Patent Publication Number: US-2023147811-A1

Title: Modulators of growth hormone receptor

Description:
FIELD 
     The present embodiments provide methods, compounds, and compositions for treating, preventing, or ameliorating a disease associated with excess growth hormone using antisense compounds or oligonucleotides targeted to growth hormone receptor (GHR). 
     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 BIOL0226USC3SEQ_ST25.txt, created on May 18, 2022 which is 1028 Kb in size. The information in the electronic format of the sequence listing is incorporated herein by reference in its entirety. 
     BACKGROUND 
     Growth hormone is produced in the pituitary and secreted into the bloodstream where it binds to growth hormone receptor (GHR) on many cell types, causing production of insulin-like growth factor-1 (IGF-1). IGF-1 is produced mainly in the liver, but also in adipose tissue and the kidney, and secreted into the bloodstream. Several disorders, such as acromegaly and gigantism, are associated with elevated growth hormone levels and/or elevated IGF-I levels in plasma and/or tissues. 
     Excessive production of growth hormone can lead to diseases such as acromegaly or gigantism. Acromegaly and gigantism are associated with excess growth hormone, often caused by a pituitary tumor, and affects 40-50 per million people worldwide with about 15,000 patients in each of the US and Europe and an annual incidence of about 4-5 per million people. Acromegaly and gigantism are initially characterized by abnormal growth of the hands and feet and bony changes in the facial features. Many of the growth related outcomes are mediated by elevated levels of serum IGF-1. 
     SUMMARY 
     Embodiments provided herein relate to methods, compounds, and compositions for treating, preventing, or ameliorating a disease associated with excess growth hormone. Several embodiments provided herein are drawn to antisense compounds or oligonucleotides targeted to growth hormone receptor (GHR). Several embodiments are directed to treatment, prevention, or amelioration of acromegaly with antisense compounds or oligonucleotides targeted to growth hormone receptor (GHR). 
    
    
     DETAILED DESCRIPTION 
     It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed. Herein, the use of the singular includes the plural unless specifically stated otherwise. As used herein, the use of “or” means “and/or” unless stated otherwise. Furthermore, the use of the term “including” as well as other forms, such as “includes” and “included”, is not limiting. Also, terms such as “element” or “component” encompass both elements and components comprising one unit and elements and components that comprise more than one subunit, unless specifically stated otherwise. 
     The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. All documents, or portions of documents, cited in this application, including, but not limited to, patents, patent applications, articles, books, and treatises, are hereby expressly incorporated by reference for the portions of the document discussed herein, as well as in their entirety. 
     Unless otherwise indicated, the following terms have the following meanings: 
     “2′-O-methoxyethyl” (also 2′-MOE and 2′-O(CH 2 ) 2 —OCH 3 ) refers to an O-methoxy-ethyl modification at the 2′ position of a furanose ring. A 2′-O-methoxyethyl modified sugar is a modified sugar. 
     “2′-MOE nucleoside” (also 2′-O-methoxyethyl nucleoside) means a nucleoside comprising a 2′-MOE modified sugar moiety. 
     “2′-substituted nucleoside” means a nucleoside comprising a substituent at the 2′-position of the furanosyl ring other than H or OH. In certain embodiments, 2′ substituted nucleosides include nucleosides with bicyclic sugar modifications. 
     “3′ target site” refers to the nucleotide of a target nucleic acid which is complementary to the 3′-most nucleotide of a particular antisense compound. 
     “5′ target site” refers to the nucleotide of a target nucleic acid which is complementary to the 5′-most nucleotide of a particular antisense compound. 
     “5-methylcytosine” means a cytosine modified with a methyl group attached to the 5 position. A 5-methylcytosine is a modified nucleobase. 
     “About” means within ±10% of a value. For example, if it is stated, “the compounds affected at least about 70% inhibition of GHR”, it is implied that GHR levels are inhibited within a range of 60% and 80%. 
     “Administration” or “administering” refers to routes of introducing an antisense compound provided herein to a subject to perform its intended function. An example of a route of administration that can be used includes, but is not limited to parenteral administration, such as subcutaneous, intravenous, or intramuscular injection or infusion. 
     “Amelioration” refers to a lessening of at least one indicator, sign, or symptom of an associated disease, disorder, or condition. In certain embodiments, amelioration includes a delay or slowing in the progression of one or more indicators of a condition or disease. The severity of indicators may be determined by subjective or objective measures, which are known to those skilled in the art. 
     “Animal” refers to a human or non-human animal, including, but not limited to, mice, rats, rabbits, dogs, cats, pigs, and non-human primates, including, but not limited to, monkeys and chimpanzees. 
     “Antisense activity” means any detectable or measurable activity attributable to the hybridization of an antisense compound to its target nucleic acid. In certain embodiments, antisense activity is a decrease in the amount or expression of a target nucleic acid or protein encoded by such target nucleic acid. 
     “Antisense compound” means an oligomeric compound that is capable of undergoing hybridization to a target nucleic acid through hydrogen bonding. Examples of antisense compounds include single-stranded and double-stranded compounds, such as, antisense oligonucleotides, siRNAs, shRNAs, ssRNAs, and occupancy-based compounds. 
     “Antisense inhibition” means reduction of 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. 
     “Antisense mechanisms” are all those mechanisms involving hybridization of a compound with target nucleic acid, wherein the outcome or effect of the hybridization is either target degradation or target occupancy with concomitant stalling of the cellular machinery involving, for example, transcription or splicing. 
     “Antisense oligonucleotide” means a single-stranded oligonucleotide having a nucleobase sequence that permits hybridization to a corresponding region or segment of a target nucleic acid. 
     “Base complementarity” refers to the capacity for the precise base pairing of nucleobases of an antisense oligonucleotide with corresponding nucleobases in a target nucleic acid (i.e., hybridization), and is mediated by Watson-Crick, Hoogsteen or reversed Hoogsteen hydrogen binding between corresponding nucleobases. 
     “Bicyclic sugar moiety” means a modified sugar moiety comprising a 4 to 7 membered ring (including but not limited to a furanosyl) comprising a bridge connecting two atoms of the 4 to 7 membered ring to form a second ring, resulting in a bicyclic structure. In certain embodiments, the 4 to 7 membered ring is a sugar ring. In certain embodiments the 4 to 7 membered ring is a furanosyl. In certain such embodiments, the bridge connects the 2′-carbon and the 4′-carbon of the furanosyl. 
     “Bicyclic nucleic acid” or “BNA” or “BNA nucleosides” means nucleic acid monomers having a bridge connecting two carbon atoms between the 4′ and 2′ position of the nucleoside sugar unit, thereby forming a bicyclic sugar. Examples of such bicyclic sugar include, but are not limited to A) α-L-Methyleneoxy (4′-CH 2 —O-2′) LNA, (B) β-D-Methyleneoxy (4′-CH 2 —O-2′) LNA, (C) Ethyleneoxy (4′-(CH 2 ) 2 —O-2′) LNA, (D) Aminooxy (4′-CH 2 —O—N(R)-2′) LNA and (E) Oxyamino (4′-CH 2 —N(R)—O-2′) LNA, as depicted below. 
     
       
         
         
             
             
         
       
     
     As used herein, LNA compounds include, but are not limited to, compounds having at least one bridge between the 4′ and the 2′ position of the sugar wherein each of the bridges independently comprises 1 or from 2 to 4 linked groups independently selected from —[C(R 1 )(R 2 )] n —, —C(R 1 )═C(R 2 )—, —C(R 1 )═N—, —C(═NR 1 )—, —C(═O)—, —C(═S)—, —O—, —Si(R 1 ) 2 —, —S(═O) x — and —N(R 1 )—; wherein: x is 0, 1, or 2; n is 1, 2, 3, or 4; each R 1  and R 2  is, independently, H, a protecting group, hydroxyl, C 1 -C 12  alkyl, substituted C 1 -C 12  alkyl, C 2 -C 12  alkenyl, substituted C 2 -C 12  alkenyl, C 2 -C 12  alkynyl, substituted C 2 -C 12  alkynyl, C 5 -C 20  aryl, substituted C 5 -C 20  aryl, a heterocycle radical, a substituted heterocycle radical, heteroaryl, substituted heteroaryl, C 5 -C 7  alicyclic radical, substituted C 5 -C 7  alicyclic radical, halogen, OJ 1 , NJ 1 J 2 , SJ 1 , N 3 , COOJ 1 , acyl (C(═O)—H), substituted acyl, CN, sulfonyl (S(═O) 2 -J 1 ), or sulfoxyl (S(═O)-J 1 ); and each J 1  and J 2  is, independently, H, C 1 -C 12  alkyl, substituted C 1 -C 12  alkyl, C 2 -C 12  alkenyl, substituted C 2 -C 12  alkenyl, C 2 -C 12  alkynyl, substituted C 2 -C 12  alkynyl, C 5 -C 20  aryl, substituted C 5 -C 20  aryl, acyl (C(═O)—H), substituted acyl, a heterocycle radical, a substituted heterocycle radical, C 1 -C 12  aminoalkyl, substituted C 1 -C 12  aminoalkyl or a protecting group. 
     Examples of 4′-2′ bridging groups encompassed within the definition of LNA include, but are not limited to one of formulae: —[C(R 1 )(R 2 )] n —, —[C(R 1 )(R 2 )] n —O—, —C(R 1 R 2 )—N(R 1 )—O— or —C(R 1 R 2 )—O—N(R 1 )—. Furthermore, other bridging groups encompassed with the definition of LNA are 4′-CH 2 -2′, 4′-(CH 2 ) 2 -2′, 4′-(CH 2 ) 3 -2′, 4′-CH 2 —O-2′, 4′-(CH 2 ) 2 —O-2′, 4′-CH 2 —O—N(R 1 )-2′ and 4′-CH 2 —N(R 1 )—O-2′- bridges, wherein each R 1  and R 2  is, independently, H, a protecting group or C 1 -C 12  alkyl. 
     Also included within the definition of LNA according to the invention are LNAs in which the 2′-hydroxyl group of the ribosyl sugar ring is connected to the 4′ carbon atom of the sugar ring, thereby forming a methyleneoxy (4′-CH 2 —O-2′) bridge to form the bicyclic sugar moiety. The bridge can also be a methylene (—CH 2 —) group connecting the 2′ oxygen atom and the 4′ carbon atom, for which the term methyleneoxy (4′-CH 2 —O-2′) LNA is used. Furthermore; in the case of the bicyclic sugar moiety having an ethylene bridging group in this position, the term ethyleneoxy (4′-CH 2 CH 2 —O-2′) LNA is used. α-L-methyleneoxy (4′-CH 2 —O-2′), an isomer of methyleneoxy (4′-CH 2 —O-2′) LNA is also encompassed within the definition of LNA, as used herein. 
     “Cap structure” or “terminal cap moiety” means chemical modifications, which have been incorporated at either terminus of an antisense compound. 
     “cEt” or “constrained ethyl” means a bicyclic sugar moiety comprising a bridge connecting the 4′-carbon and the 2′-carbon, wherein the bridge has the formula: 4′-CH(CH 3 )—O-2′. 
     “Constrained ethyl nucleoside” (also cEt nucleoside) means a nucleoside comprising a bicyclic sugar moiety comprising a 4′-CH(CH 3 )—O-2′ bridge. 
     “Chemically distinct region” refers to a region of an antisense compound that is in some way chemically different than another region of the same antisense compound. For example, a region having 2′-O-methoxyethyl nucleotides is chemically distinct from a region having nucleotides without 2′-O-methoxyethyl modifications. 
     “Chimeric antisense compounds” means antisense compounds that have at least 2 chemically distinct regions, each position having a plurality of subunits. 
     “Complementarity” means the capacity for pairing between nucleobases of a first nucleic acid and a second nucleic acid. 
     “Comprise,” “comprises” and “comprising” will be understood to imply the inclusion of a stated step or element or group of steps or elements but not the exclusion of any other step or element or group of steps or elements. 
     “Contiguous nucleobases” means nucleobases immediately adjacent to each other. 
     “Deoxyribonucleotide” means a nucleotide having a hydrogen at the 2′ position of the sugar portion of the nucleotide. Deoxyribonucleotides may be modified with any of a variety of substituents. 
     “Designing” or “Designed to” refer to the process of designing an oligomeric compound that specifically hybridizes with a selected nucleic acid molecule. 
     “Effective amount” means the amount of active pharmaceutical agent sufficient to effectuate a desired physiological outcome in an individual in need of the agent. The effective amount may vary among individuals depending on the health and physical condition of the individual to be treated, the taxonomic group of the individuals to be treated, the formulation of the composition, assessment of the individual&#39;s medical condition, and other relevant factors. 
     “Efficacy” means the ability to produce a desired effect. 
     “Expression” includes all the functions by which a gene&#39;s coded information is converted into structures present and operating in a cell. Such structures include, but are not limited to the products of transcription and translation. 
     “Fully complementary” or “100% complementary” means each nucleobase of a first nucleic acid has a complementary nucleobase in 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. 
     “Gapmer” means a chimeric antisense compound in which an internal region having a plurality of nucleosides that support RNase H cleavage is positioned between external regions having one or more nucleosides, wherein the nucleosides comprising the internal region are chemically distinct from the nucleoside or nucleosides comprising the external regions. The internal region may be referred to as the “gap” and the external regions may be referred to as the “wings.” 
     “Growth Hormone Receptor (GHR)” means any nucleic acid or protein of GHR. “GHR nucleic acid” means any nucleic acid encoding GHR. For example, in certain embodiments, a GHR nucleic acid includes a DNA sequence encoding GHR, an RNA sequence transcribed from DNA encoding GHR (including genomic DNA comprising introns and exons), including a non-protein encoding (i.e. non-coding) RNA sequence, and an mRNA sequence encoding GHR. “GHR mRNA” means an mRNA encoding a GHR protein. 
     “GHR specific inhibitor” refers to any agent capable of specifically inhibiting GHR RNA and/or GHR protein expression or activity at the molecular level. For example, GHR specific inhibitors include nucleic acids (including antisense compounds), peptides, antibodies, small molecules, and other agents capable of inhibiting the expression of GHR RNA and/or GHR protein. 
     “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 embodiments, complementary nucleic acid molecules include, but are not limited to, an antisense oligonucleotide and a nucleic acid target. 
     “Identifying an animal having, or at risk for having, a disease, disorder and/or condition” means identifying an animal having been diagnosed with the disease, disorder and/or condition or identifying an animal predisposed to develop the disease, disorder and/or condition. Such identification may be accomplished by any method including evaluating an individual&#39;s medical history and standard clinical tests or assessments. 
     “Immediately adjacent” means there are no intervening elements between the immediately adjacent elements. 
     “Individual” means a human or non-human animal selected for treatment or therapy. 
     “Inhibiting the expression or activity” refers to a reduction, blockade of the expression or activity and does not necessarily indicate a total elimination of expression or activity. 
     “Internucleoside linkage” refers to the chemical bond between nucleosides. 
     “Lengthened” antisense oligonucleotides are those that have one or more additional nucleosides relative to an antisense oligonucleotide disclosed herein. 
     “Linked deoxynucleoside” means a nucleic acid base (A, G, C, T, U) substituted by deoxyribose linked by a phosphate ester to form a nucleotide. 
     “Linked nucleosides” means adjacent nucleosides linked together by an internucleoside linkage. 
     “Mismatch” or “non-complementary nucleobase” refers to the case when a nucleobase of a first nucleic acid is not capable of pairing with the corresponding nucleobase of a second or target nucleic acid. 
     “Modified internucleoside linkage” refers to a substitution or any change from a naturally occurring internucleoside bond (i.e. a phosphodiester internucleoside bond). 
     “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 nucleoside” means a nucleoside having, independently, a modified sugar moiety and/or modified nucleobase. 
     “Modified nucleotide” means a nucleotide having, independently, a modified sugar moiety, modified internucleoside linkage, or modified nucleobase. 
     “Modified oligonucleotide” means an oligonucleotide comprising at least one modified internucleoside linkage, a modified sugar, and/or a modified nucleobase. 
     “Modified sugar” means substitution and/or any change from a natural sugar moiety. 
     “Modulating” refers to changing or adjusting a feature in a cell, tissue, organ or organism. For example, modulating GHR mRNA can mean to increase or decrease the level of GHR mRNA and/or GHR protein in a cell, tissue, organ or organism. A “modulator” effects the change in the cell, tissue, organ or organism. For example, a GHR antisense compound can be a modulator that decreases the amount of GHR mRNA and/or GHR protein in a cell, tissue, organ or organism. 
     “Monomer” refers to a single unit of an oligomer. Monomers include, but are not limited to, nucleosides and nucleotides, whether naturally occurring or modified. 
     “Motif” means the pattern of unmodified and modified nucleosides in an antisense compound. 
     “Natural sugar moiety” means a sugar moiety found in DNA (2′-H) or RNA (2′-OH). 
     “Naturally occurring internucleoside linkage” means a 3′ to 5′ phosphodiester linkage. 
     “Non-complementary nucleobase” refers to a pair of nucleobases that do not form hydrogen bonds with one another or otherwise support hybridization. 
     “Nucleic acid” refers to molecules composed of monomeric nucleotides. A nucleic acid includes, but is not limited to, ribonucleic acids (RNA), deoxyribonucleic acids (DNA), single-stranded nucleic acids, and double-stranded nucleic acids. 
     “Nucleobase” means a heterocyclic moiety capable of pairing with a base of another nucleic acid. 
     “Nucleobase complementarity” refers to a nucleobase that is capable of base pairing with another nucleobase. For example, in DNA, adenine (A) is complementary to thymine (T). For example, in RNA, adenine (A) is complementary to uracil (U). In certain embodiments, complementary nucleobase refers to a nucleobase of an antisense compound that is capable of base pairing with a nucleobase of its target nucleic acid. For example, if a nucleobase at a certain position of an antisense compound is capable of hydrogen bonding with a nucleobase at a certain position of a target nucleic acid, then the position of hydrogen bonding between the oligonucleotide and the target nucleic acid is considered to be complementary at that nucleobase pair. 
     “Nucleobase sequence” means the order of contiguous nucleobases independent of any sugar, linkage, and/or nucleobase modification. 
     “Nucleoside” means a nucleobase linked to a sugar. 
     “Nucleoside mimetic” includes those structures used to replace the sugar or the sugar and the base and not necessarily the linkage at one or more positions of an oligomeric compound such as for example nucleoside mimetics having morpholino, cyclohexenyl, cyclohexyl, tetrahydropyranyl, bicyclo or tricyclo sugar mimetics, e.g., non furanose sugar units. Nucleotide mimetic includes those structures used to replace the nucleoside and the linkage at one or more positions of an oligomeric compound such as for example peptide nucleic acids or morpholinos (morpholinos linked by —N(H)—C(═O)—O— or other non-phosphodiester linkage). Sugar surrogate overlaps with the slightly broader term nucleoside mimetic but is intended to indicate replacement of the sugar unit (furanose ring) only. The tetrahydropyranyl rings provided herein are illustrative of an example of a sugar surrogate wherein the furanose sugar group has been replaced with a tetrahydropyranyl ring system. “Mimetic” refers to groups that are substituted for a sugar, a nucleobase, and/or internucleoside linkage. Generally, a mimetic is used in place of the sugar or sugar-internucleoside linkage combination, and the nucleobase is maintained for hybridization to a selected target. 
     “Nucleotide” means a nucleoside having a phosphate group covalently linked to the sugar portion of the nucleoside. 
     “Oligomeric compound” means a polymer of linked monomeric subunits which is capable of hybridizing to at least a region of a nucleic acid molecule. 
     “Oligonucleoside” means an oligonucleotide in which the internucleoside linkages do not contain a phosphorus atom. 
     “Oligonucleotide” means a polymer of linked nucleosides each of which can be modified or unmodified, independent one from another. 
     “Parenteral administration” means administration through injection or infusion. Parenteral administration includes subcutaneous administration, intravenous administration, intramuscular administration, intraarterial administration, intraperitoneal administration, or intracranial administration, e.g. intrathecal or intracerebroventricular administration. 
     “Pharmaceutical composition” means a mixture of substances suitable for administering to an individual. For example, a pharmaceutical composition may comprise one or more active pharmaceutical agents and a sterile aqueous solution. 
     “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. 
     “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. 
     “Portion” means a defined number of contiguous (i.e., linked) nucleobases of a nucleic acid. 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 
     “Prevent” refers to delaying or forestalling the onset, development or progression of a disease, disorder, or condition for a period of time from minutes to indefinitely. Prevent also means reducing the risk of developing a disease, disorder, or condition. 
     “Prophylactically effective amount” refers to an amount of a pharmaceutical agent that provides a prophylactic or preventative benefit to an animal. 
     “Region” is defined as a portion of the target nucleic acid having at least one identifiable structure, function, or characteristic. 
     “Ribonucleotide” means a nucleotide having a hydroxy at the 2′ position of the sugar portion of the nucleotide. Ribonucleotides may be modified with any of a variety of substituents. 
     “Segments” are defined as smaller or sub-portions of regions within a target nucleic acid. 
     “Side effects” means physiological disease and/or conditions attributable to a treatment other than the desired effects. In certain embodiments, side effects include injection site reactions, liver function test abnormalities, renal function abnormalities, liver toxicity, renal toxicity, central nervous system abnormalities, myopathies, and malaise. 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. 
     “Sites,” as used herein, are defined as unique nucleobase positions within a target nucleic acid. 
     “Slows progression” means decrease in the development of the said disease. 
     “Specifically hybridizable” refers to an antisense compound having a sufficient degree of complementarity between an antisense oligonucleotide and a target nucleic acid to induce a desired effect, while exhibiting minimal or no effects on non-target nucleic acids under conditions in which specific binding is desired, i.e., under physiological conditions in the case of in vivo assays and therapeutic treatments. “Stringent hybridization conditions” or “stringent conditions” refer to conditions under which an oligomeric compound will hybridize to its target sequence, but to a minimal number of other sequences. 
     “Subject” means a human or non-human animal selected for treatment or therapy. 
     “Target” refers to a protein, the modulation of which is desired. 
     “Target gene” refers to a gene encoding a target. 
     “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. 
     “Target nucleic acid,” “target RNA,” “target RNA transcript” and “nucleic acid target” all mean a nucleic acid capable of being targeted by antisense compounds. 
     “Target region” means a portion 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. 
     “Therapeutically effective amount” means an amount of a pharmaceutical agent that provides a therapeutic benefit to an individual. 
     “Treat” refers to administering a pharmaceutical composition to an animal in order to effect an alteration or improvement of a disease, disorder, or condition in the animal. In certain embodiments, one or more pharmaceutical compositions can be administered to the animal. 
     “Unmodified” nucleobases mean the purine bases adenine (A) and guanine (G), and the pyrimidine bases thymine (T), cytosine (C) and uracil (U). 
     “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). 
     Certain Embodiments 
     Certain embodiments provide methods, compounds and compositions for inhibiting growth hormone receptor (GHR) expression. 
     Certain embodiments provide antisense compounds targeted to a GHR nucleic acid. In certain embodiments, the GHR nucleic acid has the sequence set forth in GENBANK Accession No. NM_000163.4 (incorporated herein as SEQ ID NO: 1), GENBANK Accession No. NT_006576.16 truncated from nucleotides 42411001 to 42714000 (incorporated herein as SEQ ID NO: 2), GENBANK Accession No X06562.1 (incorporated herein as SEQ ID NO: 3), GENBANK Accession No. DR006395.1 (incorporated herein as SEQ ID NO: 4), GENBANK Accession No. DB052048.1 (incorporated herein as SEQ ID NO: 5), GENBANK Accession No. AF230800.1 (incorporated herein as SEQ ID NO: 6), the complement of GENBANK Accession No. AA398260.1 (incorporated herein as SEQ ID NO: 7), GENBANK Accession No. BC136496.1 (incorporated herein as SEQ ID NO: 8), GENBANK Accession No. NM_001242399.2 (incorporated herein as SEQ ID NO: 9), GENBANK Accession No. NM_001242400.2 (incorporated herein as SEQ ID NO: 10), GENBANK Accession No. NM_001242401.3 (incorporated herein as SEQ ID NO: 11), GENBANK Accession No. NM_001242402.2 (incorporated herein as SEQ ID NO: 12), GENBANK Accession No. NM_001242403.2 (incorporated herein as SEQ ID NO: 13), GENBANK Accession No. NM_001242404.2 (incorporated herein as SEQ ID NO: 14), GENBANK Accession No. NM_001242405.2 (incorporated herein as SEQ ID NO: 15), GENBANK Accession No. NM_001242406.2 (incorporated herein as SEQ ID NO: 16), GENBANK Accession No. NM_001242460.1 (incorporated herein as SEQ ID NO: 17), GENBANK Accession NM_001242461.1 (incorporated herein as SEQ ID NO: 18), or GENBANK Accession No. NM_001242462.1 (incorporated herein as SEQ ID NO: 19). 
     Certain embodiments provide a compound comprising a modified oligonucleotide consisting of 10 to 30 linked nucleosides and having a nucleobase sequence comprising at least 8 contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs: 20-2295. 
     Certain embodiments provide a compound comprising a modified oligonucleotide consisting of 10 to 30 linked nucleosides complementary within nucleotides 30-51, 63-82, 103-118, 143-159, 164-197, 206-259, 361-388, 554-585, 625-700, 736-776, 862-887, 923-973, 978-996, 1127-1142, 1170-1195, 1317-1347, 1360-1383, 1418-1449, 1492-1507, 1524-1548, 1597-1634, 1641-1660, 1683-1698, 1744-1768, 1827-1860, 1949-2002, 2072-2092, 2095-2110, 2306-2321, 2665-2683, 2685-2719, 2739-2770, 2859-2880, 2941-2960, 2963-2978, 3037-3052, 3205-3252, 3306-3332, 3371-3386, 3518-3542, 3975-3990, 4041-4087, 4418-4446, 4528-4546, 7231-7246, 7570-7585, 8395-8410, 9153-9168, 9554-9569, 9931-9946, 10549-10564, 11020-11035, 11793-11808, 12214-12229, 12474-12489, 12905-12920, 13400-13415, 13717-13732, 14149-14164, 14540-14555, 15264-15279, 15849-15864, 16530-16545, 17377-17392, 17581-17596, 17943-17958, 18353-18368, 18636-18651, 19256-19271, 19814-19829, 20365-20380, 20979-20994, 21566-21581, 22150-22165, 22803-22818, 29049-29064, 29554-29569, 30245-30260, 30550-30565, 30915-30930, 31468-31483, 32366-32381, 32897-32912, 33187-33202, 33780-33795, 34407-34422, 34846-34861, 35669-35684, 36312-36327, 36812-36827, 37504-37519, 38841-38856, 40250-40265, 40706-40721, 40922-40937, 41424-41439, 41999-42014, 42481-42496, 42700-42715, 43291-43306, 43500-43515, 43947-43962, 44448-44463, 45162-45177, 46010-46025, 46476-46491, 47447-47462, 47752-47767, 48001-48016, 48423-48438, 50195-50210, 50470-50485, 51104-51119, 51756-51771, 52015-52030, 52230-52245, 52588-52603, 53532-53547, or 54645-54660 of SEQ ID NO: 1, wherein said modified oligonucleotide is at least 90% complementary to SEQ ID NO: 1. 
     Certain embodiments provide a compound comprising a modified oligonucleotide consisting of 10 to 30 linked nucleosides having a nucleobase sequence comprising a portion of at least 8 contiguous nucleobases 100% complementary to an equal length portion of nucleobases 30-51, 63-82, 103-118, 143-159, 164-197, 206-259, 361-388, 554-585, 625-700, 736-776, 862-887, 923-973, 978-996, 1127-1142, 1170-1195, 1317-1347, 1360-1383, 1418-1449, 1492-1507, 1524-1548, 1597-1634, 1641-1660, 1683-1698, 1744-1768, 1827-1860, 1949-2002, 2072-2092, 2095-2110, 2306-2321, 2665-2683, 2685-2719, 2739-2770, 2859-2880, 2941-2960, 2963-2978, 3037-3052, 3205-3252, 3306-3332, 3371-3386, 3518-3542, 3975-3990, 4041-4087, 4418-4446, 4528-4546, 7231-7246, 7570-7585, 8395-8410, 9153-9168, 9554-9569, 9931-9946, 10549-10564, 11020-11035, 11793-11808, 12214-12229, 12474-12489, 12905-12920, 13400-13415, 13717-13732, 14149-14164, 14540-14555, 15264-15279, 15849-15864, 16530-16545, 17377-17392, 17581-17596, 17943-17958, 18353-18368, 18636-18651, 19256-19271, 19814-19829, 20365-20380, 20979-20994, 21566-21581, 22150-22165, 22803-22818, 29049-29064, 29554-29569, 30245-30260, 30550-30565, 30915-30930, 31468-31483, 32366-32381, 32897-32912, 33187-33202, 33780-33795, 34407-34422, 34846-34861, 35669-35684, 36312-36327, 36812-36827, 37504-37519, 38841-38856, 40250-40265, 40706-40721, 40922-40937, 41424-41439, 41999-42014, 42481-42496, 42700-42715, 43291-43306, 43500-43515, 43947-43962, 44448-44463, 45162-45177, 46010-46025, 46476-46491, 47447-47462, 47752-47767, 48001-48016, 48423-48438, 50195-50210, 50470-50485, 51104-51119, 51756-51771, 52015-52030, 52230-52245, 52588-52603, 53532-53547, or 54645-54660 of SEQ ID NO: 1, wherein the nucleobase sequence of the modified oligonucleotide is complementary to SEQ ID NO: 1. 
     Certain embodiments provide a compound comprising a modified oligonucleotide consisting of 10 to 30 linked nucleosides complementary within nucleotides 2571-2586, 2867-3059, 3097-3116, 3341-3695, 4024-4039, 4446-4894, 5392-5817, 6128-6265, 6499-6890, 7231-7246, 8395-8410, 9153-9168, 9554-9569, 9931-9946, 10549-10564, 10660-10679, 11020-11035, 11793-12229, 12469-12920, 13351-13415, 13717-13732, 14149-14164, 14361-14555, 14965-15279, 15849-16001, 16253-16272, 16447-16545, 17130-17149, 17377-17669, 17927-17958, 18353-18368, 18636-18773, 19661-19918, 20288-20470, 20979-20994, 21215-21606, 21820-21837, 22150-22165, 22518-22536, 22803-22818, 26494-26522, 29049-29069, 29323-29489, 30550-30565, 30915-31191, 31468-31483, 32363-32382, 32827-33202, 33635-33795, 34138-34157, 34407-34422, 34845-34864, 35466-35485, 35669-35684, 36023-36042, 36266-36327, 36721-36827, 37032-37130, 37276-37295, 37504-37675, 38094-38118, 38841-38856, 39716-40538, 40706-40937, 41164-41183, 41342-41439, 42141-42164, 42700-42760, 43173-43537, 43765-46025, 46476-46532, 48423-48438, 50072-50210, 50470-50485, 50719-51234, 51747-51797, 52015-52143, 52230-52245, 52573-52652, 53466-54660, 54886-54901, 63751-64662, 64882-65099, 65363-65378, 65600-65615, 65988-66183, 66566-66581, 66978-67080, 67251-67270, 67662-67929, 68727-68742, 69203-69242, 69565-69620, 69889-70145, 70352-70584, 70925-71071, 71314-71329, 71617-71769, 72107-72241, 72584-72670, 73061-73076, 73350-73369, 73689-73723, 74107-74131, 74317-74557, 74947-75009, 75192-75207, 75979-76066, 76410-77095, 77292-77307, 77638-77869, 78122-78326, 79006-79021, 79478-79505, 80277-80292, 80575-80939, 81207-81222, 81524-81543, 81761-81776, 82233-82248, 82738-83198, 83330-83416, 83884-84063, 84381-85964, 86220-86392, 86554-86655, 86901-86920, 87181-87262, 88063-88082, 88293-88308, 88605-88967, 89160-89175, 89940-90255, 90473-90528, 91073-91088, 91273-91292, 91647-91662, 91930-92126, 92356-92371, 93190-93443, 93762-94111, 94374-94389, 94581-94653, 94839-94858, 95292-95583, 95829-95844, 96137-96503, 96793-97013, 97539-97554, 97800-97889, 98132-98151, 98624-98672, 98810-99115, 99258-99273, 99478-99503, 99791-99858, 100281-100300, 100406-100421, 100742-100828, 101080-101103, 101242-101320, 101788-101906, 102549-102568, 103566-103625, 104067-104086, 104277-104858, 105255-105274, 106147-106364, 106632-106647, 106964-107735, 108514-108788, 109336-109505, 109849-109864, 110403-110442, 110701-110974, 111203-111322, 112030-112049, 112499-112514, 112842-112861, 113028-113056, 113646-113665, 113896-113911, 114446-114465, 115087-115106, 119269-119284, 119659-119703, 120376-120497, 120738-120845, 121209-121228, 121823-122013, 122180-122199, 122588-122770, 123031-123050, 123152-123167, 123671-124055, 124413-124608, 125178-125197, 125533-125616, 126357-126434, 126736-126751, 126998-127236, 127454-127682, 128467-128482, 128813-129111, 129976-130013, 130308-130323, 131036-131056, 131286-131305, 131676-131691, 132171-132517, 133168-133241, 133522-133877, 134086-134101, 134240-134259, 134441-134617, 135015-135030, 135431-135519, 135818-135874, 136111-136130, 136282-136595, 136996-137152, 137372-137387, 137750-137765, 138048-138067, 138782-139840, 140343-140358, 140593-140701, 141116-141131, 141591-141719, 142113-142342, 143021-143048, 143185-143486, 143836-144109, 144558-144650, 144990-145078, 145428-145525, 145937-145952, 146235-146386, 147028-147043, 147259-147284, 147671-147686, 148059-148154, 148564-148579, 148904-149084, 149491-149506, 149787-149877, 150236-150251, 150588-151139, 151373-151659, 152201-152388, 152549-152771, 153001-153026, 153349-153364, 153831-154112, 154171-154186, 154502-154521, 154724-154828, 155283-155304, 155591-155616, 155889-155992, 156233-156612, 156847-156907, 157198-157223, 157330-157349, 157552-157567, 157927-158029, 158542-158631, 159216-159267, 159539-159793, 160352-160429, 160812-160827, 161248-161267, 161461-161607, 161821-161969, 162064-162083, 162132-162147, 162531-162770, 163019-163557, 164839-165059, 165419-165575, 165856-165875, 166241-166450, 166837-166852, 167107-167122, 168004-168019, 168760-168823, 169062-169092, 169134-169153, 169601-169711, 170081-170291, 170407-170426, 170703-170814, 171021-171036, 171207-171226, 171431-171568, 171926-171945, 172447-172462, 172733-172956, 173045-173756, 174122-174885, 175014-177830, 178895-180539, 181514-187644, 187857-189904, 190109-194159, 194425-195723, 196536-196873, 197326-197961, 198145-198170, 198307-198381, 198715-199007, 199506-199563, 199816-199838, 200249-200635, 201258-201861, 202079-202094, 202382-202717, 203098-203934, 204181-204740, 205549-205915, 206412-206764, 207510-207532, 209999-210014, 210189-210296, 210502-210583, 210920-211418, 211836-212223, 212606-212816, 213025-213044, 213425-213440, 213825-213933, 214479-214498, 214622-214647, 214884-214951, 215446-215508, 215932-215951, 216192-217595, 218132-218248, 218526-218541, 218734-21219037, 219342-219633, 219886-220705, 221044-221059, 221483-221607, 221947-221962, 222569-222584, 222914-222998, 223436-223451, 223948-224122, 224409-224430, 224717-224769, 225133-225148, 225436-225761, 226785-226898, 227025-227040, 227218-227251, 227485-227500, 227914-228837, 229174-229189, 229423-229438, 229615-229640, 230042-230057, 230313-230595, 231218-231345, 231817-232037, 232088-232408, 232823-232848, 232884-232899, 233210-233225, 233623-233646, 234447-234466, 234876-234918, 235258-235328, 235770-235785, 236071-236213, 236684-237196, 237585-237698, 237949-237557, 244873-244897, 245319-245334, 245701-245780, 246152-246523, 246936-247031, 247203-247240, 247431-247450, 247644-247659, 248223-248363, 248694-248762, 249494-249509, 250001-250020, 250693-250708, 251214-251233, 251601-251637, 251950-252060, 252665-252680, 252838-252863, 253140-253166, 253594-253819, 254036-254083, 254246-254345, 254641-254660, 254905-254920, 255397-255422, 255618-255633, 255992-256704, 257018-257092, 257317-257332, 257818-259305, 259500-259515, 261294-261656, 262021-262036, 262453-262779, 263338-266518, 266861-267131, 267375-268051, 268366-269447, 270038-271850, 271950-271969, 272631-274145, 274205-275747, 275808-276636, 276932-277064, 277391-278380, 278932-279063, 279303-281001, 281587-281610, 282229-283668, 290035-290474, 290924-292550, 292860-294408, 295475-297012, 297587-298115, 298161-298418, 298489-298738, 299082-299187, 299276-299669, 299723-299749, 299788-300504, or 300835-301295 of SEQ ID NO: 2, wherein said modified oligonucleotide is at least 90% complementary to SEQ ID NO: 2. 
     Certain embodiments provide a compound comprising a modified oligonucleotide consisting of 10 to 30 linked nucleosides having a nucleobase sequence comprising a portion of at least 8 contiguous nucleobases 100% complementary to an equal length portion of nucleobases 2571-2586, 2867-3059, 3097-3116, 3341-3695, 4024-4039, 4446-4894, 5392-5817, 6128-6265, 6499-6890, 7231-7246, 8395-8410, 9153-9168, 9554-9569, 9931-9946, 10549-10564, 10660-10679, 11020-11035, 11793-12229, 12469-12920, 13351-13415, 13717-13732, 14149-14164, 14361-14555, 14965-15279, 15849-16001, 16253-16272, 16447-16545, 17130-17149, 17377-17669, 17927-17958, 18353-18368, 18636-18773, 19661-19918, 20288-20470, 20979-20994, 21215-21606, 21820-21837, 22150-22165, 22518-22536, 22803-22818, 26494-26522, 29049-29069, 29323-29489, 30550-30565, 30915-31191, 31468-31483, 32363-32382, 32827-33202, 33635-33795, 34138-34157, 34407-34422, 34845-34864, 35466-35485, 35669-35684, 36023-36042, 36266-36327, 36721-36827, 37032-37130, 37276-37295, 37504-37675, 38094-38118, 38841-38856, 39716-40538, 40706-40937, 41164-41183, 41342-41439, 42141-42164, 42700-42760, 43173-43537, 43765-46025, 46476-46532, 48423-48438, 50072-50210, 50470-50485, 50719-51234, 51747-51797, 52015-52143, 52230-52245, 52573-52652, 53466-54660, 54886-54901, 63751-64662, 64882-65099, 65363-65378, 65600-65615, 65988-66183, 66566-66581, 66978-67080, 67251-67270, 67662-67929, 68727-68742, 69203-69242, 69565-69620, 69889-70145, 70352-70584, 70925-71071, 71314-71329, 71617-71769, 72107-72241, 72584-72670, 73061-73076, 73350-73369, 73689-73723, 74107-74131, 74317-74557, 74947-75009, 75192-75207, 75979-76066, 76410-77095, 77292-77307, 77638-77869, 78122-78326, 79006-79021, 79478-79505, 80277-80292, 80575-80939, 81207-81222, 81524-81543, 81761-81776, 82233-82248, 82738-83198, 83330-83416, 83884-84063, 84381-85964, 86220-86392, 86554-86655, 86901-86920, 87181-87262, 88063-88082, 88293-88308, 88605-88967, 89160-89175, 89940-90255, 90473-90528, 91073-91088, 91273-91292, 91647-91662, 91930-92126, 92356-92371, 93190-93443, 93762-94111, 94374-94389, 94581-94653, 94839-94858, 95292-95583, 95829-95844, 96137-96503, 96793-97013, 97539-97554, 97800-97889, 98132-98151, 98624-98672, 98810-99115, 99258-99273, 99478-99503, 99791-99858, 100281-100300, 100406-100421, 100742-100828, 101080-101103, 101242-101320, 101788-101906, 102549-102568, 103566-103625, 104067-104086, 104277-104858, 105255-105274, 106147-106364, 106632-106647, 106964-107735, 108514-108788, 109336-109505, 109849-109864, 110403-110442, 110701-110974, 111203-111322, 112030-112049, 112499-112514, 112842-112861, 113028-113056, 113646-113665, 113896-113911, 114446-114465, 115087-115106, 119269-119284, 119659-119703, 120376-120497, 120738-120845, 121209-121228, 121823-122013, 122180-122199, 122588-122770, 123031-123050, 123152-123167, 123671-124055, 124413-124608, 125178-125197, 125533-125616, 126357-126434, 126736-126751, 126998-127236, 127454-127682, 128467-128482, 128813-129111, 129976-130013, 130308-130323, 131036-131056, 131286-131305, 131676-131691, 132171-132517, 133168-133241, 133522-133877, 134086-134101, 134240-134259, 134441-134617, 135015-135030, 135431-135519, 135818-135874, 136111-136130, 136282-136595, 136996-137152, 137372-137387, 137750-137765, 138048-138067, 138782-139840, 140343-140358, 140593-140701, 141116-141131, 141591-141719, 142113-142342, 143021-143048, 143185-143486, 143836-144109, 144558-144650, 144990-145078, 145428-145525, 145937-145952, 146235-146386, 147028-147043, 147259-147284, 147671-147686, 148059-148154, 148564-148579, 148904-149084, 149491-149506, 149787-149877, 150236-150251, 150588-151139, 151373-151659, 152201-152388, 152549-152771, 153001-153026, 153349-153364, 153831-154112, 154171-154186, 154502-154521, 154724-154828, 155283-155304, 155591-155616, 155889-155992, 156233-156612, 156847-156907, 157198-157223, 157330-157349, 157552-157567, 157927-158029, 158542-158631, 159216-159267, 159539-159793, 160352-160429, 160812-160827, 161248-161267, 161461-161607, 161821-161969, 162064-162083, 162132-162147, 162531-162770, 163019-163557, 164839-165059, 165419-165575, 165856-165875, 166241-166450, 166837-166852, 167107-167122, 168004-168019, 168760-168823, 169062-169092, 169134-169153, 169601-169711, 170081-170291, 170407-170426, 170703-170814, 171021-171036, 171207-171226, 171431-171568, 171926-171945, 172447-172462, 172733-172956, 173045-173756, 174122-174885, 175014-177830, 178895-180539, 181514-187644, 187857-189904, 190109-194159, 194425-195723, 196536-196873, 197326-197961, 198145-198170, 198307-198381, 198715-199007, 199506-199563, 199816-199838, 200249-200635, 201258-201861, 202079-202094, 202382-202717, 203098-203934, 204181-204740, 205549-205915, 206412-206764, 207510-207532, 209999-210014, 210189-210296, 210502-210583, 210920-211418, 211836-212223, 212606-212816, 213025-213044, 213425-213440, 213825-213933, 214479-214498, 214622-214647, 214884-214951, 215446-215508, 215932-215951, 216192-217595, 218132-218248, 218526-218541, 218734-21219037, 219342-219633, 219886-220705, 221044-221059, 221483-221607, 221947-221962, 222569-222584, 222914-222998, 223436-223451, 223948-224122, 224409-224430, 224717-224769, 225133-225148, 225436-225761, 226785-226898, 227025-227040, 227218-227251, 227485-227500, 227914-228837, 229174-229189, 229423-229438, 229615-229640, 230042-230057, 230313-230595, 231218-231345, 231817-232037, 232088-232408, 232823-232848, 232884-232899, 233210-233225, 233623-233646, 234447-234466, 234876-234918, 235258-235328, 235770-235785, 236071-236213, 236684-237196, 237585-237698, 237949-237557, 244873-244897, 245319-245334, 245701-245780, 246152-246523, 246936-247031, 247203-247240, 247431-247450, 247644-247659, 248223-248363, 248694-248762, 249494-249509, 250001-250020, 250693-250708, 251214-251233, 251601-251637, 251950-252060, 252665-252680, 252838-252863, 253140-253166, 253594-253819, 254036-254083, 254246-254345, 254641-254660, 254905-254920, 255397-255422, 255618-255633, 255992-256704, 257018-257092, 257317-257332, 257818-259305, 259500-259515, 261294-261656, 262021-262036, 262453-262779, 263338-266518, 266861-267131, 267375-268051, 268366-269447, 270038-271850, 271950-271969, 272631-274145, 274205-275747, 275808-276636, 276932-277064, 277391-278380, 278932-279063, 279303-281001, 281587-281610, 282229-283668, 290035-290474, 290924-292550, 292860-294408, 295475-297012, 297587-298115, 298161-298418, 298489-298738, 299082-299187, 299276-299669, 299723-299749, 299788-300504, or 300835-301295 of SEQ ID NO: 2, wherein the nucleobase sequence of the modified oligonucleotide is complementary to SEQ ID NO: 2. In certain aspects, the compound comprises a modified oligonucleotide consisting of 10 to 30 linked nucleosides complementary within nucleotides 155594-155613, 72107-72126, 153921-153940, 159252-159267, 213425-213440, 153004-153019, 155597-155612, 248233-248248 of SEQ ID NO: 2. 
     Certain embodiments provide a compound comprising a modified oligonucleotide consisting of 10 to 30 linked nucleosides and having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 20-2295. 
     Certain embodiments provide a compound comprising a modified oligonucleotide consisting of the nucleobase sequence of any one of SEQ ID NOs: 20-2295. 
     In certain embodiments, an antisense compound or oligonucleotide targeted to a growth hormone receptor nucleic acid is complementary within the following nucleotide regions of SEQ ID NO: 1: 30-51, 63-82, 103-118, 143-159, 164-197, 206-259, 361-388, 554-585, 625-700, 736-776, 862-887, 923-973, 978-996, 1127-1142, 1170-1195, 1317-1347, 1360-1383, 1418-1449, 1492-1507, 1524-1548, 1597-1634, 1641-1660, 1683-1698, 1744-1768, 1827-1860, 1949-2002, 2072-2092, 2095-2110, 2306-2321, 2665-2683, 2685-2719, 2739-2770, 2859-2880, 2941-2960, 2963-2978, 3037-3052, 3205-3252, 3306-3332, 3371-3386, 3518-3542, 3975-3990, 4041-4087, 4418-4446, 4528-4546, 7231-7246, 7570-7585, 8395-8410, 9153-9168, 9554-9569, 9931-9946, 10549-10564, 11020-11035, 11793-11808, 12214-12229, 12474-12489, 12905-12920, 13400-13415, 13717-13732, 14149-14164, 14540-14555, 15264-15279, 15849-15864, 16530-16545, 17377-17392, 17581-17596, 17943-17958, 18353-18368, 18636-18651, 19256-19271, 19814-19829, 20365-20380, 20979-20994, 21566-21581, 22150-22165, 22803-22818, 29049-29064, 29554-29569, 30245-30260, 30550-30565, 30915-30930, 31468-31483, 32366-32381, 32897-32912, 33187-33202, 33780-33795, 34407-34422, 34846-34861, 35669-35684, 36312-36327, 36812-36827, 37504-37519, 38841-38856, 40250-40265, 40706-40721, 40922-40937, 41424-41439, 41999-42014, 42481-42496, 42700-42715, 43291-43306, 43500-43515, 43947-43962, 44448-44463, 45162-45177, 46010-46025, 46476-46491, 47447-47462, 47752-47767, 48001-48016, 48423-48438, 50195-50210, 50470-50485, 51104-51119, 51756-51771, 52015-52030, 52230-52245, 52588-52603, 53532-53547, or 54645-54660. 
     In certain embodiments, an antisense compound or oligonucleotide targeted to a growth hormone receptor nucleic acid target the following nucleotide regions of SEQ ID NO: 1: 30-51, 63-82, 103-118, 143-159, 164-197, 206-259, 361-388, 554-585, 625-700, 736-776, 862-887, 923-973, 978-996, 1127-1142, 1170-1195, 1317-1347, 1360-1383, 1418-1449, 1492-1507, 1524-1548, 1597-1634, 1641-1660, 1683-1698, 1744-1768, 1827-1860, 1949-2002, 2072-2092, 2095-2110, 2306-2321, 2665-2683, 2685-2719, 2739-2770, 2859-2880, 2941-2960, 2963-2978, 3037-3052, 3205-3252, 3306-3332, 3371-3386, 3518-3542, 3975-3990, 4041-4087, 4418-4446, 4528-4546, 7231-7246, 7570-7585, 8395-8410, 9153-9168, 9554-9569, 9931-9946, 10549-10564, 11020-11035, 11793-11808, 12214-12229, 12474-12489, 12905-12920, 13400-13415, 13717-13732, 14149-14164, 14540-14555, 15264-15279, 15849-15864, 16530-16545, 17377-17392, 17581-17596, 17943-17958, 18353-18368, 18636-18651, 19256-19271, 19814-19829, 20365-20380, 20979-20994, 21566-21581, 22150-22165, 22803-22818, 29049-29064, 29554-29569, 30245-30260, 30550-30565, 30915-30930, 31468-31483, 32366-32381, 32897-32912, 33187-33202, 33780-33795, 34407-34422, 34846-34861, 35669-35684, 36312-36327, 36812-36827, 37504-37519, 38841-38856, 40250-40265, 40706-40721, 40922-40937, 41424-41439, 41999-42014, 42481-42496, 42700-42715, 43291-43306, 43500-43515, 43947-43962, 44448-44463, 45162-45177, 46010-46025, 46476-46491, 47447-47462, 47752-47767, 48001-48016, 48423-48438, 50195-50210, 50470-50485, 51104-51119, 51756-51771, 52015-52030, 52230-52245, 52588-52603, 53532-53547, or 54645-54660. 
     In certain embodiments, antisense compounds or oligonucleotides target a region of a growth hormone receptor nucleic acid. In certain embodiments, such compounds or oligonucleotides targeted to a region of a GHR nucleic acid have a contiguous nucleobase portion that is complementary to an equal length nucleobase portion of the region. For example, the portion can be at least an 8, 9, 10, 11, 12, 13, 14, 15, or 16 contiguous nucleobases portion complementary to an equal length portion of a region recited herein. In certain embodiments, such compounds or oligonucleotide target the following nucleotide regions of SEQ ID NO: 1: 30-51, 63-82, 103-118, 143-159, 164-197, 206-259, 361-388, 554-585, 625-700, 736-776, 862-887, 923-973, 978-996, 1127-1142, 1170-1195, 1317-1347, 1360-1383, 1418-1449, 1492-1507, 1524-1548, 1597-1634, 1641-1660, 1683-1698, 1744-1768, 1827-1860, 1949-2002, 2072-2092, 2095-2110, 2306-2321, 2665-2683, 2685-2719, 2739-2770, 2859-2880, 2941-2960, 2963-2978, 3037-3052, 3205-3252, 3306-3332, 3371-3386, 3518-3542, 3975-3990, 4041-4087, 4418-4446, 4528-4546, 7231-7246, 7570-7585, 8395-8410, 9153-9168, 9554-9569, 9931-9946, 10549-10564, 11020-11035, 11793-11808, 12214-12229, 12474-12489, 12905-12920, 13400-13415, 13717-13732, 14149-14164, 14540-14555, 15264-15279, 15849-15864, 16530-16545, 17377-17392, 17581-17596, 17943-17958, 18353-18368, 18636-18651, 19256-19271, 19814-19829, 20365-20380, 20979-20994, 21566-21581, 22150-22165, 22803-22818, 29049-29064, 29554-29569, 30245-30260, 30550-30565, 30915-30930, 31468-31483, 32366-32381, 32897-32912, 33187-33202, 33780-33795, 34407-34422, 34846-34861, 35669-35684, 36312-36327, 36812-36827, 37504-37519, 38841-38856, 40250-40265, 40706-40721, 40922-40937, 41424-41439, 41999-42014, 42481-42496, 42700-42715, 43291-43306, 43500-43515, 43947-43962, 44448-44463, 45162-45177, 46010-46025, 46476-46491, 47447-47462, 47752-47767, 48001-48016, 48423-48438, 50195-50210, 50470-50485, 51104-51119, 51756-51771, 52015-52030, 52230-52245, 52588-52603, 53532-53547, or 54645-54660. 
     In certain embodiments, an antisense compound or oligonucleotide targeted to a growth hormone receptor nucleic acid is complementary within the following nucleotide regions of SEQ ID NO: 2: 2571-2586, 2867-3059, 3097-3116, 3341-3695, 4024-4039, 4446-4894, 5392-5817, 6128-6265, 6499-6890, 7231-7246, 8395-8410, 9153-9168, 9554-9569, 9931-9946, 10549-10564, 10660-10679, 11020-11035, 11793-12229, 12469-12920, 13351-13415, 13717-13732, 14149-14164, 14361-14555, 14965-15279, 15849-16001, 16253-16272, 16447-16545, 17130-17149, 17377-17669, 17927-17958, 18353-18368, 18636-18773, 19661-19918, 20288-20470, 20979-20994, 21215-21606, 21820-21837, 22150-22165, 22518-22536, 22803-22818, 26494-26522, 29049-29069, 29323-29489, 30550-30565, 30915-31191, 31468-31483, 32363-32382, 32827-33202, 33635-33795, 34138-34157, 34407-34422, 34845-34864, 35466-35485, 35669-35684, 36023-36042, 36266-36327, 36721-36827, 37032-37130, 37276-37295, 37504-37675, 38094-38118, 38841-38856, 39716-40538, 40706-40937, 41164-41183, 41342-41439, 42141-42164, 42700-42760, 43173-43537, 43765-46025, 46476-46532, 48423-48438, 50072-50210, 50470-50485, 50719-51234, 51747-51797, 52015-52143, 52230-52245, 52573-52652, 53466-54660, 54886-54901, 63751-64662, 64882-65099, 65363-65378, 65600-65615, 65988-66183, 66566-66581, 66978-67080, 67251-67270, 67662-67929, 68727-68742, 69203-69242, 69565-69620, 69889-70145, 70352-70584, 70925-71071, 71314-71329, 71617-71769, 72107-72241, 72584-72670, 73061-73076, 73350-73369, 73689-73723, 74107-74131, 74317-74557, 74947-75009, 75192-75207, 75979-76066, 76410-77095, 77292-77307, 77638-77869, 78122-78326, 79006-79021, 79478-79505, 80277-80292, 80575-80939, 81207-81222, 81524-81543, 81761-81776, 82233-82248, 82738-83198, 83330-83416, 83884-84063, 84381-85964, 86220-86392, 86554-86655, 86901-86920, 87181-87262, 88063-88082, 88293-88308, 88605-88967, 89160-89175, 89940-90255, 90473-90528, 91073-91088, 91273-91292, 91647-91662, 91930-92126, 92356-92371, 93190-93443, 93762-94111, 94374-94389, 94581-94653, 94839-94858, 95292-95583, 95829-95844, 96137-96503, 96793-97013, 97539-97554, 97800-97889, 98132-98151, 98624-98672, 98810-99115, 99258-99273, 99478-99503, 99791-99858, 100281-100300, 100406-100421, 100742-100828, 101080-101103, 101242-101320, 101788-101906, 102549-102568, 103566-103625, 104067-104086, 104277-104858, 105255-105274, 106147-106364, 106632-106647, 106964-107735, 108514-108788, 109336-109505, 109849-109864, 110403-110442, 110701-110974, 111203-111322, 112030-112049, 112499-112514, 112842-112861, 113028-113056, 113646-113665, 113896-113911, 114446-114465, 115087-115106, 119269-119284, 119659-119703, 120376-120497, 120738-120845, 121209-121228, 121823-122013, 122180-122199, 122588-122770, 123031-123050, 123152-123167, 123671-124055, 124413-124608, 125178-125197, 125533-125616, 126357-126434, 126736-126751, 126998-127236, 127454-127682, 128467-128482, 128813-129111, 129976-130013, 130308-130323, 131036-131056, 131286-131305, 131676-131691, 132171-132517, 133168-133241, 133522-133877, 134086-134101, 134240-134259, 134441-134617, 135015-135030, 135431-135519, 135818-135874, 136111-136130, 136282-136595, 136996-137152, 137372-137387, 137750-137765, 138048-138067, 138782-139840, 140343-140358, 140593-140701, 141116-141131, 141591-141719, 142113-142342, 143021-143048, 143185-143486, 143836-144109, 144558-144650, 144990-145078, 145428-145525, 145937-145952, 146235-146386, 147028-147043, 147259-147284, 147671-147686, 148059-148154, 148564-148579, 148904-149084, 149491-149506, 149787-149877, 150236-150251, 150588-151139, 151373-151659, 152201-152388, 152549-152771, 153001-153026, 153349-153364, 153831-154112, 154171-154186, 154502-154521, 154724-154828, 155283-155304, 155591-155616, 155889-155992, 156233-156612, 156847-156907, 157198-157223, 157330-157349, 157552-157567, 157927-158029, 158542-158631, 159216-159267, 159539-159793, 160352-160429, 160812-160827, 161248-161267, 161461-161607, 161821-161969, 162064-162083, 162132-162147, 162531-162770, 163019-163557, 164839-165059, 165419-165575, 165856-165875, 166241-166450, 166837-166852, 167107-167122, 168004-168019, 168760-168823, 169062-169092, 169134-169153, 169601-169711, 170081-170291, 170407-170426, 170703-170814, 171021-171036, 171207-171226, 171431-171568, 171926-171945, 172447-172462, 172733-172956, 173045-173756, 174122-174885, 175014-177830, 178895-180539, 181514-187644, 187857-189904, 190109-194159, 194425-195723, 196536-196873, 197326-197961, 198145-198170, 198307-198381, 198715-199007, 199506-199563, 199816-199838, 200249-200635, 201258-201861, 202079-202094, 202382-202717, 203098-203934, 204181-204740, 205549-205915, 206412-206764, 207510-207532, 209999-210014, 210189-210296, 210502-210583, 210920-211418, 211836-212223, 212606-212816, 213025-213044, 213425-213440, 213825-213933, 214479-214498, 214622-214647, 214884-214951, 215446-215508, 215932-215951, 216192-217595, 218132-218248, 218526-218541, 218734-21219037, 219342-219633, 219886-220705, 221044-221059, 221483-221607, 221947-221962, 222569-222584, 222914-222998, 223436-223451, 223948-224122, 224409-224430, 224717-224769, 225133-225148, 225436-225761, 226785-226898, 227025-227040, 227218-227251, 227485-227500, 227914-228837, 229174-229189, 229423-229438, 229615-229640, 230042-230057, 230313-230595, 231218-231345, 231817-232037, 232088-232408, 232823-232848, 232884-232899, 233210-233225, 233623-233646, 234447-234466, 234876-234918, 235258-235328, 235770-235785, 236071-236213, 236684-237196, 237585-237698, 237949-237557, 244873-244897, 245319-245334, 245701-245780, 246152-246523, 246936-247031, 247203-247240, 247431-247450, 247644-247659, 248223-248363, 248694-248762, 249494-249509, 250001-250020, 250693-250708, 251214-251233, 251601-251637, 251950-252060, 252665-252680, 252838-252863, 253140-253166, 253594-253819, 254036-254083, 254246-254345, 254641-254660, 254905-254920, 255397-255422, 255618-255633, 255992-256704, 257018-257092, 257317-257332, 257818-259305, 259500-259515, 261294-261656, 262021-262036, 262453-262779, 263338-266518, 266861-267131, 267375-268051, 268366-269447, 270038-271850, 271950-271969, 272631-274145, 274205-275747, 275808-276636, 276932-277064, 277391-278380, 278932-279063, 279303-281001, 281587-281610, 282229-283668, 290035-290474, 290924-292550, 292860-294408, 295475-297012, 297587-298115, 298161-298418, 298489-298738, 299082-299187, 299276-299669, 299723-299749, 299788-300504, or 300835-301295. 
     In certain embodiments, an antisense compound or oligonucleotide targeted to a growth hormone receptor nucleic acid target the following nucleotide regions of SEQ ID NO: 2: 2571-2586, 2867-3059, 3097-3116, 3341-3695, 4024-4039, 4446-4894, 5392-5817, 6128-6265, 6499-6890, 7231-7246, 8395-8410, 9153-9168, 9554-9569, 9931-9946, 10549-10564, 10660-10679, 11020-11035, 11793-12229, 12469-12920, 13351-13415, 13717-13732, 14149-14164, 14361-14555, 14965-15279, 15849-16001, 16253-16272, 16447-16545, 17130-17149, 17377-17669, 17927-17958, 18353-18368, 18636-18773, 19661-19918, 20288-20470, 20979-20994, 21215-21606, 21820-21837, 22150-22165, 22518-22536, 22803-22818, 26494-26522, 29049-29069, 29323-29489, 30550-30565, 30915-31191, 31468-31483, 32363-32382, 32827-33202, 33635-33795, 34138-34157, 34407-34422, 34845-34864, 35466-35485, 35669-35684, 36023-36042, 36266-36327, 36721-36827, 37032-37130, 37276-37295, 37504-37675, 38094-38118, 38841-38856, 39716-40538, 40706-40937, 41164-41183, 41342-41439, 42141-42164, 42700-42760, 43173-43537, 43765-46025, 46476-46532, 48423-48438, 50072-50210, 50470-50485, 50719-51234, 51747-51797, 52015-52143, 52230-52245, 52573-52652, 53466-54660, 54886-54901, 63751-64662, 64882-65099, 65363-65378, 65600-65615, 65988-66183, 66566-66581, 66978-67080, 67251-67270, 67662-67929, 68727-68742, 69203-69242, 69565-69620, 69889-70145, 70352-70584, 70925-71071, 71314-71329, 71617-71769, 72107-72241, 72584-72670, 73061-73076, 73350-73369, 73689-73723, 74107-74131, 74317-74557, 74947-75009, 75192-75207, 75979-76066, 76410-77095, 77292-77307, 77638-77869, 78122-78326, 79006-79021, 79478-79505, 80277-80292, 80575-80939, 81207-81222, 81524-81543, 81761-81776, 82233-82248, 82738-83198, 83330-83416, 83884-84063, 84381-85964, 86220-86392, 86554-86655, 86901-86920, 87181-87262, 88063-88082, 88293-88308, 88605-88967, 89160-89175, 89940-90255, 90473-90528, 91073-91088, 91273-91292, 91647-91662, 91930-92126, 92356-92371, 93190-93443, 93762-94111, 94374-94389, 94581-94653, 94839-94858, 95292-95583, 95829-95844, 96137-96503, 96793-97013, 97539-97554, 97800-97889, 98132-98151, 98624-98672, 98810-99115, 99258-99273, 99478-99503, 99791-99858, 100281-100300, 100406-100421, 100742-100828, 101080-101103, 101242-101320, 101788-101906, 102549-102568, 103566-103625, 104067-104086, 104277-104858, 105255-105274, 106147-106364, 106632-106647, 106964-107735, 108514-108788, 109336-109505, 109849-109864, 110403-110442, 110701-110974, 111203-111322, 112030-112049, 112499-112514, 112842-112861, 113028-113056, 113646-113665, 113896-113911, 114446-114465, 115087-115106, 119269-119284, 119659-119703, 120376-120497, 120738-120845, 121209-121228, 121823-122013, 122180-122199, 122588-122770, 123031-123050, 123152-123167, 123671-124055, 124413-124608, 125178-125197, 125533-125616, 126357-126434, 126736-126751, 126998-127236, 127454-127682, 128467-128482, 128813-129111, 129976-130013, 130308-130323, 131036-131056, 131286-131305, 131676-131691, 132171-132517, 133168-133241, 133522-133877, 134086-134101, 134240-134259, 134441-134617, 135015-135030, 135431-135519, 135818-135874, 136111-136130, 136282-136595, 136996-137152, 137372-137387, 137750-137765, 138048-138067, 138782-139840, 140343-140358, 140593-140701, 141116-141131, 141591-141719, 142113-142342, 143021-143048, 143185-143486, 143836-144109, 144558-144650, 144990-145078, 145428-145525, 145937-145952, 146235-146386, 147028-147043, 147259-147284, 147671-147686, 148059-148154, 148564-148579, 148904-149084, 149491-149506, 149787-149877, 150236-150251, 150588-151139, 151373-151659, 152201-152388, 152549-152771, 153001-153026, 153349-153364, 153831-154112, 154171-154186, 154502-154521, 154724-154828, 155283-155304, 155591-155616, 155889-155992, 156233-156612, 156847-156907, 157198-157223, 157330-157349, 157552-157567, 157927-158029, 158542-158631, 159216-159267, 159539-159793, 160352-160429, 160812-160827, 161248-161267, 161461-161607, 161821-161969, 162064-162083, 162132-162147, 162531-162770, 163019-163557, 164839-165059, 165419-165575, 165856-165875, 166241-166450, 166837-166852, 167107-167122, 168004-168019, 168760-168823, 169062-169092, 169134-169153, 169601-169711, 170081-170291, 170407-170426, 170703-170814, 171021-171036, 171207-171226, 171431-171568, 171926-171945, 172447-172462, 172733-172956, 173045-173756, 174122-174885, 175014-177830, 178895-180539, 181514-187644, 187857-189904, 190109-194159, 194425-195723, 196536-196873, 197326-197961, 198145-198170, 198307-198381, 198715-199007, 199506-199563, 199816-199838, 200249-200635, 201258-201861, 202079-202094, 202382-202717, 203098-203934, 204181-204740, 205549-205915, 206412-206764, 207510-207532, 209999-210014, 210189-210296, 210502-210583, 210920-211418, 211836-212223, 212606-212816, 213025-213044, 213425-213440, 213825-213933, 214479-214498, 214622-214647, 214884-214951, 215446-215508, 215932-215951, 216192-217595, 218132-218248, 218526-218541, 218734-21219037, 219342-219633, 219886-220705, 221044-221059, 221483-221607, 221947-221962, 222569-222584, 222914-222998, 223436-223451, 223948-224122, 224409-224430, 224717-224769, 225133-225148, 225436-225761, 226785-226898, 227025-227040, 227218-227251, 227485-227500, 227914-228837, 229174-229189, 229423-229438, 229615-229640, 230042-230057, 230313-230595, 231218-231345, 231817-232037, 232088-232408, 232823-232848, 232884-232899, 233210-233225, 233623-233646, 234447-234466, 234876-234918, 235258-235328, 235770-235785, 236071-236213, 236684-237196, 237585-237698, 237949-237557, 244873-244897, 245319-245334, 245701-245780, 246152-246523, 246936-247031, 247203-247240, 247431-247450, 247644-247659, 248223-248363, 248694-248762, 249494-249509, 250001-250020, 250693-250708, 251214-251233, 251601-251637, 251950-252060, 252665-252680, 252838-252863, 253140-253166, 253594-253819, 254036-254083, 254246-254345, 254641-254660, 254905-254920, 255397-255422, 255618-255633, 255992-256704, 257018-257092, 257317-257332, 257818-259305, 259500-259515, 261294-261656, 262021-262036, 262453-262779, 263338-266518, 266861-267131, 267375-268051, 268366-269447, 270038-271850, 271950-271969, 272631-274145, 274205-275747, 275808-276636, 276932-277064, 277391-278380, 278932-279063, 279303-281001, 281587-281610, 282229-283668, 290035-290474, 290924-292550, 292860-294408, 295475-297012, 297587-298115, 298161-298418, 298489-298738, 299082-299187, 299276-299669, 299723-299749, 299788-300504, or 300835-301295. 
     In certain embodiments, antisense compounds or oligonucleotides target a region of a growth hormone receptor nucleic acid. In certain embodiments, such compounds or oligonucleotides targeted to a region of a GHR nucleic acid have a contiguous nucleobase portion that is complementary to an equal length nucleobase portion of the region. For example, the portion can be at least an 8, 9, 10, 11, 12, 13, 14, 15, or 16 contiguous nucleobases portion complementary to an equal length portion of a region recited herein. In certain embodiments, such compounds or oligonucleotide target the following nucleotide regions of SEQ ID NO: 2: 2571-2586, 2867-3059, 3097-3116, 3341-3695, 4024-4039, 4446-4894, 5392-5817, 6128-6265, 6499-6890, 7231-7246, 8395-8410, 9153-9168, 9554-9569, 9931-9946, 10549-10564, 10660-10679, 11020-11035, 11793-12229, 12469-12920, 13351-13415, 13717-13732, 14149-14164, 14361-14555, 14965-15279, 15849-16001, 16253-16272, 16447-16545, 17130-17149, 17377-17669, 17927-17958, 18353-18368, 18636-18773, 19661-19918, 20288-20470, 20979-20994, 21215-21606, 21820-21837, 22150-22165, 22518-22536, 22803-22818, 26494-26522, 29049-29069, 29323-29489, 30550-30565, 30915-31191, 31468-31483, 32363-32382, 32827-33202, 33635-33795, 34138-34157, 34407-34422, 34845-34864, 35466-35485, 35669-35684, 36023-36042, 36266-36327, 36721-36827, 37032-37130, 37276-37295, 37504-37675, 38094-38118, 38841-38856, 39716-40538, 40706-40937, 41164-41183, 41342-41439, 42141-42164, 42700-42760, 43173-43537, 43765-46025, 46476-46532, 48423-48438, 50072-50210, 50470-50485, 50719-51234, 51747-51797, 52015-52143, 52230-52245, 52573-52652, 53466-54660, 54886-54901, 63751-64662, 64882-65099, 65363-65378, 65600-65615, 65988-66183, 66566-66581, 66978-67080, 67251-67270, 67662-67929, 68727-68742, 69203-69242, 69565-69620, 69889-70145, 70352-70584, 70925-71071, 71314-71329, 71617-71769, 72107-72241, 72584-72670, 73061-73076, 73350-73369, 73689-73723, 74107-74131, 74317-74557, 74947-75009, 75192-75207, 75979-76066, 76410-77095, 77292-77307, 77638-77869, 78122-78326, 79006-79021, 79478-79505, 80277-80292, 80575-80939, 81207-81222, 81524-81543, 81761-81776, 82233-82248, 82738-83198, 83330-83416, 83884-84063, 84381-85964, 86220-86392, 86554-86655, 86901-86920, 87181-87262, 88063-88082, 88293-88308, 88605-88967, 89160-89175, 89940-90255, 90473-90528, 91073-91088, 91273-91292, 91647-91662, 91930-92126, 92356-92371, 93190-93443, 93762-94111, 94374-94389, 94581-94653, 94839-94858, 95292-95583, 95829-95844, 96137-96503, 96793-97013, 97539-97554, 97800-97889, 98132-98151, 98624-98672, 98810-99115, 99258-99273, 99478-99503, 99791-99858, 100281-100300, 100406-100421, 100742-100828, 101080-101103, 101242-101320, 101788-101906, 102549-102568, 103566-103625, 104067-104086, 104277-104858, 105255-105274, 106147-106364, 106632-106647, 106964-107735, 108514-108788, 109336-109505, 109849-109864, 110403-110442, 110701-110974, 111203-111322, 112030-112049, 112499-112514, 112842-112861, 113028-113056, 113646-113665, 113896-113911, 114446-114465, 115087-115106, 119269-119284, 119659-119703, 120376-120497, 120738-120845, 121209-121228, 121823-122013, 122180-122199, 122588-122770, 123031-123050, 123152-123167, 123671-124055, 124413-124608, 125178-125197, 125533-125616, 126357-126434, 126736-126751, 126998-127236, 127454-127682, 128467-128482, 128813-129111, 129976-130013, 130308-130323, 131036-131056, 131286-131305, 131676-131691, 132171-132517, 133168-133241, 133522-133877, 134086-134101, 134240-134259, 134441-134617, 135015-135030, 135431-135519, 135818-135874, 136111-136130, 136282-136595, 136996-137152, 137372-137387, 137750-137765, 138048-138067, 138782-139840, 140343-140358, 140593-140701, 141116-141131, 141591-141719, 142113-142342, 143021-143048, 143185-143486, 143836-144109, 144558-144650, 144990-145078, 145428-145525, 145937-145952, 146235-146386, 147028-147043, 147259-147284, 147671-147686, 148059-148154, 148564-148579, 148904-149084, 149491-149506, 149787-149877, 150236-150251, 150588-151139, 151373-151659, 152201-152388, 152549-152771, 153001-153026, 153349-153364, 153831-154112, 154171-154186, 154502-154521, 154724-154828, 155283-155304, 155591-155616, 155889-155992, 156233-156612, 156847-156907, 157198-157223, 157330-157349, 157552-157567, 157927-158029, 158542-158631, 159216-159267, 159539-159793, 160352-160429, 160812-160827, 161248-161267, 161461-161607, 161821-161969, 162064-162083, 162132-162147, 162531-162770, 163019-163557, 164839-165059, 165419-165575, 165856-165875, 166241-166450, 166837-166852, 167107-167122, 168004-168019, 168760-168823, 169062-169092, 169134-169153, 169601-169711, 170081-170291, 170407-170426, 170703-170814, 171021-171036, 171207-171226, 171431-171568, 171926-171945, 172447-172462, 172733-172956, 173045-173756, 174122-174885, 175014-177830, 178895-180539, 181514-187644, 187857-189904, 190109-194159, 194425-195723, 196536-196873, 197326-197961, 198145-198170, 198307-198381, 198715-199007, 199506-199563, 199816-199838, 200249-200635, 201258-201861, 202079-202094, 202382-202717, 203098-203934, 204181-204740, 205549-205915, 206412-206764, 207510-207532, 209999-210014, 210189-210296, 210502-210583, 210920-211418, 211836-212223, 212606-212816, 213025-213044, 213425-213440, 213825-213933, 214479-214498, 214622-214647, 214884-214951, 215446-215508, 215932-215951, 216192-217595, 218132-218248, 218526-218541, 218734-21219037, 219342-219633, 219886-220705, 221044-221059, 221483-221607, 221947-221962, 222569-222584, 222914-222998, 223436-223451, 223948-224122, 224409-224430, 224717-224769, 225133-225148, 225436-225761, 226785-226898, 227025-227040, 227218-227251, 227485-227500, 227914-228837, 229174-229189, 229423-229438, 229615-229640, 230042-230057, 230313-230595, 231218-231345, 231817-232037, 232088-232408, 232823-232848, 232884-232899, 233210-233225, 233623-233646, 234447-234466, 234876-234918, 235258-235328, 235770-235785, 236071-236213, 236684-237196, 237585-237698, 237949-237557, 244873-244897, 245319-245334, 245701-245780, 246152-246523, 246936-247031, 247203-247240, 247431-247450, 247644-247659, 248223-248363, 248694-248762, 249494-249509, 250001-250020, 250693-250708, 251214-251233, 251601-251637, 251950-252060, 252665-252680, 252838-252863, 253140-253166, 253594-253819, 254036-254083, 254246-254345, 254641-254660, 254905-254920, 255397-255422, 255618-255633, 255992-256704, 257018-257092, 257317-257332, 257818-259305, 259500-259515, 261294-261656, 262021-262036, 262453-262779, 263338-266518, 266861-267131, 267375-268051, 268366-269447, 270038-271850, 271950-271969, 272631-274145, 274205-275747, 275808-276636, 276932-277064, 277391-278380, 278932-279063, 279303-281001, 281587-281610, 282229-283668, 290035-290474, 290924-292550, 292860-294408, 295475-297012, 297587-298115, 298161-298418, 298489-298738, 299082-299187, 299276-299669, 299723-299749, 299788-300504, or 300835-301295. 
     In certain embodiments, antisense compounds or oligonucleotides target intron 1 of a growth hormone receptor nucleic acid. In certain aspects, antisense compounds or oligonucleotides target within nucleotides 3058-144965 (intron 1) of a growth hormone receptor nucleic acid having the nucleobase sequence of SEQ ID NO: 2 (GENBANK Accession No. NT_006576.16 truncated from nucleotides 42411001 to 42714000). 
     In certain embodiments, antisense compounds or oligonucleotides target intron 2 of a growth hormone receptor nucleic acid. In certain aspects, antisense compounds or oligonucleotides target within nucleotides 145047-208139 (intron 2) of a growth hormone receptor nucleic acid having the nucleobase sequence of SEQ ID NO: 2 (GENBANK Accession No. NT_006576.16 truncated from nucleotides 42411001 to 42714000). 
     In certain embodiments, antisense compounds or oligonucleotides target intron 3 of a growth hormone receptor nucleic acid. In certain aspects, antisense compounds or oligonucleotides target within nucleotides 208206-267991 (intron 3) of a growth hormone receptor nucleic acid having the nucleobase sequence of SEQ ID NO: 2 (GENBANK Accession No. NT_006576.16 truncated from nucleotides 42411001 to 42714000). 
     In certain embodiments, antisense compounds or oligonucleotides target intron 4 of a growth hormone receptor nucleic acid. In certain aspects, antisense compounds or oligonucleotides target within nucleotides 268122-274018 (intron 4) of a growth hormone receptor nucleic acid having the nucleobase sequence of SEQ ID NO: 2 (GENBANK Accession No. NT_006576.16 truncated from nucleotides 42411001 to 42714000). 
     In certain embodiments, antisense compounds or oligonucleotides target intron 5 of a growth hormone receptor nucleic acid. In certain aspects, antisense compounds or oligonucleotides target within nucleotides 274192-278925 (intron 5) of a growth hormone receptor nucleic acid having the nucleobase sequence of SEQ ID NO: 2 (GENBANK Accession No. NT_006576.16 truncated from nucleotides 42411001 to 42714000). 
     In certain embodiments, antisense compounds or oligonucleotides target intron 6 of a growth hormone receptor nucleic acid. In certain aspects, antisense compounds or oligonucleotides target within nucleotides 279105-290308 (intron 6) of a growth hormone receptor nucleic acid having the nucleobase sequence of SEQ ID NO: 2 (GENBANK Accession No. NT_006576.16 truncated from nucleotides 42411001 to 42714000). 
     In certain embodiments, antisense compounds or oligonucleotides target intron 7 of a growth hormone receptor nucleic acid. In certain aspects, antisense compounds or oligonucleotides target within nucleotides 290475-292530 (intron 7) of a growth hormone receptor nucleic acid having the nucleobase sequence of SEQ ID NO: 2 (GENBANK Accession No. NT_006576.16 truncated from nucleotides 42411001 to 42714000). 
     In certain embodiments, antisense compounds or oligonucleotides target intron 8 of a growth hormone receptor nucleic acid. In certain aspects, antisense compounds or oligonucleotides target within nucleotides 292622-297153 (intron 8) of a growth hormone receptor nucleic acid having the nucleobase sequence of SEQ ID NO: 2 (GENBANK Accession No. NT_006576.16 truncated from nucleotides 42411001 to 42714000). 
     In certain embodiments, antisense compounds or oligonucleotides target intron 9 of a growth hormone receptor nucleic acid. In certain aspects, antisense compounds or oligonucleotides target within nucleotides 297224-297554 (intron 9) of a growth hormone receptor nucleic acid having the nucleobase sequence of SEQ ID NO: 2 (GENBANK Accession No. NT_006576.16 truncated from nucleotides 42411001 to 42714000). 
     In certain embodiments, any of the foregoing compounds or oligonucleotides comprises at least one modified sugar. In certain aspects, at least one modified sugar comprises a 2′-O-methoxyethyl group. In certain aspects, at least one modified sugar is a bicyclic sugar, such as a 4′-CH(CH 3 )—O-2′ group, a 4′-CH 2 —O-2′ group, or a 4′-(CH 2 ) 2 —O-2′-group. In certain aspects, the modified oligonucleotide comprises at least one modified internucleoside linkage, such as a phosphorothioate internucleoside linkage. 
     In certain embodiments, any of the foregoing compounds or oligonucleotides comprises at least one modified nucleobase, such as 5-methylcytosine. 
     In certain embodiments, any of the foregoing compounds or oligonucleotides comprises:
         a gap segment consisting of linked deoxynucleosides;   a 5′ wing segment consisting of linked nucleosides; and   a 3′ wing segment consisting of linked nucleosides;       

     wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment and wherein each nucleoside of each wing segment comprises a modified sugar. 
     Certain embodiments provide a compound comprising a modified oligonucleotide consisting of 10 to 30 linked nucleosides having a nucleobase sequence comprising the sequence recited in SEQ ID NO: 918, 479, 703, 1800, 1904, 2122, 2127, or 2194. 
     In certain aspects, the modified oligonucleotide has a nucleobase sequence comprising the sequence recited in SEQ ID NOs: 918, 479 or 703, wherein the modified oligonucleotide comprises 
     a gap segment consisting of ten linked deoxynucleosides; 
     a 5′ wing segment consisting of five linked nucleosides; and 
     a 3′ wing segment consisting of five linked nucleosides; 
     wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment, wherein each nucleoside of each wing segment comprises a 2′-O-methoxyethyl sugar; wherein each internucleoside linkage is a phosphorothioate linkage and wherein each cytosine is a 5-methylcytosine. 
     In certain aspects, the modified oligonucleotide has a nucleobase sequence comprising the sequence recited in SEQ ID NOs: 1800, 1904, 2122, 2127, or 2194, wherein the modified oligonucleotide comprises:
         a gap segment consisting of ten linked deoxynucleosides;   a 5′ wing segment consisting of 3 linked nucleosides; and   a 3′ wing segment consisting of 3 linked nucleosides;       

     wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment, wherein each nucleoside of each wing segment comprises a 2′-O-methoxyethyl sugar or a constrained ethyl sugar; and wherein each internucleoside linkage is a phosphorothioate linkage. 
     Certain embodiments provide a compound comprising a modified oligonucleotide consisting of 20 linked nucleosides having a nucleobase sequence consisting of the sequence recited in SEQ ID NO: 703. In certain aspects, the modified oligonucleotide comprises at least one modified sugar. In certain aspects, the at least one modified sugar comprises a 2′-O-methoxyethyl group. In certain aspects, the at least one modified sugar is a bicyclic sugar, such as a 4′-CH(CH 3 )—O-2′ group, a 4′-CH 2 —O-2′ group, or a 4′-(CH 2 ) 2 —O-2′-group. In certain aspects, the modified oligonucleotide comprises at least one modified internucleoside linkage, such as a phosphorothioate internucleoside linkage. In certain aspects, the modified oligonucleotide comprises at least one modified nucleobase, such as a 5-methylcytosine. In certain aspects, the modified oligonucleotide comprises:
         a gap segment consisting of linked deoxynucleosides;   a 5′ wing segment consisting of linked nucleosides; and   a 3′ wing segment consisting of linked nucleosides;       

     wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment and wherein each nucleoside of each wing segment comprises a modified sugar. 
     Certain embodiments provide a compound comprising a modified oligonucleotide consisting of 20 linked nucleosides having a nucleobase sequence consisting of the sequence recited in SEQ ID NO: 703, wherein the modified oligonucleotide comprises:
         a gap segment consisting of ten linked deoxynucleosides;   a 5′ wing segment consisting of five linked nucleosides; and   a 3′ wing segment consisting of five linked nucleosides;       

     wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment; wherein each nucleoside of each wing segment comprises a 2′-O-methoxyethyl sugar; wherein each internucleoside linkage is a phosphorothioate linkage; and wherein each cytosine is a 5-methylcytosine. 
     In any of the foregoing embodiments, the compound or oligonucleotide can be at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% complementary to a nucleic acid encoding growth hormone receptor. 
     In any of the foregoing embodiments, the nucleic acid encoding growth hormone receptor can comprise the nucleotide sequence of any one of SEQ ID NOs: 1-19. 
     In any of the foregoing embodiments, the compound or oligonucleotide can be single-stranded. 
     Certain embodiments provide a composition comprising the compound of any of the aforementioned embodiments or salt thereof and at least one of a pharmaceutically acceptable carrier or diluent. In certain aspects, the composition has a viscosity less than about 40 centipoise (cP), less than about 30 centipose (cP), less than about 20 centipose (cP), less than about 15 centipose (cP), or less than about 10 centipose (cP). In certain aspects, the composition having any of the aforementioned viscosities comprises a compound provided herein at a concentration of about 100 mg/mL, about 125 mg/mL, about 150 mg/mL, about 175 mg/mL, about 200 mg/mL, about 225 mg/mL, about 250 mg/mL, about 275 mg/mL, or about 300 mg/mL. In certain aspects, the composition having any of the aforementioned viscosities and/or compound concentrations has a temperature of room temperature or about 20° C., about 21° C., about 22° C., about 23° C., about 24° C., about 25° C., about 26° C., about 27° C., about 28° C., about 29° C., or about 30° C. 
     Certain embodiments provide a method of treating a disease associated with excess growth hormone in a human comprising administering to the human a therapeutically effective amount of the compound or composition of any of the aforementioned embodiments, thereby treating the disease associated with excess growth hormone. In certain aspects, the disease associated with excess growth hormone is acromegaly. In certain aspects, the treatment reduces IGF-1 levels. 
     Certain embodiments provide a method of preventing a disease associated with excess growth hormone in a human comprising administering to the human a therapeutically effective amount of a compound or composition of any of the aforementioned embodiments, thereby preventing the disease associated with excess growth hormone. In certain embodiments, the disease associated with excess growth hormone is acromegaly. 
     Certain embodiments provide a method of reducing growth hormone receptor (GHR) levels in a human comprising administering to the human a therapeutically effective amount of the compound or composition of any of the aforementioned embodiments, thereby reducing GHR levels in the human. In certain aspects, the human has a disease associated with excess growth hormone. In certain aspects, the disease associated with excess growth hormone is acromegaly. 
     In certain aspects, the foregoing methods comprise co-administering the compound or composition and a second agent. In certain aspects, the compound or composition and the second agent are administered concomitantly. 
     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 is 10 to 30 subunits in length. In certain embodiments, an antisense compound is 12 to 30 subunits in length. In certain embodiments, an antisense compound is 12 to 22 subunits in length. In certain embodiments, an antisense compound is 14 to 30 subunits in length. In certain embodiments, an antisense compound is 14 to 20 subunits in length. In certain embodiments, an antisense compound is 15 to 30 subunits in length. In certain embodiments, an antisense compound is 15 to 20 subunits in length. In certain embodiments, an antisense compound is 16 to 30 subunits in length. In certain embodiments, an antisense compound is 16 to 20 subunits in length. In certain embodiments, an antisense compound is 17 to 30 subunits in length. In certain embodiments, an antisense compound is 17 to 20 subunits in length. In certain embodiments, an antisense compound is 18 to 30 subunits in length. In certain embodiments, an antisense compound is 18 to 21 subunits in length. In certain embodiments, an antisense compound is 18 to 20 subunits in length. In certain embodiments, an antisense compound is 20 to 30 subunits in length. In other words, such antisense compounds are from 12 to 30 linked subunits, 14 to 30 linked subunits, 14 to 20 subunits, 15 to 30 subunits, 15 to 20 subunits, 16 to 30 subunits, 16 to 20 subunits, 17 to 30 subunits, 17 to 20 subunits, 18 to 30 subunits, 18 to 20 subunits, 18 to 21 subunits, 20 to 30 subunits, or 12 to 22 linked subunits, respectively. In certain embodiments, an antisense compound is 14 subunits in length. In certain embodiments, an antisense compound is 16 subunits in length. In certain embodiments, an antisense compound is 17 subunits in length. In certain embodiments, an antisense compound is 18 subunits in length. In certain embodiments, an antisense compound is 19 subunits in length. In certain embodiments, an antisense compound is 20 subunits in length. In other embodiments, the antisense compound is 8 to 80, 12 to 50, 13 to 30, 13 to 50, 14 to 30, 14 to 50, 15 to 30, 15 to 50, 16 to 30, 16 to 50, 17 to 30, 17 to 50, 18 to 22, 18 to 24, 18 to 30, 18 to 50, 19 to 22, 19 to 30, 19 to 50, or 20 to 30 linked subunits. In certain such embodiments, the antisense compounds are 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, or 80 linked subunits in length, or a range defined by any two of the above values. In some embodiments the antisense compound is an antisense oligonucleotide, and the linked subunits are nucleotides. 
     In certain embodiments antisense oligonucleotides may be shortened or truncated. For example, a single subunit may be deleted from the 5′ end (5′ truncation), or alternatively from the 3′ end (3′ truncation). A shortened or truncated antisense compound targeted to a GHR 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 or 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. 
     Certain Antisense Compound Motifs and Mechanisms 
     In certain embodiments, antisense compounds have chemically modified subunits arranged in patterns, or motifs, to confer to the antisense compounds properties such as enhanced 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 confer another desired property e.g., serve as a substrate for the cellular endonuclease RNase H, which cleaves the RNA strand of an RNA:DNA duplex. 
     Antisense activity may result from any mechanism involving the hybridization of the antisense compound (e.g., oligonucleotide) with a target nucleic acid, wherein the hybridization ultimately results in a biological effect. In certain embodiments, the amount and/or activity of the target nucleic acid is modulated. In certain embodiments, the amount and/or activity of the target nucleic acid is reduced. In certain embodiments, hybridization of the antisense compound to the target nucleic acid ultimately results in target nucleic acid degradation. In certain embodiments, hybridization of the antisense compound to the target nucleic acid does not result in target nucleic acid degradation. In certain such embodiments, the presence of the antisense compound hybridized with the target nucleic acid (occupancy) results in a modulation of antisense activity. In certain embodiments, antisense compounds having a particular chemical motif or pattern of chemical modifications are particularly suited to exploit one or more mechanisms. In certain embodiments, antisense compounds function through more than one mechanism and/or through mechanisms that have not been elucidated. Accordingly, the antisense compounds described herein are not limited by particular mechanism. 
     Antisense mechanisms include, without limitation, RNase H mediated antisense; RNAi mechanisms, which utilize the RISC pathway and include, without limitation, siRNA, ssRNA and microRNA mechanisms; and occupancy based mechanisms. Certain antisense compounds may act through more than one such mechanism and/or through additional mechanisms. 
     RNase H-Mediated Antisense 
     In certain embodiments, antisense activity results at least in part from degradation of target RNA by RNase H. RNase H is a cellular endonuclease that cleaves the RNA strand of an RNA:DNA duplex. It is known in the art that single-stranded antisense compounds which are “DNA-like” elicit RNase H activity in mammalian cells. Accordingly, antisense compounds comprising at least a portion of DNA or DNA-like nucleosides may activate RNase H, resulting in cleavage of the target nucleic acid. In certain embodiments, antisense compounds that utilize RNase H comprise one or more modified nucleosides. In certain embodiments, such antisense compounds comprise at least one block of 1-8 modified nucleosides. In certain such embodiments, the modified nucleosides do not support RNase H activity. In certain embodiments, such antisense compounds are gapmers, as described herein. In certain such embodiments, the gap of the gapmer comprises DNA nucleosides. In certain such embodiments, the gap of the gapmer comprises DNA-like nucleosides. In certain such embodiments, the gap of the gapmer comprises DNA nucleosides and DNA-like nucleosides. 
     Certain antisense compounds having a gapmer motif are considered chimeric antisense compounds. In a gapmer an internal region 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. In certain embodiments, 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 constrained ethyl). In certain embodiments, nucleosides in the wings may include several modified sugar moieties, including, for example 2′-MOE and bicyclic sugar moieties such as constrained ethyl or LNA. In certain embodiments, wings may include several modified and unmodified sugar moieties. In certain embodiments, wings may include various combinations of 2′-MOE nucleosides, bicyclic sugar moieties such as constrained ethyl nucleosides or LNA nucleosides, and 2′-deoxynucleosides. 
     Each distinct region may comprise uniform sugar moieties, variant, or alternating sugar moieties. The wing-gap-wing motif is frequently described as “X—Y—Z”, where “X” represents the length of the 5′-wing, “Y” represents the length of the gap, and “Z” represents the length of the 3′-wing. “X” and “Z” may comprise uniform, variant, or alternating sugar moieties. In certain embodiments, “X” and “Y” may include one or more 2′-deoxynucleosides. “Y” may comprise 2′-deoxynucleosides. As used herein, a gapmer described as “X—Y—Z” has a configuration such that the gap is positioned immediately adjacent to each of the 5′-wing and the 3′ wing. Thus, no intervening nucleotides exist between the 5′-wing and gap, or the gap and the 3′-wing. Any of the antisense compounds described herein can have a gapmer motif. In certain embodiments, “X” and “Z” are the same; in other embodiments they are different. In certain embodiments, “Y” is between 8 and 15 nucleosides. X, Y, or Z can be any of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30 or more nucleosides. 
     In certain embodiments, the antisense compound targeted to a GHR nucleic acid has a gapmer motif in which the gap consists of 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 linked nucleosides. 
     In certain embodiments, the antisense oligonucleotide has a sugar motif described by Formula A as follows: (J) m -(B) n -(J) p -(B) r -(A) t -(D) g -(A) v -(B) w -(J) x -(B) y -(J) z    
     wherein: 
     each A is independently a 2′-substituted nucleoside; 
     each B is independently a bicyclic nucleoside; 
     each J is independently either a 2′-substituted nucleoside or a 2′-deoxynucleoside; 
     each D is a 2′-deoxynucleoside; 
     m is 0-4; n is 0-2; p is 0-2; r is 0-2; t is 0-2; v is 0-2; w is 0-4; x is 0-2; y is 0-2; z is 0-4; g is 6-14; 
     provided that: 
     at least one of m, n, and r is other than 0; 
     at least one of w and y is other than 0; 
     the sum of m, n, p, r, and t is from 2 to 5; and 
     the sum of v, w, x, y, and z is from 2 to 5. 
     RNAi Compounds 
     In certain embodiments, antisense compounds are interfering RNA compounds (RNAi), which include double-stranded RNA compounds (also referred to as short-interfering RNA or siRNA) and single-stranded RNAi compounds (or ssRNA). Such compounds work at least in part through the RISC pathway to degrade and/or sequester a target nucleic acid (thus, include microRNA/microRNA-mimic compounds). In certain embodiments, antisense compounds comprise modifications that make them particularly suited for such mechanisms. 
     i. ssRNA Compounds 
     In certain embodiments, antisense compounds including those particularly suited for use as single-stranded RNAi compounds (ssRNA) comprise a modified 5′-terminal end. In certain such embodiments, the 5′-terminal end comprises a modified phosphate moiety. In certain embodiments, such modified phosphate is stabilized (e.g., resistant to degradation/cleavage compared to unmodified 5′-phosphate). In certain embodiments, such 5′-terminal nucleosides stabilize the 5′-phosphorous moiety. Certain modified 5′-terminal nucleosides may be found in the art, for example in WO/2011/139702. 
     In certain embodiments, the 5′-nucleoside of an ssRNA compound has Formula IIc: 
     
