance of LDL and reduction of plasma LDL-C levels in humans. A human genomic PCSK9 transgenic mouse model was recently established. This mouse line expresses hemizygous transgene in the presence of endogenous mouse PCSK9 (i.e., both genes are simultaneously expressed). It was found that the transgenic PCSK9 mice responded to chronic dosing with BMS-844421 and related human PCSK9 ASOs with decreased liver mRNA expression and decreased circulating human PCSK9 protein levels. 
     The present study examined the dose response to BMS-844421 in the hemizygous genomic transgenic mouse model on a normal chow diet. Experiments were conducted comparing the effects of BMS-844421 (human specific PCSK9 ASO) to those of ISIS 394816 (murine specific PCSK9 ASO) in this model alone and in combination. BMS-844421 exhibited dose-dependent suppression of liver target mRNA, reflected in dose-dependent decreases in plasma human PCSK9 levels. Both liver mRNA and plasma protein gave ED50 values of approximately 15 mg/kg (given twice weekly) for BMS-844421, while the suppression of plasma PCSK9 protein was greater than liver PCSK9 mRNA at each dose in this model. Trends for increased LDLR protein in liver total membrane fraction, and a feedback effect on liver HMGCoA reductase mRNA expression were observed, but no changes in plasma lipids were seen for BMS-844421 treated hemizygous mice. The combination of ISIS 394816+BMS-844421 (each at 15 mg/kg) elicted a greater increase in liver LDLR protein than either ASO alone, consistent with the proposed mechanism of action and the dual expression of both human and murine PCSK9 in this model. 
     18.1. Materials and Methods 
     The sequences of BMS-844421 and other ASOs tested in this report are given in Table 35. The negative control ISIS 141923 is not complementary to any known gene. The design of the dose response study is described in the beginning of the Results section (section 18.2. below). 
     
       
         
           
               
             
               
                 TABLE 35 
               
             
            
               
                   
               
               
                 Nucleotide sequences of ASOs 
               
            
           
           
               
               
               
            
               
                   
                   
                 SEQ ID 
               
               
                 ASO 
                 Sequence 
                 NO 
               
               
                   
               
               
                 BMS 844421, human 
                 5′-CCTTGGCCACGCCGGCATCC-3′ 
                 248 
               
               
                 PCSK9 specific* 
                   
                   
               
               
                   
               
               
                 ISIS 141923, non- 
                 5′-CCTTCCCTGAAGGTTCCTCC-3′ 
                 465 
               
               
                 targeting 
                   
                   
               
               
                   
               
               
                 ISIS 394816, murine 
                 5′-GGGCTCATAGCACATTATCC-3′ 
                 466 
               
               
                 PCSK9 specific 
               
               
                   
               
               
                 *BMS-844421 is identical to ISIS 405879 
               
            
           
         
       