       
         
         
             
             
         
       
     
     wherein: 
     T 1  is an optionally protected phosphorus moiety; 
     T 2  is an internucleoside linking group linking the compound of Formula IIc to the oligomeric compound; 
     A has one of the formulas: 
     
       
         
         
             
             
         
       
     
     Q 1  and Q 2  are each, independently, H, halogen, C 1 -C 6  alkyl, substituted C 1 -C 6  alkyl, C 1 -C 6  alkoxy, substituted C 1 -C 6  alkoxy, C 2 -C 6  alkenyl, substituted C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, substituted C 2 -C 6  alkynyl or N(R 3 )(R 4 ); 
     Q 3  is O, S, N(R 5 ) or C(R 6 )(R 7 ); 
     each R 3 , R 4  R 5 , R 6  and R 7  is, independently, H, C 1 -C 6  alkyl, substituted C 1 -C 6  alkyl or C 1 -C 6  alkoxy; 
     M 3  is O, S, NR 14 , C(R 15 )(R 16 ), C(R 15 )(R 16 )C(R 17 )(R 18 ), C(R 15 )═C(R 17 ), OC(R 15 )(R 16 ) or OC(R 15 )(Bx 2 ); 
     R 14  is H, C 1 -C 6  alkyl, substituted C 1 -C 6  alkyl, C 1 -C 6  alkoxy, substituted C 1 -C 6  alkoxy, C 2 -C 6  alkenyl, substituted C 2 -C 6  alkenyl, C 2 -C 6  alkynyl or substituted C 2 -C 6  alkynyl; 
     R 15 , R 16 , R 17  and R 18  are each, independently, H, halogen, C 1 -C 6  alkyl, substituted C 1 -C 6  alkyl, C 1 -C 6  alkoxy, substituted C 1 -C 6  alkoxy, C 2 -C 6  alkenyl, substituted C 2 -C 6  alkenyl, C 2 -C 6  alkynyl or substituted C 2 -C 6  alkynyl; 
     Bx 1  is a heterocyclic base moiety; 
     or if Bx 2  is present then Bx 2  is a heterocyclic base moiety and Bx 1  is H, halogen, C 1 -C 6  alkyl, substituted C 1 -C 6  alkyl, C 1 -C 6  alkoxy, substituted C 1 -C 6  alkoxy, C 2 -C 6  alkenyl, substituted C 2 -C 6  alkenyl, C 2 -C 6  alkynyl or substituted C 2 -C 6  alkynyl; 
     J 4 , J 5 , J 6  and J 7  are each, independently, H, halogen, C 1 -C 6  alkyl, substituted C 1 -C 6  alkyl, C 1 -C 6  alkoxy, substituted C 1 -C 6  alkoxy, C 2 -C 6  alkenyl, substituted C 2 -C 6  alkenyl, C 2 -C 6  alkynyl or substituted C 2 -C 6  alkynyl; 
     or J 4  forms a bridge with one of J 5  or J 7  wherein said bridge comprises from 1 to 3 linked biradical groups selected from O, S, NR 19 , C(R 20 )(R 21 ), C(R 20 )═C(R 21 ), C[═C(R 20 )(R 21 )] and C(═O) and the other two of J 5 , J 6  and J 7  are each, independently, H, halogen, C 1 -C 6  alkyl, substituted C 1 -C 6  alkyl, C 1 -C 6  alkoxy, substituted C 1 -C 6  alkoxy, C 2 -C 6  alkenyl, substituted C 2 -C 6  alkenyl, C 2 -C 6  alkynyl or substituted C 2 -C 6  alkynyl; 
     each R 19 , R 20  and R 21  is, independently, H, C 1 -C 6  alkyl, substituted C 1 -C 6  alkyl, C 1 -C 6  alkoxy, substituted C 1 -C 6  alkoxy, C 2 -C 6  alkenyl, substituted C 2 -C 6  alkenyl, C 2 -C 6  alkynyl or substituted C 2 -C 6  alkynyl; 
     G is H, OH, halogen or O—[C(R 8 )(R 9 )] n —[(C═O) m —X 1 ] j —Z; 
     each R 8  and R 9  is, independently, H, halogen, C 1 -C 6  alkyl or substituted C 1 -C 6  alkyl; 
     X 1  is O, S or N(E 1 ); 
     Z is H, halogen, C 1 -C 6  alkyl, substituted C 1 -C 6  alkyl, C 2 -C 6  alkenyl, substituted C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, substituted C 2 -C 6  alkynyl or N(E 2 )(E 3 ); 
     E 1 , E 2  and E 3  are each, independently, H, C 1 -C 6  alkyl or substituted C 1 -C 6  alkyl; n is from 1 to about 6; 
     m is 0 or 1; 
     j is 0 or 1; 
     each substituted group comprises one or more optionally protected substituent groups independently selected from halogen, OJ 1 , N(J 1 )(J 2 ), =NJ 1 , SJ 1 , N 3 , CN, OC(═X 2 )J 1 , OC(═X 2 )N(J 1 )(J 2 ) and C(═X 2 )N(J 1 )(J 2 ); 
     X 2  is O, S or NJ 3 ; 
     each J 1 , J 2  and J 3  is, independently, H or C 1 -C 6  alkyl; 
     when j is 1 then Z is other than halogen or N(E 2 )(E 3 ); and 
     wherein said oligomeric compound comprises from 8 to 40 monomeric subunits and is hybridizable to at least a portion of a target nucleic acid. 
     In certain embodiments, M 3  is O, CH═CH, OCH 2  or OC(H)(Bx 2 ). In certain embodiments, M 3  is O. 
     In certain embodiments, J 4 , J 5 , J 6  and J 7  are each H. In certain embodiments, J 4  forms a bridge with one of J 5  or J 7 . 
     In certain embodiments, A has one of the formulas: 
     
       
         
         
             
             
         
       
     
     wherein: 
     Q 1  and Q 2  are each, independently, H, halogen, C 1 -C 6  alkyl, substituted C 1 -C 6  alkyl, C 1 -C 6  alkoxy or substituted C 1 -C 6  alkoxy. In certain embodiments, Q 1  and Q 2  are each H. In certain embodiments, Q 1  and Q 2  are each, independently, H or halogen. In certain embodiments, Q 1  and Q 2  is H and the other of Q 1  and Q 2  is F, CH 3  or OCH 3 . 
     In certain embodiments, T 1  has the formula: 
     
       
         
         
             
             
         
       
     
     wherein: 
     R a  and R e  are each, independently, protected hydroxyl, protected thiol, C 1 -C 6  alkyl, substituted C 1 -C 6  alkyl, C 1 -C 6  alkoxy, substituted C 1 -C 6  alkoxy, protected amino or substituted amino; and 
     R b  is O or S. In certain embodiments, R b  is O and R a  and R e  are each, independently, OCH 3 , OCH 2 CH 3  or CH(CH 3 ) 2 . 
     In certain embodiments, G is halogen, OCH 3 , OCH 2 F, OCHF 2 , OCF 3 , OCH 2 CH 3 , O(CH 2 ) 2 F, OCH 2 CHF 2 , OCH 2 CF 3 , OCH 2 —CH═CH 2 , O(CH 2 ) 2 —OCH 3 , O(CH 2 ) 2 —SCH 3 , O(CH 2 ) 2 —OCF 3 , O(CH 2 ) 3 —N(R 10 )(R 11 ), O(CH 2 ) 2 —ON(R 10 )(R 11 ), O(CH 2 ) 2 —O(CH 2 ) 2 —N(R 10 )(R 11 ), OCH 2 C(═O)—N(R 10 )(R 11 ), OCH 2 C(═O)—N(R 12 )—(CH 2 ) 2 —N(R 10 )(R 11 ) or O(CH 2 ) 2 —N(R 12 )—C(═NR 13 )[N(R 10 )(R 11 )] wherein R 10 , R 11 , R 12  and R 13  are each, independently, H or C 1 -C 6  alkyl. In certain embodiments, G is halogen, OCH 3 , OCF 3 , OCH 2 CH 3 , OCH 2 CF 3 , OCH 2 —CH═CH 2 , O(CH 2 ) 2 —OCH 3 , O(CH 2 ) 2 —O(CH 2 ) 2 —N(CH 3 ) 2 , OCH 2 C(═O)—N(H)CH 3 , OCH 2 C(═O)—N(H)—(CH 2 ) 2 —N(CH 3 ) 2  or OCH 2 —N(H)—C(═NH)NH 2 . In certain embodiments, G is F, OCH 3  or O(CH 2 ) 2 —OCH 3 . In certain embodiments, G is O(CH 2 ) 2 —OCH 3 . 
     In certain embodiments, the 5-terminal nucleoside has Formula IIe: 
     
       
         
         
             
             
         
       
     
     In certain embodiments, antisense compounds, including those particularly suitable for ssRNA comprise one or more type of modified sugar moieties and/or naturally occurring sugar moieties arranged along an oligonucleotide or region thereof in a defined pattern or sugar modification motif. Such motifs may include any of the sugar modifications discussed herein and/or other known sugar modifications. 
     In certain embodiments, the oligonucleotides comprise or consist of a region having uniform sugar modifications. In certain such embodiments, each nucleoside of the region comprises the same RNA-like sugar modification. In certain embodiments, each nucleoside of the region is a 2′-F nucleoside. In certain embodiments, each nucleoside of the region is a 2′-OMe nucleoside. In certain embodiments, each nucleoside of the region is a 2′-MOE nucleoside. In certain embodiments, each nucleoside of the region is a cEt nucleoside. In certain embodiments, each nucleoside of the region is an LNA nucleoside. In certain embodiments, the uniform region constitutes all or essentially all of the oligonucleotide. In certain embodiments, the region constitutes the entire oligonucleotide except for 1-4 terminal nucleosides. 
     In certain embodiments, oligonucleotides comprise one or more regions of alternating sugar modifications, wherein the nucleosides alternate between nucleotides having a sugar modification of a first type and nucleotides having a sugar modification of a second type. In certain embodiments, nucleosides of both types are RNA-like nucleosides. In certain embodiments the alternating nucleosides are selected from: 2′-OMe, 2′-F, 2′-MOE, LNA, and cEt. In certain embodiments, the alternating modifications are 2′-F and 2′-OMe. Such regions may be contiguous or may be interrupted by differently modified nucleosides or conjugated nucleosides. 
     In certain embodiments, the alternating region of alternating modifications each consist of a single nucleoside (i.e., the pattern is (AB) x A y  wherein A is a nucleoside having a sugar modification of a first type and B is a nucleoside having a sugar modification of a second type; x is 1-20 and y is 0 or 1). In certain embodiments, one or more alternating regions in an alternating motif includes more than a single nucleoside of a type. For example, oligonucleotides may include one or more regions of any of the following nucleoside motifs: 
     AABBAA; 
     ABBABB; 
     AABAAB; 
     ABBABAABB; 
     ABABAA; 
     AABABAB; 
     ABABAA; 
     ABBAABBABABAA; 
     BABBAABBABABAA; or 
     ABABBAABBABABAA; 
     wherein A is a nucleoside of a first type and B is a nucleoside of a second type. In certain embodiments, A and B are each selected from 2′-F, 2′-OMe, BNA, and MOE. 
     In certain embodiments, oligonucleotides having such an alternating motif also comprise a modified 5′ terminal nucleoside, such as those of formula IIc or IIe. 
     In certain embodiments, oligonucleotides comprise a region having a 2-2-3 motif Such regions comprises the following motif: 
       -(A) 2 -(B) x -(A) 2 -(C) y -(A) 3 - 
     wherein: A is a first type of modified nucleoside; 
     B and C, are nucleosides that are differently modified than A, however, B and C may have the same or different modifications as one another; 
     x and y are from 1 to 15. 
     In certain embodiments, A is a 2′-OMe modified nucleoside. In certain embodiments, B and C are both 2′-F modified nucleosides. In certain embodiments, A is a 2′-OMe modified nucleoside and B and C are both 2′-F modified nucleosides. 
     In certain embodiments, oligonucleosides have the following sugar motif: 
       5′-(Q)-(AB) x A y -(D) z  
 
     wherein: 
     Q is a nucleoside comprising a stabilized phosphate moiety. In certain embodiments, Q is a nucleoside having Formula IIc or IIe; 
     A is a first type of modified nucleoside; 
     B is a second type of modified nucleoside; 
     D is a modified nucleoside comprising a modification different from the nucleoside adjacent to it. Thus, if y is 0, then D must be differently modified than B and if y is 1, then D must be differently modified than A. In certain embodiments, D differs from both A and B. 
     X is 5-15; 
     Y is 0 or 1; 
     Z is 0-4. 
     In certain embodiments, oligonucleosides have the following sugar motif: 
       5′-(Q)-(A) x -(D) z  
 
     wherein: 
     Q is a nucleoside comprising a stabilized phosphate moiety. In certain embodiments, Q is a nucleoside having Formula IIc or IIe; 
     A is a first type of modified nucleoside; 
     D is a modified nucleoside comprising a modification different from A. 
     X is 11-30; 
     Z is 0-4. 
     In certain embodiments A, B, C, and D in the above motifs are selected from: 2′-OMe, 2′-F, 2′-MOE, LNA, and cEt. In certain embodiments, D represents terminal nucleosides. In certain embodiments, such terminal nucleosides are not designed to hybridize to the target nucleic acid (though one or more might hybridize by chance). In certain embodiments, the nucleobase of each D nucleoside is adenine, regardless of the identity of the nucleobase at the corresponding position of the target nucleic acid. In certain embodiments the nucleobase of each D nucleoside is thymine. 
     In certain embodiments, antisense compounds, including those particularly suited for use as ssRNA comprise modified internucleoside linkages arranged along the oligonucleotide or region thereof in a defined pattern or modified internucleoside linkage motif. In certain embodiments, oligonucleotides comprise a region having an alternating internucleoside linkage motif. In certain embodiments, oligonucleotides comprise a region of uniformly modified internucleoside linkages. In certain such embodiments, the oligonucleotide comprises a region that is uniformly linked by phosphorothioate internucleoside linkages. In certain embodiments, the oligonucleotide is uniformly linked by phosphorothioate internucleoside linkages. In certain embodiments, each internucleoside linkage of the oligonucleotide is selected from phosphodiester and phosphorothioate. In certain embodiments, each internucleoside linkage of the oligonucleotide is selected from phosphodiester and phosphorothioate and at least one internucleoside linkage is phosphorothioate. 
     In certain embodiments, the oligonucleotide comprises at least 6 phosphorothioate internucleoside linkages. In certain embodiments, the oligonucleotide comprises at least 8 phosphorothioate internucleoside linkages. In certain embodiments, the oligonucleotide comprises at least 10 phosphorothioate internucleoside linkages. In certain embodiments, the oligonucleotide comprises at least one block of at least 6 consecutive phosphorothioate internucleoside linkages. In certain embodiments, the oligonucleotide comprises at least one block of at least 8 consecutive phosphorothioate internucleoside linkages. In certain embodiments, the oligonucleotide comprises at least one block of at least 10 consecutive phosphorothioate internucleoside linkages. In certain embodiments, the oligonucleotide comprises at least one block of at least one 12 consecutive phosphorothioate internucleoside linkages. In certain such embodiments, at least one such block is located at the 3′ end of the oligonucleotide. In certain such embodiments, at least one such block is located within 3 nucleosides of the 3′ end of the oligonucleotide. 
     Oligonucleotides having any of the various sugar motifs described herein, may have any linkage motif. For example, the oligonucleotides, including but not limited to those described above, may have a linkage motif selected from non-limiting the table below: 
                                     5′ most linkage    Central region    3′-region                  PS    Alternating PO/PS    6 PS        PS    Alternating PO/PS    7 PS        PS    Alternating PO/PS    8 PS                    
ii. siRNA Compounds
 
     In certain embodiments, antisense compounds are double-stranded RNAi compounds (siRNA). In such embodiments, one or both strands may comprise any modification motif described above for ssRNA. In certain embodiments, ssRNA compounds may be unmodified RNA. In certain embodiments, siRNA compounds may comprise unmodified RNA nucleosides, but modified internucleoside linkages. 
     Several embodiments relate to double-stranded compositions wherein each strand comprises a motif defined by the location of one or more modified or unmodified nucleosides. In certain embodiments, compositions are provided comprising a first and a second oligomeric compound that are fully or at least partially hybridized to form a duplex region and further comprising a region that is complementary to and hybridizes to a nucleic acid target. It is suitable that such a composition comprise a first oligomeric compound that is an antisense strand having full or partial complementarity to a nucleic acid target and a second oligomeric compound that is a sense strand having one or more regions of complementarity to and forming at least one duplex region with the first oligomeric compound. 
     The compositions of several embodiments modulate gene expression by hybridizing to a nucleic acid target resulting in loss of its normal function. In some embodiments, the target nucleic acid is GHR. In certain embodiment, the degradation of the targeted GHR is facilitated by an activated RISC complex that is formed with compositions of the invention. 
     Several embodiments are directed to double-stranded compositions wherein one of the strands is useful in, for example, influencing the preferential loading of the opposite strand into the RISC (or cleavage) complex. The compositions are useful for targeting selected nucleic acid molecules and modulating the expression of one or more genes. In some embodiments, the compositions of the present invention hybridize to a portion of a target RNA resulting in loss of normal function of the target RNA. 
     Certain embodiments are drawn to double-stranded compositions wherein both the strands comprises a hemimer motif, a fully modified motif, a positionally modified motif or an alternating motif. Each strand of the compositions of the present invention can be modified to fulfil a particular role in for example the siRNA pathway. Using a different motif in each strand or the same motif with different chemical modifications in each strand permits targeting the antisense strand for the RISC complex while inhibiting the incorporation of the sense strand. Within this model, each strand can be independently modified such that it is enhanced for its particular role. The antisense strand can be modified at the 5′-end to enhance its role in one region of the RISC while the 3′-end can be modified differentially to enhance its role in a different region of the RISC. 
     The double-stranded oligonucleotide molecules can be a double-stranded polynucleotide molecule comprising self-complementary sense and antisense regions, wherein the antisense region comprises nucleotide sequence that is complementary to nucleotide sequence in a target nucleic acid molecule or a portion thereof and the sense region having nucleotide sequence corresponding to the target nucleic acid sequence or a portion thereof. The double-stranded oligonucleotide molecules can be assembled from two separate oligonucleotides, where one strand is the sense strand and the other is the antisense strand, wherein the antisense and sense strands are self-complementary (i.e. each strand comprises nucleotide sequence that is complementary to nucleotide sequence in the other strand; such as where the antisense strand and sense strand form a duplex or double-stranded structure, for example wherein the double-stranded region is about 15 to about 30, e.g., about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 base pairs; the antisense strand comprises nucleotide sequence that is complementary to nucleotide sequence in a target nucleic acid molecule or a portion thereof and the sense strand comprises nucleotide sequence corresponding to the target nucleic acid sequence or a portion thereof (e.g., about 15 to about 25 or more nucleotides of the double-stranded oligonucleotide molecule are complementary to the target nucleic acid or a portion thereof). Alternatively, the double-stranded oligonucleotide is assembled from a single oligonucleotide, where the self-complementary sense and antisense regions of the siRNA are linked by means of a nucleic acid based or non-nucleic acid-based linker(s). 
     The double-stranded oligonucleotide can be a polynucleotide with a duplex, asymmetric duplex, hairpin or asymmetric hairpin secondary structure, having self-complementary sense and antisense regions, wherein the antisense region comprises nucleotide sequence that is complementary to nucleotide sequence in a separate target nucleic acid molecule or a portion thereof and the sense region having nucleotide sequence corresponding to the target nucleic acid sequence or a portion thereof. The double-stranded oligonucleotide can be a circular single-stranded polynucleotide having two or more loop structures and a stem comprising self-complementary sense and antisense regions, wherein the antisense region comprises nucleotide sequence that is complementary to nucleotide sequence in a target nucleic acid molecule or a portion thereof and the sense region having nucleotide sequence corresponding to the target nucleic acid sequence or a portion thereof, and wherein the circular polynucleotide can be processed either in vivo or in vitro to generate an active siRNA molecule capable of mediating RNAi. 
     In certain embodiments, the double-stranded oligonucleotide comprises separate sense and antisense sequences or regions, wherein the sense and antisense regions are covalently linked by nucleotide or non-nucleotide linkers molecules as is known in the art, or are alternately non-covalently linked by ionic interactions, hydrogen bonding, van der waals interactions, hydrophobic interactions, and/or stacking interactions. In certain embodiments, the double-stranded oligonucleotide comprises nucleotide sequence that is complementary to nucleotide sequence of a target gene. In another embodiment, the double-stranded oligonucleotide interacts with nucleotide sequence of a target gene in a manner that causes inhibition of expression of the target gene. 
     As used herein, double-stranded oligonucleotides need not be limited to those molecules containing only RNA, but further encompasses chemically modified nucleotides and non-nucleotides. In certain embodiments, the short interfering nucleic acid molecules lack 2′-hydroxy (2′-OH) containing nucleotides. In certain embodiments short interfering nucleic acids optionally do not include any ribonucleotides (e.g., nucleotides having a 2′-OH group). Such double-stranded oligonucleotides that do not require the presence of ribonucleotides within the molecule to support RNAi can however have an attached linker or linkers or other attached or associated groups, moieties, or chains containing one or more nucleotides with 2′-OH groups. Optionally, double-stranded oligonucleotides can comprise ribonucleotides at about 5, 10, 20, 30, 40, or 50% of the nucleotide positions. As used herein, the term siRNA is meant to be equivalent to other terms used to describe nucleic acid molecules that are capable of mediating sequence specific RNAi, for example short interfering RNA (siRNA), double-stranded RNA (dsRNA), micro-RNA (miRNA), short hairpin RNA (shRNA), short interfering oligonucleotide, short interfering nucleic acid, short interfering modified oligonucleotide, chemically modified siRNA, post-transcriptional gene silencing RNA (ptgsRNA), and others. In addition, as used herein, the term RNAi is meant to be equivalent to other terms used to describe sequence specific RNA interference, such as post transcriptional gene silencing, translational inhibition, or epigenetics. For example, double-stranded oligonucleotides can be used to epigenetically silence genes at both the post-transcriptional level and the pre-transcriptional level. In a non-limiting example, epigenetic regulation of gene expression by siRNA molecules of the invention can result from siRNA mediated modification of chromatin structure or methylation pattern to alter gene expression (see, for example, Verdel et al., 2004, Science, 303, 672-676; Pal-Bhadra et al., 2004, Science, 303, 669-672; Allshire, 2002, Science, 297, 1818-1819; Volpe et al., 2002, Science, 297, 1833-1837; Jenuwein, 2002, Science, 297, 2215-2218; and Hall et al., 2002, Science, 297, 2232-2237). 
     It is contemplated that compounds and compositions of several embodiments provided herein can target GHR by a dsRNA-mediated gene silencing or RNAi mechanism, including, e.g., “hairpin” or stem-loop double-stranded RNA effector molecules in which a single RNA strand with self-complementary sequences is capable of assuming a double-stranded conformation, or duplex dsRNA effector molecules comprising two separate strands of RNA. In various embodiments, the dsRNA consists entirely of ribonucleotides or consists of a mixture of ribonucleotides and deoxynucleotides, such as the RNA/DNA hybrids disclosed, for example, by WO 00/63364, filed Apr. 19, 2000, or U.S. Ser. No. 60/130,377, filed Apr. 21, 1999. The dsRNA or dsRNA effector molecule may be a single molecule with a region of self-complementarity such that nucleotides in one segment of the molecule base pair with nucleotides in another segment of the molecule. In various embodiments, a dsRNA that consists of a single molecule consists entirely of ribonucleotides or includes a region of ribonucleotides that is complementary to a region of deoxyribonucleotides. Alternatively, the dsRNA may include two different strands that have a region of complementarity to each other. 
     In various embodiments, both strands consist entirely of ribonucleotides, one strand consists entirely of ribonucleotides and one strand consists entirely of deoxyribonucleotides, or one or both strands contain a mixture of ribonucleotides and deoxyribonucleotides. In certain embodiments, the regions of complementarity are at least 70, 80, 90, 95, 98, or 100% complementary to each other and to a target nucleic acid sequence. In certain embodiments, the region of the dsRNA that is present in a double-stranded conformation includes at least 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 50, 75, 100, 200, 500, 1000, 2000 or 5000 nucleotides or includes all of the nucleotides in a cDNA or other target nucleic acid sequence being represented in the dsRNA. In some embodiments, the dsRNA does not contain any single stranded regions, such as single stranded ends, or the dsRNA is a hairpin. In other embodiments, the dsRNA has one or more single stranded regions or overhangs. In certain embodiments, RNA/DNA hybrids include a DNA strand or region that is an antisense strand or region (e.g, has at least 70, 80, 90, 95, 98, or 100% complementarity to a target nucleic acid) and an RNA strand or region that is a sense strand or region (e.g, has at least 70, 80, 90, 95, 98, or 100% identity to a target nucleic acid), and vice versa. 
     In various embodiments, the RNA/DNA hybrid is made in vitro using enzymatic or chemical synthetic methods such as those described herein or those described in WO 00/63364, filed Apr. 19, 2000, or U.S. Ser. No. 60/130,377, filed Apr. 21, 1999. In other embodiments, a DNA strand synthesized in vitro is complexed with an RNA strand made in vivo or in vitro before, after, or concurrent with the transformation of the DNA strand into the cell. In yet other embodiments, the dsRNA is a single circular nucleic acid containing a sense and an antisense region, or the dsRNA includes a circular nucleic acid and either a second circular nucleic acid or a linear nucleic acid (see, for example, WO 00/63364, filed Apr. 19, 2000, or U.S. Ser. No. 60/130,377, filed Apr. 21, 1999.) Exemplary circular nucleic acids include lariat structures in which the free 5′ phosphoryl group of a nucleotide becomes linked to the 2′ hydroxyl group of another nucleotide in a loop back fashion. 
     In other embodiments, the dsRNA includes one or more modified nucleotides in which the 2′ position in the sugar contains a halogen (such as fluorine group) or contains an alkoxy group (such as a methoxy group) which increases the half-life of the dsRNA in vitro or in vivo compared to the corresponding dsRNA in which the corresponding 2′ position contains a hydrogen or an hydroxyl group. In yet other embodiments, the dsRNA includes one or more linkages between adjacent nucleotides other than a naturally-occurring phosphodiester linkage. Examples of such linkages include phosphoramide, phosphorothioate, and phosphorodithioate linkages. The dsRNAs may also be chemically modified nucleic acid molecules as taught in U.S. Pat. No. 6,673,661. In other embodiments, the dsRNA contains one or two capped strands, as disclosed, for example, by WO 00/63364, filed Apr. 19, 2000, or U.S. Ser. No. 60/130,377, filed Apr. 21, 1999. 
     In other embodiments, the dsRNA can be any of the at least partially dsRNA molecules disclosed in WO 00/63364, as well as any of the dsRNA molecules described in U.S. Provisional Application 60/399,998; and U.S. Provisional Application 60/419,532, and PCT/US2003/033466, the teaching of which is hereby incorporated by reference. Any of the dsRNAs may be expressed in vitro or in vivo using the methods described herein or standard methods, such as those described in WO 00/63364. 
     Occupancy 
     In certain embodiments, antisense compounds are not expected to result in cleavage or the target nucleic acid via RNase H or to result in cleavage or sequestration through the RISC pathway. In certain such embodiments, antisense activity may result from occupancy, wherein the presence of the hybridized antisense compound disrupts the activity of the target nucleic acid. In certain such embodiments, the antisense compound may be uniformly modified or may comprise a mix of modifications and/or modified and unmodified nucleosides. 
     Target Nucleic Acids, Target Regions and Nucleotide Sequences 
     Nucleotide sequences that encode growth hormone receptor (GHR) targetable with the compounds provided herein include, without limitation, the following: GENBANK Accession No. NM_000163.4 (incorporated herein as SEQ ID NO: 1), GENBANK Accession No. NT_006576.16 truncated from nucleotides 42411001 to 42714000 (incorporated herein as SEQ ID NO: 2), GENBANK Accession No X06562.1 (incorporated herein as SEQ ID NO: 3), GENBANK Accession No. DR006395.1 (incorporated herein as SEQ ID NO: 4), GENBANK Accession No. DB052048.1 (incorporated herein as SEQ ID NO: 5), GENBANK Accession No. AF230800.1 (incorporated herein as SEQ ID NO: 6), the complement of GENBANK Accession No. AA398260.1 (incorporated herein as SEQ ID NO: 7), GENBANK Accession No. BC136496.1 (incorporated herein as SEQ ID NO: 8), GENBANK Accession No. NM_001242399.2 (incorporated herein as SEQ ID NO: 9), GENBANK Accession No. NM_001242400.2 (incorporated herein as SEQ ID NO: 10), GENBANK Accession No. NM_001242401.3 (incorporated herein as SEQ ID NO: 11), GENBANK Accession No. NM_001242402.2 (incorporated herein as SEQ ID NO: 12), GENBANK Accession No. NM_001242403.2 (incorporated herein as SEQ ID NO: 13), GENBANK Accession No. NM_001242404.2 (incorporated herein as SEQ ID NO: 14), GENBANK Accession No. NM_001242405.2 (incorporated herein as SEQ ID NO: 15), GENBANK Accession No. NM_001242406.2 (incorporated herein as SEQ ID NO: 16), GENBANK Accession No. NM_001242460.1 (incorporated herein as SEQ ID NO: 17), GENBANK Accession NM_001242461.1 (incorporated herein as SEQ ID NO: 18), GENBANK Accession No. NM_001242462.1 (incorporated herein as SEQ ID NO: 19), or GENBANK Accession No NW_001120958.1 truncated from nucleotides 4410000 to 4720000 (incorporated herein as SEQ ID NO: 2296). 
     Hybridization 
     In some embodiments, hybridization occurs between an antisense compound disclosed herein and a GHR 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 certain embodiments, the antisense compounds provided herein are specifically hybridizable with a GHR nucleic acid. 
     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 GHR nucleic acid). 
     Non-complementary nucleobases between an antisense compound and a GHR 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 GHR 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 certain embodiments, the antisense compounds provided herein, or a specified portion thereof, are, or are at least, 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% complementary to a GHR nucleic acid, a target region, target segment, or specified portion thereof. Percent complementarity of an antisense compound with a target nucleic acid can be determined using routine methods. 
     For example, an antisense compound in which 18 of 20 nucleobases of the antisense compound are complementary to a target region, and would therefore specifically hybridize, would represent 90 percent complementarity. In this example, the remaining noncomplementary nucleobases may be clustered or interspersed with complementary nucleobases and need not be contiguous to each other or to complementary nucleobases. As such, an antisense compound which is 18 nucleobases in length having four noncomplementary nucleobases which are flanked by two regions of complete complementarity with the target nucleic acid would have 77.8% overall complementarity with the target nucleic acid and would thus fall within the scope of the present invention. Percent complementarity of an antisense compound with a region of a target nucleic acid can be determined routinely using BLAST programs (basic local alignment search tools) and PowerBLAST programs known in the art (Altschul et al.,  J. Mol. Biol.,  1990, 215, 403 410; Zhang and Madden, Genome Res., 1997, 7, 649 656). Percent homology, sequence identity or complementarity, can be determined by, for example, the Gap program (Wisconsin Sequence Analysis Package, Version 8 for Unix, Genetics Computer Group, University Research Park, Madison Wis.), using default settings, which uses the algorithm of Smith and Waterman (Adv. Appl. Math., 1981, 2, 482 489). 
     In certain embodiments, the antisense compounds provided herein, or specified portions thereof, are fully complementary (i.e. 100% complementary) to a target nucleic acid, or specified portion thereof. For example, an antisense compound may be fully complementary to a GHR nucleic acid, or a target region, or a target segment or target sequence thereof. 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. For example, a 20 nucleobase antisense compound is fully complementary to a target sequence that is 400 nucleobases long, so long as there is a corresponding 20 nucleobase portion of the target nucleic acid that is fully complementary to the antisense compound. Fully complementary can also be used in reference to a specified portion of the first and/or the second nucleic acid. For example, a 20 nucleobase portion of a 30 nucleobase antisense compound can be “fully complementary” to a target sequence that is 400 nucleobases long. The 20 nucleobase portion of the 30 nucleobase oligonucleotide is fully complementary to the target sequence if the target sequence has a corresponding 20 nucleobase portion wherein each nucleobase is complementary to the 20 nucleobase portion of the antisense compound. At the same time, the entire 30 nucleobase antisense compound may or may not be fully complementary to the target sequence, depending on whether the remaining 10 nucleobases of the antisense compound are also complementary to the target sequence. 
     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 certain embodiments, antisense compounds that are, or are up to 11, 12, 13, 14, 15, 16, 17, 18, 19, or 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 GHR nucleic acid, or specified portion thereof. 
     In certain embodiments, antisense compounds that are, or are up to 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 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 GHR nucleic acid, or specified portion thereof. 
     The antisense compounds provided 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 certain embodiments, the antisense compounds, are complementary to at least an 8 nucleobase portion of a target segment. In certain embodiments, the antisense compounds are complementary to at least a 9 nucleobase portion of a target segment. In certain embodiments, the antisense compounds are complementary to at least a 10 nucleobase portion of a target segment. In certain embodiments, the antisense compounds are complementary to at least an 11 nucleobase portion of a target segment. In certain embodiments, the antisense compounds are complementary to at least a 12 nucleobase portion of a target segment. In certain embodiments, the antisense compounds are complementary to at least a 13 nucleobase portion of a target segment. In certain embodiments, the antisense compounds are complementary to at least a 14 nucleobase portion of a target segment. In certain embodiments, the antisense compounds are complementary to at least a 15 nucleobase portion of a target segment. Also contemplated are antisense compounds that are complementary to at least a 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more nucleobase portion of a target segment, or a range defined by any two of these values. 
     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, or portion thereof. 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 certain embodiments, the antisense compounds, or portions thereof, are, or are at least, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to one or more of the antisense compounds or SEQ ID NOs, or a portion thereof, disclosed herein. 
     In certain embodiments, a portion of the antisense compound is compared to an equal length portion of the target nucleic acid. In certain embodiments, an 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 nucleobase portion is compared to an equal length portion of the target nucleic acid. 
     In certain embodiments, a portion of the antisense oligonucleotide is compared to an equal length portion of the target nucleic acid. In certain embodiments, an 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 nucleobase portion is compared to an equal length portion of the target nucleic acid. 
     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 certain embodiments, antisense compounds targeted to a GHR nucleic acid comprise one or more modified internucleoside linkages. In certain embodiments, the modified internucleoside linkages are phosphorothioate linkages. In certain embodiments, each internucleoside linkage of an antisense compound is a phosphorothioate internucleoside linkage. 
     Modified Sugar Moieties 
     Antisense compounds can optionally contain one or more nucleosides wherein the sugar group has been modified. Such sugar modified nucleosides may impart enhanced nuclease stability, increased binding affinity, or some other beneficial biological property to the antisense compounds. In certain embodiments, nucleosides comprise chemically modified ribofuranose ring moieties. Examples of chemically modified ribofuranose rings include without limitation, addition of substitutent groups (including 5′ and 2′ substituent groups, bridging of non-geminal ring atoms to form bicyclic nucleic acids (BNA), replacement of the ribosyl ring oxygen atom with S, N(R), or C(R 1 )(R 2 ) (R, R 1  and R 2  are each independently H, C 1 -C 12  alkyl or a protecting group) and combinations thereof. Examples of chemically modified sugars include 2′-F-5′-methyl substituted nucleoside (see PCT International Application WO 2008/101157 Published on 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 published U.S. Patent Application US2005-0130923, published on Jun. 16, 2005) or alternatively 5′-substitution of a BNA (see PCT International Application WO 2007/134181 Published on Nov. 22, 2007 wherein LNA is substituted with for example a 5′-methyl or a 5′-vinyl group). 
     Examples of nucleosides having modified sugar moieties include without limitation nucleosides comprising 5′-vinyl, 5′-methyl (R or S), 4-S, 2′-F, 2′-OCH 3 , 2′-OCH 2 CH 3 , 2′-OCH 2 CH 2 F and 2′-O(CH 2 ) 2 OCH 3  substituent groups. The substituent at the 2′ position can also be selected from allyl, amino, azido, thio, O-allyl, O—C 1 -C 10  alkyl, OCF 3 , OCH 2 F, O(CH 2 ) 2 SCH 3 , O(CH 2 ) 2 —O—N(R m )(R n ), O—CH 2 —C(═O)—N(R m )(R n ), and O—CH 2 —C(═O)—N(R l )—(CH 2 ) 2 —N(R m )(R n ), where each R l , R m  and R n  is, independently, H or substituted or unsubstituted C 1 -C 10  alkyl. 
     As used herein, “bicyclic nucleosides” refer to modified nucleosides comprising a bicyclic sugar moiety. Examples of bicyclic nucleosides include without limitation nucleosides comprising abridge between the 4′ and the 2′ ribosyl ring atoms. In certain embodiments, antisense compounds provided herein include one or more bicyclic nucleosides comprising a 4′ to 2′ bridge. Examples of such 4′ to 2′ bridged bicyclic nucleosides, include but are not limited to one of the formulae: 4′-(CH 2 )—O-2′ (LNA); 4′-(CH 2 )—S-2′; 4′-(CH 2 ) 2 —O-2′ (ENA); 4′-CH(CH 3 )—O-2′ (also referred to as constrained ethyl or cEt) and 4′-CH(CH 2 OCH 3 )—O-2′ (and analogs thereof see U.S. Pat. No. 7,399,845, issued on Jul. 15, 2008); 4′-C(CH 3 )(CH 3 )—O-2′ (and analogs thereof see published International Application WO/2009/006478, published Jan. 8, 2009); 4′-CH 2 —N(OCH 3 )-2′ (and analogs thereof see published International Application WO/2008/150729, published Dec. 11, 2008); 4′-CH 2 —O—N(CH 3 )-2′ (see published U.S. Patent Application US2004-0171570, published Sep. 2, 2004); 4′-CH 2 —N(R)—O-2′, wherein R is H, C 1 -C 12  alkyl, or a protecting group (see U.S. Pat. No. 7,427,672, issued on Sep. 23, 2008); 4′-CH 2 —C(H)(CH 3 )-2′ (see Chattopadhyaya et al.,  J. Org. Chem.,  2009, 74, 118-134); and 4′-CH 2 —C(═CH 2 )-2′ (and analogs thereof see published International Application WO 2008/154401, published on Dec. 8, 2008). 
     Further reports related to bicyclic nucleosides can also be found in published literature (see for example: Singh et al.,  Chem. Commun.,  1998, 4, 455-456; Koshkin et al.,  Tetrahedron,  1998, 54, 3607-3630; Wahlestedt et al.,  Proc. Natl. Acad. Sci. U.S.A,  2000, 97, 5633-5638; Kumar et al.,  Bioorg. Med. Chem. Lett.,  1998, 8, 2219-2222; Singh et al.,  J. Org. Chem.,  1998, 63, 10035-10039; Srivastava et al.,  J. Am. Chem. Soc.,  2007, 129(26) 8362-8379; Elayadi et al.,  Curr. Opinion Invest. Drugs,  2001, 2, 558-561; Braasch et al.,  Chem. Biol.,  2001, 8, 1-7; and Orum et al.,  Curr. Opinion Mol. Ther.,  2001, 3, 239-243; U.S. Pat. Nos. 6,268,490; 6,525,191; 6,670,461; 6,770,748; 6,794,499; 7,034,133; 7,053,207; 7,399,845; 7,547,684; and 7,696,345; U.S. Patent Publication No. US2008-0039618; US2009-0012281; U.S. Patent Ser. Nos. 60/989,574; 61/026,995; 61/026,998; 61/056,564; 61/086,231; 61/097,787; and 61/099,844; Published PCT International applications WO 1994/014226; WO 2004/106356; WO 2005/021570; WO 2007/134181; WO 2008/150729; WO 2008/154401; and WO 2009/006478. Each of the foregoing bicyclic nucleosides can be prepared having one or more stereochemical sugar configurations including for example α-L-ribofuranose and β-D-ribofuranose (see PCT international application PCT/DK98/00393, published on Mar. 25, 1999 as WO 99/14226). 
     In certain embodiments, bicyclic sugar moieties of BNA nucleosides include, but are not limited to, compounds having at least one bridge between the 4′ and the 2′ position of the pentofuranosyl sugar moiety wherein such bridges independently comprises 1 or from 2 to 4 linked groups independently selected from —[C(R a )(R b )] n , —C(R a )═C(R b )—, —C(R a )═N—, —C(═O)—, —C(═NR a )—, —C(═S)—, —O—, —Si(R a ) 2 —, —S(═O) x —, and —N(R a )—; wherein: 
     x is 0, 1, or 2; 
     n is 1, 2, 3, or 4; 
     each R a  and R b  is, independently, H, a protecting group, hydroxyl, C 1 -C 12  alkyl, substituted C 1 -C 12  alkyl, C 2 -C 12  alkenyl, substituted C 2 -C 12  alkenyl, C 2 -C 12  alkynyl, substituted C 2 -C 12  alkynyl, C 5 -C 20  aryl, substituted C 5 -C 20  aryl, heterocycle radical, substituted heterocycle radical, heteroaryl, substituted heteroaryl, C 5 -C 7  alicyclic radical, substituted C 5 -C 7  alicyclic radical, halogen, OJ 1 , NJ 1 J 2 , SJ 1 , N 3 , COOJ 1 , acyl (C(═O)—H), substituted acyl, CN, sulfonyl (S(═O) 2 -J 1 ), or sulfoxyl (S(═O)-J 1 ); and 
     each J 1  and J 2  is, independently, H, C 1 -C 12  alkyl, substituted C 1 -C 12  alkyl, C 2 -C 12  alkenyl, substituted C 2 -C 12  alkenyl, C 2 -C 12  alkynyl, substituted C 2 -C 12  alkynyl, C 5 -C 20  aryl, substituted C 5 -C 20  aryl, acyl (C(═O)—H), substituted acyl, a heterocycle radical, a substituted heterocycle radical, C 1 -C 12  aminoalkyl, substituted C 1 -C 12  aminoalkyl or a protecting group. 
     In certain embodiments, the bridge of a bicyclic sugar moiety is —[C(R a )(R b )] n , —[C(R a )(R b )] n O—, —C(R a R b )—N(R)—O— or —C(R a R b )—O—N(R)—. In certain embodiments, the bridge is 4′-CH 2 -2′, 4′-(CH 2 ) 2 -2′, 4′-(CH 2 ) 3 -2′, 4′-CH 2 —O-2′, 4′-(CH 2 ) 2 —O-2′, 4′-CH 2 —O—N(R)-2′ and 4′-CH 2 —N(R)—O-2′- wherein each R is, independently, H, a protecting group or C 1 -C 12  alkyl. 
     In certain embodiments, bicyclic nucleosides are further defined by isomeric configuration. For example, a nucleoside comprising a 4′-2′ methylene-oxy bridge, may be in the α-L configuration or in the p-D configuration. Previously, α-L-methyleneoxy (4′-CH 2 —O-2′) BNA&#39;s have been incorporated into antisense oligonucleotides that showed antisense activity (Frieden et al.,  Nucleic Acids Research,  2003, 21, 6365-6372). 
     In certain embodiments, bicyclic nucleosides include, but are not limited to, (A) α-L-methyleneoxy (4′-CH 2 —O-2′) BNA, (B) β-D-methyleneoxy (4′-CH 2 —O-2′) BNA, (C) ethyleneoxy (4′-(CH 2 ) 2 —O-2′) BNA, (D) aminooxy (4′-CH 2 —O—N(R)-2′) BNA, (E) oxyamino (4′-CH 2 —N(R)—O-2′) BNA, and (F) methyl(methyleneoxy) (4′-CH(CH 3 )—O-2′) BNA, (G) methylene-thio (4′-CH 2 —S-2′) BNA, (H) methylene-amino (4′-CH 2 —N(R)-2′) BNA, (I) methyl carbocyclic (4′-CH 2 —CH(CH 3 )-2′) BNA, (J) propylene carbocyclic (4′-(CH 2 ) 3 -2′) BNA and (K) vinyl BNA as depicted below: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     wherein Bx is the base moiety and R is independently H, a protecting group, C 1 -C 12  alkyl or C 1 -C 12  alkoxy. 
     In certain embodiments, bicyclic nucleosides are provided having Formula I: 
     
       
         
         
             
             
         