     
     Parameters evaluated at study termination included hepatic mRNA, hepatic LDLR protein levels, plasma concentrations of total cholesterol, LDL, HDL, triglycerides, transaminases, and organ and body weights. Whole liver was processed for RNA, and protein, and held for possible histological examination and hepatic triglyceride levels. Blood and liver samples were obtained 24 hr after the prior dose. Blood samples were obtained from tail vein or retro orbital plexus and EDTA, chilled on ice, and plasma samples were obtained by standard procedures. For mRNA assays, liver samples (30-50 mg each) were placed in eppendorf tubes containing 1000 uL of TRIzol (Invitrogen #15596-018) and homogenized using stainless steel beads on a Tissue Lyser instrument (Qiagen, Valencia, Calif.). Chloroform (200 μL) was added to each tube, the contents were mixed vigorously by hand and tubes were centrifuged at 12,000×g for 20 minutes at 4° C. About 300 μL of each supernatant was removed and placed in 1.5 mL microcentrifuge tubes. One volume of 70% EtOH was added, the mixtures were vortexed thoroughly and transferred to RNeasy Mini Spin Columns (QIAgen Cat. No. 74106). RNA was purified, treated with DNase and eluted into microcentrifuge tubes following QIAgen&#39;s manufacturer&#39;s instructions. 
     Plasma human PCSK9 levels were assayed using the human specific ELISA with mAb 4H5 as capture antibody. 
     18.2. Results 
     A dose-response study was run in human PCSK9 genomic transgenic mouse line 66 mice on a normal chow diet. Groups of 6 mice (3 males, 3 females) received the following treatments for 6 weeks. BMS-844421 was administered p.o. at 5, 10, 15, and 30 mg/kg per dose given twice weekly (on Tuesdays and Fridays) for 6 weeks. Controls received saline, and an additional group received the non-targeting negative control ASO ISIS 141923 (30 mg/kg twice weekly). The murine PCSK9 ASO ISIS 394816 was administered to another group at 15 mg/kg per dose. The final group received BMS-844421 (15 mg/kg) plus ISIS 394816 (15 mg/kg) combined. 
     Liver mRNA assayed by qRT-PCR showed that BMS-844421 decreased liver PCSK9 mRNA in a dose dependent manner, with greatest effect at the top dose studied ( FIG.  14   ). The negative control ASO, ISIS 141923, had no significant effect on target mRNA, while the murine targeted ASO, ISIS 394816, decreased human PCSK9 mRNA by 33%, suggesting partial cross-hybridization to human PCSK9 mRNA. 
     The ASO effects on plasma human PCSK9 followed a similar pattern as mRNA, while the effects of the higher doses of BMS-844421 resulted in greater effects, up to 70% suppression at 30 mg/kg/dose ( FIG.  15   ). ISIS 394816 suppressed approximately 30% (similar to mRNA effects), while ISIS 141923 had no significant effect. 
     Plasma human PCSK9 levels exhibited time dependent suppression with effects at 6 weeks, greater than at 3 wks for all doses of BMS-844421 ( FIG.  16   ). At 3 wks dosing, only the highest dose of BMS-844421 showed significant suppression. As seen in  FIG.  17   , data for 6 wks treatment with BMS-844421 showed a sigmoidal dose-response curve, with ED50 approximately 15 mg/kg/dose (given twice weekly). Plotting the mRNA and protein data together showed that the two endpoints generally, though imperfectly, reflect each other, with protein showing greater sensitivity to suppression ( FIG.  18   ). 
     Male transgenic mice responded more sensitively to BMS-844421 than the female transgenic mice in this study ( FIG.  19   ). The data was not the result of different plasma baseline levels of human PCSK9 between males and females, which is human PCSK9=67+/−31 ng/mL in males and 60+/−27 ng/mL in females in the predosing samples. The difference in PCSK9 protein response for males vs. females was less apparent for liver target mRNA ( FIG.  20   ). 
     Levels of endogenous mouse PCSK9 mRNA in liver were decreased by ISIS 394816 (and the combination of ISIS 394816 with BMS-844421), but were not decreased by BMS-844421 only ( FIG.  21   ). 
     A key cholesterol regulatory gene, HMGCoA reductase (HMGR), is known to respond to sterol feedback in the liver. An assay of endogenous mouse liver HMGR mRNA revealed 45% suppression of HMGR with BMS-844421 as well as ISIS 394816 ( FIG.  22   ). These findings are consistent with downregulation of PCSK9 promoting higher levels of LDLR, in turn leading to increased cholesterol in the regulatory pool in liver cells, resulting in downregulation of HMGR. 5 Similar, though quantitatively lesser effects, were also seen for the sterol pathway genes LDLR mRNA and for SREBP2 mRNA. 
     LDLR protein levels were assayed in liver samples from the same study. Total hepatic membranes were prepared, and western blots of SDS-PAGE gels were assayed with anti-LDLR antibodies. As a control, transferrin receptor (TR) protein levels were measured with anti-TR antibodies. Liver samples from the ASO study were pooled from n=3 for the preparation of the membrane fraction. Pairs of pools for each group were assayed. Treatment with BMS-844421, and especially the combination of BMS-844421 with the murine ASO ISIS 394816, led to increases up to &gt;2-fold in levels of LDLR protein, compared to the level of TR protein ( FIG.  23    and  FIG.  24   ). 
     The ELISA assay uses a monoclonal capture antibody and a polyclonal detector antibody developed against human recombinant PCSK9 produced in baculovirus. The recombinant human PCSK9 protein also serves as standard antigen for the ELISA assay. Cynomolgus monkey plasma PCSK9 was readily detectable using this assay. Human PCSK9 protein in plasma of human PCSK9 transgenic mouse lines was specifically detected with no cross-reactivity to murine PCSK9. 
     Despite these pharmacodynamic responses to BMS-844421, hemizygous transgenic mice did not exhibit changes in plasma LDL-C or total cholesterol following ASO treatment, including BMS-844421 (Table 36). However, normal chow fed mice have low levels of LDL-C (Table 36). It is plausible that these low LDL-C levels are not readily decreased by increases in LDLR protein. Another possible explanation is that the hemizygous expression of human PCSK9, i.e., the gene specifically targeted by BMS-844421, contributes only about ⅓ to ½ of the total murine+human PCSK9 in this hemizygous transgenic mouse model. 
     