       
     
     wherein: 
     Bx is a heterocyclic base moiety; 
     -Q a -Q b -Q c - is —CH 2 —N(R c )—CH 2 —, —C(═O)—N(R c )—CH 2 —, —CH 2 —O—N(R c )—, —CH 2 —N(R c )—O— or —N(R c )—O—CH 2 ; 
     R c  is C 1 -C 12  alkyl or an amino protecting group; and 
     T a  and T b  are each, independently H, a hydroxyl protecting group, a conjugate group, a reactive phosphorus group, a phosphorus moiety or a covalent attachment to a support medium. 
     In certain embodiments, bicyclic nucleosides are provided having Formula II: 
     
       
         
         
             
             
         
       
     
     wherein: 
     Bx is a heterocyclic base moiety; 
     T a  and T b  are each, independently H, a hydroxyl protecting group, a conjugate group, a reactive phosphorus group, a phosphorus moiety or a covalent attachment to a support medium; 
     Z a  is C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, substituted C 1 -C 6  alkyl, substituted C 2 -C 6  alkenyl, substituted C 2 -C 6  alkynyl, acyl, substituted acyl, substituted amide, thiol or substituted thio. 
     In one embodiment, each of the substituted groups is, independently, mono or poly substituted with substituent groups independently selected from halogen, oxo, hydroxyl, OJ c , NJ c J d , SJ c , N 3 , OC(═X)J c , and NJ e C(═X)NJ c J d , wherein each J c , J d  and J e  is, independently, H, C 1 -C 6  alkyl, or substituted C 1 -C 6  alkyl and X is O or NJ c . 
     In certain embodiments, bicyclic nucleosides are provided having Formula III: 
     
       
         
         
             
             
         
       
     
     wherein: 
     Bx is a heterocyclic base moiety; 
     T a  and T b  are each, independently H, a hydroxyl protecting group, a conjugate group, a reactive phosphorus group, a phosphorus moiety or a covalent attachment to a support medium; 
     Z b  is C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, substituted C 1 -C 6  alkyl, substituted C 2 -C 6  alkenyl, substituted C 2 -C 6  alkynyl or substituted acyl (C(═O)—). 
     In certain embodiments, bicyclic nucleosides are provided having Formula IV: 
     
       
         
         
             
             
         
       
     
     wherein: 
     Bx is a heterocyclic base moiety; 
     T a  and T b  are each, independently H, a hydroxyl protecting group, a conjugate group, a reactive phosphorus group, a phosphorus moiety or a covalent attachment to a support medium; 
     R d  is C 1 -C 6  alkyl, substituted C 1 -C 6  alkyl, C 2 -C 6  alkenyl, substituted C 2 -C 6  alkenyl, C 2 -C 6  alkynyl or substituted C 2 -C 6  alkynyl;
         each q a , q b , q c  and q d  is, independently, H, halogen, C 1 -C 6  alkyl, substituted C 1 -C 6  alkyl, C 2 -C 6  alkenyl, substituted C 2 -C 6  alkenyl, C 2 -C 6  alkynyl or substituted C 2 -C 6  alkynyl, C 1 -C 6  alkoxyl, substituted C 1 -C 6  alkoxyl, acyl, substituted acyl, C 1 -C 6  aminoalkyl or substituted C 1 -C 6  aminoalkyl;       

     In certain embodiments, bicyclic nucleosides are provided having Formula V: 
     
       
         
         
             
             
         
       
     
     wherein: 
     Bx is a heterocyclic base moiety; 
     T a  and T b  are each, independently H, a hydroxyl protecting group, a conjugate group, a reactive phosphorus group, a phosphorus moiety or a covalent attachment to a support medium; 
     q a , q b , q e  and q f  are each, independently, hydrogen, halogen, C 1 -C 12  alkyl, substituted C 1 -C 12  alkyl, C 2 -C 12  alkenyl, substituted C 2 -C 12  alkenyl, C 2 -C 12  alkynyl, substituted C 2 -C 12  alkynyl, C 1 -C 12  alkoxy, substituted C 1 -C 12  alkoxy, OJ j , SJ j , SOJ j , SO 2 J j , NJ j J k , N 3 , CN, C(═O)OJ j , C(═O)NJ j J k , C(═O)J j , O—C(═O)NJ j J k , N(H)C(═NH)NJ j J k , N(H)C(═O)NJ j J k  or N(H)C(═S)NJ j J k ; 
     or q e  and q f  together are ═C(q g )(q h ); 
     q g  and q h  are each, independently, H, halogen, C 1 -C 12  alkyl or substituted C 1 -C 12  alkyl. 
     The synthesis and preparation of the methyleneoxy (4′-CH 2 —O-2′) BNA monomers adenine, cytosine, guanine, 5-methyl-cytosine, thymine and uracil, along with their oligomerization, and nucleic acid recognition properties have been described (Koshkin et al.,  Tetrahedron,  1998, 54, 3607-3630). BNAs and preparation thereof are also described in WO 98/39352 and WO 99/14226. 
     Analogs of methyleneoxy (4′-CH 2 —O-2′) BNA and 2′-thio-BNAs, have also been prepared (Kumar et al.,  Bioorg. Med. Chem. Lett.,  1998, 8, 2219-2222). Preparation of locked nucleoside analogs comprising oligodeoxyribonucleotide duplexes as substrates for nucleic acid polymerases has also been described (Wengel et al., WO 99/14226). Furthermore, synthesis of 2′-amino-BNA, a novel comformationally restricted high-affinity oligonucleotide analog has been described in the art (Singh et al.,  J. Org. Chem.,  1998, 63, 10035-10039). In addition, 2′-amino- and 2′-methylamino-BNA&#39;s have been prepared and the thermal stability of their duplexes with complementary RNA and DNA strands has been previously reported. 
     In certain embodiments, bicyclic nucleosides are provided having Formula VI: 
     
       
         
         
             
             
         
       
     
     wherein: 
     Bx is a heterocyclic base moiety; 
     T a  and T b  are each, independently H, a hydroxyl protecting group, a conjugate group, a reactive phosphorus group, a phosphorus moiety or a covalent attachment to a support medium; 
     each q i , q j , q k  and q l  is, independently, H, halogen, C 1 -C 12  alkyl, substituted C 1 -C 12  alkyl, C 2 -C 12  alkenyl, substituted C 2 -C 12  alkenyl, C 2 -C 12  alkynyl, substituted C 2 -C 12  alkynyl, C 1 -C 12  alkoxyl, substituted C 1 -C 12  alkoxyl, OJ j , SJ j , SOJ j , SO 2 J j , NJ j J k , N 3 , CN, C(═O)OJ j , C(═O)NJ j J k , C(═O)J j , O—C(═O)NJ j J k , N(H)C(═NH)NJ j J k , N(H)C(═O)NJ j J k  or N(H)C(═S)NJ j J k ; and 
     q i  and q j  or q l  and q k  together are ═C(q g )(q h ), wherein q g  and q h  are each, independently, H, halogen, C 1 -C 12  alkyl or substituted C 1 -C 12  alkyl. 
     One carbocyclic bicyclic nucleoside having a 4′-(CH 2 ) 3 -2′ bridge and the alkenyl analog bridge 4′-CH═CH—CH 2 -2′ have been described (Freier et al.,  Nucleic Acids Research,  1997, 25(22), 4429-4443 and Albaek et al.,  J. Org. Chem.,  2006, 71, 7731-7740). The synthesis and preparation of carbocyclic bicyclic nucleosides along with their oligomerization and biochemical studies have also been described (Srivastava et al.,  J. Am. Chem. Soc.,  2007, 129(26), 8362-8379). 
     As used herein, “4′-2′ bicyclic nucleoside” or “4′ to 2′ bicyclic nucleoside” refers to a bicyclic nucleoside comprising a furanose ring comprising a bridge connecting two carbon atoms of the furanose ring connects the 2′ carbon atom and the 4′ carbon atom of the sugar ring. 
     As used herein, “monocylic nucleosides” refer to nucleosides comprising modified sugar moieties that are not bicyclic sugar moieties. In certain embodiments, the sugar moiety, or sugar moiety analogue, of a nucleoside may be modified or substituted at any position. 
     As used herein, “2′-modified sugar” means a furanosyl sugar modified at the 2′ position. In certain embodiments, such modifications include substituents selected from: a halide, including, but not limited to substituted and unsubstituted alkoxy, substituted and unsubstituted thioalkyl, substituted and unsubstituted amino alkyl, substituted and unsubstituted alkyl, substituted and unsubstituted allyl, and substituted and unsubstituted alkynyl. In certain embodiments, 2′ modifications are selected from substituents including, but not limited to: O[(CH 2 ) n O] m CH 3 , O(CH 2 ) n NH 2 , O(CH 2 ) n CH 3 , O(CH 2 ) n F, O(CH 2 ) n ONH 2 , OCH 2 C(═O)N(H)CH 3 , and O(CH 2 ) n ON[(CH 2 ) n CH 3 ] 2 , where n and m are from 1 to about 10. Other 2′-substituent groups can also be selected from: C 1 -C 12  alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aralkyl, O-alkaryl or O-aralkyl, SH, SCH 3 , OCN, Cl, Br, CN, F, CF 3 , OCF 3 , SOCH 3 , SO 2 CH 3 , ONO 2 , NO 2 , N 3 , NH 2 , heterocycloalkyl, heterocycloalkaryl, aminoalkylamino, polyalkylamino, substituted silyl, an RNA cleaving group, a reporter group, an intercalator, a group for improving pharmacokinetic properties, or a group for improving the pharmacodynamic properties of an antisense compound, and other substituents having similar properties. In certain embodiments, modified nucleosides comprise a 2′-MOE side chain (Baker et al., J. Biol. Chem., 1997, 272, 11944-12000). Such 2′-MOE substitution have been described as having improved binding affinity compared to unmodified nucleosides and to other modified nucleosides, such as 2′-O-methyl, O-propyl, and O-aminopropyl. Oligonucleotides having the 2′-MOE substituent also have been shown to be antisense inhibitors of gene expression with promising features for in vivo use (Martin,  Helv. Chim. Acta,  1995, 78, 486-504; Altmann et al.,  Chimia,  1996, 50, 168-176; Altmann et al.,  Biochem. Soc. Trans.,  1996, 24, 630-637; and Altmann et al.,  Nucleosides Nucleotides,  1997, 16, 917-926). 
     As used herein, a “modified tetrahydropyran nucleoside” or “modified THP nucleoside” means a nucleoside having a six-membered tetrahydropyran “sugar” substituted in for the pentofuranosyl residue in normal nucleosides (a sugar surrogate). Modified THP nucleosides include, but are not limited to, what is referred to in the art as hexitol nucleic acid (HNA), anitol nucleic acid (ANA), manitol nucleic acid (MNA) (see Leumann,  Bioorg. Med. Chem.,  2002, 10, 841-854) or fluoro HNA (F-HNA) having a tetrahydropyran ring system as illustrated below: 
     
       
         
         
             
             
         
       
     
     In certain embodiments, sugar surrogates are selected having Formula VII: 
     
       
         
         
             
             
         
       
     
     wherein independently for each of said at least one tetrahydropyran nucleoside analog of Formula VII: 
     Bx is a heterocyclic base moiety; 
     T a  and T b  are each, independently, an internucleoside linking group linking the tetrahydropyran nucleoside analog to the antisense compound or one of T a  and T b  is an internucleoside linking group linking the tetrahydropyran nucleoside analog to the antisense compound and the other of T a  and T b  is H, a hydroxyl protecting group, a linked conjugate group or a 5′ or 3′-terminal group; 
     q 1 , q 2 , q 3 , q 4 , q 5 , q 6  and q 7  are each independently, H, C 1 -C 6  alkyl, substituted C 1 -C 6  alkyl, C 2 -C 6  alkenyl, substituted C 2 -C 6  alkenyl, C 2 -C 6  alkynyl or substituted C 2 -C 6  alkynyl; and each of R 1  and R 2  is selected from hydrogen, hydroxyl, halogen, substituted or unsubstituted alkoxy, NJ 1 J 2 , SJ 1 , N 3 , OC(═X)J 1 , OC(═X)NJ 1 J 2 , NJ 3 C(═X)NJ 1 J 2  and CN, wherein X is O, S or NJ 1  and each J 1 , J 2  and J 3  is, independently, H or C 1 -C 6  alkyl. 
     In certain embodiments, the modified THP nucleosides of Formula VII are provided wherein q 1 , q 2 , q 3 , q 4 , q 5 , q 6  and q 7  are each H. In certain embodiments, at least one of q 1 , q 2 , q 3 , q 4 , q 5 , q 6  and q 7  is other than H. In certain embodiments, at least one of q 1 , q 2 , q 3 , q 4 , q 5 , q 6  and q 7  is methyl. In certain embodiments, THP nucleosides of Formula VII are provided wherein one of R 1  and R 2  is fluoro. In certain embodiments, R 1  is fluoro and R 2  is H; R 1  is methoxy and R 2  is H, and R 1  is methoxyethoxy and R 2  is H. 
     In certain embodiments, sugar surrogates comprise rings having more than 5 atoms and more than one heteroatom. For example nucleosides comprising morpholino sugar moieties and their use in oligomeric compounds has been reported (see for example: Braasch et al., Biochemistry, 2002, 41, 4503-4510; and U.S. Pat. Nos. 5,698,685; 5,166,315; 5,185,444; and 5,034,506). As used here, the term “morpholino” means a sugar surrogate having the following formula: 
     
       
         
         
             
             
         
       
     
     In certain embodiments, morpholinos may be modified, for example by adding or altering various substituent groups from the above morpholino structure. Such sugar surrogates are referred to herein as “modified morpholinos.” 
     Combinations of modifications are also provided without limitation, such as 2′-F-5′-methyl substituted nucleosides (see PCT International Application WO 2008/101157 published on Aug. 21, 2008 for other disclosed 5′,2′-bis substituted nucleosides) and replacement of the ribosyl ring oxygen atom with S and further substitution at the 2′-position (see published U.S. Patent Application US2005-0130923, published on Jun. 16, 2005) or alternatively 5′-substitution of a bicyclic nucleic acid (see PCT International Application WO 2007/134181, published on Nov. 22, 2007 wherein a 4′-CH 2 —O-2′ bicyclic nucleoside is further substituted at the 5′ position with a 5′-methyl or a 5′-vinyl group). The synthesis and preparation of carbocyclic bicyclic nucleosides along with their oligomerization and biochemical studies have also been described (see, e.g., Srivastava et al.,  J. Am. Chem. Soc.  2007, 129(26), 8362-8379). 
     In certain embodiments, antisense compounds comprise one or more modified cyclohexenyl nucleosides, which is a nucleoside having a six-membered cyclohexenyl in place of the pentofuranosyl residue in naturally occurring nucleosides. Modified cyclohexenyl nucleosides include, but are not limited to those described in the art (see for example commonly owned, published PCT Application WO 2010/036696, published on Apr. 10, 2010, Robeyns et al.,  J Am. Chem. Soc.,  2008, 130(6), 1979-1984; Horvith et al.,  Tetrahedron Letters,  2007, 48, 3621-3623; Nauwelaerts et al.,  J. Am. Chem. Soc.,  2007, 129(30), 9340-9348; Gu et al.,  Nucleosides, Nucleotides  &amp;  Nucleic Acids,  2005, 24(5-7), 993-998; Nauwelaerts et al.,  Nucleic Acids Research,  2005, 33(8), 2452-2463; Robeyns et al.,  Acta Crystallographica, Section F: Structural Biology and Crystallization Communications,  2005, F61(6), 585-586; Gu et al.,  Tetrahedron,  2004, 60(9), 2111-2123; Gu et al.,  Oligonucleotides,  2003, 13(6), 479-489; Wang et al.,  J. Org. Chem.,  2003, 68, 4499-4505; Verbeure et al.,  Nucleic Acids Research,  2001, 29(24), 4941-4947; Wang et al.,  J. Org. Chem.,  2001, 66, 8478-82; Wang et al.,  Nucleosides, Nucleotides  &amp;  Nucleic Acids,  2001, 20(4-7), 785-788; Wang et al.,  J. Am. Chem.,  2000, 122, 8595-8602; Published PCT application, WO 06/047842; and Published PCT Application WO 01/049687; the text of each is incorporated by reference herein, in their entirety). Certain modified cyclohexenyl nucleosides have Formula X. 
     
       
         
         
             
             
         
       
     
     wherein independently for each of said at least one cyclohexenyl nucleoside analog of Formula X: 
     Bx is a heterocyclic base moiety; 
     T 3  and T 4  are each, independently, an internucleoside linking group linking the cyclohexenyl nucleoside analog to an antisense compound or one of T 3  and T 4  is an internucleoside linking group linking the tetrahydropyran nucleoside analog to an antisense compound and the other of T 3  and T 4  is H, a hydroxyl protecting group, a linked conjugate group, or a 5′ or 3′-terminal group; and 
     q 1 , q 2 , q 3 , q 4 , q 5 , q 6 , q 7 , q 8  and q 9  are each, independently, H, C 1 -C 6  alkyl, substituted C 1 -C 6  alkyl, C 2 -C 6  alkenyl, substituted C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, substituted C 2 -C 6  alkynyl or other sugar substituent group. 
     As used herein, “2′-modified” or “2′-substituted” refers to a nucleoside comprising a sugar comprising a substituent at the 2′ position other than H or OH. 2′-modified nucleosides, include, but are not limited to, bicyclic nucleosides wherein the bridge connecting two carbon atoms of the sugar ring connects the 2′ carbon and another carbon of the sugar ring; and nucleosides with non-bridging 2′-substituents, such as allyl, amino, azido, thio, O-allyl, O—C 1 -C 10  alkyl, —OCF 3 , O—(CH 2 ) 2 O—CH 3 , 2′-O(CH 2 ) 2 SCH 3 , O—(CH 2 ) 2 —O—N(R m )(R n ), or O—CH 2 —C(═O)—N(R m )(R n ), where each R m  and R n  is, independently, H or substituted or unsubstituted C 1 -C 10  alkyl. 2′-modified nucleosides may further comprise other modifications, for example at other positions of the sugar and/or at the nucleobase. 
     As used herein, “2′-F” refers to a nucleoside comprising a sugar comprising a fluoro group at the 2′ position of the sugar ring. 
     As used herein, “2′-OMe” or “2′-OCH 3 ” or “2′-O-methyl” each refers to a nucleoside comprising a sugar comprising an —OCH 3  group at the 2′ position of the sugar ring. 
     As used herein, “MOE” or “2′-MOE” or “2′-OCH 2 CH 2 OCH 3 ” or “2′-O-methoxyethyl” each refers to a nucleoside comprising a sugar comprising a —OCH 2 CH 2 OCH 3  group at the 2′ position of the sugar ring. 
     As used herein, “oligonucleotide” refers to a compound comprising a plurality of linked nucleosides. In certain embodiments, one or more of the plurality of nucleosides is modified. In certain embodiments, an oligonucleotide comprises one or more ribonucleosides (RNA) and/or deoxyribonucleosides (DNA). 
     Many other bicyclo and tricyclo sugar surrogate ring systems are also known in the art that can be used to modify nucleosides for incorporation into antisense compounds (see for example review article: Leumann,  Bioorg. Med. Chem.,  2002, 10, 841-854). 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. Some representative U.S. patents that teach the preparation of such modified sugars include without limitation, U.S. Pat. Nos. 4,981,957; 5,118,800; 5,319,080; 5,359,044; 5,393,878; 5,446,137; 5,466,786; 5,514,785; 5,519,134; 5,567,811; 5,576,427; 5,591,722; 5,597,909; 5,610,300; 5,627,053; 5,639,873; 5,646,265; 5,670,633; 5,700,920; 5,792,847 and 6,600,032 and International Application PCT/US2005/019219, filed Jun. 2, 2005 and published as WO 2005/121371 on Dec. 22, 2005, and each of which is herein incorporated by reference in its entirety. 
     In nucleotides having modified sugar moieties, the nucleobase moieties (natural, modified or a combination thereof) are maintained for hybridization with an appropriate nucleic acid target. 
     In certain embodiments, antisense compounds comprise one or more nucleosides having modified sugar moieties. In certain embodiments, the modified sugar moiety is 2′-MOE. In certain embodiments, the 2′-MOE modified nucleosides are arranged in a gapmer motif. In certain embodiments, the modified sugar moiety is a bicyclic nucleoside having a (4′-CH(CH 3 )—O-2′) bridging group. In certain embodiments, the (4′-CH(CH 3 )—O-2′) modified nucleosides are arranged throughout the wings of 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 can 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 modified 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 can 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 certain embodiments, antisense compounds targeted to a GHR nucleic acid comprise one or more modified nucleobases. In certain embodiments, shortened or gap-widened antisense oligonucleotides targeted to a GHR nucleic acid comprise one or more modified nucleobases. In certain embodiments, the modified nucleobase is 5-methylcytosine. In certain embodiments, each cytosine is a 5-methylcytosine. 
     Conjugated Antisense Compounds 
     Antisense compounds may be covalently linked to one or more moieties or conjugates which enhance the activity, 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. 
     In certain embodiments, antisense compounds, including, but not limited to those particularly suited for use as ssRNA, are modified by attachment of one or more conjugate groups. In general, conjugate groups modify one or more properties of the attached oligonucleotide, including but not limited to pharmacodynamics, pharmacokinetics, stability, binding, absorption, cellular distribution, cellular uptake, charge and clearance. Conjugate groups are routinely used in the chemical arts and are linked directly or via an optional conjugate linking moiety or conjugate linking group to a parent compound such as an oligonucleotide. Conjugate groups includes without limitation, intercalators, reporter molecules, polyamines, polyamides, polyethylene glycols, thioethers, polyethers, cholesterols, thiocholesterols, cholic acid moieties, folate, lipids, phospholipids, biotin, phenazine, phenanthridine, anthraquinone, adamantane, acridine, fluoresceins, rhodamines, coumarins and dyes. Certain conjugate groups have been described previously, for example: cholesterol moiety (Letsinger et al., Proc. Natl. Acad. Sci. USA, 1989, 86, 6553-6556), cholic acid (Manoharan et al., Bioorg. Med. Chem. Let., 1994, 4, 1053-1060), a thioether, e.g., hexyl-S-tritylthiol (Manoharan et al., Ann. N.Y. Acad. Sci., 1992, 660, 306-309; Manoharan et al., Bioorg. Med. Chem. Let., 1993, 3, 2765-2770), a thiocholesterol (Oberhauser et al., Nucl. Acids Res., 1992, 20, 533-538), an aliphatic chain, e.g., do-decan-diol or undecyl residues (Saison-Behmoaras et al., EMBO J., 1991, 10, 1111-1118; Kabanov et al., FEBS Lett., 1990, 259, 327-330; Svinarchuk et al., Biochimie, 1993, 75, 49-54), a phospholipid, e.g., di-hexadecyl-rac-glycerol or triethyl-ammonium 1,2-di-O-hexadecyl-rac-glycero-3-H-phosphonate (Manoharan et al., Tetrahedron Lett., 1995, 36, 3651-3654; Shea et al., Nucl. Acids Res., 1990, 18, 3777-3783), a polyamine or a polyethylene glycol chain (Manoharan et al., Nucleosides &amp; Nucleotides, 1995, 14, 969-973), or adamantane acetic acid (Manoharan et al., Tetrahedron Lett., 1995, 36, 3651-3654), a palmityl moiety (Mishra et al., Biochim. Biophys. Acta, 1995, 1264, 229-237), or an octadecylamine or hexylamino-carbonyl-oxycholesterol moiety (Crooke et al., J. Pharmacol. Exp. Ther., 1996, 277, 923-937). 
     For additional conjugates including those useful for ssRNA and their placement within antisense compounds, see e.g., U.S. Application No. 61/583,963. 
     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. 
     Cells may be treated with antisense oligonucleotides when the 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 may be mixed with LIPOFECTIN in OPTI-MEM 1 (Invitrogen, Carlsbad, Calif.) to achieve the desired final concentration of antisense oligonucleotide and a LIPOFECTIN concentration that may range from 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 may range from 2 to 12 ug/mL per 100 nM antisense oligonucleotide. 
     Another technique used to introduce antisense oligonucleotides into cultured cells includes electroporation. 
     Yet another technique used to introduce antisense oligonucleotides into cultured cells includes free uptake of the oligonucleotides by the cells. 
     Cells are treated with antisense oligonucleotides by routine methods. Cells may be 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 when transfected with LIPOFECTAMINE. Antisense oligonucleotides are used at higher concentrations ranging from 625 to 20,000 nM when transfected using electroporation. 
     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. 
     Certain Indications 
     Certain embodiments provided herein relate to methods of treating, preventing, or ameliorating a disease associated with excess growth hormone in a subject by administering a GHR specific inhibitor, such as an antisense compound or oligonucleotide targeted to GHR. In certain aspects, the disease associated with excess growth hormone is acromegaly. In certain aspects, the disease associated with excess growth hormone is gigantism. 
     Certain embodiments provide a method of treating, preventing, or ameliorating acromegaly in a subject by administering a GHR specific inhibitor, such as an antisense compound or oligonucleotide targeted to GHR. Acromegaly is a disease associated with excess growth hormone (GH). In over 90 percent of acromegaly patients, the overproduction of growth hormones is caused by a benign tumor of the pituitary gland, called an adenoma, which produces excess growth hormone and compresses surrounding brain tissues. Expansion of the adenoma can cause headaches and visual impairment that often accompany acromegaly. In some instances, acromegaly is caused by tumors of the pancreas, lungs, or adrenal glands that lead to an excess of GH, either by producing GH or by producing Growth Hormone Releasing Hormone (GHRH), the hormone that stimulates the pituitary to make GH. 
     Acromegaly most commonly affects adults in middle age and can result in severe disfigurement, complicating conditions, and premature death. Because of its pathogenesis and slow progression, acromegaly often goes undiagnosed until changes in external features become noticeable, such as changes in the face. Acromegaly is often associated with gigantism. 
     Features of acromegaly include soft tissue swelling resulting in enlargement of the hands, feet, nose, lips and ears, and a general thickening of the skin; soft tissue swelling of internal organs, such as the heart and kidney; vocal cord swelling resulting in a low voice and slow speech; expansion of the skull; pronounced eyebrow protrusion, often with ocular distension; pronounced lower jaw protrusion and enlargement of the tongue; teeth gapping; and carpal tunnel syndrome. In certain embodiments, any one or combination of these features of acromegaly can be treated, prevented, or ameliorated by administering a compound or composition targeted to GHR provided herein. 
     EXAMPLES 
     Non-Limiting Disclosure and Incorporation by Reference 
     While certain compounds, compositions and methods described herein have been described with specificity in accordance with certain embodiments, the following examples serve only to illustrate the compounds described herein and are not intended to limit the same. Each of the references recited in the present application is incorporated herein by reference in its entirety. 
     Example 1: Antisense Inhibition of Human Growth Hormone Receptor in Hep3B Cells by MOE Gapmers 
     Antisense oligonucleotides were designed targeting a growth hormone receptor (GHR) nucleic acid and were tested for their effects on GHR mRNA in vitro. The antisense oligonucleotides were tested in a series of experiments that had similar culture conditions. The results for each experiment are presented in separate tables shown below. Cultured Hep3B cells at a density of 20,000 cells per well were transfected using electroporation with 4,500 nM antisense oligonucleotide. After a treatment period of approximately 24 hours, RNA was isolated from the cells and GHR mRNA levels were measured by quantitative real-time PCR. Human primer probe set RTS3437_MGB (forward sequence CGAGTTCAGTGAGGTGCTCTATGT, designated herein as SEQ ID NO: 2297; reverse sequence AAGAGCCATGGAAAGTAGAAATCTTC, designated herein as SEQ ID NO: 2298; probe sequence TTCCTCAGATGAGCCAATT, designated herein as SEQ ID NO: 2299) was used to measure mRNA levels. GHR mRNA levels were adjusted according to total RNA content, as measured by RIBOGREEN®. Results are presented as percent inhibition of GHR, relative to untreated control cells. 
     The newly designed chimeric antisense oligonucleotides in the Tables below were designed as 5-10-5 MOE or 3-10-4 MOE gapmers. The 5-10-5 MOE gapmers are 20 nucleosides in length, wherein the central gap segment comprises of ten 2′-deoxynucleosides and is flanked by wing segments on the 5′ direction and the 3′ direction comprising five nucleosides each. The 3-10-4 MOE gapmers are 17 nucleosides in length, wherein the central gap segment comprises of ten 2′-deoxynucleosides and is flanked by wing segments on the 5′ direction and the 3′ direction comprising three and four nucleosides respectively. Each nucleoside in the 5′ wing segment and each nucleoside in the 3′ wing segment has a 2′-MOE modification. The internucleoside linkages throughout each gapmer are phosphorothioate (P═S) linkages. All cytosine residues throughout each gapmer are 5-methylcytosines. “Start site” indicates the 5′-most nucleoside to which the gapmer is targeted in the human gene sequence. “Stop site” indicates the 3′-most nucleoside to which the gapmer is targeted human gene sequence. Each gapmer listed in the Tables below is targeted to either the human GHR mRNA, designated herein as SEQ ID NO: 1 (GENBANK Accession No. NM_000163.4) or the human GHR genomic sequence, designated herein as SEQ ID NO: 2 (GENBANK Accession No. NT_006576.16 truncated from nucleotides 42411001 to 42714000). ‘n/a’ indicates that the antisense oligonucleotide does not target that particular gene sequence with 100% complementarity. In case the sequence alignment for a target gene in a particular table is not shown, it is understood that none of the oligonucleotides presented in that table align with 100% complementarity with that target gene. 
     
       
         
           
               
             
               
                 TABLE 1 
               
             
            
               
                   
               
               
                 Inhibition of GHR mRNA by 5-10-5 MOE gapmers targeting exonic regions of SEQ ID NO: 1 and 2 
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                   
                 SEQ 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
                 ID 
                 SEQ 
                   
                   
                   
                 SEQ 
                 SEQ 
                   
               
               
                   
                 NO: 
                 ID 
                   
                   
                   
                 ID 
                 ID 
                   
               
               
                   
                 1 
                 NO: 1 
                   
                   
                   
                 NO: 2 
                 NO: 2 
                 SEQ 
               
               
                   
                 Start 
                 Stop 
                 Target 
                   
                 % 
                 Start 
                 Stop 
                 ID 
               
               
                 ISIS NO 
                 Site 
                 Site 
                 Region 
                 Sequence 
                 inhibition 
                 Site 
                 Site 
                 NO 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                 523266 
                 164 
                 183 
                 Exon 1 
                 ACCTCCGAGCTTCGCCTCTG 
                 64 
                 3040 
                 3059 
                 20 
               
               
                   
               
               
                 523267 
                 171 
                 190 
                 Exon- 
                 CTGTAGGACCTCCGAGCTTC 
                 31 
                 n/a 
                 n/a 
                 21 
               
               
                   
                   
                   
                 exon 
                   
                   
                   
                   
                   
               
               
                   
                   
                   
                 junction 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 523268 
                 178 
                 197 
                 Exon- 
                 TCCATACCTGTAGGACCTCC 
                 37 
                 n/a 
                 n/a 
                 22 
               
               
                   
                   
                   
                 exon 
                   
                   
                   
                   
                   
               
               
                   
                   
                   
                 junction 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 523271 
                 206 
                 225 
                 Exon 2 
                 TGCCAAGGTCAACAGCAGCT 
                 80 
                 144990 
                 145009 
                 23 
               
               
                   
               
               
                 523272 
                 213 
                 232 
                 Exon 2 
                 CTGCCAGTGCCAAGGTCAAC 
                 53 
                 144997 
                 145016 
                 24 
               
               
                   
               
               
                 523273 
                 220 
                 239 
                 Exon 2 
                 CTTGATCCTGCCAGTGCCAA 
                 49 
                 145004 
                 145023 
                 25 
               
               
                   
               
               
                 523274 
                 227 
                 246 
                 Exon 2 
                 AGCATCACTTGATCCTGCCA 
                 67 
                 145011 
                 145030 
                 26 
               
               
                   
               
               
                 523275 
                 234 
                 253 
                 Exon 2 
                 CAGAAAAAGCATCACTTGAT 
                 0 
                 145018 
                 145037 
                 27 
               
               
                   
               
               
                 523276 
                 241 
                 260 
                 Exon 2 
                 TCACTTCCAGAAAAAGCATC 
                 1 
                 145025 
                 145044 
                 28 
               
               
                   
               
               
                 523284 
                 361 
                 380 
                 Exon 4 
                 GTCTCTCGCTCAGGTGAACG 
                 48 
                 268024 
                 268043 
                 29 
               
               
                   
               
               
                 523285 
                 368 
                 387 
                 Exon 4 
                 TGAAAAAGTCTCTCGCTCAG 
                 15 
                 268031 
                 268050 
                 30 
               
               
                   
               
               
                 523286 
                 375 
                 394 
                 Exon 4 
                 AGTGGCATGAAAAAGTCTCT 
                 14 
                 268038 
                 268057 
                 31 
               
               
                   
               
               
                 523287 
                 382 
                 401 
                 Exon 4 
                 TCTGTCCAGTGGCATGAAAA 
                 4 
                 268045 
                 268064 
                 32 
               
               
                   
               
               
                 523301 
                 625 
                 644 
                 Exon 6 
                 GGATCTGGTTGCACTATTTC 
                 36 
                 n/a 
                 n/a 
                 33 
               
               
                   
               
               
                 523302 
                 632 
                 651 
                 Exon 6 
                 AATGGGTGGATCTGGTTGCA 
                 28 
                 278926 
                 278945 
                 34 
               
               
                   
               
               
                 523303 
                 647 
                 666 
                 Exon 6 
                 AGTCCAGTTGAGGGCAATGG 
                 26 
                 278941 
                 278960 
                 35 
               
               
                   
               
               
                 523304 
                 654 
                 673 
                 Exon 6 
                 TCAGTAAAGTCCAGTTGAGG 
                 0 
                 278948 
                 278967 
                 36 
               
               
                   
               
               
                 523305 
                 675 
                 694 
                 Exon 6 
                 GAATCCCAGTTAAACTGACG 
                 19 
                 278969 
                 278988 
                 37 
               
               
                   
               
               
                 523306 
                 682 
                 701 
                 Exon 6 
                 TCTGCATGAATCCCAGTTAA 
                 39 
                 278976 
                 278995 
                 38 
               
               
                   
               
               
                 523309 
                 736 
                 755 
                 Exon 6 
                 ATCCATCCTTTCTGAATATC 
                 34 
                 279030 
                 279049 
                 39 
               
               
                   
               
               
                 523310 
                 743 
                 762 
                 Exon 6 
                 CAGAACCATCCATCCTTTCT 
                 31 
                 279037 
                 279056 
                 40 
               
               
                   
               
               
                 523311 
                 750 
                 769 
                 Exon 6 
                 CATACTCCAGAACCATCCAT 
                 44 
                 279044 
                 279063 
                 41 
               
               
                   
               
               
                 523312 
                 757 
                 776 
                 Exon 6 
                 TGAAGTTCATACTCCAGAAC 
                 23 
                 279051 
                 279070 
                 42 
               
               
                   
               
               
                 523313 
                 764 
                 783 
                 Exon 6 
                 TTTGTATTGAAGTTCATACT 
                 6 
                 279058 
                 279077 
                 43 
               
               
                   
               
               
                 523314 
                 771 
                 790 
                 Exon 6 
                 TTACTTCTTTGTATTGAAGT 
                 0 
                 279065 
                 279084 
                 44 
               
               
                   
               
               
                 523315 
                 778 
                 797 
                 Exon 6 
                 GTTTCATTTACTTCTTTGTA 
                 3 
                 279072 
                 279091 
                 45 
               
               
                   
               
               
                 523316 
                 785 
                 804 
                 Exon 6 
                 CCATTTAGTTTCATTTACTT 
                 0 
                 279079 
                 279098 
                 46 
               
               
                   
               
               
                 523317 
                 792 
                 811 
                 Exon 4- 
                 TCATTTTCCATTTAGTTTCA 
                 19 
                 n/a 
                 n/a 
                 47 
               
               
                   
                   
                   
                 exon 5 
                   
                   
                   
                   
                   
               
               
                   
                   
                   
                 junction 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 523323 
                 862 
                 881 
                 Exon 7 
                 ACACGCACTTCATATTCCTT 
                 63 
                 290360 
                 290379 
                 48 
               
               
                   
               
               
                 523324 
                 869 
                 888 
                 Exon 7 
                 GGATCTCACACGCACTTCAT 
                 80 
                 290367 
                 290386 
                 49 
               
               
                   
               
               
                 523328 
                 926 
                 945 
                 Exon 7 
                 AAGTGTTACATAGAGCACCT 
                 56 
                 290424 
                 290443 
                 50 
               
               
                   
               
               
                 523329 
                 933 
                 952 
                 Exon 7 
                 TCTGAGGAAGTGTTACATAG 
                 53 
                 290431 
                 290450 
                 51 
               
               
                   
               
               
                 523330 
                 957 
                 976 
                 Exon 7 
                 CTTCTTCACATGTAAATTGG 
                 32 
                 290455 
                 290474 
                 52 
               
               
                   
               
               
                 523331 
                 964 
                 983 
                 Exon 5- 
                 TAGAAATCTTCTTCACATGT 
                 4 
                 n/a 
                 n/a 
                 53 
               
               
                   
                   
                   
                 exon 6 
                   
                   
                   
                   
                   
               
               
                   
                   
                   
                 junction 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 523332 
                 971 
                 990 
                 Exon 5- 
                 TGGAAAGTAGAAATCTTCTT 
                 9 
                 n/a 
                 n/a 
                 54 
               
               
                   
                   
                   
                 exon 6 
                   
                   
                   
                   
                   
               
               
                   
                   
                   
                 junction 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 523333 
                 978 
                 997 
                 Exon 8 
                 AGAGCCATGGAAAGTAGAAA 
                 46 
                 292532 
                 292551 
                 55 
               
               
                   
               
               
                 523334 
                 985 
                 1004 
                 Exon 8 
                 ATAATTAAGAGCCATGGAAA 
                 0 
                 292539 
                 292558 
                 56 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 2 
               
             
            
               
                   
               
               
                 Inhibition of GHR mRNA by 5-10-5 MOE gapmers targeting exonic regions of SEQ ID NO: 1 and 2 
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                   
                 SEQ 
                 SEQ 
                   
                   
                   
                   
                   
                   
               
               
                   
                 ID 
                 ID 
                   
                   
                   
                   
                   
                   
               
               
                   
                 NO: 
                 NO: 
                   
                   
                   
                 SEQ ID 
                 SEQ ID 
                   
               
               
                   
                 1 
                 1 
                   
                   
                   
                 NO: 2 
                 NO: 2 
                 SEQ 
               
               
                 ISIS 
                 Start 
                 Stop 
                 Target 
                   
                 % 
                 Start 
                 Stop 
                 ID 
               
               
                 NO 
                 Site 
                 Site 
                 Region 
                 Sequence 
                 inhibition 
                 Site 
                 Site 
                 NO 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                 523421 
                 2072 
                 2091 
                 exon 10 
                 CAGTTGGTCTGTGCTCACAT 
                 76 
                 298489 
                 298508 
                 57 
               
               
                   
               
               
                 533002 
                 207 
                 226 
                 exon 2 
                 GTGCCAAGGTCAACAGCAGC 
                 63 
                 144991 
                 145010 
                 58 
               
               
                   
               
               
                 533003 
                 208 
                 227 
                 exon 2 
                 AGTGCCAAGGTCAACAGCAG 
                 62 
                 144992 
                 145011 
                 59 
               
               
                   
               
               
                 533004 
                 225 
                 244 
                 exon 2 
                 CATCACTTGATCCTGCCAGT 
                 53 
                 145009 
                 145028 
                 60 
               
               
                   
               
               
                 533005 
                 226 
                 245 
                 exon 2 
                 GCATCACTTGATCCTGCCAG 
                 80 
                 145010 
                 145029 
                 61 
               
               
                   
               
               
                 533006 
                 228 
                 247 
                 exon 2 
                 AAGCATCACTTGATCCTGCC 
                 75 
                 145012 
                 145031 
                 62 
               
               
                   
               
               
                 533007 
                 229 
                 248 
                 exon 2 
                 AAAGCATCACTTGATCCTGC 
                 61 
                 145013 
                 145032 
                 63 
               
               
                   
               
               
                 533019 
                 867 
                 886 
                 exon 7 
                 ATCTCACACGCACTTCATAT 
                 35 
                 290365 
                 290384 
                 64 
               
               
                   
               
               
                 533020 
                 868 
                 887 
                 exon 7 
                 GATCTCACACGCACTTCATA 
                 47 
                 290366 
                 290385 
                 65 
               
               
                   
               
               
                 533021 
                 870 
                 889 
                 exon 7 
                 TGGATCTCACACGCACTTCA 
                 86 
                 290368 
                 290387 
                 66 
               
               
                   
               
               
                 533022 
                 871 
                 890 
                 exon 7 
                 TTGGATCTCACACGCACTTC 
                 70 
                 290369 
                 290388 
                 67 
               
               
                   
               
               
                 533037 
                 1360 
                 1379 
                 exon 10 
                 TCCAGAATGTCAGGTTCACA 
                 59 
                 297777 
                 297796 
                 68 
               
               
                   
               
               
                 533038 
                 1361 
                 1380 
                 exon 10 
                 CTCCAGAATGTCAGGTTCAC 
                 74 
                 297778 
                 297797 
                 69 
               
               
                   
               
               
                 533039 
                 1363 
                 1382 
                 exon 10 
                 GTCTCCAGAATGTCAGGTTC 
                 45 
                 297780 
                 297799 
                 70 
               
               
                   
               
               
                 533040 
                 1364 
                 1383 
                 exon 10 
                 AGTCTCCAGAATGTCAGGTT 
                 51 
                 297781 
                 297800 
                 71 
               
               
                   
               
               
                 533042 
                 1525 
                 1544 
                 exon 10 
                 GCTTGGATAACACTGGGCTG 
                 41 
                 297942 
                 297961 
                 72 
               
               
                   
               
               
                 533043 
                 1526 
                 1545 
                 exon 10 
                 TGCTTGGATAACACTGGGCT 
                 46 
                 297943 
                 297962 
                 73 
               
               
                   
               
               
                 533044 
                 1528 
                 1547 
                 exon 10 
                 TCTGCTTGGATAACACTGGG 
                 55 
                 297945 
                 297964 
                 74 
               
               
                   
               
               
                 533045 
                 1529 
                 1548 
                 exon 10 
                 CTCTGCTTGGATAACACTGG 
                 47 
                 297946 
                 297965 
                 75 
               
               
                   
               
               
                 533046 
                 1530 
                 1549 
                 exon 10 
                 TCTCTGCTTGGATAACACTG 
                 54 
                 297947 
                 297966 
                 76 
               
               
                   
               
               
                 533047 
                 1744 
                 1763 
                 exon 10 
                 CAGAGTGAGACCATTTCCGG 
                 47 
                 298161 
                 298180 
                 77 
               
               
                   
               
               
                 533048 
                 1745 
                 1764 
                 exon 10 
                 GCAGAGTGAGACCATTTCCG 
                 60 
                 298162 
                 298181 
                 78 
               
               
                   
               
               
                 533049 
                 1747 
                 1766 
                 exon 10 
                 TGGCAGAGTGAGACCATTTC 
                 65 
                 298164 
                 298183 
                 79 
               
               
                   
               
               
                 533050 
                 1748 
                 1767 
                 exon 10 
                 TTGGCAGAGTGAGACCATTT 
                 47 
                 298165 
                 298184 
                 80 
               
               
                   
               
               
                 533051 
                 1749 
                 1768 
                 exon 10 
                 CTTGGCAGAGTGAGACCATT 
                 30 
                 298166 
                 298185 
                 81 
               
               
                   
               
               
                 533066 
                 2685 
                 2704 
                 exon 10 
                 CAGTGTGTAGTGTAATATAA 
                 53 
                 299102 
                 299121 
                 82 
               
               
                   
               
               
                 533067 
                 2686 
                 2705 
                 exon 10 
                 ACAGTGTGTAGTGTAATATA 
                 68 
                 299103 
                 299122 
                 83 
               
               
                   
               
               
                 533068 
                 2688 
                 2707 
                 exon 10 
                 ACACAGTGTGTAGTGTAATA 
                 62 
                 299105 
                 299124 
                 84 
               
               
                   
               
               
                 533069 
                 2689 
                 2708 
                 exon 10 
                 TACACAGTGTGTAGTGTAAT 
                 55 
                 299106 
                 299125 
                 85 
               
               
                   
               
               
                 533070 
                 2690 
                 2709 
                 exon 10 
                 GTACACAGTGTGTAGTGTAA 
                 50 
                 299107 
                 299126 
                 86 
               
               
                   
               
               
                 533071 
                 3205 
                 3224 
                 exon 10 
                 TGTACCTTATTCCCTTCCTG 
                 68 
                 299622 
                 299641 
                 87 
               
               
                   
               
               
                 533072 
                 3206 
                 3225 
                 exon 10 
                 TTGTACCTTATTCCCTTCCT 
                 61 
                 299623 
                 299642 
                 88 
               
               
                   
               
               
                 533073 
                 3208 
                 3227 
                 exon 10 
                 TCTTGTACCTTATTCCCTTC 
                 60 
                 299625 
                 299644 
                 89 
               
               
                   
               
               
                 533074 
                 3209 
                 3228 
                 exon 10 
                 TTCTTGTACCTTATTCCCTT 
                 46 
                 299626 
                 299645 
                 90 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 3 
               
             
            
               
                   
               
               
                 Inhibition of GHR mRNA by 5-10-5 MOE gapmers targeting intronic and exonic regions of SEQ ID NO: 1 
               
               
                 and 2 
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                   
                 SEQ 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
                 ID 
                 SEQ 
                   
                   
                   
                 SEQ 
                 SEQ 
                   
               
               
                   
                 NO: 
                 ID 
                   
                   
                   
                 ID 
                 ID 
                   
               
               
                   
                 1 
                 NO: 1 
                   
                   
                   
                 NO: 2 
                 NO: 2 
                   
               
               
                 ISIS 
                 Start 
                 Stop 
                 Target 
                   
                 % 
                 Start 
                 Stop 
                 SEQ 
               
               
                 NO 
                 Site 
                 Site 
                 Region 
                 Sequence 
                 inhibition 
                 Site 
                 Site 
                 ID NO 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                 532174 
                 n/a 
                 n/a 
                 Intron 1 
                 ACATGTACCCAAACCAACAC 
                 37 
                 18731 
                 18750 
                 91 
               
               
                   
               
               
                 533086 
                 3210 
                 3229 
                 Exon 10 
                 CTTCTTGTACCTTATTCCCT 
                 72 
                 299627 
                 299646 
                 92 
               
               
                   
               
               
                 533087 
                 3212 
                 3231 
                 Exon 10 
                 TGCTTCTTGTACCTTATTCC 
                 77 
                 299629 
                 299648 
                 93 
               
               
                   
               
               
                 533088 
                 3213 
                 3232 
                 Exon 10 
                 ATGCTTCTTGTACCTTATTC 
                 63 
                 299630 
                 299649 
                 94 
               
               
                   
               
               
                 533089 
                 3215 
                 3234 
                 Exon 10 
                 AAATGCTTCTTGTACCTTAT 
                 67 
                 299632 
                 299651 
                 95 
               
               
                   
               
               
                 533090 
                 3216 
                 3235 
                 Exon 10 
                 AAAATGCTTCTTGTACCTTA 
                 50 
                 299633 
                 299652 
                 96 
               
               
                   
               
               
                 533091 
                 3217 
                 3236 
                 Exon 10 
                 CAAAATGCTTCTTGTACCTT 
                 44 
                 299634 
                 299653 
                 97 
               
               
                   
               
               
                 533092 
                 3518 
                 3537 
                 Exon 10 
                 CTTCTGAATGCTTGCTTTGA 
                 29 
                 299935 
                 299954 
                 98 
               
               
                   
               
               
                 533093 
                 3519 
                 3538 
                 Exon 10 
                 TCTTCTGAATGCTTGCTTTG 
                 47 
                 299936 
                 299955 
                 99 
               
               
                   
               
               
                 533094 
                 3521 
                 3540 
                 Exon 10 
                 TTTCTTCTGAATGCTTGCTT 
                 63 
                 299938 
                 299957 
                 100 
               
               
                   
               
               
                 533095 
                 3522 
                 3541 
                 Exon 10 
                 TTTTCTTCTGAATGCTTGCT 
                 51 
                 299939 
                 299958 
                 101 
               
               
                   
               
               
                 533096 
                 3523 
                 3542 
                 Exon 10 
                 TTTTTCTTCTGAATGCTTGC 
                 34 
                 299940 
                 299959 
                 102 
               
               
                   
               
               
                 533097 
                 4041 
                 4060 
                 Exon 10 
                 TGCGATAAATGGGAAATACT 
                 36 
                 300458 
                 300477 
                 103 
               
               
                   
               
               
                 533098 
                 4042 
                 4061 
                 Exon 10 
                 CTGCGATAAATGGGAAATAC 
                 52 
                 300459 
                 300478 
                 104 
               
               
                   
               
               
                 533099 
                 4043 
                 4062 
                 Exon 10 
                 TCTGCGATAAATGGGAAATA 
                 41 
                 300460 
                 300479 
                 105 
               
               
                   
               
               
                 533100 
                 4045 
                 4064 
                 Exon 10 
                 GGTCTGCGATAAATGGGAAA 
                 40 
                 300462 
                 300481 
                 106 
               
               
                   
               
               
                 533101 
                 4046 
                 4065 
                 Exon 10 
                 AGGTCTGCGATAAATGGGAA 
                 39 
                 300463 
                 300482 
                 107 
               
               
                   
               
               
                 533102 
                 4048 
                 4067 
                 Exon 10 
                 AAAGGTCTGCGATAAATGGG 
                 34 
                 300465 
                 300484 
                 108 
               
               
                   
               
               
                 533103 
                 4049 
                 4068 
                 Exon 10 
                 AAAAGGTCTGCGATAAATGG 
                 35 
                 300466 
                 300485 
                 109 
               
               
                   
               
               
                 533104 
                 4050 
                 4069 
                 Exon 10 
                 AAAAAGGTCTGCGATAAATG 
                 15 
                 300467 
                 300486 
                 110 
               
               
                   
               
               
                 533115 
                 n/a 
                 n/a 
                 Intron 1 
                 CATGAAGGCCACTCTTCCAA 
                 63 
                 12777 
                 12796 
                 111 
               
               
                   
               
               
                 533116 
                 n/a 
                 n/a 
                 Intron 1 
                 CCATGAAGGCCACTCTTCCA 
                 78 
                 12778 
                 12797 
                 112 
               
               
                   
               
               
                 533117 
                 n/a 
                 n/a 
                 Intron 1 
                 CCCATGAAGGCCACTCTTCC 
                 71 
                 12779 
                 12798 
                 113 
               
               
                   
               
               
                 533118 
                 n/a 
                 n/a 
                 Intron 1 
                 TGCCCATGAAGGCCACTCTT 
                 66 
                 12781 
                 12800 
                 114 
               
               
                   
               
               
                 533119 
                 n/a 
                 n/a 
                 Intron 1 
                 TTGCCCATGAAGGCCACTCT 
                 60 
                 12782 
                 12801 
                 115 
               
               
                   
               
               
                 533120 
                 n/a 
                 n/a 
                 Intron 1 
                 GTTGCCCATGAAGGCCACTC 
                 74 
                 12783 
                 12802 
                 116 
               
               
                   
               
               
                 533121 
                 n/a 
                 n/a 
                 Intron 1 
                 GGTCTTTCATGAATCAAGCT 
                 79 
                 17927 
                 17946 
                 117 
               
               
                   
               
               
                 533122 
                 n/a 
                 n/a 
                 Intron 1 
                 TGGTCTTTCATGAATCAAGC 
                 83 
                 17928 
                 17947 
                 118 
               
               
                   
               
               
                 533123 
                 n/a 
                 n/a 
                 Intron 1 
                 ATGGTCTTTCATGAATCAAG 
                 83 
                 17929 
                 17948 
                 119 
               
               
                   
               
               
                 533124 
                 n/a 
                 n/a 
                 Intron 1 
                 TGATGGTCTTTCATGAATCA 
                 78 
                 17931 
                 17950 
                 120 
               
               
                   
               
               
                 533125 
                 n/a 
                 n/a 
                 Intron 1 
                 CTGATGGTCTTTCATGAATC 
                 82 
                 17932 
                 17951 
                 121 
               
               
                   
               
               
                 533126 
                 n/a 
                 n/a 
                 Intron 1 
                 GCTGATGGTCTTTCATGAAT 
                 74 
                 17933 
                 17952 
                 122 
               
               
                   
               
               
                 533127 
                 n/a 
                 n/a 
                 Intron 1 
                 GTACCCAAACCAACACTAAT 
                 57 
                 18727 
                 18746 
                 123 
               
               
                   
               
               
                 533128 
                 n/a 
                 n/a 
                 Intron 1 
                 TGTACCCAAACCAACACTAA 
                 65 
                 18728 
                 18747 
                 124 
               
               
                   
               
               
                 533129 
                 n/a 
                 n/a 
                 Intron 1 
                 ATGTACCCAAACCAACACTA 
                 64 
                 18729 
                 18748 
                 125 
               
               
                   
               
               
                 533130 
                 n/a 
                 n/a 
                 Intron 1 
                 GACATGTACCCAAACCAACA 
                 63 
                 18732 
                 18751 
                 126 
               
               
                   
               
               
                 533131 
                 n/a 
                 n/a 
                 Intron 1 
                 AGACATGTACCCAAACCAAC 
                 81 
                 18733 
                 18752 
                 127 
               
               
                   
               
               
                 533132 
                 n/a 
                 n/a 
                 Intron 1 
                 AGGAATGGAAAACCAAATAT 
                 49 
                 26494 
                 26513 
                 128 
               
               
                   
               
               
                 533133 
                 n/a 
                 n/a 
                 Intron 1 
                 CAGGAATGGAAAACCAAATA 
                 74 
                 26495 
                 26514 
                 129 
               
               
                   
                   
                   
                   
                   
                   
                 121986 
                 122005 
                   
               
               
                   
               
               
                 533134 
                 n/a 
                 n/a 
                 Intron 1 
                 TCAGGAATGGAAAACCAAAT 
                 73 
                 26496 
                 26515 
                 130 
               
               
                   
                   
                   
                   
                   
                   
                 121987 
                 122006 
                   
               
               
                   
               
               
                 533135 
                 n/a 
                 n/a 
                 Intron 1 
                 ACTCAGGAATGGAAAACCAA 
                 77 
                 26498 
                 26517 
                 131 
               
               
                   
                   
                   
                   
                   
                   
                 113032 
                 113051 
                   
               
               
                   
                   
                   
                   
                   
                   
                 121989 
                 122008 
                   
               
               
                   
               
               
                 533136 
                 n/a 
                 n/a 
                 Intron 1 
                 AACTCAGGAATGGAAAACCA 
                 79 
                 26499 
                 26518 
                 132 
               
               
                   
                   
                   
                   
                   
                   
                 113033 
                 113052 
                   
               
               
                   
                   
                   
                   
                   
                   
                 121990 
                 122009 
                   
               
               
                   
               
               
                 533137 
                 n/a 
                 n/a 
                 Intron 1 
                 TAACTCAGGAATGGAAAACC 
                 67 
                 26500 
                 26519 
                 133 
               
               
                   
                   
                   
                   
                   
                   
                 113034 
                 113053 
                   
               
               
                   
                   
                   
                   
                   
                   
                 121991 
                 122010 
                   
               
               
                   
               
               
                 533138 
                 n/a 
                 n/a 
                 Intron 1 
                 CAAAATTACTGCAGTCACAG 
                 67 
                 39716 
                 39735 
                 134 
               
               
                   
               
               
                 533139 
                 n/a 
                 n/a 
                 Intron 1 
                 ACAAAATTACTGCAGTCACA 
                 81 
                 39717 
                 39736 
                 135 
               
               
                   
               
               
                 533140 
                 n/a 
                 n/a 
                 Intron 1 
                 TACAAAATTACTGCAGTCAC 
                 81 
                 39718 
                 39737 
                 136 
               
               
                   
               
               
                 533141 
                 n/a 
                 n/a 
                 Intron 1 
                 CATACAAAATTACTGCAGTC 
                 67 
                 39720 
                 39739 
                 137 
               
               
                   
               
               
                 533142 
                 n/a 
                 n/a 
                 Intron 1 
                 ACATACAAAATTACTGCAGT 
                 48 
                 39721 
                 39740 
                 138 
               
               
                   
               
               
                 533143 
                 n/a 
                 n/a 
                 Intron 1 
                 AACATACAAAATTACTGCAG 
                 53 
                 39722 
                 39741 
                 139 
               
               
                   
               
               
                 533144 
                 n/a 
                 n/a 
                 Intron 1 
                 TTTTAGTATGAACCTTAAAA 
                 0 
                 42139 
                 42158 
                 140 
               
               
                   
               
               
                 533145 
                 n/a 
                 n/a 
                 Intron 1 
                 CTTTTAGTATGAACCTTAAA 
                 38 
                 42140 
                 42159 
                 141 
               
               
                   
               
               
                 533146 
                 n/a 
                 n/a 
                 Intron 1 
                 TCTTTTAGTATGAACCTTAA 
                 57 
                 42141 
                 42160 
                 142 
               
               
                   
               
               
                 533147 
                 n/a 
                 n/a 
                 Intron 1 
                 AATCTTTTAGTATGAACCTT 
                 60 
                 42143 
                 42162 
                 143 
               
               
                   
               
               
                 533148 
                 n/a 
                 n/a 
                 Intron 1 
                 CAATCTTTTAGTATGAACCT 
                 70 
                 42144 
                 42163 
                 144 
               
               
                   
               
               
                 533149 
                 n/a 
                 n/a 
                 Intron 1 
                 ACAATCTTTTAGTATGAACC 
                 60 
                 42145 
                 42164 
                 145 
               
               
                   
               
               
                 533150 
                 n/a 
                 n/a 
                 Intron 1 
                 AAGTTATGTGACTCTGAGCA 
                 67 
                 43174 
                 43193 
                 146 
               
               
                   
               
               
                 533151 
                 n/a 
                 n/a 
                 Intron 1 
                 CAAGTTATGTGACTCTGAGC 
                 67 
                 43175 
                 43194 
                 147 
               
               
                   
               
               
                 533152 
                 n/a 
                 n/a 
                 Intron 1 
                 TCAAGTTATGTGACTCTGAG 
                 63 
                 43176 
                 43195 
                 148 
               
               
                   
               
               
                 533153 
                 n/a 
                 n/a 
                 Intron 1 
                 AGTTCTCCATTAGGGTTCTG 
                 83 
                 50948 
                 50967 
                 149 
               
               
                   
               
               
                 533154 
                 n/a 
                 n/a 
                 Intron 1 
                 TAGTTCTCCATTAGGGTTCT 
                 76 
                 50949 
                 50968 
                 150 
               
               
                   
               
               
                 533155 
                 n/a 
                 n/a 
                 Intron 1 
                 ATAGTTCTCCATTAGGGTTC 
                 51 
                 50950 
                 50969 
                 151 
               
               
                   
               
               
                 533156 
                 n/a 
                 n/a 
                 Intron 1 
                 AAGCAGGTTGGCAGACAGAC 
                 79 
                 53467 
                 53486 
                 152 
               
               
                   
               
               
                 533157 
                 n/a 
                 n/a 
                 Intron 1 
                 GAAGCAGGTTGGCAGACAGA 
                 60 
                 53468 
                 53487 
                 153 
               
               
                   
               
               
                 533158 
                 n/a 
                 n/a 
                 Intron 1 
                 GGAAGCAGGTTGGCAGACAG 
                 67 
                 53469 
                 53488 
                 154 
               
               
                   
               
               
                 533159 
                 n/a 
                 n/a 
                 Intron 1 
                 TCTTCTTGTGAGCTGGCTTC 
                 61 
                 64882 
                 64901 
                 155 
               
               
                   
               
               
                 533160 
                 n/a 
                 n/a 
                 Intron 1 
                 GTCTTCTTGTGAGCTGGCTT 
                 83 
                 64883 
                 64902 
                 156 
               
               
                   
               
               
                 533161 
                 n/a 
                 n/a 
                 Intron 1 
                 AGTCTTCTTGTGAGCTGGCT 
                 81 
                 64884 
                 64903 
                 157 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 4 
               
             
            
               
                   
               
               
                 Inhibition of GHR mRNA by 5-10-5 MOE gapmers targeting intronic and exonic regions of SEQ ID NO: 1 
               
               
                 and 2 
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                   
                 SEQ 
                 SEQ 
                   
                   
                   
                   
                   
                   
               
               
                   
                 ID 
                 ID 
                   
                   
                   
                   
                 SEQ 
                   
               
               
                   
                 NO: 
                 NO: 
                   
                   
                   
                   
                 ID 
                   
               
               
                   
                 1 
                 1 
                   
                   
                   
                 SEQ ID 
                 NO: 2 
                 SEQ 
               
               
                 ISIS 
                 Start 
                 Stop 
                 Target 
                   
                 % 
                 NO: 2 
                 Stop 
                 ID 
               
               
                 NO 
                 Site 
                 Site 
                 Region 
                 Sequence 
                 inhibition 
                 Start Site 
                 Site 
                 NO 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                 533133 
                 n/a 
                 n/a 
                 Intron 1 
                 CAGGAATGGAAAACCAAATA 
                 76 
                 26495 
                 26514 
                 129 
               
               
                   
                   
                   
                   
                   
                   
                 121986 
                 122005 
                   
               
               
                   
               
               
                 533134 
                 n/a 
                 n/a 
                 Intron 1 
                 TCAGGAATGGAAAACCAAAT 
                 83 
                 26496 
                 26515 
                 130 
               
               
                   
                   
                   
                   
                   
                   
                 121987 
                 122006 
                   
               
               
                   
               
               
                 533174 
                 n/a 
                 n/a 
                 Intron 1 
                 TAAGTCTTCTTGTGAGCTGG 
                 73 
                 64886 
                 64905 
                 158 
               
               
                   
               
               
                 533175 
                 n/a 
                 n/a 
                 Intron 1 
                 TTAAGTCTTCTTGTGAGCTG 
                 58 
                 64887 
                 64906 
                 159 
               
               
                   
               
               
                 533176 
                 n/a 
                 n/a 
                 Intron 1 
                 ATTAAGTCTTCTTGTGAGCT 
                 51 
                 64888 
                 64907 
                 160 
               
               
                   
               
               
                 533177 
                 n/a 
                 n/a 
                 Intron 1 
                 TCTCTTCCACTCACATCCAT 
                 72 
                 65989 
                 66008 
                 161 
               
               
                   
               
               
                 533178 
                 n/a 
                 n/a 
                 Intron 1 
                 GTCTCTTCCACTCACATCCA 
                 86 
                 65990 
                 66009 
                 162 
               
               
                   
               
               
                 533179 
                 n/a 
                 n/a 
                 Intron 1 
                 AGTCTCTTCCACTCACATCC 
                 80 
                 65991 
                 66010 
                 163 
               
               
                   
               
               
                 533180 
                 n/a 
                 n/a 
                 Intron 1 
                 TAAGTATTTGTAGCAGTTGC 
                 31 
                 78195 
                 78214 
                 164 
               
               
                   
               
               
                 533181 
                 n/a 
                 n/a 
                 Intron 1 
                 CTAAGTATTTGTAGCAGTTG 
                 14 
                 78196 
                 78215 
                 165 
               
               
                   
               
               
                 533182 
                 n/a 
                 n/a 
                 Intron 1 
                 GCTAAGTATTTGTAGCAGTT 
                 59 
                 78197 
                 78216 
                 166 
               
               
                   
               
               
                 533183 
                 n/a 
                 n/a 
                 Intron 1 
                 TGGCTAAGTATTTGTAGCAG 
                 34 
                 78199 
                 78218 
                 167 
               
               
                   
               
               
                 533184 
                 n/a 
                 n/a 
                 Intron 1 
                 TTGGCTAAGTATTTGTAGCA 
                 18 
                 78200 
                 78219 
                 168 
               
               
                   
               
               
                 533185 
                 n/a 
                 n/a 
                 Intron 1 
                 TTTGGCTAAGTATTTGTAGC 
                 21 
                 78201 
                 78220 
                 169 
               
               
                   
               
               
                 533186 
                 n/a 
                 n/a 
                 Intron 1 
                 AAAATGTCAACAGTGCATAG 
                 61 
                 80636 
                 80655 
                 170 
               
               
                   
               
               
                 533187 
                 n/a 
                 n/a 
                 Intron 1 
                 CAAAATGTCAACAGTGCATA 
                 78 
                 80637 
                 80656 
                 171 
               
               
                   
               
               
                 533188 
                 n/a 
                 n/a 
                 Intron 1 
                 CCAAAATGTCAACAGTGCAT 
                 85 
                 80638 
                 80657 
                 172 
               
               
                   
               
               
                 533189 
                 n/a 
                 n/a 
                 Intron 1 
                 GCCCAAAATGTCAACAGTGC 
                 82 
                 80640 
                 80659 
                 173 
               
               
                   
               
               
                 533190 
                 n/a 
                 n/a 
                 Intron 1 
                 GGCCCAAAATGTCAACAGTG 
                 60 
                 80641 
                 80660 
                 174 
               
               
                   
               
               
                 533191 
                 n/a 
                 n/a 
                 Intron 1 
                 TGGCCCAAAATGTCAACAGT 
                 31 
                 80642 
                 80661 
                 175 
               
               
                   
               
               
                 533192 
                 n/a 
                 n/a 
                 Intron 1 
                 CAGAATCTTCTCTTTGGCCA 
                 66 
                 98624 
                 98643 
                 176 
               
               
                   
               
               
                 533193 
                 n/a 
                 n/a 
                 Intron 1 
                 GCAGAATCTTCTCTTTGGCC 
                 81 
                 98625 
                 98644 
                 177 
               
               
                   
               
               
                 533194 
                 n/a 
                 n/a 
                 Intron 1 
                 TGCAGAATCTTCTCTTTGGC 
                 72 
                 98626 
                 98645 
                 178 
               
               
                   
               
               
                 533195 
                 n/a 
                 n/a 
                 Intron 1 
                 TTTGCAGAATCTTCTCTTTG 
                 33 
                 98628 
                 98647 
                 179 
               
               
                   
               
               
                 533196 
                 n/a 
                 n/a 
                 Intron 1 
                 ATTTGCAGAATCTTCTCTTT 
                 27 
                 98629 
                 98648 
                 180 
               
               
                   
               
               
                 533197 
                 n/a 
                 n/a 
                 Intron 1 
                 AATTTGCAGAATCTTCTCTT 
                 38 
                 98630 
                 98649 
                 181 
               
               
                   
               
               
                 533198 
                 n/a 
                 n/a 
                 Intron 1 
                 ATAAAGCTATGCCATAAAGC 
                 37 
                 99478 
                 99497 
                 182 
               
               
                   
               
               
                 533199 
                 n/a 
                 n/a 
                 Intron 1 
                 CATAAAGCTATGCCATAAAG 
                 14 
                 99479 
                 99498 
                 183 
               
               
                   
               
               
                 533200 
                 n/a 
                 n/a 
                 Intron 1 
                 CCATAAAGCTATGCCATAAA 
                 30 
                 99480 
                 99499 
                 184 
               
               
                   
               
               
                 533201 
                 n/a 
                 n/a 
                 Intron 1 
                 GACCATAAAGCTATGCCATA 
                 54 
                 99482 
                 99501 
                 185 
               
               
                   
               
               
                 533202 
                 n/a 
                 n/a 
                 Intron 1 
                 TGACCATAAAGCTATGCCAT 
                 64 
                 99483 
                 99502 
                 186 
               
               
                   
               
               
                 533203 
                 n/a 
                 n/a 
                 Intron 1 
                 CTGACCATAAAGCTATGCCA 
                 61 
                 99484 
                 99503 
                 187 
               
               
                   
               
               
                 533204 
                 n/a 
                 n/a 
                 Intron 1 
                 CAAAAAGTTGAGCTGAGAAA 
                 0 
                 101078 
                 101097 
                 188 
               
               
                   
               
               
                 533205 
                 n/a 
                 n/a 
                 Intron 1 
                 CCAAAAAGTTGAGCTGAGAA 
                 28 
                 101079 
                 101098 
                 189 
               
               
                   
               
               
                 533206 
                 n/a 
                 n/a 
                 Intron 1 
                 CCCAAAAAGTTGAGCTGAGA 
                 52 
                 101080 
                 101099 
                 190 
               
               
                   
               
               
                 533207 
                 n/a 
                 n/a 
                 Intron 1 
                 CACCCAAAAAGTTGAGCTGA 
                 60 
                 101082 
                 101101 
                 191 
               
               
                   
               
               
                 533208 
                 n/a 
                 n/a 
                 Intron 1 
                 ACACCCAAAAAGTTGAGCTG 
                 34 
                 101083 
                 101102 
                 192 
               
               
                   
               
               
                 533209 
                 n/a 
                 n/a 
                 Intron 1 
                 TACACCCAAAAAGTTGAGCT 
                 36 
                 101084 
                 101103 
                 193 
               
               
                   
               
               
                 533210 
                 n/a 
                 n/a 
                 Intron 1 
                 CTTTTAATGGCACCCAAGCA 
                 41 
                 103566 
                 103585 
                 194 
               
               
                   
               
               
                 533211 
                 n/a 
                 n/a 
                 Intron 1 
                 GCTTTTAATGGCACCCAAGC 
                 54 
                 103567 
                 103586 
                 195 
               
               
                   
               
               
                 533212 
                 n/a 
                 n/a 
                 Intron 1 
                 TGCTTTTAATGGCACCCAAG 
                 67 
                 103568 
                 103587 
                 196 
               
               
                   
               
               
                 533213 
                 n/a 
                 n/a 
                 Intron 1 
                 AATGCTTTTAATGGCACCCA 
                 73 
                 103570 
                 103589 
                 197 
               
               
                   
               
               
                 533214 
                 n/a 
                 n/a 
                 Intron 1 
                 AAATGCTTTTAATGGCACCC 
                 73 
                 103571 
                 103590 
                 198 
               
               
                   
               
               
                 533215 
                 n/a 
                 n/a 
                 Intron 1 
                 GAAATGCTTTTAATGGCACC 
                 41 
                 103572 
                 103591 
                 199 
               
               
                   
               
               
                 533216 
                 n/a 
                 n/a 
                 Intron 1 
                 TAATTCTTAAGGGCCCTCTG 
                 36 
                 106963 
                 106982 
                 200 
               
               
                   
               
               
                 533217 
                 n/a 
                 n/a 
                 Intron 1 
                 ATAATTCTTAAGGGCCCTCT 
                 45 
                 106964 
                 106983 
                 201 
               
               
                   
               
               
                 533218 
                 n/a 
                 n/a 
                 Intron 1 
                 CATAATTCTTAAGGGCCCTC 
                 50 
                 106965 
                 106984 
                 202 
               
               
                   
               
               
                 533219 
                 n/a 
                 n/a 
                 Intron 1 
                 AGCATAATTCTTAAGGGCCC 
                 48 
                 106967 
                 106986 
                 203 
               
               
                   
               
               
                 533220 
                 n/a 
                 n/a 
                 Intron 1 
                 TAGCATAATTCTTAAGGGCC 
                 52 
                 106968 
                 106987 
                 204 
               
               
                   
               
               
                 533221 
                 n/a 
                 n/a 
                 Intron 1 
                 TTAGCATAATTCTTAAGGGC 
                 28 
                 106969 
                 106988 
                 205 
               
               
                   
               
               
                 533222 
                 n/a 
                 n/a 
                 Intron 1 
                 AGGAATGGAAAACCAAACAT 
                 13 
                 113028 
                 113047 
                 206 
               
               
                   
               
               
                 533223 
                 n/a 
                 n/a 
                 Intron 1 
                 CAGGAATGGAAAACCAAACA 
                 64 
                 113029 
                 113048 
                 207 
               
               
                   
               
               
                 533224 
                 n/a 
                 n/a 
                 Intron 1 
                 TCAGGAATGGAAAACCAAAC 
                 61 
                 113030 
                 113049 
                 208 
               
               
                   
               
               
                 533225 
                 n/a 
                 n/a 
                 Intron 1 
                 AGGAATGGAAAACCAAATAC 
                 18 
                 121985 
                 122004 
                 209 
               
               
                   
               
               
                 533226 
                 n/a 
                 n/a 
                 Intron 1 
                 CATGACTATGTTCTGGCAAG 
                 37 
                 125591 
                 125610 
                 210 
               
               
                   
               
               
                 533227 
                 n/a 
                 n/a 
                 Intron 1 
                 ACATGACTATGTTCTGGCAA 
                 44 
                 125592 
                 125611 
                 211 
               
               
                   
               
               
                 533228 
                 n/a 
                 n/a 
                 Intron 1 
                 CACATGACTATGTTCTGGCA 
                 63 
                 125593 
                 125612 
                 212 
               
               
                   
               
               
                 533229 
                 n/a 
                 n/a 
                 Intron 1 
                 GTCACATGACTATGTTCTGG 
                 47 
                 125595 
                 125614 
                 213 
               
               
                   
               
               
                 533230 
                 n/a 
                 n/a 
                 Intron 1 
                 GGTCACATGACTATGTTCTG 
                 49 
                 125596 
                 125615 
                 214 
               
               
                   
               
               
                 533231 
                 n/a 
                 n/a 
                 Intron 1 
                 TGGTCACATGACTATGTTCT 
                 30 
                 125597 
                 125616 
                 215 
               
               
                   
               
               
                 533232 
                 n/a 
                 n/a 
                 Intron 2 
                 CTGAATTCTGAGCTCTGGAA 
                 73 
                 145428 
                 145447 
                 216 
               
               
                   
               
               
                 533233 
                 n/a 
                 n/a 
                 Intron 2 
                 CCTGAATTCTGAGCTCTGGA 
                 88 
                 145429 
                 145448 
                 217 
               
               
                   
               
               
                 533234 
                 n/a 
                 n/a 
                 Intron 2 
                 GCCTGAATTCTGAGCTCTGG 
                 92 
                 145430 
                 145449 
                 218 
               
               
                   
               
               
                 533235 
                 n/a 
                 n/a 
                 Intron 2 
                 AAGCCTGAATTCTGAGCTCT 
                 83 
                 145432 
                 145451 
                 219 
               
               
                   
               
               
                 533236 
                 n/a 
                 n/a 
                 Intron 2 
                 CAAGCCTGAATTCTGAGCTC 
                 68 
                 145433 
                 145452 
                 220 
               
               
                   
               
               
                 533237 
                 n/a 
                 n/a 
                 Intron 2 
                 ACAAGCCTGAATTCTGAGCT 
                 81 
                 145434 
                 145453 
                 221 
               
               
                   
               
               
                 533238 
                 n/a 
                 n/a 
                 Intron 2 
                 GGATCTCAGCTGCAATTCTT 
                 72 
                 146235 
                 146254 
                 222 
               
               
                   
               
               
                 533239 
                 n/a 
                 n/a 
                 Intron 2 
                 AGGATCTCAGCTGCAATTCT 
                 53 
                 146236 
                 146255 
                 223 
               
               
                   
               
               
                 533240 
                 n/a 
                 n/a 
                 Intron 2 
                 GAGGATCTCAGCTGCAATTC 
                 69 
                 146237 
                 146256 
                 224 
               
               
                   
               
               
                 533241 
                 n/a 
                 n/a 
                 Intron 2 
                 CAGAGGATCTCAGCTGCAAT 
                 69 
                 146239 
                 146258 
                 225 
               
               
                   
               
               
                 533242 
                 n/a 
                 n/a 
                 Intron 2 
                 GCAGAGGATCTCAGCTGCAA 
                 76 
                 146240 
                 146259 
                 226 
               
               
                   
               
               
                 533243 
                 230 
                 249 
                 Exon 2 
                 AAAAGCATCACTTGATCCTG 
                 23 
                 145014 
                 145033 
                 227 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 5 
               
             
            
               
                   
               
               
                 Inhibition of GHR mRNA by 3-10-4 MOE gapmers targeting intronic and exonic regions of SEQ ID NO: 1 
               
               
                 and 2 
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                   
                 SEQ 
                 SEQ 
                   
                   
                   
                   
                   
                   
               
               
                   
                 ID 
                 ID 
                   
                   
                   
                   
                   
                   
               
               
                   
                 NO: 
                 NO: 
                   
                   
                   
                 SEQ 
                 SEQ ID 
                   
               
               
                   
                 1 
                 1 
                   
                   
                   
                 ID NO: 
                 NO: 2 
                   
               
               
                 ISIS 
                 Start 
                 Stop 
                 Target 
                   
                 % 
                 2 Start 
                 Stop 
                 SEQ 
               
               
                 NO 
                 Site 
                 Site 
                 Region 
                 Sequence 
                 inhibition 
                 Site 
                 Site 
                 ID NO 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                 539284 
                 206 
                 222 
                 Exon 2 
                 CAAGGTCAACAGCAGCT 
                 62 
                 144990 
                 145006 
                 228 
               
               
                   
               
               
                 539285 
                 207 
                 223 
                 Exon 2 
                 CCAAGGTCAACAGCAGC 
                 74 
                 144991 
                 145007 
                 229 
               
               
                   
               
               
                 539286 
                 208 
                 224 
                 Exon 2 
                 GCCAAGGTCAACAGCAG 
                 73 
                 144992 
                 145008 
                 230 
               
               
                   
               
               
                 539290 
                 869 
                 885 
                 Exon 7 
                 TCTCACACGCACTTCAT 
                 29 
                 290367 
                 290383 
                 231 
               
               
                   
               
               
                 539291 
                 870 
                 886 
                 Exon 7 
                 ATCTCACACGCACTTCA 
                 51 
                 290368 
                 290384 
                 232 
               
               
                   
               
               
                 539292 
                 871 
                 887 
                 Exon 7 
                 GATCTCACACGCACTTC 
                 56 
                 290369 
                 290385 
                 233 
               
               
                   
               
               
                 539299 
                 n/a 
                 n/a 
                 Intron 1 
                 CTTTCATGAATCAAGCT 
                 63 
                 17927 
                 17943 
                 234 
               
               
                   
               
               
                 539300 
                 n/a 
                 n/a 
                 Intron 1 
                 TCTTTCATGAATCAAGC 
                 49 
                 17928 
                 17944 
                 235 
               
               
                   
               
               
                 539301 
                 n/a 
                 n/a 
                 Intron 1 
                 GTCTTTCATGAATCAAG 
                 61 
                 17929 
                 17945 
                 236 
               
               
                   
               
               
                 539302 
                 n/a 
                 n/a 
                 Intron 1 
                 GGTCTTTCATGAATCAA 
                 93 
                 17930 
                 17946 
                 237 
               
               
                   
               
               
                 539303 
                 n/a 
                 n/a 
                 Intron 1 
                 ATGGTCTTTCATGAATC 
                 74 
                 17932 
                 17948 
                 238 
               
               
                   
               
               
                 539304 
                 n/a 
                 n/a 
                 Intron 1 
                 GATGGTCTTTCATGAAT 
                 56 
                 17933 
                 17949 
                 239 
               
               
                   
               
               
                 539305 
                 n/a 
                 n/a 
                 Intron 1 
                 TATATCAATATTCTCCC 
                 42 
                 21820 
                 21836 
                 240 
               
               
                   
               
               
                 539306 
                 n/a 
                 n/a 
                 Intron 1 
                 TTATATCAATATTCTCC 
                 33 
                 21821 
                 21837 
                 241 
               
               
                   
               
               
                 539307 
                 n/a 
                 n/a 
                 Intron 1 
                 GTTATATCAATATTCTC 
                 12 
                 21822 
                 21838 
                 242 
               
               
                   
               
               
                 539308 
                 n/a 
                 n/a 
                 Intron 1 
                 TTTCTTTAGCAATAGTT 
                 21 
                 22518 
                 22534 
                 243 
               
               
                   
               
               
                 539309 
                 n/a 
                 n/a 
                 Intron 1 
                 CTTTCTTTAGCAATAGT 
                 38 
                 22519 
                 22535 
                 244 
               
               
                   
               
               
                 539310 
                 n/a 
                 n/a 
                 Intron 1 
                 GCTTTCTTTAGCAATAG 
                 39 
                 22520 
                 22536 
                 245 
               
               
                   
               
               
                 539311 
                 n/a 
                 n/a 
                 Intron 1 
                 AGGAATGGAAAACCAAA 
                 18 
                 26497 
                 26513 
                 246 
               
               
                   
                   
                   
                   
                   
                   
                 113031 
                 113047 
                   
               
               
                   
                   
                   
                   
                   
                   
                 121988 
                 122004 
                   
               
               
                   
               
               
                 539312 
                 n/a 
                 n/a 
                 Intron 1 
                 CAGGAATGGAAAACCAA 
                 40 
                 26498 
                 26514 
                 247 
               
               
                   
                   
                   
                   
                   
                   
                 113032 
                 113048 
                   
               
               
                   
                   
                   
                   
                   
                   
                 121989 
                 122005 
                   
               
               
                   
               
               
                 539313 
                 n/a 
                 n/a 
                 Intron 1 
                 TCAGGAATGGAAAACCA 
                 49 
                 26499 
                 26515 
                 248 
               
               
                   
                   
                   
                   
                   
                   
                 113033 
                 113049 
                   
               
               
                   
                   
                   
                   
                   
                   
                 121990 
                 122006 
                   
               
               
                   
               
               
                 539314 
                 n/a 
                 n/a 
                 Intron 1 
                 TCTCCATTAGGGTTCTG 
                 87 
                 50948 
                 50964 
                 249 
               
               
                   
               
               
                 539315 
                 n/a 
                 n/a 
                 Intron 1 
                 TTCTCCATTAGGGTTCT 
                 57 
                 50949 
                 50965 
                 250 
               
               
                   
               
               
                 539316 
                 n/a 
                 n/a 
                 Intron 1 
                 GTTCTCCATTAGGGTTC 
                 73 
                 50950 
                 50966 
                 251 
               
               
                   
               
               
                 539317 
                 n/a 
                 n/a 
                 Intron 1 
                 AGGTTGGCAGACAGACA 
                 73 
                 53466 
                 53482 
                 252 
               
               
                   
               
               
                 539318 
                 n/a 
                 n/a 
                 Intron 1 
                 CAGGTTGGCAGACAGAC 
                 84 
                 53467 
                 53483 
                 253 
               
               
                   
               
               
                 539319 
                 n/a 
                 n/a 
                 Intron 1 
                 GCAGGTTGGCAGACAGA 
                 85 
                 53468 
                 53484 
                 254 
               
               
                   
               
               
                 539320 
                 n/a 
                 n/a 
                 Intron 1 
                 CTTCTTGTGAGCTGGCT 
                 87 
                 64884 
                 64900 
                 255 
               
               
                   
               
               
                 539321 
                 n/a 
                 n/a 
                 Intron 1 
                 TCTTCTTGTGAGCTGGC 
                 89 
                 64885 
                 64901 
                 256 
               
               
                   
               
               
                 539322 
                 n/a 
                 n/a 
                 Intron 1 
                 GTCTTCTTGTGAGCTGG 
                 87 
                 64886 
                 64902 
                 257 
               
               
                   
               
               
                 539323 
                 n/a 
                 n/a 
                 Intron 1 
                 AGTCTTCTTGTGAGCTG 
                 70 
                 64887 
                 64903 
                 258 
               
               
                   
               
               
                 539324 
                 n/a 
                 n/a 
                 Intron 1 
                 TCTTCCACTCACATCCA 
                 65 
                 65990 
                 66006 
                 259 
               
               
                   
               
               
                 539325 
                 n/a 
                 n/a 
                 Intron 1 
                 CTCTTCCACTCACATCC 
                 78 
                 65991 
                 66007 
                 260 
               
               
                   
               
               
                 539326 
                 n/a 
                 n/a 
                 Intron 1 
                 TCTCTTCCACTCACATC 
                 68 
                 65992 
                 66008 
                 261 
               
               
                   
               
               
                 539327 
                 n/a 
                 n/a 
                 Intron 1 
                 GTCTCTTCCACTCACAT 
                 74 
                 65993 
                 66009 
                 262 
               
               
                   
               
               
                 539328 
                 n/a 
                 n/a 
                 Intron 1 
                 ATAGATTTTGACTTCCC 
                 57 
                 72107 
                 72123 
                 263 
               
               
                   
               
               
                 539329 
                 n/a 
                 n/a 
                 Intron 1 
                 CATAGATTTTGACTTCC 
                 35 
                 72108 
                 72124 
                 264 
               
               
                   
               
               
                 539330 
                 n/a 
                 n/a 
                 Intron 1 
                 GCATAGATTTTGACTTC 
                 53 
                 72109 
                 72125 
                 265 
               
               
                   
               
               
                 539331 
                 n/a 
                 n/a 
                 Intron 1 
                 AAAATGTCAACAGTGCA 
                 86 
                 80639 
                 80655 
                 266 
               
               
                   
               
               
                 539332 
                 n/a 
                 n/a 
                 Intron 1 
                 CAAAATGTCAACAGTGC 
                 73 
                 80640 
                 80656 
                 267 
               
               
                   
               
               
                 539333 
                 n/a 
                 n/a 
                 Intron 1 
                 CCAAAATGTCAACAGTG 
                 34 
                 80641 
                 80657 
                 268 
               
               
                   
               
               
                 539334 
                 n/a 
                 n/a 
                 Intron 1 
                 CCCAAAATGTCAACAGT 
                 66 
                 80642 
                 80658 
                 269 
               
               
                   
               
               
                 539335 
                 n/a 
                 n/a 
                 Intron 1 
                 CATGACTATGTTCTGGC 
                 67 
                 125594 
                 125610 
                 270 
               
               
                   
               
               
                 539336 
                 n/a 
                 n/a 
                 Intron 1 
                 ACATGACTATGTTCTGG 
                 42 
                 125595 
                 125611 
                 271 
               
               
                   
               
               
                 539337 
                 n/a 
                 n/a 
                 Intron 1 
                 CACATGACTATGTTCTG 
                 29 
                 125596 
                 125612 
                 272 
               
               
                   
               
               
                 539338 
                 n/a 
                 n/a 
                 Intron 2 
                 GAATTCTGAGCTCTGGA 
                 77 
                 145429 
                 145445 
                 273 
               
               
                   
               
               
                 539339 
                 n/a 
                 n/a 
                 Intron 2 
                 TGAATTCTGAGCTCTGG 
                 84 
                 145430 
                 145446 
                 274 
               
               
                   
               
               
                 539340 
                 n/a 
                 n/a 
                 Intron 2 
                 CTGAATTCTGAGCTCTG 
                 80 
                 145431 
                 145447 
                 275 
               
               
                   
               
               
                 539341 
                 n/a 
                 n/a 
                 Intron 2 
                 CCTGAATTCTGAGCTCT 
                 84 
                 145432 
                 145448 
                 276 
               
               
                   
               
               
                 539342 
                 n/a 
                 n/a 
                 Intron 2 
                 GCCTGAATTCTGAGCTC 
                 84 
                 145433 
                 145449 
                 277 
               
               
                   
               
               
                 539343 
                 n/a 
                 n/a 
                 Intron 2 
                 AGCCTGAATTCTGAGCT 
                 80 
                 145434 
                 145450 
                 278 
               
               
                   
               
               
                 539344 
                 n/a 
                 n/a 
                 Intron 2 
                 ATATTGTAATTCTTGGT 
                 0 
                 148059 
                 148075 
                 279 
               
               
                   
               
               
                 539345 
                 n/a 
                 n/a 
                 Intron 2 
                 GATATTGTAATTCTTGG 
                 20 
                 148060 
                 148076 
                 280 
               
               
                   
               
               
                 539346 
                 n/a 
                 n/a 
                 Intron 2 
                 TGATATTGTAATTCTTG 
                 13 
                 148061 
                 148077 
                 281 
               
               
                   
               
               
                 539347 
                 n/a 
                 n/a 
                 Intron 2 
                 CTGATATTGTAATTCTT 
                 8 
                 148062 
                 148078 
                 282 
               
               
                   
               
               
                 539348 
                 n/a 
                 n/a 
                 Intron 2 
                 CCTGATATTGTAATTCT 
                 67 
                 148063 
                 148079 
                 283 
               
               
                   
               
               
                 539349 
                 n/a 
                 n/a 
                 Intron 2 
                 GCCTGATATTGTAATTC 
                 73 
                 148064 
                 148080 
                 284 
               
               
                   
               
               
                 539350 
                 n/a 
                 n/a 
                 Intron 2 
                 TGCCTGATATTGTAATT 
                 32 
                 148065 
                 148081 
                 285 
               
               
                   
               
               
                 539351 
                 n/a 
                 n/a 
                 Intron 2 
                 AATTATGTGCTTTGCCT 
                 58 
                 148907 
                 148923 
                 286 
               
               
                   
               
               
                 539352 
                 n/a 
                 n/a 
                 Intron 2 
                 CAATTATGTGCTTTGCC 
                 82 
                 148908 
                 148924 
                 287 
               
               
                   
               
               
                 539353 
                 n/a 
                 n/a 
                 Intron 2 
                 TCAATTATGTGCTTTGC 
                 68 
                 148909 
                 148925 
                 288 
               
               
                   
               
               
                 539354 
                 n/a 
                 n/a 
                 Intron 2 
                 GTCAATTATGTGCTTTG 
                 80 
                 148910 
                 148926 
                 289 
               
               
                   
               
               
                 539355 
                 n/a 
                 n/a 
                 Intron 2 
                 GCCATCACCAAACACCA 
                 94 
                 150972 
                 150988 
                 290 
               
               
                   
               
               
                 539356 
                 n/a 
                 n/a 
                 Intron 2 
                 TGCCATCACCAAACACC 
                 84 
                 150973 
                 150989 
                 291 
               
               
                   
               
               
                 539357 
                 n/a 
                 n/a 
                 Intron 2 
                 TTGCCATCACCAAACAC 
                 74 
                 150974 
                 150990 
                 292 
               
               
                   
               
               
                 539358 
                 n/a 
                 n/a 
                 Intron 2 
                 TGGTGACTCTGCCTGAT 
                 85 
                 151387 
                 151403 
                 293 
               
               
                   
               
               
                 539359 
                 n/a 
                 n/a 
                 Intron 2 
                 CTGGTGACTCTGCCTGA 
                 86 
                 151388 
                 151404 
                 294 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 6 
               
             
            
               
                   
               
               
                 inhibition of GHR mRNA by 5-10-5 MOE gapmers targeting intron 1 of SEQ ID NO: 2 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                   
                   
                 SEQ 
                 SEQ 
                   
               
               
                   
                   
                   
                 ID 
                 ID 
                   
               
               
                   
                   
                   
                 NO: 2 
                 NO: 2 
                 SEQ 
               
               
                 ISIS 
                   
                 % 
                 Start 
                 Stop 
                 ID 
               
               
                 NO 
                 Sequence 
                 inhibition 
                 Site 
                 Site 
                 NO 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 523561 
                 TATTTCAGAAAGACTTTCTG 
                 11 
                 10373 
                 10392 
                 295 
               
               
                   
               
               
                 523562 
                 AGGAAAAAATCAAGGAGTTA 
                 8 
                 11173 
                 11192 
                 296 
               
               
                   
               
               
                 523563 
                 TATTTACTGAACACCTATTC 
                 12 
                 11973 
                 11992 
                 297 
               
               
                   
               
               
                 523564 
                 GCCCATGAAGGCCACTCTTC 
                 70 
                 12780 
                 12799 
                 298 
               
               
                   
               
               
                 523565 
                 ACCTATAAATAAAGTGAGGA 
                 0 
                 13581 
                 13600 
                 299 
               
               
                   
               
               
                 523566 
                 GTTTCATAACCTGCTAATAA 
                 40 
                 14451 
                 14470 
                 300 
               
               
                   
               
               
                 523567 
                 ATGTGCCTTACAGTTATCAG 
                 36 
                 15251 
                 15270 
                 301 
               
               
                   
               
               
                 523568 
                 TTCTGAATTTAGAATTATAG 
                 0 
                 16051 
                 16070 
                 302 
               
               
                   
               
               
                 523569 
                 GTTTATAATCTAGCAGTTAC 
                 26 
                 17130 
                 17149 
                 303 
               
               
                   
               
               
                 523570 
                 GATGGTCTTTCATGAATCAA 
                 62 
                 17930 
                 17949 
                 304 
               
               
                   
               
               
                 523571 
                 CATGTACCCAAACCAACACT 
                 65 
                 18730 
                 18749 
                 305 
               
               
                   
               
               
                 523572 
                 TAAAATACAGCCTACATCAT 
                 0 
                 19637 
                 19656 
                 306 
               
               
                   