       
         
           
               
             
               
                 TABLE 36 
               
             
            
               
                   
               
               
                 Plasma lipids at 6 wk treatment with ASOs in transgenic mice 
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                 Total 
                   
                   
               
               
                 Both Sexes 
                 Triglycerides 
                 Cholesterol 
                 HDL 
                 LDL 
               
               
                   
               
               
                 Saline 
                 72 ± 14  
                 108 ± 8.2 
                 57 ± 6.4 
                 14 ± 1 
               
               
                 Missense 
                 64 ± 9.2 
                 110 ± 8.6 
                 57 ± 7.1 
                 15 ± 1 
               
               
                 BMS-844421 
                 54 ± 8.6 
                 129 ± 7.3 
                 67 ± 4.6 
                 18 ± 2 
               
               
                 (30 mg/kg) 
                   
                   
                   
                   
               
               
                 BMS-844421 
                 54 ± 9.0 
                 126 ± 9.2 
                 65 ± 5.5 
                 18 ± 1 
               
               
                 (15 mg/kg) 
                   
                   
                   
                   
               
               
                 BMS-844421 
                 53 ± 9.4 
                 118 ± 9.3 
                 61 ± 6.9 
                 17 ± 2 
               
               
                 (10 mg/kg) 
                   
                   
                   
                   
               
               
                 BMS-844421 
                 56 ± 9.7 
                 117 ± 8.5 
                 61 ± 6.1 
                 17 ± 1 
               
               
                 (5 mg/kg) 
                   
                   
                   
                   
               
               
                 Mouse ASO 
                 50 ± 7.0 
                 84.2 ± 2.9  
                 45 ± 3.0 
                 11 ± 2 
               
               
                 I-394816 
                   
                   
                   
                   
               
               
                 (15 mg/kg) 
                   
                   
                   
                   
               
               
                 BMS-844421 + 
                 55 ± 9.3 
                  92 ± 5.3 
                 48 ± 4.6 
                 12 ± 2 
               
               
                 I-394816 
                   
                   
                   
                   
               
               
                 (15 mg/kg each) 
                   
                   
                   
                   
               
               
                 WT Littermates 
                 60 ± 8.1 
                 111.7 ± 7.2     
                 57 ± 5.3 
                 15 ± 1 
               
               
                   
               
            
           
         
       
     
     There were no changes in ALT or AST (not shown), suggesting that no liver abnormalities were present after 6 wks treatment. 
     18.3. Conclusions 
     The recently established human genomic PCSK9 transgenic mouse model responded to human PCSK9 ASO treatment with robust downregulation of human PCSK9 at both the mRNA and protein levels in liver. Plasma human PCSK9 was also decreased with the magnitude of decrease somewhat greater than liver mRNA suppression, suggesting that plasma PCSK9 levels are a good readout for suppression of the target mRNA. The ED50 for both endpoints was approximately 15 mg/kg (per dose given twice weekly). The transgenic mice did not exhibit significant changes in plasma LDL-C or total cholesterol following BMS-844421 or ISIS 394816 treatment, nor for the combination of the two ASOs. A trend for increasing liver LDLR protein was observed following treatment with BMS-844421, suggesting a functional effect consistent with the downregulation of PCSK9 mRNA and protein. Consistent with this was the downregulation of the sterol response gene HMGR in liver. 
     The limited pharmacodynamic responses in this model appear to be related both to the small LDL window in normal chow diet fed mice, and to the co-expression of the human PCSK9 gene with the endogenous murine PCSK9 gene. In the hemizygous mice, human PCSK9 appears to represent only about ⅓ of the total human+murine PCSK9 expressed. Consistent with this, in a previous study the murine specific PCSK9 ASO ISIS 394816 administered to human apoB-CETP double transgenic mice produced up to 90% suppression of liver PCSK9 mRNA and a corresponding decrease of up to 80% in plasma LDL-C levels.