               
               
                 523573 
                 CCATCACTACAACAAACTCA 
                 39 
                 20451 
                 20470 
                 307 
               
               
                   
               
               
                 523574 
                 ATCTGAAATGATCCCCTTTC 
                 33 
                 21283 
                 21302 
                 308 
               
               
                   
               
               
                 523575 
                 TGTTGCCCCTCCAAAAAGAC 
                 12 
                 22144 
                 22163 
                 309 
               
               
                   
               
               
                 523576 
                 ATTAAAATTTTAAATGATGT 
                 0 
                 22944 
                 22963 
                 310 
               
               
                   
               
               
                 523577 
                 CTCAGGAATGGAAAACCAAA 
                 71 
                 26497 
                 26516 
                 311 
               
               
                   
                   
                   
                 113031 
                 113050 
                   
               
               
                   
                   
                   
                 121988 
                 122007 
                   
               
               
                   
               
               
                 523578 
                 AAAATTCTAGAAGATAACAT 
                 0 
                 27838 
                 27857 
                 312 
               
               
                   
               
               
                 523579 
                 CTAGAAGTCCTAGCCAGAGT 
                 2 
                 28748 
                 28767 
                 313 
               
               
                   
               
               
                 523580 
                 AACCGATATCACAGAAATAC 
                 0 
                 29548 
                 29567 
                 314 
               
               
                   
               
               
                 523581 
                 AAGATAGACAGTAACATAAT 
                 0 
                 30348 
                 30367 
                 315 
               
               
                   
               
               
                 523582 
                 GCACTACAAGAACTGCTTAA 
                 40 
                 31172 
                 31191 
                 316 
               
               
                   
               
               
                 523583 
                 TTTCCAGACAAAGAATTCAG 
                 6 
                 31978 
                 31997 
                 317 
               
               
                   
               
               
                 523584 
                 GTAGACAGCCTTTCTGGAAC 
                 20 
                 32827 
                 32846 
                 318 
               
               
                   
               
               
                 523585 
                 CATCCTACATAGTGGCTGTG 
                 47 
                 33635 
                 33654 
                 319 
               
               
                   
               
               
                 523586 
                 CAGAACAGTGTGTGGAGACT 
                 8 
                 34452 
                 34471 
                 320 
               
               
                   
               
               
                 523587 
                 AGCTTTAAAAATACCTCTGC 
                 52 
                 35466 
                 35485 
                 321 
               
               
                   
               
               
                 523588 
                 CCCAGGTACTTGCTCTCAGA 
                 22 
                 36266 
                 36285 
                 322 
               
               
                   
               
               
                 523589 
                 TTACACCTGATTCTAGAAAT 
                 30 
                 37066 
                 37085 
                 323 
               
               
                   
               
               
                 523590 
                 CTTTTCTCTACAACCTCACA 
                 34 
                 38094 
                 38113 
                 324 
               
               
                   
               
               
                 523591 
                 TAGTAGTTTGAATTTCAAAG 
                 1 
                 38909 
                 38928 
                 325 
               
               
                   
               
               
                 523592 
                 ATACAAAATTACTGCAGTCA 
                 60 
                 39719 
                 39738 
                 326 
               
               
                   
               
               
                 523593 
                 GCCACTGCCAAAAAGGAGGA 
                 30 
                 40519 
                 40538 
                 327 
               
               
                   
               
               
                 523594 
                 TGACAGAAACAGAGCTATGA 
                 33 
                 41342 
                 41361 
                 328 
               
               
                   
               
               
                 523595 
                 ATCTTTTAGTATGAACCTTA 
                 65 
                 42142 
                 42161 
                 329 
               
               
                   
               
               
                 523596 
                 AGTTATGTGACTCTGAGCAC 
                 63 
                 43173 
                 43192 
                 330 
               
               
                   
               
               
                 523597 
                 ACTATGCCCTAGTTACTTCT 
                 29 
                 43973 
                 43992 
                 331 
               
               
                   
               
               
                 523598 
                 TATAGTGGAAGTGATAGATC 
                 0 
                 44812 
                 44831 
                 332 
               
               
                   
               
               
                 523599 
                 TGTTTTCTGAAATGGAATGT 
                 0 
                 45733 
                 45752 
                 333 
               
               
                   
               
               
                 523600 
                 GCTGTAAATGTAATGAGTGT 
                 34 
                 46553 
                 46572 
                 334 
               
               
                   
               
               
                 523601 
                 GAGAGAAGCCATGGCCCTAG 
                 20 
                 47392 
                 47411 
                 335 
               
               
                   
               
               
                 523602 
                 CTCTCTTTCCCAGAACAAGA 
                 32 
                 48210 
                 48229 
                 336 
               
               
                   
               
               
                 523603 
                 TCCAAAATGTCCAGTATAAT 
                 33 
                 50072 
                 50091 
                 337 
               
               
                   
               
               
                 523604 
                 GTTCTCCATTAGGGTTCTGG 
                 74 
                 50947 
                 50966 
                 338 
               
               
                   
               
               
                 523605 
                 TTAGTCACCCATCCACCACT 
                 41 
                 51747 
                 51766 
                 339 
               
               
                   
               
               
                 523606 
                 CATGAATTCACCGAGTTAGG 
                 51 
                 52573 
                 52592 
                 340 
               
               
                   
               
               
                 523607 
                 AGCAGGTTGGCAGACAGACA 
                 62 
                 53466 
                 53485 
                 341 
               
               
                   
               
               
                 523608 
                 GAAAGACTTAAATTTTCACA 
                 0 
                 54306 
                 54325 
                 342 
               
               
                   
               
               
                 523609 
                 TAGTAGAGGAAAAGGAGAAT 
                 0 
                 55730 
                 55749 
                 343 
               
               
                   
               
               
                 523610 
                 AAACAGGGTCTGGAGTGGAC 
                 3 
                 61243 
                 61262 
                 344 
               
               
                   
               
               
                 523611 
                 CAAGCTGATAATTAAAAAGA 
                 0 
                 62462 
                 62481 
                 345 
               
               
                   
               
               
                 523612 
                 ATAAAGATACATTTTCTGGG 
                 8 
                 63277 
                 63296 
                 346 
               
               
                   
               
               
                 523613 
                 CAGGATTCTTCCTGCCTGGC 
                 47 
                 64085 
                 64104 
                 347 
               
               
                   
               
               
                 523614 
                 AAGTCTTCTTGTGAGCTGGC 
                 71 
                 64885 
                 64904 
                 348 
               
               
                   
               
               
                 523615 
                 CTCTTCCACTCACATCCATT 
                 63 
                 65988 
                 66007 
                 349 
               
               
                   
               
               
                 523616 
                 CCTATATCAGAAGACAAATG 
                 5 
                 66806 
                 66825 
                 350 
               
               
                   
               
               
                 523617 
                 TCAAAACCCTGCCAAGGTAC 
                 44 
                 67662 
                 67681 
                 351 
               
               
                   
               
               
                 523618 
                 TCATATTCTACTTCTGTTTA 
                 11 
                 68462 
                 68481 
                 352 
               
               
                   
               
               
                 523619 
                 CATTCCAGTGTTTCAGTAAG 
                 13 
                 69262 
                 69281 
                 353 
               
               
                   
               
               
                 523620 
                 GGCCTGGAATTAATCCTCAG 
                 49 
                 70114 
                 70133 
                 354 
               
               
                   
               
               
                 523621 
                 AATGCCCTCTCCCTGTGCCT 
                 48 
                 70925 
                 70944 
                 355 
               
               
                   
               
               
                 523622 
                 TTTATAATCAACCTTTGCTA 
                 9 
                 71741 
                 71760 
                 356 
               
               
                   
               
               
                 523623 
                 ATATAACTACTTAAAATAAT 
                 0 
                 72541 
                 72560 
                 357 
               
               
                   
               
               
                 523624 
                 TTAGCCAGGATATGGTTGCC 
                 50 
                 73350 
                 73369 
                 358 
               
               
                   
               
               
                 523625 
                 CTACCTCCATCAAAGAAAAT 
                 0 
                 74190 
                 74209 
                 359 
               
               
                   
               
               
                 523626 
                 GCATGCATAGATAAGTTTGA 
                 20 
                 74990 
                 75009 
                 360 
               
               
                   
               
               
                 523627 
                 ATGAGAGTAAATGGATTTTC 
                 10 
                 75790 
                 75809 
                 361 
               
               
                   
               
               
                 523628 
                 TTGGCAATCCTTGCTTAAAA 
                 34 
                 76598 
                 76617 
                 362 
               
               
                   
               
               
                 523629 
                 GAATTAAGCCAGACTTATTT 
                 3 
                 77398 
                 77417 
                 363 
               
               
                   
               
               
                 523630 
                 GGCTAAGTATTTGTAGCAGT 
                 55 
                 78198 
                 78217 
                 364 
               
               
                   
               
               
                 523631 
                 TTGCCTGTGTGCAACTGGCG 
                 0 
                 79005 
                 79024 
                 365 
               
               
                   
               
               
                 523632 
                 GTGGCCTTAGTAGGCCAGCT 
                 0 
                 79827 
                 79846 
                 366 
               
               
                   
               
               
                 523633 
                 CCCAAAATGTCAACAGTGCA 
                 70 
                 80639 
                 80658 
                 367 
               
               
                   
               
               
                 523634 
                 TTAAGCCTTCAATTTGAAAA 
                 0 
                 81455 
                 81474 
                 368 
               
               
                   
               
               
                 523635 
                 TGCTCAGAAGGTTGAGCATA 
                 0 
                 82261 
                 82280 
                 369 
               
               
                   
               
               
                 523636 
                 TTAATGCTTTCCCAAAGCTC 
                 35 
                 83061 
                 83080 
                 370 
               
               
                   
               
               
                 523637 
                 AAAAGACTTCATACCTTTAC 
                 52 
                 83884 
                 83903 
                 371 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 7 
               
             
            
               
                   
               
               
                 Inhibition of GHR mRNA by 5-10-5 MOE gapmers  
               
               
                 targeting intron 1 of SEQ ID NO: 2 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                   
                   
                 SEQ 
                 SEQ 
                   
               
               
                   
                   
                   
                 ID 
                 ID 
                   
               
               
                   
                   
                 % 
                 NO: 
                 NO: 
                   
               
               
                   
                   
                 inhi- 
                 2 
                 2 
                 SEQ 
               
               
                 ISIS 
                   
                 bi- 
                 Start 
                 Stop 
                 ID 
               
               
                 NO 
                 Sequence 
                 tion 
                 Site 
                 Site 
                 NO 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 532146 
                 GGCCCCCTGGCACAACAGGA 
                 60 
                 3097 
                 3116 
                 372 
               
               
                   
               
               
                 532147 
                 TCTAGGGTGATTCAGGTGGA 
                 62 
                 4537 
                 4556 
                 373 
               
               
                   
               
               
                 532148 
                 CTTAGATTAATGCAAAACAA 
                 25 
                 4875 
                 4894 
                 374 
               
               
                   
               
               
                 532149 
                 AGGCAGAGGAGGGTGGAACC 
                 34 
                 6246 
                 6265 
                 375 
               
               
                   
               
               
                 532150 
                 AGTCTAATGAGATCTGATGG 
                 76 
                 6499 
                 6518 
                 376 
               
               
                   
               
               
                 532151 
                 GCTGAAATGAGTTAAGACTT 
                 89 
                 6737 
                 6756 
                 377 
               
               
                   
               
               
                 532152 
                 ACTTTGGACTGTGGATTTTT 
                 78 
                 6765 
                 6784 
                 378 
               
               
                   
               
               
                 532153 
                 GCATATTTACACAATGCCTG 
                 84 
                 6871 
                 6890 
                 379 
               
               
                   
               
               
                 532154 
                 GGAAATGCCTGGATGTCCAG 
                 27 
                 7241 
                 7260 
                 380 
               
               
                   
               
               
                 532155 
                 CTGCTGATTTTGGAATGGAG 
                 68 
                 10660 
                 10679 
                 381 
               
               
                   
               
               
                 532156 
                 ACTGAACACCTATTCTATGG 
                 51 
                 11968 
                 11987 
                 382 
               
               
                   
               
               
                 532157 
                 TTTACTGAACACCTATTCTA 
                 23 
                 11971 
                 11990 
                 383 
               
               
                   
               
               
                 532158 
                 CCCTCAAATTATCCACAAAC 
                 89 
                 12053 
                 12072 
                 384 
               
               
                   
               
               
                 532159 
                 CTTCTAAATGTTTCCAAGGC 
                 63 
                 12186 
                 12205 
                 385 
               
               
                   
               
               
                 532160 
                 TTACATCCTGTAGGCTAATT 
                 82 
                 12469 
                 12488 
                 386 
               
               
                   
               
               
                 532161 
                 CCACTAGCCTGGCCAGACTT 
                 73 
                 12487 
                 12506 
                 387 
               
               
                   
               
               
                 532162 
                 CTGGTAGATGATCTCAAGTT 
                 84 
                 13351 
                 13370 
                 388 
               
               
                   
               
               
                 532163 
                 AAAGAATTGAGTTATAAATC 
                 23 
                 13670 
                 13689 
                 389 
               
               
                   
               
               
                 532164 
                 AACTCATCTCTGGCCAGCAG 
                 89 
                 14361 
                 14380 
                 390 
               
               
                   
               
               
                 532165 
                 CAACATCATTGTATTTTCTG 
                 33 
                 14965 
                 14984 
                 391 
               
               
                   
               
               
                 532166 
                 TCTTAGCTTACCAATGAGGA 
                 81 
                 15085 
                 15104 
                 392 
               
               
                   
               
               
                 532167 
                 TTCCCAGAGCCAAAGCTCAA 
                 77 
                 15982 
                 16001 
                 393 
               
               
                   
               
               
                 532168 
                 TTTGGCCAATCCCAGCTTAT 
                 59 
                 16253 
                 16272 
                 394 
               
               
                   
               
               
                 532169 
                 GTTTGCAAATCTTCATTCAC 
                 71 
                 16447 
                 16466 
                 395 
               
               
                   
               
               
                 532170 
                 CAATAGTCCCTGAGGCTTGG 
                 74 
                 16476 
                 16495 
                 396 
               
               
                   
               
               
                 532171 
                 TTTCCCCAGATTAAATGCCC 
                 85 
                 17650 
                 17669 
                 397 
               
               
                   
               
               
                 532172 
                 TTCAATAATGCAGTTATTAT 
                 0 
                 18308 
                 18327 
                 398 
               
               
                   
               
               
                 532173 
                 AAATTCTTGGGCTTAAGCAC 
                 69 
                 18638 
                 18657 
                 399 
               
               
                   
               
               
                 532174 
                 ACATGTACCCAAACCAACAC 
                 71 
                 18731 
                 18750 
                 91 
               
               
                   
               
               
                 532175 
                 TGATCCAAATTCAGTACCTA 
                 82 
                 18752 
                 18771 
                 400 
               
               
                   
               
               
                 532176 
                 GATGATCCAAATTCAGTACC 
                 54 
                 18754 
                 18773 
                 401 
               
               
                   
               
               
                 532177 
                 CAATATTCATCTTTATATTC 
                 25 
                 19106 
                 19125 
                 402 
               
               
                   
               
               
                 532178 
                 ATTGCTCTTAAGATAAGTAA 
                 41 
                 19661 
                 19680 
                 403 
               
               
                   
               
               
                 532179 
                 CAGCTCCCTGAATATCTCTT 
                 74 
                 19783 
                 19802 
                 404 
               
               
                   
               
               
                 532180 
                 ACTTCACAAATATATTATAA 
                 0 
                 19885 
                 19904 
                 405 
               
               
                   
               
               
                 532181 
                 GTACAGTCAACTTTACTTCA 
                 89 
                 19899 
                 19918 
                 406 
               
               
                   
               
               
                 532182 
                 CAATTCCCACTCTTGTCAAC 
                 55 
                 20288 
                 20307 
                 407 
               
               
                   
               
               
                 532183 
                 TCAACTGCTTTCTGGAGCAG 
                 66 
                 21215 
                 21234 
                 408 
               
               
                   
               
               
                 532184 
                 ACTGCTGAGCACCTCCAAAA 
                 73 
                 21454 
                 21473 
                 409 
               
               
                   
               
               
                 532185 
                 CTTAGATTCCTGGTTTATCA 
                 78 
                 21587 
                 21606 
                 410 
               
               
                   
               
               
                 532186 
                 AGTTATATCAATATTCTCCC 
                 88 
                 21820 
                 21839 
                 411 
               
               
                   
               
               
                 532187 
                 TATACCATCTTCCCCATAAA 
                 32 
                 22038 
                 22057 
                 412 
               
               
                   
               
               
                 532188 
                 GGCTTTCTTTAGCAATAGTT 
                 86 
                 22518 
                 22537 
                 413 
               
               
                   
               
               
                 532189 
                 TACCAGGGATGTAGGTTTAC 
                 82 
                 29050 
                 29069 
                 414 
               
               
                   
               
               
                 532190 
                 TCACAGCTGAATTCTATCTG 
                 80 
                 29323 
                 29342 
                 415 
               
               
                   
               
               
                 532191 
                 GGAGATGGACAAATTCCTGC 
                 77 
                 29470 
                 29489 
                 416 
               
               
                   
               
               
                 532192 
                 CTAGACATGTCATCAAGACA 
                 19 
                 30294 
                 30313 
                 417 
               
               
                   
               
               
                 532193 
                 CAAATTAATAAAACAATTAC 
                 10 
                 30385 
                 30404 
                 418 
               
               
                   
               
               
                 532194 
                 TATTCTTATATCAGACAAAA 
                 30 
                 30532 
                 30551 
                 419 
               
               
                   
               
               
                 532195 
                 TCAAGGGATCCCTGCCATTC 
                 32 
                 32361 
                 32380 
                 420 
               
               
                   
               
               
                 532196 
                 CGTCAAGGGATCCCTGCCAT 
                 47 
                 32363 
                 32382 
                 421 
               
               
                   
               
               
                 532197 
                 GGCACTCCCAGTCTCCAGCT 
                 83 
                 34138 
                 34157 
                 422 
               
               
                   
               
               
                 532198 
                 TTTCTCCAGCAGAAGTGTCA 
                 60 
                 34845 
                 34864 
                 423 
               
               
                   
               
               
                 532199 
                 AAGTCCTCTTCCGCCTCCCT 
                 82 
                 36023 
                 36042 
                 424 
               
               
                   
               
               
                 532200 
                 GGAATTTACCAAAAACAGTT 
                 63 
                 36721 
                 36740 
                 425 
               
               
                   
               
               
                 532201 
                 AGTTAGGTATTGTCCATTTT 
                 74 
                 37032 
                 37051 
                 426 
               
               
                   
               
               
                 532202 
                 ACATGGGTATCTTCTAGGAA 
                 77 
                 37111 
                 37130 
                 427 
               
               
                   
               
               
                 532203 
                 TCAGTTTCAGAGAGACAAAA 
                 41 
                 37276 
                 37295 
                 428 
               
               
                   
               
               
                 532204 
                 TTTGCCAGGTCCTATGTCGA 
                 69 
                 37656 
                 37675 
                 429 
               
               
                   
               
               
                 532205 
                 ATTCCCTTTTCTCTACAACC 
                 70 
                 38099 
                 38118 
                 430 
               
               
                   
               
               
                 532206 
                 ATGATAAGAGCCAAGATTTG 
                 13 
                 38994 
                 39013 
                 431 
               
               
                   
               
               
                 532207 
                 GAAAAAAGGTCCACTGTGGT 
                 49 
                 40356 
                 40375 
                 432 
               
               
                   
               
               
                 532208 
                 CCTGTCCTGGAATAGTTTCA 
                 49 
                 41164 
                 41183 
                 433 
               
               
                   
               
               
                 532209 
                 TAGAAAAGTAAATAAGGAAT 
                 15 
                 41501 
                 41520 
                 434 
               
               
                   
               
               
                 532210 
                 TTATAAAACTATGCAATAGG 
                 0 
                 41889 
                 41908 
                 435 
               
               
                   
               
               
                 532211 
                 TTATTTCATATTTCCAGAAA 
                 0 
                 42675 
                 42694 
                 436 
               
               
                   
               
               
                 532212 
                 CATGAATTACAGCTAAAGAT 
                 20 
                 42741 
                 42760 
                 437 
               
               
                   
               
               
                 532213 
                 TTGCATGTATGTGTTTCTGA 
                 62 
                 43518 
                 43537 
                 438 
               
               
                   
               
               
                 532214 
                 TCAATCTCTTTATACCCTTA 
                 75 
                 43765 
                 43784 
                 439 
               
               
                   
               
               
                 532215 
                 TCTTCAATCTCTTTATACCC 
                 58 
                 43768 
                 43787 
                 440 
               
               
                   
               
               
                 532216 
                 CTATGCCCTAGTTACTTCTA 
                 47 
                 43972 
                 43991 
                 441 
               
               
                   
               
               
                 532217 
                 AAAGAGAATCTCTTCCTTTT 
                 27 
                 44070 
                 44089 
                 442 
               
               
                   
               
               
                 532218 
                 TCATTAAAGATTATTATAAC 
                 0 
                 44222 
                 44241 
                 443 
               
               
                   
               
               
                 532219 
                 TTTGGATGAGTGGAAGGCTA 
                 0 
                 44528 
                 44547 
                 444 
               
               
                   
               
               
                 532220 
                 GGAAATGGCCTTTTTCCTTA 
                 72 
                 45400 
                 45419 
                 445 
               
               
                   
               
               
                 532221 
                 GGAGAAGCCCTCTGCCTGTA 
                 60 
                 46477 
                 46496 
                 446 
               
               
                   
               
               
                 532222 
                 AAACCATATTGTCCACCAGA 
                 84 
                 46510 
                 46529 
                 447 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 8 
               
             
            
               
                   
               
               
                 Inhibition of GHR mRNA by 5-10-5 MOE gapmers 
               
               
                 targeting intron 1 of SEQ ID NO: 2 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                   
                   
                 SEQ 
                 SEQ 
                   
               
               
                   
                   
                   
                 ID 
                 ID 
                   
               
               
                   
                   
                 % 
                 NO: 
                 NO: 
                   
               
               
                   
                   
                 inhi- 
                 2 
                 2 
                 SEQ 
               
               
                 ISIS 
                   
                 bi- 
                 Start 
                 Stop 
                 ID 
               
               
                 NO 
                 Sequence 
                 tion 
                 Site 
                 Site 
                 NO 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 532223 
                 CTCAAACCATATTGTCCACC 
                 90 
                 46513 
                 46532 
                 448 
               
               
                   
               
               
                 532224 
                 GTGTAAATAGTGACTTGTAC 
                 76 
                 50123 
                 50142 
                 449 
               
               
                   
               
               
                 532225 
                 TGAGGCACAGGAAAGTTAAC 
                 52 
                 50719 
                 50738 
                 450 
               
               
                   
               
               
                 532226 
                 AGCTATAGTTCTCCATTAGG 
                 74 
                 50954 
                 50973 
                 451 
               
               
                   
               
               
                 532227 
                 TTACTTGCTGACTAAGCCAT 
                 69 
                 51071 
                 51090 
                 452 
               
               
                   
               
               
                 532228 
                 GTTTGTCAACTCAACATCAA 
                 73 
                 51215 
                 51234 
                 453 
               
               
                   
               
               
                 532229 
                 GACTATTTGTATATATATAC 
                 33 
                 51491 
                 51510 
                 454 
               
               
                   
               
               
                 532230 
                 ATGACTATTTGTATATATAT 
                 11 
                 51493 
                 51512 
                 455 
               
               
                   
               
               
                 532231 
                 ACTCTTCCTTATATTTGCTC 
                 76 
                 51778 
                 51797 
                 456 
               
               
                   
               
               
                 532232 
                 ATACACTGACTTTTAACATT 
                 67 
                 52039 
                 52058 
                 457 
               
               
                   
               
               
                 532233 
                 CTTAGAAACAGTAGTTTCAT 
                 42 
                 52124 
                 52143 
                 458 
               
               
                   
               
               
                 532234 
                 CTGAGCTTTGCCTTAAGAAT 
                 79 
                 52633 
                 52652 
                 459 
               
               
                   
               
               
                 532235 
                 CACCAGACAGCAGGTAGAGC 
                 81 
                 53540 
                 53559 
                 460 
               
               
                   
               
               
                 532236 
                 GAGATGGAGTAGAAGGCAAA 
                 43 
                 55926 
                 55945 
                 461 
               
               
                   
               
               
                 532237 
                 TAGGAAAGGAAGAATACACT 
                 33 
                 63881 
                 63900 
                 462 
               
               
                   
               
               
                 532238 
                 TAGACCAGGAAGGGTGAGAG 
                 27 
                 64376 
                 64395 
                 463 
               
               
                   
               
               
                 532239 
                 AAGTTGGATCTGGCATGCAT 
                 64 
                 64574 
                 64593 
                 464 
               
               
                   
               
               
                 532240 
                 AAAGTTGGATCTGGCATGCA 
                 70 
                 64575 
                 64594 
                 465 
               
               
                   
               
               
                 532241 
                 CCATAACTCTTCTAACTGGG 
                 84 
                 64643 
                 64662 
                 466 
               
               
                   
               
               
                 532242 
                 ATATTAAAGTTTGAGAACTA 
                 37 
                 65080 
                 65099 
                 467 
               
               
                   
               
               
                 532243 
                 CTTAACTACAAAATGCTGGA 
                 71 
                 66164 
                 66183 
                 468 
               
               
                   
               
               
                 532244 
                 TGAGCAGCTGTCCTCAGTTC 
                 43 
                 67061 
                 67080 
                 469 
               
               
                   
               
               
                 532245 
                 GAGTTCATAAAAGTTTTACT 
                 26 
                 67251 
                 67270 
                 470 
               
               
                   
               
               
                 532246 
                 CTATCCACACCATTCCATAA 
                 73 
                 69203 
                 69222 
                 471 
               
               
                   
               
               
                 532247 
                 AACATCTAAGTAATGCAAAC 
                 58 
                 69223 
                 69242 
                 472 
               
               
                   
               
               
                 532248 
                 TTTGCATTCAAAGCCCTGGG 
                 91 
                 69565 
                 69584 
                 473 
               
               
                   
               
               
                 532249 
                 TCCATATTATAGGCTATGAT 
                 73 
                 69889 
                 69908 
                 474 
               
               
                   
               
               
                 532250 
                 ATTTTATGATAATGTAAAAC 
                 27 
                 69942 
                 69961 
                 475 
               
               
                   
               
               
                 532251 
                 GAGATCACATTTTCTGAGTA 
                 50 
                 70352 
                 70371 
                 476 
               
               
                   
               
               
                 532252 
                 ACCTCCCTAGGATTACCTCA 
                 56 
                 71617 
                 71636 
                 477 
               
               
                   
               
               
                 532253 
                 AAAATCTGATTTATAATCAA 
                 40 
                 71750 
                 71769 
                 478 
               
               
                   
               
               
                 532254 
                 AGCATAGATTTTGACTTCCC 
                 92 
                 72107 
                 72126 
                 479 
               
               
                   
               
               
                 532255 
                 AAAGTCATATACACAGGTCT 
                 53 
                 72584 
                 72603 
                 480 
               
               
                   
               
               
                 532256 
                 CTCATAGCAAATTCCCAGAA 
                 66 
                 73689 
                 73708 
                 481 
               
               
                   
               
               
                 532257 
                 CAACATGGAGGCTAGCATGT 
                 55 
                 74112 
                 74131 
                 482 
               
               
                   
               
               
                 532258 
                 AGACTAAGTGGCCTGAATGT 
                 52 
                 74317 
                 74336 
                 483 
               
               
                   
               
               
                 532259 
                 ACCTACCATGTCACTCTCAA 
                 61 
                 74418 
                 74437 
                 484 
               
               
                   
               
               
                 532260 
                 AACTTTCTTGTGTTTTATCA 
                 9 
                 75511 
                 75530 
                 485 
               
               
                   
               
               
                 532261 
                 TTTGCAAGACAAAGAAATGA 
                 31 
                 75915 
                 75934 
                 486 
               
               
                   
               
               
                 532262 
                 CATGCAAAGTGTTCCTCTTC 
                 63 
                 76024 
                 76043 
                 487 
               
               
                   
               
               
                 532263 
                 AGTGCTTTGCTTTCTCTTAT 
                 79 
                 76047 
                 76066 
                 488 
               
               
                   
               
               
                 532264 
                 GAACAAGAAACACTTGGTAA 
                 44 
                 76555 
                 76574 
                 489 
               
               
                   
               
               
                 532265 
                 AGTGTTCCAATTAAATGGCA 
                 34 
                 76643 
                 76662 
                 490 
               
               
                   
               
               
                 532266 
                 AAACAATGCCCTTGTAGTGA 
                 57 
                 76703 
                 76722 
                 491 
               
               
                   
               
               
                 532267 
                 TATTCTAGGTTTTGAGGTGA 
                 60 
                 76752 
                 76771 
                 492 
               
               
                   
               
               
                 532268 
                 ATATTCTAGGTTTTGAGGTG 
                 24 
                 76753 
                 76772 
                 493 
               
               
                   
               
               
                 532269 
                 GTTTTCCATTCTTTAAGAAA 
                 41 
                 76896 
                 76915 
                 494 
               
               
                   
               
               
                 532270 
                 AGCAATCCATTGATTGTATG 
                 59 
                 77044 
                 77063 
                 495 
               
               
                   
               
               
                 532271 
                 AATTATGGCAAAATGGAAAA 
                 37 
                 77076 
                 77095 
                 496 
               
               
                   
               
               
                 532272 
                 ACATTTGCTTATGAGACTAT 
                 62 
                 77638 
                 77657 
                 497 
               
               
                   
               
               
                 532273 
                 GCAGAGATAATCCTATGATG 
                 42 
                 77841 
                 77860 
                 498 
               
               
                   
               
               
                 532274 
                 TCCATCTGTTACCTCTCTGT 
                 77 
                 78122 
                 78141 
                 499 
               
               
                   
               
               
                 532275 
                 TTTGCCTGAAGGGCAGAACC 
                 40 
                 79478 
                 79497 
                 500 
               
               
                   
               
               
                 532276 
                 GAAAAAATCAGATTTTCACA 
                 0 
                 79664 
                 79683 
                 501 
               
               
                   
               
               
                 532277 
                 AACTTAATTTAATCATTTCT 
                 0 
                 79959 
                 79978 
                 502 
               
               
                   
               
               
                 532278 
                 TTTGGTTGTCATGAGTTGAG 
                 67 
                 80756 
                 80775 
                 503 
               
               
                   
               
               
                 532279 
                 TTCCATCTCTAGGGCACTTT 
                 74 
                 80900 
                 80919 
                 504 
               
               
                   
               
               
                 532280 
                 AGAGCTTATTTTCAAAATTC 
                 36 
                 80920 
                 80939 
                 505 
               
               
                   
               
               
                 532281 
                 ATAAAGAGCAAACAAACATA 
                 42 
                 81524 
                 81543 
                 506 
               
               
                   
               
               
                 532282 
                 TATAAATTCCTTGGTCTGAT 
                 33 
                 82835 
                 82854 
                 507 
               
               
                   
               
               
                 532283 
                 AAAATATAAATTCCTTGGTC 
                 13 
                 82839 
                 82858 
                 508 
               
               
                   
               
               
                 532284 
                 TTTTATAACAGCCTCTGACA 
                 38 
                 82959 
                 82978 
                 509 
               
               
                   
               
               
                 532285 
                 AAAAGACCATGTTGCTTATT 
                 72 
                 83179 
                 83198 
                 510 
               
               
                   
               
               
                 532286 
                 ATAGTCAGTCAGAATGTGGT 
                 72 
                 83330 
                 83349 
                 511 
               
               
                   
               
               
                 532287 
                 TGCCTTAGCTTGGAAAAGAC 
                 78 
                 83897 
                 83916 
                 512 
               
               
                   
               
               
                 532288 
                 AGGGCTAGCTGATGCCTCTC 
                 69 
                 84026 
                 84045 
                 513 
               
               
                   
               
               
                 532289 
                 TTGGACTGGGCTCAAACAGA 
                 72 
                 84381 
                 84400 
                 514 
               
               
                   
               
               
                 532290 
                 AAAGTCAGGCTAGAGGGACT 
                 49 
                 85713 
                 85732 
                 515 
               
               
                   
               
               
                 532291 
                 TCCTTGTTTTCTTGTAATGA 
                 50 
                 85945 
                 85964 
                 516 
               
               
                   
               
               
                 532292 
                 ACACCAGAGGAAGGAAATCA 
                 44 
                 86554 
                 86573 
                 517 
               
               
                   
               
               
                 532293 
                 GATGTACACCATTTTGAATT 
                 15 
                 86629 
                 86648 
                 518 
               
               
                   
               
               
                 532294 
                 TGCTCTGGCCTAGCCTATGT 
                 62 
                 86901 
                 86920 
                 519 
               
               
                   
               
               
                 532295 
                 CAGAGGTGTCTCCCAAGAAA 
                 60 
                 89940 
                 89959 
                 520 
               
               
                   
               
               
                 532296 
                 AAAGAGAATGGATCAAAGCT 
                 36 
                 91930 
                 91949 
                 521 
               
               
                   
               
               
                 532297 
                 GATTTGCAGAACAAATCTTG 
                 37 
                 93332 
                 93351 
                 522 
               
               
                   
               
               
                 532298 
                 TGGTTATGAAGGTTGGACCA 
                 52 
                 94839 
                 94858 
                 523 
               
               
                   
               
               
                 532299 
                 TGGCTAATTAATGGGCAATT 
                 63 
                 95292 
                 95311 
                 524 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 9 
               
             
            
               
                   
               
               
                 inhibition of GHR mRNA by 5-10-5 MOE gapmers 
               
               
                 targeting intron 1 of SEQ ID NO: 2 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                   
                   
                 SEQ 
                 SEQ 
                   
               
               
                   
                   
                   
                 ID 
                 ID 
                   
               
               
                   
                   
                 % 
                 NO: 
                 NO: 
                   
               
               
                   
                   
                 inhi- 
                 2 
                 2 
                 SEQ 
               
               
                 ISIS 
                   
                 bi- 
                 Start 
                 Stop 
                 ID 
               
               
                 NO 
                 Sequence 
                 tion 
                 Site 
                 Site 
                 NO 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 532300 
                 CTGTGCCATATTGCCTCTAA 
                 87 
                 95471 
                 95490 
                 525 
               
               
                   
               
               
                 532301 
                 GATTTCAACCAGCTCACCTG 
                 48 
                 95510 
                 95529 
                 526 
               
               
                   
               
               
                 532302 
                 GCAAAAGGGAACCCTGAAGC 
                 71 
                 95564 
                 95583 
                 527 
               
               
                   
               
               
                 532303 
                 CTAAGTGTTATAACAAACAC 
                 43 
                 96137 
                 96156 
                 528 
               
               
                   
               
               
                 532304 
                 GTCCATTGGTATAAAACTCA 
                 84 
                 96282 
                 96301 
                 529 
               
               
                   
               
               
                 532305 
                 TTTCAATACAATAAGATTTA 
                 34 
                 96793 
                 96812 
                 530 
               
               
                   
               
               
                 532306 
                 GTCCTTAGACCCCTCAATGG 
                 62 
                 96987 
                 97006 
                 531 
               
               
                   
               
               
                 532307 
                 GAGGATTTATTCATCTAGGC 
                 68 
                 97806 
                 97825 
                 532 
               
               
                   
               
               
                 532308 
                 CAGTGGGAGGATCAGATATC 
                 46 
                 97870 
                 97889 
                 533 
               
               
                   
               
               
                 532309 
                 ATCCCATCCAGCAGCTGGAC 
                 67 
                 98132 
                 98151 
                 534 
               
               
                   
               
               
                 532310 
                 AACTTGGGATGAGTTACTGA 
                 56 
                 98653 
                 98672 
                 535 
               
               
                   
               
               
                 532311 
                 GAAGGCTACCTAAAAGAAAT 
                 43 
                 98810 
                 98829 
                 536 
               
               
                   
               
               
                 532312 
                 AAAGAAATATTCACAACATT 
                 39 
                 99096 
                 99115 
                 537 
               
               
                   
               
               
                 532313 
                 ATGCTTATACTGCTGCTGTA 
                 69 
                 99791 
                 99810 
                 538 
               
               
                   
               
               
                 532314 
                 TCCTCACTTCAATCACCTTT 
                 70 
                 99819 
                 99838 
                 539 
               
               
                   
               
               
                 532315 
                 CTCTTTCTTCATAAATAAGT 
                 33 
                 100809 
                 100828 
                 540 
               
               
                   
               
               
                 532316 
                 TGGTAATCTGTGTCCCTTTA 
                 96 
                 101242 
                 101261 
                 541 
               
               
                   
               
               
                 532317 
                 TAATAAAAAAGTTTGAAACA 
                 41 
                 102549 
                 102568 
                 542 
               
               
                   
               
               
                 532318 
                 GGTGGTGGCAAGAGAAAAAT 
                 56 
                 103015 
                 103034 
                 543 
               
               
                   
               
               
                 532319 
                 CAAAAGGCCCTTTTTACATG 
                 28 
                 103034 
                 103053 
                 544 
               
               
                   
               
               
                 532320 
                 ACTCTACTGGTACCAATTTA 
                 31 
                 103173 
                 103192 
                 545 
               
               
                   
               
               
                 532321 
                 TCTGAACTTTTATGCTCTGT 
                 76 
                 103606 
                 103625 
                 546 
               
               
                   
               
               
                 532322 
                 AACTTTTGCCTGGGCATCCA 
                 16 
                 104067 
                 104086 
                 547 
               
               
                   
               
               
                 532323 
                 TGACTCCATGTCTCACATCC 
                 66 
                 104392 
                 104411 
                 548 
               
               
                   
               
               
                 532324 
                 TTACTTCCTAGATACAACAG 
                 53 
                 104541 
                 104560 
                 549 
               
               
                   
               
               
                 532325 
                 CTGGCCCCCATGATTCAATT 
                 44 
                 104835 
                 104854 
                 550 
               
               
                   
               
               
                 532326 
                 AAGACTGGCCCCCATGATTC 
                 49 
                 104839 
                 104858 
                 551 
               
               
                   
               
               
                 532327 
                 TGTCACTGGTCTGTGTATTT 
                 60 
                 106233 
                 106252 
                 552 
               
               
                   
               
               
                 532328 
                 ACAGAGTAGATTTAGCATAA 
                 23 
                 106980 
                 106999 
                 553 
               
               
                   
               
               
                 532329 
                 TAAACAGGTGTACTATTACA 
                 27 
                 107030 
                 107049 
                 554 
               
               
                   
               
               
                 532330 
                 GCTTTATCAACTAAGTTTAT 
                 22 
                 107716 
                 107735 
                 555 
               
               
                   
               
               
                 532331 
                 CAGAACTTCTTTTAAAATTG 
                 8 
                 107763 
                 107782 
                 556 
               
               
                   
               
               
                 532332 
                 GAATACAGACATACCTTGAA 
                 25 
                 108514 
                 108533 
                 557 
               
               
                   
               
               
                 532333 
                 CCATGACAACAATTTCAGAG 
                 58 
                 109486 
                 109505 
                 558 
               
               
                   
               
               
                 532334 
                 ACAAATAGCAATGAATGGGT 
                 45 
                 110878 
                 110897 
                 559 
               
               
                   
               
               
                 532335 
                 CAACAAATAGCAATGAATGG 
                 47 
                 110880 
                 110899 
                 560 
               
               
                   
               
               
                 532336 
                 GTACACAAATCAGTAGCTCT 
                 72 
                 115087 
                 115106 
                 561 
               
               
                   
               
               
                 532337 
                 CTATGTCAAAAAGACTGAAA 
                 4 
                 116370 
                 116389 
                 562 
               
               
                   
               
               
                 532338 
                 ATATACAGAACATTTCATCC 
                 13 
                 116743 
                 116762 
                 563 
               
               
                   
               
               
                 532339 
                 AGAATAGATAAGAACTCACC 
                 32 
                 117195 
                 117214 
                 564 
               
               
                   
               
               
                 532340 
                 AGGAAAGATACAGTCATTTT 
                 5 
                 117507 
                 117526 
                 565 
               
               
                   
               
               
                 532341 
                 GCACAAAGAACACCTGGGAA 
                 43 
                 117781 
                 117800 
                 566 
               
               
                   
               
               
                 532342 
                 CAAGAAGTCTGGGATTATGT 
                 0 
                 117938 
                 117957 
                 567 
               
               
                   
               
               
                 532343 
                 GTTAGTTATTAAGCTAATCA 
                 48 
                 118245 
                 118264 
                 568 
               
               
                   
               
               
                 532344 
                 AACCATTATTTATAGGCTAA 
                 14 
                 119127 
                 119146 
                 569 
               
               
                   
               
               
                 532345 
                 CCAGAATGCGATCACTTCTT 
                 76 
                 120826 
                 120845 
                 570 
               
               
                   
               
               
                 532346 
                 CCAGAAATTATCCTCCTCTC 
                 70 
                 121209 
                 121228 
                 571 
               
               
                   
               
               
                 532347 
                 AGGGAAATGCAAATTAAAAC 
                 20 
                 122479 
                 122498 
                 572 
               
               
                   
               
               
                 532348 
                 GCATCAAGATACAGAAAAAT 
                 24 
                 122751 
                 122770 
                 573 
               
               
                   
               
               
                 532349 
                 GAATGTTTATGAGATTTTTC 
                 0 
                 123571 
                 123590 
                 574 
               
               
                   
               
               
                 532350 
                 GCCAATTATATTGCCACATT 
                 23 
                 124413 
                 124432 
                 575 
               
               
                   
               
               
                 532351 
                 ATACTTGCTTATGTAGAAAT 
                 45 
                 124589 
                 124608 
                 576 
               
               
                   
               
               
                 532352 
                 TAATACTTGCTTATGTAGAA 
                 3 
                 124591 
                 124610 
                 577 
               
               
                   
               
               
                 532353 
                 GAACACATGGCATTCTGATA 
                 36 
                 125178 
                 125197 
                 578 
               
               
                   
               
               
                 532354 
                 CAGAATTTGCAGTATAAATC 
                 0 
                 126051 
                 126070 
                 579 
               
               
                   
               
               
                 532355 
                 TATGTTTTGAAATCTTATTT 
                 0 
                 126157 
                 126176 
                 580 
               
               
                   
               
               
                 532356 
                 ACTCACTGCTACCTCATTAA 
                 11 
                 126998 
                 127017 
                 581 
               
               
                   
               
               
                 532357 
                 AAGCAGTGATAGGGTATCTG 
                 59 
                 127080 
                 127099 
                 582 
               
               
                   
               
               
                 532358 
                 ATGAGGCCTATTACAATGGA 
                 14 
                 127170 
                 127189 
                 583 
               
               
                   
               
               
                 532359 
                 CTGGAGTCTCATGAGGCCTA 
                 53 
                 127180 
                 127199 
                 584 
               
               
                   
               
               
                 532360 
                 TGACTATCAGCCTTTTAATC 
                 45 
                 127663 
                 127682 
                 585 
               
               
                   
               
               
                 532361 
                 TTCAGAGAACAACCTTTGAA 
                 0 
                 127959 
                 127978 
                 586 
               
               
                   
               
               
                 532362 
                 AGCCATGTGTGATCTGATGT 
                 53 
                 128813 
                 128832 
                 587 
               
               
                   
               
               
                 532363 
                 GAAATTTACTCCAAACTAGC 
                 17 
                 128992 
                 129011 
                 588 
               
               
                   
               
               
                 532364 
                 AACATCCAGACCACCATCTA 
                 35 
                 130094 
                 130113 
                 589 
               
               
                   
               
               
                 532365 
                 GTACCAAACCATTCATGCTC 
                 56 
                 131036 
                 131055 
                 590 
               
               
                   
               
               
                 532366 
                 AGTACCAAACCATTCATGCT 
                 24 
                 131037 
                 131056 
                 591 
               
               
                   
               
               
                 532367 
                 TTATAGAGCTTGAGATTGAC 
                 7 
                 132165 
                 132184 
                 592 
               
               
                   
               
               
                 532368 
                 AGTCCATTATAGAGCTTGAG 
                 58 
                 132171 
                 132190 
                 593 
               
               
                   
               
               
                 532369 
                 AACCATGAGATGCAATGCAG 
                 40 
                 132498 
                 132517 
                 594 
               
               
                   
               
               
                 532370 
                 AGGATTGAGAATCGCTGATT 
                 42 
                 133168 
                 133187 
                 595 
               
               
                   
               
               
                 532371 
                 TCTAAAGCATGGCCAGGATT 
                 48 
                 133182 
                 133201 
                 596 
               
               
                   
               
               
                 532372 
                 GGGACTGAGTATTGATACTT 
                 44 
                 133222 
                 133241 
                 597 
               
               
                   
               
               
                 532373 
                 AGAAGTAGGGTGTTCCAGAT 
                 29 
                 133523 
                 133542 
                 598 
               
               
                   
               
               
                 532374 
                 AGAAATAGTCTTCCTACTAA 
                 0 
                 133547 
                 133566 
                 599 
               
               
                   
               
               
                 532375 
                 GCCTCCTTTAAGCTTCTATG 
                 22 
                 134240 
                 134259 
                 600 
               
               
                   
               
               
                 532376 
                 GGCCTGCCTTTACTTTCCCA 
                 36 
                 134598 
                 134617 
                 601 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 10 
               
             
            
               
                   
               
               
                 Inhibition of GHR mRNA by 5-10-5 MOE gapmers 
               
               
                 targeting introns 1 and 2 of SEQ ID NO: 2 
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                   
                 SEQ 
                 SEQ 
                   
                   
                   
                 SEQ 
                 SEQ 
                   
               
               
                   
                 ID 
                 ID 
                   
                   
                   
                 ID 
                 ID 
                   
               
               
                   
                 NO: 
                 NO: 
                   
                   
                 % 
                 NO: 
                 NO: 
                   
               
               
                   
                 1 
                 1 
                   
                   
                 inhi- 
                 2 
                 2 
                 SEQ 
               
               
                 ISIS 
                 Start 
                 Stop 
                   
                 Target 
                 bi- 
                 Start 
                 Stop 
                 ID 
               
               
                 NO 
                 Site 
                 Site 
                 Sequence 
                 region 
                 tion 
                 Site 
                 Site 
                 NO 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                 523638 
                 n/a 
                 n/a 
                 ACCTCAGTGGACTCTTTCCA 
                 Intron 1 
                 4 
                 84684 
                 84703 
                 602 
               
               
                   
               
               
                 523639 
                 n/a 
                 n/a 
                 CAAACCTAAGTTCAAGTCCT 
                 Intron 1 
                 62 
                 85523 
                 85542 
                 603 
               
               
                   
               
               
                 523640 
                 n/a 
                 n/a 
                 AGTTTCACTTCTTGAATCAA 
                 Intron 1 
                 38 
                 86373 
                 86392 
                 604 
               
               
                   
               
               
                 523641 
                 n/a 
                 n/a 
                 AAGATCAAATGAGGTCAAGG 
                 Intron 1 
                 30 
                 87181 
                 87200 
                 605 
               
               
                   
               
               
                 523642 
                 n/a 
                 n/a 
                 TAGATACAAATTTCATCACA 
                 Intron 1 
                 23 
                 88063 
                 88082 
                 606 
               
               
                   
               
               
                 523643 
                 n/a 
                 n/a 
                 ATTCCTAAAATAGGAGCAGG 
                 Intron 1 
                 45 
                 88870 
                 88889 
                 607 
               
               
                   
               
               
                 523644 
                 n/a 
                 n/a 
                 TTTTTATGTTGTATAAGATA 
                 Intron 1 
                 0 
                 89670 
                 89689 
                 608 
               
               
                   
               
               
                 523645 
                 n/a 
                 n/a 
                 GTTCAGCCAATACATGAGTA 
                 Intron 1 
                 48 
                 90473 
                 90492 
                 609 
               
               
                   
               
               
                 523646 
                 n/a 
                 n/a 
                 CCAGAGGGAGTTCATTACCA 
                 Intron 1 
                 62 
                 91273 
                 91292 
                 610 
               
               
                   
               
               
                 523647 
                 n/a 
                 n/a 
                 TCTCTCTAATTCAACCTTAT 
                 Intron 1 
                 44 
                 92107 
                 92126 
                 611 
               
               
                   
               
               
                 523648 
                 n/a 
                 n/a 
                 ATAATCCTCAGACCTCTTTA 
                 Intron 1 
                 29 
                 92925 
                 92944 
                 612 
               
               
                   
               
               
                 523649 
                 n/a 
                 n/a 
                 CACTGTGGCAGAATTCCAAG 
                 Intron 1 
                 28 
                 93762 
                 93781 
                 613 
               
               
                   
               
               
                 523650 
                 n/a 
                 n/a 
                 ACACCTTGGTGCCTAGAAGC 
                 Intron 1 
                 54 
                 94581 
                 94600 
                 614 
               
               
                   
               
               
                 523651 
                 n/a 
                 n/a 
                 GTAGCAATGACACCTAAGAA 
                 Intron 1 
                 58 
                 95394 
                 95413 
                 615 
               
               
                   
               
               
                 523652 
                 n/a 
                 n/a 
                 TTTAAAATAATAAATGCTTA 
                 Intron 1 
                 0 
                 96194 
                 96213 
                 616 
               
               
                   
               
               
                 523653 
                 n/a 
                 n/a 
                 TCATTTGGTCCTTAGACCCC 
                 Intron 1 
                 27 
                 96994 
                 97013 
                 617 
               
               
                   
               
               
                 523654 
                 n/a 
                 n/a 
                 TTATTCATCTAGGCCGAGTG 
                 Intron 1 
                 57 
                 97800 
                 97819 
                 618 
               
               
                   
               
               
                 523655 
                 n/a 
                 n/a 
                 TTGCAGAATCTTCTCTTTGG 
                 Intron 1 
                 65 
                 98627 
                 98646 
                 619 
               
               
                   
               
               
                 523656 
                 n/a 
                 n/a 
                 ACCATAAAGCTATGCCATAA 
                 Intron 1 
                 63 
                 99481 
                 99500 
                 620 
               
               
                   
               
               
                 523657 
                 n/a 
                 n/a 
                 GGCAAGGAGCACAATAGGAC 
                 Intron 1 
                 20 
                 100281 
                 100300 
                 621 
               
               
                   
               
               
                 523658 
                 n/a 
                 n/a 
                 ACCCAAAAAGTTGAGCTGAG 
                 Intron 1 
                 66 
                 101081 
                 101100 
                 622 
               
               
                   
               
               
                 523659 
                 n/a 
                 n/a 
                 TAGATTTTCAGACTCTTTCT 
                 Intron 1 
                 46 
                 101887 
                 101906 
                 623 
               
               
                   
               
               
                 523660 
                 n/a 
                 n/a 
                 AATTTCAATATTGTTGTGTT 
                 Intron 1 
                 0 
                 102760 
                 102779 
                 624 
               
               
                   
               
               
                 523661 
                 n/a 
                 n/a 
                 ATGCTTTTAATGGCACCCAA 
                 Intron 1 
                 69 
                 103569 
                 103588 
                 625 
               
               
                   
               
               
                 523662 
                 n/a 
                 n/a 
                 CATGTCTCACATCCAGGTCA 
                 Intron 1 
                 37 
                 104386 
                 104405 
                 626 
               
               
                   
               
               
                 523663 
                 n/a 
                 n/a 
                 TTCACTGGAGTAGACTTTTA 
                 Intron 1 
                 45 
                 105255 
                 105274 
                 627 
               
               
                   
               
               
                 523664 
                 n/a 
                 n/a 
                 CTTATAAGGGAGGTCTGGTA 
                 Intron 1 
                 41 
                 106147 
                 106166 
                 628 
               
               
                   
               
               
                 523665 
                 n/a 
                 n/a 
                 GCATAATTCTTAAGGGCCCT 
                 Intron 1 
                 71 
                 106966 
                 106985 
                 629 
               
               
                   
               
               
                 523666 
                 n/a 
                 n/a 
                 CCACAGAACTTCTTTTAAAA 
                 Intron 1 
                 27 
                 107766 
                 107785 
                 630 
               
               
                   
               
               
                 523667 
                 n/a 
                 n/a 
                 GGTGACCATGATTTTAACAA 
                 Intron 1 
                 25 
                 108566 
                 108585 
                 631 
               
               
                   
               
               
                 523668 
                 n/a 
                 n/a 
                 AACAGCTGCATGACAATTTT 
                 Intron 1 
                 50 
                 109382 
                 109401 
                 632 
               
               
                   
               
               
                 523669 
                 n/a 
                 n/a 
                 AGAAACAGAATCAGTGACTT 
                 Intron 1 
                 44 
                 110403 
                 110422 
                 633 
               
               
                   
               
               
                 523670 
                 n/a 
                 n/a 
                 CAGATTCCAGAGAAAAGCCA 
                 Intron 1 
                 14 
                 111203 
                 111222 
                 634 
               
               
                   
               
               
                 523671 
                 n/a 
                 n/a 
                 TGTGAGAAGAACTCTATCAC 
                 Intron 1 
                 12 
                 112030 
                 112049 
                 635 
               
               
                   
               
               
                 523672 
                 n/a 
                 n/a 
                 CTCACAAATCACCACTAAAG 
                 Intron 1 
                 31 
                 112842 
                 112861 
                 636 
               
               
                   
               
               
                 523673 
                 n/a 
                 n/a 
                 CAACGAGTGGATAAAGAAAC 
                 Intron 1 
                 28 
                 113646 
                 113665 
                 637 
               
               
                   
               
               
                 523674 
                 n/a 
                 n/a 
                 ATAAAACTGGATCCTCATCT 
                 Intron 1 
                 13 
                 114446 
                 114465 
                 638 
               
               
                   
               
               
                 523675 
                 n/a 
                 n/a 
                 ATTAAAACTCTCAGCAAAAT 
                 Intron 1 
                 0 
                 115450 
                 115469 
                 639 
               
               
                   
               
               
                 523676 
                 n/a 
                 n/a 
                 AAAGACTGAAAGAACACAAA 
                 Intron 1 
                 0 
                 116361 
                 116380 
                 640 
               
               
                   
               
               
                 523677 
                 n/a 
                 n/a 
                 TATCTGCTGCCTTCAGGAGA 
                 Intron 1 
                 0 
                 117168 
                 117187 
                 641 
               
               
                   
               
               
                 523678 
                 n/a 
                 n/a 
                 TTTGAATTAACCCAATTCAA 
                 Intron 1 
                 0 
                 117999 
                 118018 
                 642 
               
               
                   
               
               
                 523679 
                 n/a 
                 n/a 
                 TCTTAATTTACAACAGAGGA 
                 Intron 1 
                 25 
                 118821 
                 118840 
                 643 
               
               
                   
               
               
                 523680 
                 n/a 
                 n/a 
                 AGAAAAGTGACAGGCTTCCC 
                 Intron 1 
                 31 
                 119659 
                 119678 
                 644 
               
               
                   
               
               
                 523681 
                 n/a 
                 n/a 
                 ATGTTCCTTGAAGATCCCAA 
                 Intron 1 
                 37 
                 120478 
                 120497 
                 645 
               
               
                   
               
               
                 523682 
                 n/a 
                 n/a 
                 ATGAATAACACTTGCCACAA 
                 Intron 1 
                 0 
                 121379 
                 121398 
                 646 
               
               
                   
               
               
                 523683 
                 n/a 
                 n/a 
                 GTATGTTTATCACAGCACAG 
                 Intron 1 
                 56 
                 122180 
                 122199 
                 647 
               
               
                   
               
               
                 523684 
                 n/a 
                 n/a 
                 AAACACTGCAATATTAGGTT 
                 Intron 1 
                 34 
                 123031 
                 123050 
                 648 
               
               
                   
               
               
                 523685 
                 n/a 
                 n/a 
                 GATTGGTGCTTTTCAAACTG 
                 Intron 1 
                 39 
                 123936 
                 123955 
                 649 
               
               
                   
               
               
                 523686 
                 n/a 
                 n/a 
                 ATTTGTAAGACAAACATGAA 
                 Intron 1 
                 9 
                 124764 
                 124783 
                 650 
               
               
                   
               
               
                 523687 
                 n/a 
                 n/a 
                 TCACATGACTATGTTCTGGC 
                 Intron 1 
                 72 
                 125594 
                 125613 
                 651 
               
               
                   
               
               
                 523688 
                 n/a 
                 n/a 
                 AGTCCTGTCCACACTATTAA 
                 Intron 1 
                 6 
                 126415 
                 126434 
                 652 
               
               
                   
               
               
                 523689 
                 n/a 
                 n/a 
                 CTGGGCTCTGCCTGCTGAAC 
                 Intron 1 
                 17 
                 127217 
                 127236 
                 653 
               
               
                   
               
               
                 523690 
                 n/a 
                 n/a 
                 AAAACCCTTAAGTATTTCCT 
                 Intron 1 
                 12 
                 128054 
                 128073 
                 654 
               
               
                   
               
               
                 523691 
                 n/a 
                 n/a 
                 CTCTGTTTCAAACCCCCCAG 
                 Intron 1 
                 21 
                 128854 
                 128873 
                 655 
               
               
                   
               
               
                 523692 
                 n/a 
                 n/a 
                 GGACAGAACACCAATCACAA 
                 Intron 1 
                 18 
                 129654 
                 129673 
                 656 
               
               
                   
               
               
                 523693 
                 n/a 
                 n/a 
                 ACCTACCCTTCAAAGTCACG 
                 Intron 1 
                 0 
                 130486 
                 130505 
                 657 
               
               
                   
               
               
                 523694 
                 n/a 
                 n/a 
                 TTCAGTTCCCAGGAGGCTTA 
                 Intron 1 
                 5 
                 131286 
                 131305 
                 658 
               
               
                   
               
               
                 523695 
                 n/a 
                 n/a 
                 TTTTGCAATGTCTAGCAATT 
                 Intron 1 
                 0 
                 132086 
                 132105 
                 659 
               
               
                   
               
               
                 523696 
                 n/a 
                 n/a 
                 ATTAAGATCAGAAAATATTA 
                 Intron 1 
                 0 
                 132953 
                 132972 
                 660 
               
               
                   
               
               
                 523697 
                 n/a 
                 n/a 
                 TTAATGAGATATTTTGCACC 
                 Intron 1 
                 34 
                 133858 
                 133877 
                 661 
               
               
                   
               
               
                 523698 
                 n/a 
                 n/a 
                 GAGAGGTTAAGTAAATCTCC 
                 Intron 1 
                 0 
                 134678 
                 134697 
                 662 
               
               
                   
               
               
                 523699 
                 n/a 
                 n/a 
                 CAGACTCAAATTTGAAAATT 
                 Intron 1 
                 14 
                 135500 
                 135519 
                 663 
               
               
                   
               
               
                 523700 
                 n/a 
                 n/a 
                 GATAAGGCAATAATACAGCC 
                 Intron 1 
                 1 
                 136306 
                 136325 
                 664 
               
               
                   
               
               
                 523701 
                 n/a 
                 n/a 
                 ATCATTTGCCAATTTCTGTG 
                 Intron 1 
                 28 
                 137133 
                 137152 
                 665 
               
               
                   
               
               
                 523702 
                 n/a 
                 n/a 
                 CAAGAAGAAAAGATGCAAAA 
                 Intron l 
                 0 
                 138035 
                 138054 
                 666 
               
               
                   
               
               
                 523703 
                 n/a 
                 n/a 
                 AATTTATTTCCTTCCTATGA 
                 Intron 1 
                 0 
                 138857 
                 138876 
                 667 
               
               
                   
               
               
                 523704 
                 n/a 
                 n/a 
                 TTTTGGAAATGTGAGAAACG 
                 Intron 1 
                 0 
                 139771 
                 139790 
                 668 
               
               
                   
               
               
                 523705 
                 n/a 
                 n/a 
                 AAACACATGAGAAAAGATGA 
                 Intron 1 
                 0 
                 140593 
                 140612 
                 669 
               
               
                   
               
               
                 523706 
                 n/a 
                 n/a 
                 TGTTGGCTCAGTGGGAATGA 
                 Intron 1 
                 0 
                 141412 
                 141431 
                 670 
               
               
                   
               
               
                 523707 
                 n/a 
                 n/a 
                 TGAACAGGTTTGCATTTCTC 
                 Intron 1 
                 42 
                 142229 
                 142248 
                 671 
               
               
                   
               
               
                 523708 
                 n/a 
                 n/a 
                 TCCTAGGTGAACAGGCTATG 
                 Intron 1 
                 38 
                 143029 
                 143048 
                 672 
               
               
                   
               
               
                 523709 
                 n/a 
                 n/a 
                 CCCTAATCAGGCTGAAATAA 
                 Intron 1 
                 0 
                 143829 
                 143848 
                 673 
               
               
                   
               
               
                 523710 
                 n/a 
                 n/a 
                 AGGGCCAGTAAGGTTTGCTT 
                 Intron 1 
                 12 
                 144631 
                 144650 
                 674 
               
               
                   
               
               
                 523711 
                 n/a 
                 n/a 
                 AGCCTGAATTCTGAGCTCTG 
                 Intron 2 
                 88 
                 145431 
                 145450 
                 675 
               
               
                   
               
               
                 523712 
                 n/a 
                 n/a 
                 AGAGGATCTCAGCTGCAATT 
                 Intron 2 
                 71 
                 146238 
                 146257 
                 676 
               
               
                   
               
               
                 523713 
                 n/a 
                 n/a 
                 GAAAATCCCTGCTCAAGTGC 
                 Intron 2 
                 67 
                 147262 
                 147281 
                 677 
               
               
                   
               
               
                 523714 
                 n/a 
                 n/a 
                 TGCCTGATATTGTAATTCTT 
                 Intron 2 
                 90 
                 148062 
                 148081 
                 678 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 11 
               
             
            
               
                   
               
               
                 Inhibition of GHR mRNA by 5-10-5 MOE gapmers 
               
               
                 targeting introns 1 and 2 of SEQ ID NO: 2 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                   
                   
                   
                 SEQ 
                 SEQ 
                   
               
               
                   
                   
                   
                   
                 ID 
                 ID 
                   
               
               
                   
                   
                   
                 % 
                 NO: 
                 NO: 
                   
               
               
                   
                   
                   
                 inhi- 
                 2 
                 2 
                 SEQ 
               
               
                 ISIS 
                   
                 Target 
                 bi- 
                 Start 
                 Stop 
                 ID 
               
               
                 NO 
                 Sequence 
                 region 
                 tion 
                 Site 
                 Site 
                 NO 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                 532377 
                 CTCATACAGTGAAGTCTTCA 
                 Intron 1 
                 73 
                 135431 
                 135450 
                 679 
               
               
                   
               
               
                 532378 
                 CTCACTAAGCTTGATTCACT 
                 Intron 1 
                 67 
                 135818 
                 135837 
                 680 
               
               
                   
               
               
                 532379 
                 GATACAGAAATCCCAGTGAC 
                 Intron 1 
                 46 
                 136111 
                 136130 
                 681 
               
               
                   
               
               
                 532380 
                 TGTGCTTGGGTGTACAGGCA 
                 Intron 1 
                 71 
                 136282 
                 136301 
                 682 
               
               
                   
               
               
                 532381 
                 TCAAGCACTTACATCATATG 
                 Intron 1 
                 42 
                 136377 
                 136396 
                 683 
               
               
                   
               
               
                 532382 
                 AGGGTTAGTTATTACACTTA 
                 Intron 1 
                 60 
                 136576 
                 136595 
                 684 
               
               
                   
               
               
                 532383 
                 AGGCTTCATGTGAGGTAACA 
                 Intron 1 
                 58 
                 136996 
                 137015 
                 685 
               
               
                   
               
               
                 532384 
                 TGAAAGCTTAGTACAAGAAG 
                 Intron 1 
                 51 
                 138048 
                 138067 
                 686 
               
               
                   
               
               
                 532385 
                 CTCTCCTCTTGGAGATCCAG 
                 Intron 1 
                 58 
                 138782 
                 138801 
                 687 
               
               
                   
               
               
                 532386 
                 GCTGAGATTTCTCTCCTCTT 
                 Intron 1 
                 78 
                 138792 
                 138811 
                 688 
               
               
                   
               
               
                 532387 
                 CTTTTGCTGAGATTTCTCTC 
                 Intron 1 
                 58 
                 138797 
                 138816 
                 689 
               
               
                   
               
               
                 532388 
                 GAACATATGTCCATAGAATG 
                 Intron 1 
                 57 
                 141700 
                 141719 
                 690 
               
               
                   
               
               
                 532389 
                 GAACAGGCTATGTAATCAAA 
                 Intron 1 
                 68 
                 143021 
                 143040 
                 691 
               
               
                   
               
               
                 532390 
                 TTTTTATTACTGTGCAAACC 
                 Intron 1 
                 41 
                 143878 
                 143897 
                 692 
               
               
                   
               
               
                 532391 
                 ACTGAGGGTGGAAATGGAAA 
                 Intron 2 
                 23 
                 145059 
                 145078 
                 693 
               
               
                   
               
               
                 532392 
                 ATGCCATACTTTTCATTTCA 
                 Intron 2 
                 87 
                 146351 
                 146370 
                 694 
               
               
                   
               
               
                 532393 
                 TCTTTAAAGATTTCCTATGC 
                 Intron 2 
                 66 
                 146367 
                 146386 
                 695 
               
               
                   
               
               
                 532394 
                 TCACAATTAAATTATGTTTA 
                 Intron 2 
                 47 
                 149858 
                 149877 
                 696 
               
               
                   
               
               
                 532395 
                 TTTGCCATCACCAAACACCA 
                 Intron 2 
                 94 
                 150972 
                 150991 
                 697 
               
               
                   
               
               
                 532396 
                 TCAGAATGCTGAAGGATGGG 
                 Intron 2 
                 70 
                 152208 
                 152227 
                 698 
               
               
                   
               
               
                 532397 
                 ACAATTGCAGGAGAGAACTG 
                 Intron 2 
                 57 
                 152296 
                 152315 
                 699 
               
               
                   
               
               
                 532398 
                 GTTCAGTCACCTGGAAAGAG 
                 Intron 2 
                 62 
                 152549 
                 152568 
                 700 
               
               
                   
               
               
                 532399 
                 CGGAGTTCAGTCACCTGGAA 
                 Intron 2 
                 77 
                 152553 
                 152572 
                 701 
               
               
                   
               
               
                 532400 
                 AATCTAAAGTTCAATGTCCA 
                 Intron 2 
                 77 
                 152752 
                 152771 
                 702 
               
               
                   
               
               
                 532401 
                 CCACCTTTGGGTGAATAGCA 
                 Intron 2 
                 95 
                 153921 
                 153940 
                 703 
               
               
                   
               
               
                 532402 
                 CAACATCAAAAGTTTCCACC 
                 Intron 2 
                 81 
                 153936 
                 153955 
                 704 
               
               
                   
               
               
                 532403 
                 AAGCTTCTATCAACCAACTG 
                 Intron 2 
                 87 
                 154093 
                 154112 
                 705 
               
               
                   
               
               
                 532404 
                 ACCATTTTCTAATAATTCAC 
                 Intron 2 
                 46 
                 154502 
                 154521 
                 706 
               
               
                   
               
               
                 532405 
                 ACCTGCACTTGGACAACTGA 
                 Intron 2 
                 60 
                 154727 
                 154746 
                 707 
               
               
                   
               
               
                 532406 
                 GTCAGTGCTTTGGTGATGTA 
                 Intron 2 
                 11 
                 155283 
                 155302 
                 708 
               
               
                   
               
               
                 532407 
                 TAGAAGCACAGGAACTAGAG 
                 Intron 2 
                 68 
                 155889 
                 155908 
                 709 
               
               
                   
               
               
                 532408 
                 TTTAATTTTATTAGAAGCAC 
                 Intron 2 
                 14 
                 155900 
                 155919 
                 710 
               
               
                   
               
               
                 532409 
                 GAGCAAGAATTAAGAAAATC 
                 Intron 2 
                 29 
                 155973 
                 155992 
                 711 
               
               
                   
               
               
                 532410 
                 CTCTGCAGTCATGTACACAA 
                 Intron 2 
                 93 
                 156594 
                 156613 
                 712 
               
               
                   
               
               
                 532411 
                 GCTTGGTTTGTCAATCCTTT 
                 Intron 2 
                 95 
                 156889 
                 156908 
                 713 
               
               
                   
               
               
                 532412 
                 GTTCTCAAGCAGGAGCCATT 
                 Intron 2 
                 70 
                 157330 
                 157349 
                 714 
               
               
                   
               
               
                 532413 
                 AGGGTGATCTTCCAAAACAA 
                 Intron 2 
                 87 
                 158612 
                 158631 
                 715 
               
               
                   
               
               
                 532414 
                 TCTCCTATGCTTCCTTTAAT 
                 Intron 2 
                 25 
                 158813 
                 158832 
                 716 
               
               
                   
               
               
                 532415 
                 GACATAAATATGTTCACTGA 
                 Intron 2 
                 81 
                 159216 
                 159235 
                 717 
               
               
                   
               
               
                 532416 
                 TTACTGAGTGACAGTACAGT 
                 Intron 2 
                 65 
                 161588 
                 161607 
                 718 
               
               
                   
               
               
                 532417 
                 CCAGGCACCAGCACAGGCAC 
                 Intron 2 
                 47 
                 161950 
                 161969 
                 719 
               
               
                   
               
               
                 532418 
                 TTAATGTCAGTAGAAAGCTG 
                 Intron 2 
                 0 
                 162349 
                 162368 
                 720 
               
               
                   
               
               
                 532419 
                 GCAGGTGGAAAGAAGATGTC 
                 Intron 2 
                 50 
                 162531 
                 162550 
                 721 
               
               
                   
               
               
                 532420 
                 GCCAGGGTCTTTACAAAGTT 
                 Intron 2 
                 93 
                 162751 
                 162770 
                 722 
               
               
                   
               
               
                 532421 
                 CATTACCTTTGTACATGTAC 
                 Intron 2 
                 83 
                 164839 
                 164858 
                 723 
               
               
                   
               
               
                 532422 
                 GAAGCAACTTCTCTGAGGTC 
                 Intron 2 
                 68 
                 165040 
                 165059 
                 724 
               
               
                   
               
               
                 532423 
                 GCCTGGCAAGAAGGGCCCTT 
                 Intron 2 
                 56 
                 165856 
                 165875 
                 725 
               
               
                   
               
               
                 532424 
                 ACACATGTTTTTAAATTTAT 
                 Intron 2 
                 21 
                 166241 
                 166260 
                 726 
               
               
                   
               
               
                 532425 
                 TCACAATGCACTAAAAGAAA 
                 Intron 2 
                 53 
                 168760 
                 168779 
                 727 
               
               
                   
               
               
                 532426 
                 TCCCAATGACTTACTGTAGA 
                 Intron 2 
                 78 
                 169073 
                 169092 
                 728 
               
               
                   
               
               
                 532427 
                 TAAGCATTTATGGAGGAATG 
                 Intron 2 
                 46 
                 169134 
                 169153 
                 729 
               
               
                   
               
               
                 532428 
                 TGAGGTGGGTGGCCAACAGG 
                 Intron 2 
                 66 
                 170081 
                 170100 
                 730 
               
               
                   
               
               
                 532429 
                 GTTTTTCATTTTGATTGCAG 
                 Intron 2 
                 88 
                 170158 
                 170177 
                 731 
               
               
                   
               
               
                 532430 
                 AGCTCAAGTGTTTTTCATTT 
                 Intron 2 
                 64 
                 170167 
                 170186 
                 732 
               
               
                   
               
               
                 532431 
                 CAATGTCACAGCTGTTTCCT 
                 Intron 2 
                 62 
                 170272 
                 170291 
                 733 
               
               
                   
               
               
                 532432 
                 GAACTTTGGAGGCTTTTAGA 
                 Intron 2 
                 55 
                 170703 
                 170722 
                 734 
               
               
                   
               
               
                 532433 
                 TGTATGCCCCAAACTCCCAT 
                 Intron 2 
                 83 
                 171431 
                 171450 
                 735 
               
               
                   
               
               
                 532434 
                 ACACAAATAAGGGAATAATA 
                 Intron 2 
                 24 
                 171549 
                 171568 
                 736 
               
               
                   
               
               
                 532435 
                 TAGTTCAGCCACTATGGAAA 
                 Intron 2 
                 47 
                 171926 
                 171945 
                 737 
               
               
                   
               
               
                 532436 
                 CTCCAAATTCCAGTCCTAGG 
                 Intron 2 
                 93 
                 172746 
                 172765 
                 738 
               
               
                   
               
               
                 532437 
                 AGTTGGCACTGCTATATCAG 
                 Intron 2 
                 66 
                 173668 
                 173687 
                 739 
               
               
                   
               
               
                 532438 
                 GGCCTTAGATTGTAAGTTTT 
                 Intron 2 
                 69 
                 174122 
                 174141 
                 740 
               
               
                   
               
               
                 532439 
                 TTTTAGTATTATTGTAGGAA 
                 Intron 2 
                 16 
                 174188 
                 174207 
                 741 
               
               
                   
               
               
                 532440 
                 TTTCATTAATGAAACCTGAT 
                 Intron 2 
                 39 
                 174812 
                 174831 
                 742 
               
               
                   
               
               
                 532441 
                 CCCTCAGCTGCCTCTTCAAT 
                 Intron 2 
                 51 
                 175014 
                 175033 
                 743 
               
               
                   
               
               
                 532442 
                 TATTGTATCCTGGCCCCTAA 
                 Intron 2 
                 68 
                 175689 
                 175708 
                 744 
               
               
                   
               
               
                 532443 
                 AGAACAAGAGCCTAGAAGTA 
                 Intron 2 
                 35 
                 176592 
                 176611 
                 745 
               
               
                   
               
               
                 532444 
                 GTGACTATGTCACTGAATTT 
                 Intron 2 
                 14 
                 176918 
                 176937 
                 746 
               
               
                   
               
               
                 532445 
                 GCCCTACCCAGCAGCCTGTG 
                 Intron 2 
                 79 
                 177540 
                 177559 
                 747 
               
               
                   
               
               
                 532446 
                 CAAACATAAAGAGAGTTCCA 
                 Intron 2 
                 79 
                 177811 
                 177830 
                 748 
               
               
                   
               
               
                 532447 
                 CTTTAAATGAAGTAGAGCTC 
                 Intron 2 
                 0 
                 178090 
                 178109 
                 749 
               
               
                   
               
               
                 532448 
                 CTGTTCAAAGAATGCAGGCC 
                 Intron 2 
                 70 
                 178905 
                 178924 
                 750 
               
               
                   
               
               
                 532449 
                 GTCTAGCCTAACAGAGATAT 
                 Intron 2 
                 47 
                 179137 
                 179156 
                 751 
               
               
                   
               
               
                 532450 
                 AAAGAGTGATGTCTAGCCTA 
                 Intron 2 
                 55 
                 179147 
                 179166 
                 752 
               
               
                   
               
               
                 532451 
                 CACTTCTTACTCCTTTGAGG 
                 Intron 2 
                 50 
                 179631 
                 179650 
                 753 
               
               
                   
               
               
                 532452 
                 TTCCACAAGAAACTCAGTTT 
                 Intron 2 
                 56 
                 181514 
                 181533 
                 754 
               
               
                   
               
               
                 532453 
                 AGAAATGCCAAAGATAGCTC 
                 Intron 2 
                 56 
                 182105 
                 182124 
                 755 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 12 
               
             
            
               
                   
               
               
                 Inhibition of GHR mRNA by 5-10-5 MOE gapmers 
               
               
                 targeting intron 2 of SEQ ID NO: 2 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                   
                   
                 SEQ 
                 SEQ 
                   
               
               
                   
                   
                   
                 ID 
                 ID 
                   
               
               
                   
                   
                 % 
                 NO: 
                 NO: 
                   
               
               
                   
                   
                 inhi- 
                 2 
                 2 
                 SEQ 
               
               
                 ISIS 
                   
                 bi- 
                 Start 
                 Stop 
                 ID 
               
               
                 NO 
                 Sequence 
                 tion 
                 Site 
                 Site 
                 NO 
               
               
                   
               
               
                 533249 
                 AGCAGAGGATCTCAGCTGCA 
                 84 
                 146241 
                 146260 
                 756 
               
               
                   
               
               
                 533250 
                 AATCCCTGCTCAAGTGCTAC 
                 75 
                 147259 
                 147278 
                 757 
               
               
                   
               
               
                 533251 
                 AAATCCCTGCTCAAGTGCTA 
                 71 
                 147260 
                 147279 
                 758 
               
               
                   
               
               
                 533252 
                 AAAATCCCTGCTCAAGTGCT 
                 73 
                 147261 
                 147280 
                 759 
               
               
                   
               
               
                 533253 
                 AGAAAATCCCTGCTCAAGTG 
                 56 
                 147263 
                 147282 
                 760 
               
               
                   
               
               
                 533254 
                 AAGAAAATCCCTGCTCAAGT 
                 58 
                 147264 
                 147283 
                 761 
               
               
                   
               
               
                 533255 
                 CAAGAAAATCCCTGCTCAAG 
                 46 
                 147265 
                 147284 
                 762 
               
               
                   
               
               
                 533256 
                 CTGATATTGTAATTCTTGGT 
                 91 
                 148059 
                 148078 
                 763 
               
               
                   
               
               
                 533257 
                 CCTGATATTGTAATTCTTGG 
                 90 
                 148060 
                 148079 
                 764 
               
               
                   
               
               
                 533258 
                 GCCTGATATTGTAATTCTTG 
                 94 
                 148061 
                 148080 
                 765 
               
               
                   
               
               
                 533259 
                 ATGCCTGATATTGTAATTCT 
                 91 
                 148063 
                 148082 
                 766 
               
               
                   
               
               
                 533260 
                 AATGCCTGATATTGTAATTC 
                 74 
                 148064 
                 148083 
                 767 
               
               
                   
               
               
                 533261 
                 CAATGCCTGATATTGTAATT 
                 76 
                 148065 
                 148084 
                 768 
               
               
                   
               
               
                 533262 
                 AATTATGTGCTTTGCCTGCA 
                 92 
                 148904 
                 148923 
                 769 
               
               
                   
               
               
                 533263 
                 CAATTATGTGCTTTGCCTGC 
                 83 
                 148905 
                 148924 
                 770 
               
               
                   
               
               
                 533264 
                 TCAATTATGTGCTTTGCCTG 
                 83 
                 148906 
                 148925 
                 771 
               
               
                   
               
               
                 533265 
                 TGTCAATTATGTGCTTTGCC 
                 91 
                 148908 
                 148927 
                 772 
               
               
                   
               
               
                 533266 
                 ATGTCAATTATGTGCTTTGC 
                 83 
                 148909 
                 148928 
                 773 
               
               
                   
               
               
                 533267 
                 GATGTCAATTATGTGCTTTG 
                 74 
                 148910 
                 148929 
                 774 
               
               
                   
               
               
                 533268 
                 CTGGTGACTCTGCCTGATGA 
                 77 
                 151385 
                 151404 
                 775 
               
               
                   
               
               
                 533269 
                 GCTGGTGACTCTGCCTGATG 
                 87 
                 151386 
                 151405 
                 776 
               
               
                   
               
               
                 533270 
                 TGCTGGTGACTCTGCCTGAT 
                 89 
                 151387 
                 151406 
                 777 
               
               
                   
               
               
                 533271 
                 GCTGCTGGTGACTCTGCCTG 
                 94 
                 151389 
                 151408 
                 778 
               
               
                   
               
               
                 533272 
                 GGCTGCTGGTGACTCTGCCT 
                 77 
                 151390 
                 151409 
                 779 
               
               
                   
               
               
                 533273 
                 TGGCTGCTGGTGACTCTGCC 
                 82 
                 151391 
                 151410 
                 780 
               
               
                   
               
               
                 533274 
                 GCTGAAGGATGGGCATCCAG 
                 85 
                 152201 
                 152220 
                 781 
               
               
                   
               
               
                 533275 
                 TGCTGAAGGATGGGCATCCA 
                 85 
                 152202 
                 152221 
                 782 
               
               
                   
               
               
                 533276 
                 ATGCTGAAGGATGGGCATCC 
                 78 
                 152203 
                 152222 
                 783 
               
               
                   
               
               
                 533277 
                 GAATGCTGAAGGATGGGCAT 
                 66 
                 152205 
                 152224 
                 784 
               
               
                   
               
               
                 533278 
                 AGAATGCTGAAGGATGGGCA 
                 81 
                 152206 
                 152225 
                 785 
               
               
                   
               
               
                 533279 
                 CAGAATGCTGAAGGATGGGC 
                 85 
                 152207 
                 152226 
                 786 
               
               
                   
               
               
                 533280 
                 TCCAGTAGTCAATATTATTT 
                 87 
                 153001 
                 153020 
                 787 
               
               
                   
               
               
                 533281 
                 ATCCAGTAGTCAATATTATT 
                 85 
                 153002 
                 153021 
                 788 
               
               
                   
               
               
                 533282 
                 TATCCAGTAGTCAATATTAT 
                 69 
                 153003 
                 153022 
                 789 
               
               
                   
               
               
                 533283 
                 GTTATCCAGTAGTCAATATT 
                 77 
                 153005 
                 153024 
                 790 
               
               
                   
               
               
                 533284 
                 GGTTATCCAGTAGTCAATAT 
                 85 
                 153006 
                 153025 
                 791 
               
               
                   
               
               
                 533285 
                 TGGTTATCCAGTAGTCAATA 
                 86 
                 153007 
                 153026 
                 792 
               
               
                   
               
               
                 533286 
                 CAACTTGAGGACAATAAGAG 
                 35 
                 155591 
                 155610 
                 793 
               
               
                   
               
               
                 533287 
                 TCAACTTGAGGACAATAAGA 
                 62 
                 155592 
                 155611 
                 794 
               
               
                   
               
               
                 533288 
                 CTCAACTTGAGGACAATAAG 
                 86 
                 155593 
                 155612 
                 795 
               
               
                   
               
               
                 533289 
                 AACTCAACTTGAGGACAATA 
                 82 
                 155595 
                 155614 
                 796 
               
               
                   
               
               
                 533290 
                 TAACTCAACTTGAGGACAAT 
                 66 
                 155596 
                 155615 
                 797 
               
               
                   
               
               
                 533291 
                 ATAACTCAACTTGAGGACAA 
                 87 
                 155597 
                 155616 
                 798 
               
               
                   
               
               
                 533292 
                 CAGGAAGAAAGGAACCTTAG 
                 77 
                 156391 
                 156410 
                 799 
               
               
                   
               
               
                 533293 
                 CCAGGAAGAAAGGAACCTTA 
                 84 
                 156392 
                 156411 
                 800 
               
               
                   
               
               
                 533294 
                 ACCAGGAAGAAAGGAACCTT 
                 86 
                 156393 
                 156412 
                 801 
               
               
                   
               
               
                 533295 
                 AGACCAGGAAGAAAGGAACC 
                 74 
                 156395 
                 156414 
                 802 
               
               
                   
               
               
                 533296 
                 TAGACCAGGAAGAAAGGAAC 
                 59 
                 156396 
                 156415 
                 803 
               
               
                   
               
               
                 533297 
                 ATAGACCAGGAAGAAAGGAA 
                 65 
                 156397 
                 156416 
                 804 
               
               
                   
               
               
                 533298 
                 TACAATGCACAGGACACGCC 
                 73 
                 157198 
                 157217 
                 805 
               
               
                   
               
               
                 533299 
                 CTACAATGCACAGGACACGC 
                 85 
                 157199 
                 157218 
                 806 
               
               
                   
               
               
                 533300 
                 GCTACAATGCACAGGACACG 
                 83 
                 157200 
                 157219 
                 807 
               
               
                   
               
               
                 533301 
                 ATGCTACAATGCACAGGACA 
                 89 
                 157202 
                 157221 
                 808 
               
               
                   
               
               
                 533302 
                 TATGCTACAATGCACAGGAC 
                 82 
                 157203 
                 157222 
                 809 
               
               
                   
               
               
                 533303 
                 ATATGCTACAATGCACAGGA 
                 84 
                 157204 
                 157223 
                 810 
               
               
                   
               
               
                 533304 
                 CTGATATTTATTGCTGTACG 
                 76 
                 158006 
                 158025 
                 811 
               
               
                   
               
               
                 533305 
                 CTCTGATATTTATTGCTGTA 
                 80 
                 158008 
                 158027 
                 812 
               
               
                   
               
               
                 533306 
                 TCTCTGATATTTATTGCTGT 
                 86 
                 158009 
                 158028 
                 813 
               
               
                   
               
               
                 533307 
                 GTCTCTGATATTTATTGCTG 
                 80 
                 158010 
                 158029 
                 814 
               
               
                   
               
               
                 533308 
                 CCAGAAGAATTACCCATGCA 
                 85 
                 165550 
                 165569 
                 815 
               
               
                   
               
               
                 533309 
                 TCCAGAAGAATTACCCATGC 
                 84 
                 165551 
                 165570 
                 816 
               
               
                   
               
               
                 533310 
                 TTCCAGAAGAATTACCCATG 
                 81 
                 165552 
                 165571 
                 817 
               
               
                   
               
               
                 533311 
                 TCTTCCAGAAGAATTACCCA 
                 58 
                 165554 
                 165573 
                 818 
               
               
                   
               
               
                 533312 
                 ATCTTCCAGAAGAATTACCC 
                 64 
                 165555 
                 165574 
                 819 
               
               
                   
               
               
                 533313 
                 CATCTTCCAGAAGAATTACC 
                 58 
                 165556 
                 165575 
                 820 
               
               
                   
               
               
                 533314 
                 TTTCTGCAGTATCCTAGCCT 
                 78 
                 166350 
                 166369 
                 821 
               
               
                   
               
               
                 533315 
                 GTTTCTGCAGTATCCTAGCC 
                 88 
                 166351 
                 166370 
                 822 
               
               
                   
               
               
                 533316 
                 AGTTTCTGCAGTATCCTAGC 
                 86 
                 166352 
                 166371 
                 823 
               
               
                   
               
               
                 533317 
                 TCAGTTTCTGCAGTATCCTA 
                 88 
                 166354 
                 166373 
                 824 
               
               
                   
               
               
                 533318 
                 TTCAGTTTCTGCAGTATCCT 
                 87 
                 166355 
                 166374 
                 825 
               
               
                   
               
               
                 533319 
                 TTTCAGTTTCTGCAGTATCC 
                 80 
                 166356 
                 166375 
                 826 
               
               
                   
               
               
                 533320 
                 GTTTCCATTTTCTTGATTCC 
                 70 
                 169601 
                 169620 
                 827 
               
               
                   
               
               
                 533321 
                 TGTTTCCATTTTCTTGATTC 
                 54 
                 169602 
                 169621 
                 828 
               
               
                   
               
               
                 533322 
                 GTGTTTCCATTTTCTTGATT 
                 55 
                 169603 
                 169622 
                 829 
               
               
                   
               
               
                 533323 
                 TGGTGTTTCCATTTTCTTGA 
                 73 
                 169605 
                 169624 
                 830 
               
               
                   
               
               
                 533324 
                 ATGGTGTTTCCATTTTCTTG 
                 76 
                 169606 
                 169625 
                 831 
               
               
                   
               
               
                 533325 
                 AATGGTGTTTCCATTTTCTT 
                 78 
                 169607 
                 169626 
                 832 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 13 
               
             
            
               
                   
               
               
                 Inhibition of GHR mRNA by 5-10-5 MOE gapmers 
               
               
                 targeting introns 2 and 3 of SEQ ID NO: 2 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                   
                   
                   
                 SEQ 
                 SEQ 
                   
               
               
                   
                   
                   
                   
                 ID 
                 ID 
                   
               
               
                   
                   
                   
                 % 
                 NO: 
                 NO: 
                   
               
               
                   
                   
                   
                 inhi- 
                 2 
                 2 
                 SEQ 
               
               
                 ISIS 
                   
                 Target 
                 bi- 
                 Start 
                 Stop 
                 ID 
               
               
                 NO 
                 Sequence 
                 region 
                 tion 
                 Site 
                 Site 
                 NO 
               
               
                   
               
               
                 533326 
                 AACCCATTTCATCCATTTAA 
                 Intron 2 
                 93 
                 175369 
                 175388 
                 833 
               
               
                   
               
               
                 533327 
                 GAACCCATTTCATCCATTTA 
                 Intron 2 
                 83 
                 175370 
                 175389 
                 834 
               
               
                   
               
               
                 533328 
                 GGAACCCATTTCATCCATTT 
                 Intron 2 
                 92 
                 175371 
                 175390 
                 835 
               
               
                   
               
               
                 533329 
                 TAGGAACCCATTTCATCCAT 
                 Intron 2 
                 91 
                 175373 
                 175392 
                 836 
               
               
                   
               
               
                 533330 
                 GTAGGAACCCATTTCATCCA 
                 Intron 2 
                 95 
                 175374 
                 175393 
                 837 
               
               
                   
               
               
                 533331 
                 GGTAGGAACCCATTTCATCC 
                 Intron 2 
                 92 
                 175375 
                 175394 
                 838 
               
               
                   
               
               
                 533332 
                 TGAGGGATTGCCTCAGTAGC 
                 Intron 2 
                 66 
                 179616 
                 179635 
                 839 
               
               
                   
               
               
                 533333 
                 TTGAGGGATTGCCTCAGTAG 
                 Intron 2 
                 72 
                 179617 
                 179636 
                 840 
               
               
                   
               
               
                 533334 
                 TTTGAGGGATTGCCTCAGTA 
                 Intron 2 
                 67 
                 179618 
                 179637 
                 841 
               
               
                   
               
               
                 533335 
                 CCTTTGAGGGATTGCCTCAG 
                 Intron 2 
                 74 
                 179620 
                 179639 
                 842 
               
               
                   
               
               
                 533336 
                 TCCTTTGAGGGATTGCCTCA 
                 Intron 2 
                 66 
                 179621 
                 179640 
                 843 
               
               
                   
               
               
                 533337 
                 CTCCTTTGAGGGATTGCCTC 
                 Intron 2 
                 76 
                 179622 
                 179641 
                 844 
               
               
                   
               
               
                 533338 
                 AACTTAGGACTTGGGACATT 
                 Intron 2 
                 64 
                 184575 
                 184594 
                 845 
               
               
                   
               
               
                 533339 
                 TAACTTAGGACTTGGGACAT 
                 Intron 2 
                 54 
                 184576 
                 184595 
                 846 
               
               
                   
               
               
                 533340 
                 CTAACTTAGGACTTGGGACA 
                 Intron 2 
                 63 
                 184577 
                 184596 
                 847 
               
               
                   
               
               
                 533341 
                 CACTAACTTAGGACTTGGGA 
                 Intron 2 
                 82 
                 184579 
                 184598 
                 848 
               
               
                   
               
               
                 533342 
                 TCACTAACTTAGGACTTGGG 
                 Intron 2 
                 77 
                 184580 
                 184599 
                 849 
               
               
                   
               
               
                 533343 
                 GTCACTAACTTAGGACTTGG 
                 Intron 2 
                 83 
                 184581 
                 184600 
                 850 
               
               
                   
               
               
                 533344 
                 TGGGCTAGATCAGGATTGGT 
                 Intron 2 
                 81 
                 188617 
                 188636 
                 851 
               
               
                   
               
               
                 533345 
                 ATGGGCTAGATCAGGATTGG 
                 Intron 2 
                 70 
                 188618 
                 188637 
                 852 
               
               
                   
               
               
                 533346 
                 CATGGGCTAGATCAGGATTG 
                 Intron 2 
                 64 
                 188619 
                 188638 
                 853 
               
               
                   
               
               
                 533347 
                 ACCATGGGCTAGATCAGGAT 
                 Intron 2 
                 82 
                 188621 
                 188640 
                 854 
               
               
                   
               
               
                 533348 
                 TACCATGGGCTAGATCAGGA 
                 Intron 2 
                 88 
                 188622 
                 188641 
                 855 
               
               
                   
               
               
                 533349 
                 CTACCATGGGCTAGATCAGG 
                 Intron 2 
                 87 
                 188623 
                 188642 
                 856 
               
               
                   
               
               
                 533350 
                 ATGAGCTTAGCAGTCACTTA 
                 Intron 2 
                 83 
                 189482 
                 189501 
                 857 
               
               
                   
               
               
                 533351 
                 CATGAGCTTAGCAGTCACTT 
                 Intron 2 
                 87 
                 189483 
                 189502 
                 858 
               
               
                   
               
               
                 533352 
                 CCATGAGCTTAGCAGTCACT 
                 Intron 2 
                 92 
                 189484 
                 189503 
                 859 
               
               
                   
               
               
                 533353 
                 GTCTCAGCAAACCTGGGATA 
                 Intron 2 
                 84 
                 190283 
                 190302 
                 860 
               
               
                   
               
               
                 533354 
                 TGTCTCAGCAAACCTGGGAT 
                 Intron 2 
                 82 
                 190284 
                 190303 
                 861 
               
               
                   
               
               
                 533355 
                 ATGTCTCAGCAAACCTGGGA 
                 Intron 2 
                 81 
                 190285 
                 190304 
                 862 
               
               
                   
               
               
                 533356 
                 GAATGTCTCAGCAAACCTGG 
                 Intron 2 
                 76 
                 190287 
                 190306 
                 863 
               
               
                   
               
               
                 533357 
                 GGAATGTCTCAGCAAACCTG 
                 Intron 2 
                 82 
                 190288 
                 190307 
                 864 
               
               
                   
               
               
                 533358 
                 AGGAATGTCTCAGCAAACCT 
                 Intron 2 
                 85 
                 190289 
                 190308 
                 865 
               
               
                   
               
               
                 533359 
                 TACAGACATAGCTCTAACCT 
                 Intron 2 
                 79 
                 191139 
                 191158 
                 866 
               
               
                   
               
               
                 533360 
                 ATACAGACATAGCTCTAACC 
                 Intron 2 
                 79 
                 191140 
                 191159 
                 867 
               
               
                   
               
               
                 533361 
                 GATACAGACATAGCTCTAAC 
                 Intron 2 
                 71 
                 191141 
                 191160 
                 868 
               
               
                   
               
               
                 533362 
                 TGGATACAGACATAGCTCTA 
                 Intron 2 
                 79 
                 191143 
                 191162 
                 869 
               
               
                   
               
               
                 533363 
                 CTGGATACAGACATAGCTCT 
                 Intron 2 
                 82 
                 191144 
                 191163 
                 870 
               
               
                   
               
               
                 533364 
                 GCTGGATACAGACATAGCTC 
                 Intron 2 
                 95 
                 191145 
                 191164 
                 871 
               
               
                   
               
               
                 533365 
                 ACACTGTTTGTGAGGGTCAA 
                 Intron 2 
                 87 
                 191939 
                 191958 
                 872 
               
               
                   
               
               
                 533366 
                 AACACTGTTTGTGAGGGTCA 
                 Intron 2 
                 81 
                 191940 
                 191959 
                 873 
               
               
                   
               
               
                 533367 
                 CAACACTGTTTGTGAGGGTC 
                 Intron 2 
                 85 
                 191941 
                 191960 
                 874 
               
               
                   
               
               
                 533368 
                 AACAACACTGTTTGTGAGGG 
                 Intron 2 
                 65 
                 191943 
                 191962 
                 875 
               
               
                   
               
               
                 533369 
                 AAACAACACTGTTTGTGAGG 
                 Intron 2 
                 76 
                 191944 
                 191963 
                 876 
               
               
                   
               
               
                 533370 
                 CAAACAACACTGTTTGTGAG 
                 Intron 2 
                 67 
                 191945 
                 191964 
                 877 
               
               
                   
               
               
                 533371 
                 TTCAAGTTTAGGATCTGCAG 
                 Intron 2 
                 73 
                 196536 
                 196555 
                 878 
               
               
                   
               
               
                 533372 
                 CTTCAAGTTTAGGATCTGCA 
                 Intron 2 
                 88 
                 196537 
                 196556 
                 879 
               
               
                   
               
               
                 533373 
                 GCTTCAAGTTTAGGATCTGC 
                 Intron 2 
                 86 
                 196538 
                 196557 
                 880 
               
               
                   
               
               
                 533374 
                 GGGCTTCAAGTTTAGGATCT 
                 Intron 2 
                 67 
                 196540 
                 196559 
                 881 
               
               
                   
               
               
                 533375 
                 AGGGCTTCAAGTTTAGGATC 
                 Intron 2 
                 66 
                 196541 
                 196560 
                 882 
               
               
                   
               
               
                 533376 
                 CAGGGCTTCAAGTTTAGGAT 
                 Intron 2 
                 74 
                 196542 
                 196561 
                 883 
               
               
                   
               
               
                 533377 
                 TGTGGCTTTAATTCACTAAT 
                 Intron 2 
                 84 
                 198145 
                 198164 
                 884 
               
               
                   
               
               
                 533378 
                 ATGTGGCTTTAATTCACTAA 
                 Intron 2 
                 86 
                 198146 
                 198165 
                 885 
               
               
                   
               
               
                 533379 
                 TATGTGGCTTTAATTCACTA 
                 Intron 2 
                 79 
                 198147 
                 198166 
                 886 
               
               
                   
               
               
                 533380 
                 GGTATGTGGCTTTAATTCAC 
                 Intron 2 
                 83 
                 198149 
                 198168 
                 887 
               
               
                   
               
               
                 533381 
                 TGGTATGTGGCTTTAATTCA 
                 Intron 2 
                 81 
                 198150 
                 198169 
                 888 
               
               
                   
               
               
                 533382 
                 GTGGTATGTGGCTTTAATTC 
                 Intron 2 
                 86 
                 198151 
                 198170 
                 889 
               
               
                   
               
               
                 533383 
                 TCTGTGTTCAGTTGCATCAC 
                 Intron 2 
                 75 
                 199817 
                 199836 
                 890 
               
               
                   
               
               
                 533384 
                 TTCTGTGTTCAGTTGCATCA 
                 Intron 2 
                 82 
                 199818 
                 199837 
                 891 
               
               
                   
               
               
                 533385 
                 GTTCTGTGTTCAGTTGCATC 
                 Intron 2 
                 86 
                 199819 
                 199838 
                 892 
               
               
                   
               
               
                 533386 
                 GTACTCATGAGGAGGCACTT 
                 Intron 2 
                 81 
                 201413 
                 201432 
                 893 
               
               
                   
               
               
                 533387 
                 GGTACTCATGAGGAGGCACT 
                 Intron 2 
                 82 
                 201414 
                 201433 
                 894 
               
               
                   
               
               
                 533388 
                 TGGTACTCATGAGGAGGCAC 
                 Intron 2 
                 78 
                 201415 
                 201434 
                 895 
               
               
                   
               
               
                 533389 
                 ATTGGTACTCATGAGGAGGC 
                 Intron 2 
                 64 
                 201417 
                 201436 
                 896 
               
               
                   
               
               
                 533390 
                 AATTGGTACTCATGAGGAGG 
                 Intron 2 
                 47 
                 201418 
                 201437 
                 897 
               
               
                   
               
               
                 533391 
                 CAATTGGTACTCATGAGGAG 
                 Intron 2 
                 54 
                 201419 
                 201438 
                 898 
               
               
                   
               
               
                 533392 
                 AAACTCTGCAACTCCAACCC 
                 Intron 2 
                 69 
                 205549 
                 205568 
                 899 
               
               
                   
               
               
                 533393 
                 GAAACTCTGCAACTCCAACC 
                 Intron 2 
                 64 
                 205550 
                 205569 
                 900 
               
               
                   
               
               
                 533394 
                 GGAAACTCTGCAACTCCAAC 
                 Intron 2 
                 83 
                 205551 
                 205570 
                 901 
               
               
                   
               
               
                 533395 
                 ATGGAAACTCTGCAACTCCA 
                 Intron 2 
                 88 
                 205553 
                 205572 
                 902 
               
               
                   
               
               
                 533396 
                 CATGGAAACTCTGCAACTCC 
                 Intron 2 
                 70 
                 205554 
                 205573 
                 903 
               
               
                   
               
               
                 533397 
                 TCATGGAAACTCTGCAACTC 
                 Intron 2 
                 69 
                 205555 
                 205574 
                 904 
               
               
                   
               
               
                 533398 
                 ACATCTGGATGTGAGGCTCG 
                 Intron 3 
                 64 
                 210559 
                 210578 
                 905 
               
               
                   
               
               
                 533399 
                 CACATCTGGATGTGAGGCTC 
                 Intron 3 
                 84 
                 210560 
                 210579 
                 906 
               
               
                   
               
               
                 533400 
                 GTCACATCTGGATGTGAGGC 
                 Intron 3 
                 75 
                 210562 
                 210581 
                 907 
               
               
                   
               
               
                 533401 
                 TGTCACATCTGGATGTGAGG 
                 Intron 3 
                 51 
                 210563 
                 210582 
                 908 
               
               
                   
               
               
                 533402 
                 CTGTCACATCTGGATGTGAG 
                 Intron 3 
                 30 
                 210564 
                 210583 
                 909 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 14 
               
             
            
               
                   
               
               
                 Inhibition of GHR mRNA by 5-10-5 MOE gapmers 
               
               
                 targeting introns 2 and 3 of SEQ ID NO: 2 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                   
                   
                   
                 SEQ 
                 SEQ 
                   
               
               
                   
                   
                   
                   
                 ID 
                 ID 
                   
               
               
                   
                   
                   
                 % 
                 NO: 
                 NO: 
                   
               
               
                   
                   
                   
                 inhi- 
                 2 
                 2 
                 SEQ 
               
               
                 ISIS 
                   
                 Target 
                 bi- 
                 Start 
                 Stop 
                 ID 
               
               
                 NO 
                 Sequence 
                 region 
                 tion 
                 Site 
                 Site 
                 NO 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                 523715 
                 GTCAATTATGTGCTTTGCCT 
                 Intron 2 
                 91 
                 148907 
                 148926 
                 910 
               
               
                   
               
               
                 523716 
                 ACATTCAAAATTCTTCCTTG 
                 Intron 2 
                 50 
                 149787 
                 149806 
                 911 
               
               
                   
               
               
                 523717 
                 ATCCTGCATATATTTTATTG 
                 Intron 2 
                 20 
                 150588 
                 150607 
                 912 
               
               
                   
               
               
                 523718 
                 CTGCTGGTGACTCTGCCTGA 
                 Intron 2 
                 77 
                 151388 
                 151407 
                 913 
               
               
                   
               
               
                 523719 
                 AATGCTGAAGGATGGGCATC 
                 Intron 2 
                 66 
                 152204 
                 152223 
                 914 
               
               
                   
               
               
                 523720 
                 TTATCCAGTAGTCAATATTA 
                 Intron 2 
                 71 
                 153004 
                 153023 
                 915 
               
               
                   
               
               
                 523721 
                 TCTCATGTTAAAGTTCTTAA 
                 Intron 2 
                 48 
                 153831 
                 153850 
                 916 
               
               
                   
               
               
                 523722 
                 TGCACTTGGACAACTGATAG 
                 Intron 2 
                 29 
                 154724 
                 154743 
                 917 
               
               
                   
               
               
                 523723 
                 ACTCAACTTGAGGACAATAA 
                 Intron 2 
                 88 
                 155594 
                 155613 
                 918 
               
               
                   
               
               
                 523724 
                 GACCAGGAAGAAAGGAACCT 
                 Intron 2 
                 72 
                 156394 
                 156413 
                 919 
               
               
                   
               
               
                 523725 
                 TGCTACAATGCACAGGACAC 
                 Intron 2 
                 80 
                 157201 
                 157220 
                 920 
               
               
                   
               
               
                 523726 
                 TCTGATATTTATTGCTGTAC 
                 Intron 2 
                 73 
                 158007 
                 158026 
                 921 
               
               
                   
               
               
                 523727 
                 ATGCTTCCTTTAATAAATGT 
                 Intron 2 
                 0 
                 158807 
                 158826 
                 922 
               
               
                   
               
               
                 523728 
                 AACATTTAGAACCTAGGAGA 
                 Intron 2 
                 20 
                 159610 
                 159629 
                 923 
               
               
                   
               
               
                 523729 
                 CAAGCTTGCAAGTAGGAAAA 
                 Intron 2 
                 51 
                 160410 
                 160429 
                 924 
               
               
                   
               
               
                 523730 
                 CCAGGCTGTTCATGCCAAGG 
                 Intron 2 
                 26 
                 161248 
                 161267 
                 925 
               
               
                   
               
               
                 523731 
                 CCTGCCAAGGGCAAGCCAGG 
                 Intron 2 
                 17 
                 162064 
                 162083 
                 926 
               
               
                   
               
               
                 523732 
                 TTTCACCTGGTGACTGGAAG 
                 Intron 2 
                 51 
                 163019 
                 163038 
                 927 
               
               
                   
               
               
                 523733 
                 ATTTTCTACCATCAAAGAGA 
                 Intron 2 
                 4 
                 163943 
                 163962 
                 928 
               
               
                   
               
               
                 523734 
                 GATTAAGTTTTCTTTAAAAA 
                 Intron 2 
                 0 
                 164746 
                 164765 
                 929 
               
               
                   
               
               
                 523735 
                 CTTCCAGAAGAATTACCCAT 
                 Intron 2 
                 56 
                 165553 
                 165572 
                 930 
               
               
                   
               
               
                 523736 
                 CAGTTTCTGCAGTATCCTAG 
                 Intron 2 
                 77 
                 166353 
                 166372 
                 931 
               
               
                   
               
               
                 523737 
                 TATTTTGAAAATGAGATTCA 
                 Intron 2 
                 0 
                 167195 
                 167214 
                 932 
               
               
                   
               
               
                 523738 
                 GTGGCCCGAGTAAAGATAAA 
                 Intron 2 
                 21 
                 167995 
                 168014 
                 933 
               
               
                   
               
               
                 523739 
                 CCTGTCAATCCTCTTATATG 
                 Intron 2 
                 37 
                 168804 
                 168823 
                 934 
               
               
                   
               
               
                 523740 
                 GGTGTTTCCATTTTCTTGAT 
                 Intron 2 
                 65 
                 169604 
                 169623 
                 935 
               
               
                   
               
               
                 523741 
                 ACAGGGTCAAAAGTTCACTT 
                 Intron 2 
                 44 
                 170407 
                 170426 
                 936 
               
               
                   
               
               
                 523742 
                 TAGGAAAGCTGAGAGAATCC 
                 Intron 2 
                 35 
                 171207 
                 171226 
                 937 
               
               
                   
               
               
                 523743 
                 AGCATATGAAAAAATACTCA 
                 Intron 2 
                 0 
                 172101 
                 172120 
                 938 
               
               
                   
               
               
                 523744 
                 CTTCAGAAATCAGCATCTGA 
                 Intron 2 
                 45 
                 172937 
                 172956 
                 939 
               
               
                   
               
               
                 523745 
                 TTACAAGTGACAGTGTTTGT 
                 Intron 2 
                 28 
                 173737 
                 173756 
                 940 
               
               
                   
               
               
                 523746 
                 ATCAGACCCTGAAGAATTTA 
                 Intron 2 
                 29 
                 174560 
                 174579 
                 941 
               
               
                   
               
               
                 523747 
                 AGGAACCCATTTCATCCATT 
                 Intron 2 
                 83 
                 175372 
                 175391 
                 942 
               
               
                   
               
               
                 523748 
                 CACATTGGTAACTTAAAGTT 
                 Intron 2 
                 18 
                 176263 
                 176282 
                 943 
               
               
                   
               
               
                 523749 
                 TATTATCTGACTCATTTCTG 
                 Intron 2 
                 16 
                 177072 
                 177091 
                 944 
               
               
                   
               
               
                 523750 
                 AAATAAGACAAAGAAAATTC 
                 Intron 2 
                 0 
                 177872 
                 177891 
                 945 
               
               
                   
               
               
                 523751 
                 TTTTAAAAATAACCAATTCA 
                 Intron 2 
                 0 
                 178788 
                 178807 
                 946 
               
               
                   
               
               
                 523752 
                 CTTTGAGGGATTGCCTCAGT 
                 Intron 2 
                 66 
                 179619 
                 179638 
                 947 
               
               
                   
               
               
                 523753 
                 ACAGTCCTCATGAACAGATT 
                 Intron 2 
                 37 
                 180513 
                 180532 
                 948 
               
               
                   
               
               
                 523754 
                 ACTATCATTAATAATATTGT 
                 Intron 2 
                 0 
                 181323 
                 181342 
                 949 
               
               
                   
               
               
                 523755 
                 ATCTAGATTTGCCTTATAAG 
                 Intron 2 
                 27 
                 182123 
                 182142 
                 950 
               
               
                   
               
               
                 523756 
                 TGGTTGAGGAAGACAGTCTC 
                 Intron 2 
                 16 
                 182962 
                 182981 
                 951 
               
               
                   
               
               
                 523757 
                 TGGCTCATAACTTCCTTAGC 
                 Intron 2 
                 43 
                 183762 
                 183781 
                 952 
               
               
                   
               
               
                 523758 
                 ACTAACTTAGGACTTGGGAC 
                 Intron 2 
                 72 
                 184578 
                 184597 
                 953 
               
               
                   
               
               
                 523759 
                 CTTATAGCATTACTAAGTGG 
                 Intron 2 
                 49 
                 185403 
                 185422 
                 954 
               
               
                   
               
               
                 523760 
                 TGGTGGCAGGAGAGAGGGAA 
                 Intron 2 
                 48 
                 186203 
                 186222 
                 955 
               
               
                   
               
               
                 523761 
                 TTTGCCAGGAAATCTTGAAA 
                 Intron 2 
                 35 
                 187003 
                 187022 
                 956 
               
               
                   
               
               
                 523762 
                 ATAACTTTTCTCTGAAATTT 
                 Intron 2 
                 8 
                 187803 
                 187822 
                 957 
               
               
                   
               
               
                 523763 
                 CCATGGGCTAGATCAGGATT 
                 Intron 2 
                 59 
                 188620 
                 188639 
                 958 
               
               
                   
               
               
                 523764 
                 TGAGCTTAGCAGTCACTTAG 
                 Intron 2 
                 62 
                 189481 
                 189500 
                 959 
               
               
                   
               
               
                 523765 
                 AATGTCTCAGCAAACCTGGG 
                 Intron 2 
                 62 
                 190286 
                 190305 
                 960 
               
               
                   
               
               
                 523766 
                 GGATACAGACATAGCTCTAA 
                 Intron 2 
                 75 
                 191142 
                 191161 
                 961 
               
               
                   
               
               
                 523767 
                 ACAACACTGTTTGTGAGGGT 
                 Intron 2 
                 66 
                 191942 
                 191961 
                 962 
               
               
                   
               
               
                 523768 
                 TCTATTTTCTAATAGCTGTT 
                 Intron 2 
                 49 
                 192742 
                 192761 
                 963 
               
               
                   
               
               
                 523769 
                 GGCCCCACCTCTGACCTTCA 
                 Intron 2 
                 7 
                 193542 
                 193561 
                 964 
               
               
                   
               
               
                 523770 
                 TGGTAAAGCTAGAAAAAAAA 
                 Intron 2 
                 0 
                 194346 
                 194365 
                 965 
               
               
                   
               
               
                 523771 
                 AAGTGGTAAATATGATCACA 
                 Intron 2 
                 23 
                 195159 
                 195178 
                 966 
               
               
                   
               
               
                 523772 
                 GGCTTCAAGTTTAGGATCTG 
                 Intron 2 
                 52 
                 196539 
                 196558 
                 967 
               
               
                   
               
               
                 523773 
                 TTGTTGACACTCTCTTTTGG 
                 Intron 2 
                 18 
                 197348 
                 197367 
                 968 
               
               
                   
               
               
                 523774 
                 GTATGTGGCTTTAATTCACT 
                 Intron 2 
                 71 
                 198148 
                 198167 
                 969 
               
               
                   
               
               
                 523775 
                 AATTAGTTGTTTTGGCAAAT 
                 Intron 2 
                 14 
                 198988 
                 199007 
                 970 
               
               
                   
               
               
                 523776 
                 CTGTGTTCAGTTGCATCACG 
                 Intron 2 
                 75 
                 199816 
                 199835 
                 971 
               
               
                   
               
               
                 523777 
                 AATGTGGAAGTTTCCTAACA 
                 Intron 2 
                 15 
                 200616 
                 200635 
                 972 
               
               
                   
               
               
                 523778 
                 TTGGTACTCATGAGGAGGCA 
                 Intron 2 
                 58 
                 201416 
                 201435 
                 973 
               
               
                   
               
               
                 523779 
                 TTTCTCTGTGTTTAAAATTG 
                 Intron 2 
                 13 
                 202308 
                 202327 
                 974 
               
               
                   
               
               
                 523780 
                 GTAAAGCACAATGAACAAAA 
                 Intron 2 
                 21 
                 203115 
                 203134 
                 975 
               
               
                   
               
               
                 523781 
                 ATCACAGATCTTTGCTACAA 
                 Intron 2 
                 51 
                 203915 
                 203934 
                 976 
               
               
                   
               
               
                 523782 
                 TCCTGCCTTTCTGAACCAAA 
                 Intron 2 
                 50 
                 204721 
                 204740 
                 977 
               
               
                   
               
               
                 523783 
                 TGGAAACTCTGCAACTCCAA 
                 Intron 2 
                 58 
                 205552 
                 205571 
                 978 
               
               
                   
               
               
                 523784 
                 ACACAGTAGGGAACAATTTT 
                 Intron 2 
                 8 
                 206412 
                 206431 
                 979 
               
               
                   
               
               
                 523785 
                 AGACAGATGGTGAAATGATG 
                 Intron 2 
                 0 
                 207219 
                 207238 
                 980 
               
               
                   
               
               
                 523786 
                 AAACAGAAAGAGAAGAAAAC 
                 Intron 2 
                 0 
                 208117 
                 208136 
                 981 
               
               
                   
               
               
                 523787 
                 CTTAGATAAATACTTCAAGA 
                 Intron 3 
                 0 
                 208938 
                 208957 
                 982 
               
               
                   
               
               
                 523788 
                 AGCCACTTCTTTTACAACCT 
                 Intron 3 
                 0 
                 209742 
                 209761 
                 983 
               
               
                   
               
               
                 523789 
                 TCACATCTGGATGTGAGGCT 
                 Intron 3 
                 80 
                 210561 
                 210580 
                 984 
               
               
                   
               
               
                 523790 
                 GACTGAAACTTAAAGGTGGG 
                 Intron 3 
                 7 
                 211399 
                 211418 
                 985 
               
               
                   
               
               
                 523791 
                 AAAGATGTGCAATCATCTAA 
                 Intron 3 
                 44 
                 212204 
                 212223 
                 986 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 15 
               
             
            
               
                   
               
               
                 Inhibition of GHR mRNA by 3-10-4 MOE gapmers 
               
               
                 targeting introns 2 and 3 of SEQ ID NO: 2 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                   
                   
                   
                 SEQ 
                 SEQ 
                   
               
               
                   
                   
                   
                   
                 ID 
                 ID 
                   
               
               
                   
                   
                   
                 % 
                 NO: 
                 NO: 
                   
               
               
                   
                   
                   
                 inhi- 
                 2 
                 2 
                 SEQ 
               
               
                 ISIS 
                   
                 Target 
                 bi- 
                 Start 
                 Stop 
                 ID 
               
               
                 NO 
                 Sequence 
                 region 
                 tion 
                 Site 
                 Site 
                 NO 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                 539360 
                 GCTGGTGACTCTGCCTG 
                 Intron 2 
                 95 
                 151389 
                 151405 
                 987 
               
               
                   
               
               
                 539361 
                 TGCTGGTGACTCTGCCT 
                 Intron 2 
                 95 
                 151390 
                 151406 
                 988 
               
               
                   
               
               
                 539362 
                 CTGCTGGTGACTCTGCC 
                 Intron 2 
                 93 
                 151391 
                 151407 
                 989 
               
               
                   
               
               
                 539363 
                 AGTAGTCAATATTATTT 
                 Intron 2 
                 31 
                 153001 
                 153017 
                 990 
               
               
                   
               
               
                 539364 
                 CAGTAGTCAATATTATT 
                 Intron 2 
                 13 
                 153002 
                 153018 
                 991 
               
               
                   
               
               
                 539365 
                 CCAGTAGTCAATATTAT 
                 Intron 2 
                 34 
                 153003 
                 153019 
                 992 
               
               
                   
               
               
                 539366 
                 CCTTTGGGTGAATAGCA 
                 Intron 2 
                 64 
                 153921 
                 153937 
                 993 
               
               
                   
               
               
                 539367 
                 ACCTTTGGGTGAATAGC 
                 Intron 2 
                 78 
                 153922 
                 153938 
                 994 
               
               
                   
               
               
                 539368 
                 CACCTTTGGGTGAATAG 
                 Intron 2 
                 40 
                 153923 
                 153939 
                 995 
               
               
                   
               
               
                 539369 
                 CAACTTGAGGACAATAA 
                 Intron 2 
                 38 
                 155594 
                 155610 
                 996 
               
               
                   
               
               
                 539370 
                 TCAACTTGAGGACAATA 
                 Intron 2 
                 63 
                 155595 
                 155611 
                 997 
               
               
                   
               
               
                 539371 
                 CTCAACTTGAGGACAAT 
                 Intron 2 
                 81 
                 155596 
                 155612 
                 998 
               
               
                   
               
               
                 539372 
                 CAGGAAGAAAGGAACCT 
                 Intron 2 
                 70 
                 156394 
                 156410 
                 999 
               
               
                   
               
               
                 539373 
                 CCAGGAAGAAAGGAACC 
                 Intron 2 
                 59 
                 156395 
                 156411 
                 1000 
               
               
                   
               
               
                 539374 
                 ACCAGGAAGAAAGGAAC 
                 Intron 2 
                 43 
                 156396 
                 156412 
                 1001 
               
               
                   
               
               
                 539375 
                 TGCAGTCATGTACACAA 
                 Intron 2 
                 93 
                 156594 
                 156610 
                 1002 
               
               
                   
               
               
                 539376 
                 CTGCAGTCATGTACACA 
                 Intron 2 
                 91 
                 156595 
                 156611 
                 1003 
               
               
                   
               
               
                 539377 
                 TCTGCAGTCATGTACAC 
                 Intron 2 
                 87 
                 156596 
                 156612 
                 1004 
               
               
                   
               
               
                 539378 
                 TGGTTTGTCAATCCTTT 
                 Intron 2 
                 95 
                 156889 
                 156905 
                 1005 
               
               
                   
               
               
                 539379 
                 TTGGTTTGTCAATCCTT 
                 Intron 2 
                 97 
                 156890 
                 156906 
                 1006 
               
               
                   
               
               
                 539380 
                 CTTGGTTTGTCAATCCT 
                 Intron 2 
                 97 
                 156891 
                 156907 
                 1007 
               
               
                   
               
               
                 539381 
                 TACAATGCACAGGACAC 
                 Intron 2 
                 65 
                 157201 
                 157217 
                 1008 
               
               
                   
               
               
                 539382 
                 CTACAATGCACAGGACA 
                 Intron 2 
                 85 
                 157202 
                 157218 
                 1009 
               
               
                   
               
               
                 539383 
                 GCTACAATGCACAGGAC 
                 Intron 2 
                 96 
                 157203 
                 157219 
                 1010 
               
               
                   
               
               
                 539384 
                 GATATTTATTGCTGTAC 
                 Intron 2 
                 43 
                 158007 
                 158023 
                 1011 
               
               
                   
               
               
                 539385 
                 TGATATTTATTGCTGTA 
                 Intron 2 
                 35 
                 158008 
                 158024 
                 1012 
               
               
                   
               
               
                 539386 
                 CTGATATTTATTGCTGT 
                 Intron 2 
                 38 
                 158009 
                 158025 
                 1013 
               
               
                   
               
               
                 539387 
                 AGGGTCTTTACAAAGTT 
                 Intron 2 
                 61 
                 162751 
                 162767 
                 1014 
               
               
                   
               
               
                 539388 
                 CAGGGTCTTTACAAAGT 
                 Intron 2 
                 65 
                 162752 
                 162768 
                 1015 
               
               
                   
               
               
                 539389 
                 CCAGGGTCTTTACAAAG 
                 Intron 2 
                 88 
                 162753 
                 162769 
                 1016 
               
               
                   
               
               
                 539390 
                 TTCTGCAGTATCCTAGC 
                 Intron 2 
                 72 
                 166352 
                 166368 
                 1017 
               
               
                   
               
               
                 539391 
                 TTTCTGCAGTATCCTAG 
                 Intron 2 
                 53 
                 166353 
                 166369 
                 1018 
               
               
                   
               
               
                 539392 
                 GTTTCTGCAGTATCCTA 
                 Intron 2 
                 84 
                 166354 
                 166370 
                 1019 
               
               
                   
               
               
                 539393 
                 AGTTTCTGCAGTATCCT 
                 Intron 2 
                 78 
                 166355 
                 166371 
                 1020 
               
               
                   
               
               
                 539394 
                 CAGTTTCTGCAGTATCC 
                 Intron 2 
                 77 
                 166356 
                 166372 
                 1021 
               
               
                   
               
               
                 539395 
                 CAAATTCCAGTCCTAGG 
                 Intron 2 
                 60 
                 172746 
                 172762 
                 1022 
               
               
                   
               
               
                 539396 
                 CCAAATTCCAGTCCTAG 
                 Intron 2 
                 75 
                 172747 
                 172763 
                 1023 
               
               
                   
               
               
                 539397 
                 TCCAAATTCCAGTCCTA 
                 Intron 2 
                 62 
                 172748 
                 172764 
                 1024 
               
               
                   
               
               
                 539398 
                 AACCCATTTCATCCATT 
                 Intron 2 
                 82 
                 175372 
                 175388 
                 1025 
               
               
                   
               
               
                 539399 
                 GAACCCATTTCATCCAT 
                 Intron 2 
                 86 
                 175373 
                 175389 
                 1026 
               
               
                   
               
               
                 539400 
                 GGAACCCATTTCATCCA 
                 Intron 2 
                 84 
                 175374 
                 175390 
                 1027 
               
               
                   
               
               
                 539401 
                 GCTTCATGTCTTTCTAG 
                 Intron 2 
                 88 
                 189119 
                 189135 
                 1028 
               
               
                   
               
               
                 539402 
                 TGCTTCATGTCTTTCTA 
                 Intron 2 
                 77 
                 189120 
                 189136 
                 1029 
               
               
                   
               
               
                 539403 
                 GTGCTTCATGTCTTTCT 
                 Intron 2 
                 95 
                 189121 
                 189137 
                 1030 
               
               
                   
               
               
                 539404 
                 TGAGCTTAGCAGTCACT 
                 Intron 2 
                 92 
                 189484 
                 189500 
                 1031 
               
               
                   
               
               
                 539405 
                 CATGAGCTTAGCAGTCA 
                 Intron 2 
                 82 
                 189486 
                 189502 
                 1032 
               
               
                   
               
               
                 539406 
                 TACAGACATAGCTCTAA 
                 Intron 2 
                 45 
                 191142 
                 191158 
                 1033 
               
               
                   
               
               
                 539407 
                 ATACAGACATAGCTCTA 
                 Intron 2 
                 53 
                 191143 
                 191159 
                 1034 
               
               
                   
               
               
                 539408 
                 GATACAGACATAGCTCT 
                 Intron 2 
                 67 
                 191144 
                 191160 
                 1035 
               
               
                   
               
               
                 539409 
                 TGTGGCTTTAATTCACT 
                 Intron 2 
                 70 
                 198148 
                 198164 
                 1036 
               
               
                   
               
               
                 539410 
                 ATGTGGCTTTAATTCAC 
                 Intron 2 
                 40 
                 198149 
                 198165 
                 1037 
               
               
                   
               
               
                 539411 
                 TATGTGGCTTTAATTCA 
                 Intron 2 
                 35 
                 198150 
                 198166 
                 1038 
               
               
                   
               
               
                 539412 
                 TGTTCAGTTGCATCACG 
                 Intron 2 
                 84 
                 199816 
                 199832 
                 1039 
               
               
                   
               
               
                 539413 
                 GTGTTCAGTTGCATCAC 
                 Intron 2 
                 80 
                 199817 
                 199833 
                 1040 
               
               
                   
               
               
                 539414 
                 TGTGTTCAGTTGCATCA 
                 Intron 2 
                 74 
                 199818 
                 199834 
                 1041 
               
               
                   
               
               
                 539415 
                 CATCTGGATGTGAGGCT 
                 Intron 3 
                 82 
                 210561 
                 210577 
                 1042 
               
               
                   
               
               
                 539416 
                 ACATCTGGATGTGAGGC 
                 Intron 3 
                 86 
                 210562 
                 210578 
                 1043 
               
               
                   
               
               
                 539417 
                 CACATCTGGATGTGAGG 
                 Intron 3 
                 55 
                 210563 
                 210579 
                 1044 
               
               
                   
               
               
                 539418 
                 TCAGGTAATTTCTGGAA 
                 Intron 3 
                 35 
                 219019 
                 219035 
                 1045 
               
               
                   
               
               
                 539419 
                 CTCAGGTAATTTCTGGA 
                 Intron 3 
                 44 
                 219020 
                 219036 
                 1046 
               
               
                   
               
               
                 539420 
                 TCTCAGGTAATTTCTGG 
                 Intron 3 
                 31 
                 219021 
                 219037 
                 1047 
               
               
                   
               
               
                 539421 
                 TTGCTTATTTACCTGGG 
                 Intron 3 
                 0 
                 225568 
                 225584 
                 1048 
               
               
                   
               
               
                 539422 
                 TTTGCTTATTTACCTGG 
                 Intron 3 
                 38 
                 225569 
                 225585 
                 1049 
               
               
                   
               
               
                 539423 
                 TTTTGCTTATTTACCTG 
                 Intron 3 
                 33 
                 225570 
                 225586 
                 1050 
               
               
                   
               
               
                 539424 
                 ATGATGTTACTACTACT 
                 Intron 3 
                 29 
                 229618 
                 229634 
                 1051 
               
               
                   
               
               
                 539425 
                 AATGATGTTACTACTAC 
                 Intron 3 
                 10 
                 229619 
                 229635 
                 1052 
               
               
                   
               
               
                 539426 
                 CAATGATGTTACTACTA 
                 Intron 3 
                 0 
                 229620 
                 229636 
                 1053 
               
               
                   
               
               
                 539427 
                 CCCCTAGAGCAATGGTC 
                 Intron 3 
                 67 
                 232826 
                 232842 
                 1054 
               
               
                   
               
               
                 539428 
                 CCCCCTAGAGCAATGGT 
                 Intron 3 
                 65 
                 232827 
                 232843 
                 1055 
               
               
                   
               
               
                 539429 
                 TCCCCCTAGAGCAATGG 
                 Intron 3 
                 45 
                 232828 
                 232844 
                 1056 
               
               
                   
               
               
                 539430 
                 TCAATTGCAGATGCTCT 
                 Intron 3 
                 78 
                 237675 
                 237691 
                 1057 
               
               
                   
               
               
                 539431 
                 CTCAATTGCAGATGCTC 
                 Intron 3 
                 82 
                 237676 
                 237692 
                 1058 
               
               
                   
               
               
                 539432 
                 GCTCAATTGCAGATGCT 
                 Intron 3 
                 92 
                 237677 
                 237693 
                 1059 
               
               
                   
               
               
                 539433 
                 AGCTCAATTGCAGATGC 
                 Intron 3 
                 85 
                 237678 
                 237694 
                 1060 
               
               
                   
               
               
                 539434 
                 GTATATTCAGTCCAAGG 
                 Intron 3 
                 73 
                 248231 
                 248247 
                 1061 
               
               
                   
               
               
                 539435 
                 AGTATATTCAGTCCAAG 
                 Intron 3 
                 70 
                 248232 
                 248248 
                 1062 
               
               
                   
               
               
                 539436 
                 CAGTATATTCAGTCCAA 
                 Intron 3 
                 40 
                 248233 
                 248249 
                 1063 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 16 
               
             
            
               
                   
               
               
                 Inhibition of GHR mRNA by 5-10-5 MOE gapmers 
               
               
                 targeting introns 1 and 3 of SEQ ID NO: 2 
               
            
           
           
               
               
               
               
               
               
               
            
               
                 ISIS 
                   
                 Target 
                 % 
                 SEQ ID NO: 2 
                 SEQ ID NO: 2 
                 SEQ 
               
               
                 NO 
                 Sequence 
                 region 
                 inhibition 
                 Start Site 
                 Stop Site 
                 ID NO 
               
               
                   
               
               
                 532502 
                 GAGTATTTCAGGCTGGAAAA 
                 Intron 3 
                 43 
                 214623 
                 214642 
                 1064 
               
               
                   
               
               
                 533404 
                 GTAACTCAGGAATGGAAAAC 
                 Intron 1 
                 56 
                  26501 
                  26520 
                 1065 
               
               
                   
                   
                   
                   
                 113035 
                 113054 
                   
               
               
                   
                   
                   
                   
                 121992 
                 122011 
                   
               
               
                   
               
               
                 533405 
                 AGTAACTCAGGAATGGAAAA 
                 Intron 1 
                 41 
                  26502 
                  26521 
                 1066 
               
               
                   
                   
                   
                   
                 113036 
                 113055 
                   
               
               
                   
                   
                   
                   
                 121993 
                 122012 
                   
               
               
                   
               
               
                 533406 
                 AAGTAACTCAGGAATGGAAA 
                 Intron 1 
                 43 
                  26503 
                  26522 
                 1067 
               
               
                   
                   
                   
                   
                 113037 
                 113056 
                   
               
               
                   
                   
                   
                   
                 121994 
                 122013 
                   
               
               
                   
               
               
                 533407 
                 GAGATTTCAAATAAATCTCA 
                 Intron 1 
                  0 
                 143207 
                 143226 
                 1068 
               
               
                   
                   
                   
                   
                 143235 
                 143254 
                   
               
               
                   
                   
                   
                   
                 143263 
                 143282 
                   
               
               
                   
                   
                   
                   
                 143291 
                 143310 
                   
               
               
                   
                   
                   
                   
                 143319 
                 143338 
                   
               
               
                   
                   
                   
                   
                 143347 
                 143366 
                   
               
               
                   
                   
                   
                   
                 143375 
                 143394 
                   
               
               
                   
                   
                   
                   
                 143403 
                 143422 
                   
               
               
                   
                   
                   
                   
                 143431 
                 143450 
                   
               
               
                   
                   
                   
                   
                 143459 
                 143478 
                   
               
               
                   
               
               
                 533408 
                 TGAGATTTCAAATAAATCTC 
                 Intron 1 
                 11 
                 143208 
                 143227 
                 1069 
               
               
                   
                   
                   
                   
                 143236 
                 143255 
                   
               
               
                   
                   
                   
                   
                 143264 
                 143283 
                   
               
               
                   
                   
                   
                   
                 143292 
                 143311 
                   
               
               
                   
                   
                   
                   
                 143320 
                 143339 
                   
               
               
                   
                   
                   
                   
                 143348 
                 143367 
                   
               
               
                   
                   
                   
                   
                 143376 
                 143395 
                   
               
               
                   
                   
                   
                   
                 143404 
                 143423 
                   
               
               
                   
                   
                   
                   
                 143432 
                 143451 
                   
               
               
                   
                   
                   
                   
                 143460 
                 143479 
                   
               
               
                   
               
               
                 533409 
                 GTGAGATTTCAAATAAATCT 
                 Intron 1 
                  0 
                 143209 
                 143228 
                 1070 
               
               
                   
                   
                   
                   
                 143237 
                 143256 
                   
               
               
                   
                   
                   
                   
                 143265 
                 143284 
                   
               
               
                   
                   
                   
                   
                 143293 
                 143312 
                   
               
               
                   
                   
                   
                   
                 143321 
                 143340 
                   
               
               
                   
                   
                   
                   
                 143349 
                 143368 
                   
               
               
                   
                   
                   
                   
                 143377 
                 143396 
                   
               
               
                   
                   
                   
                   
                 143405 
                 143424 
                   
               
               
                   
                   
                   
                   
                 143433 
                 143452 
                   
               
               
                   
                   
                   
                   
                 143461 
                 143480 
                   
               
               
                   
               
               
                 533410 
                 TGTGAGATTTCAAATAAATC 
                 Intron 1 
                  0 
                 143210 
                 143229 
                 1071 
               
               
                   
                   
                   
                   
                 143238 
                 143257 
                   
               
               
                   
                   
                   
                   
                 143266 
                 143285 
                   
               
               
                   
                   
                   
                   
                 143294 
                 143313 
                   
               
               
                   
                   
                   
                   
                 143322 
                 143341 
                   
               
               
                   
                   
                   
                   
                 143350 
                 143369 
                   
               
               
                   
                   
                   
                   
                 143378 
                 143397 
                   
               
               
                   
                   
                   
                   
                 143406 
                 143425 
                   
               
               
                   
                   
                   
                   
                 143434 
                 143453 
                   
               
               
                   
                   
                   
                   
                 143462 
                 143481 
                   
               
               
                   
               
               
                 533411 
                 TTGTGAGATTTCAAATAAAT 
                 Intron 1 
                 10 
                 143183 
                 143202 
                 1072 
               
               
                   
                   
                   
                   
                 143211 
                 143230 
                   
               
               
                   
                   
                   
                   
                 143239 
                 143258 
                   
               
               
                   
                   
                   
                   
                 143267 
                 143286 
                   
               
               
                   
                   
                   
                   
                 143295 
                 143314 
                   
               
               
                   
                   
                   
                   
                 143323 
                 143342 
                   
               
               
                   
                   
                   
                   
                 143351 
                 143370 
                   
               
               
                   
                   
                   
                   
                 143379 
                 143398 
                   
               
               
                   
                   
                   
                   
                 143407 
                 143426 
                   
               
               
                   
                   
                   
                   
                 143435 
                 143454 
                   
               
               
                   
                   
                   
                   
                 143463 
                 143482 
                   
               
               
                   
               
               
                 533412 
                 TTTGTGAGATTTCAAATAAA 
                 Intron 1 
                  0 
                 143184 
                 143203 
                 1073 
               
               
                   
                   
                   
                   
                 143212 
                 143231 
                   
               
               
                   
                   
                   
                   
                 143240 
                 143259 
                   
               
               
                   
                   
                   
                   
                 143296 
                 143315 
                   
               
               
                   
                   
                   
                   
                 143324 
                 143343 
                   
               
               
                   
                   
                   
                   
                 143352 
                 143371 
                   
               
               
                   
                   
                   
                   
                 143380 
                 143399 
                   
               
               
                   
                   
                   
                   
                 143464 
                 143483 
                   
               
               
                   
               
               
                 533413 
                 CTTTGTGAGATTTCAAATAA 
                 Intron 1 
                 20 
                 143185 
                 143204 
                 1074 
               
               
                   
                   
                   
                   
                 143213 
                 143232 
                   
               
               
                   
                   
                   
                   
                 143241 
                 143260 
                   
               
               
                   
                   
                   
                   
                 143297 
                 143316 
                   
               
               
                   
                   
                   
                   
                 143325 
                 143344 
                   
               
               
                   
                   
                   
                   
                 143353 
                 143372 
                   
               
               
                   
                   
                   
                   
                 143381 
                 143400 
                   
               
               
                   
                   
                   
                   
                 143465 
                 143484 
                   
               
               
                   
               
               
                 533414 
                 ACTTTGTGAGATTTCAAATA 
                 Intron l 
                 57 
                 143186 
                 143205 
                 1075 
               
               
                   
                   
                   
                   
                 143214 
                 143233 
                   
               
               
                   
                   
                   
                   
                 143242 
                 143261 
                   
               
               
                   
                   
                   
                   
                 143298 
                 143317 
                   
               
               
                   
                   
                   
                   
                 143326 
                 143345 
                   
               
               
                   
                   
                   
                   
                 143354 
                 143373 
                   
               
               
                   
                   
                   
                   
                 143382 
                 143401 
                   
               
               
                   
                   
                   
                   
                 143466 
                 143485 
                   
               
               
                   
               
               
                 533415 
                 CACTTTGTGAGATTTCAAAT 
                 Intron 1 
                 69 
                 143187 
                 143206 
                 1076 
               
               
                   
                   
                   
                   
                 143215 
                 143234 
                   
               
               
                   
                   
                   
                   
                 143243 
                 143262 
                   
               
               
                   
                   
                   
                   
                 143299 
                 143318 
                   
               
               
                   
                   
                   
                   
                 143327 
                 143346 
                   
               
               
                   
                   
                   
                   
                 143355 
                 143374 
                   
               
               
                   
                   
                   
                   
                 143383 
                 143402 
                   
               
               
                   
                   
                   
                   
                 143467 
                 143486 
                   
               
               
                   
               
               
                 533895 
                 AGTATTTCAGGCTGGAAAAA 
                 Intron 3 
                 35 
                 214622 
                 214641 
                 1077 
               
               
                   
               
               
                 533896 
                 TGAGTATTTCAGGCTGGAAA 
                 Intron 3 
                 55 
                 214624 
                 214643 
                 1078 
               
               
                   
               
               
                 533897 
                 TCTGAGTATTTCAGGCTGGA 
                 Intron 3 
                 71 
                 214626 
                 214645 
                 1079 
               
               
                   
               
               
                 533898 
                 ATCTGAGTATTTCAGGCTGG 
                 Intron 3 
                 77 
                 214627 
                 214646 
                 1080 
               
               
                   
               
               
                 533899 
                 TATCTGAGTATTTCAGGCTG 
                 Intron 3 
                 58 
                 214628 
                 214647 
                 1081 
               
               
                   
               
               
                 533900 
                 TTTTGTGTTATGCCTTGAGG 
                 Intron 3 
                 51 
                 221483 
                 221502 
                 1082 
               
               
                   
               
               
                 533901 
                 TTTTTGTGTTATGCCTTGAG 
                 Intron 3 
                 55 
                 221484 
                 221503 
                 1083 
               
               
                   
               
               
                 533902 
                 ATTTTTGTGTTATGCCTTGA 
                 Intron 3 
                 57 
                 221485 
                 221504 
                 1084 
               
               
                   
               
               
                 533903 
                 ATATTTTTGTGTTATGCCTT 
                 Intron 3 
                 56 
                 221487 
                 221506 
                 1085 
               
               
                   
               
               
                 533904 
                 AATATTTTTGTGTTATGCCT 
                 Intron 3 
                 61 
                 221488 
                 221507 
                 1086 
               
               
                   
               
               
                 533905 
                 AAATATTTTTGTGTTATGCC 
                 Intron 3 
                 18 
                 221489 
                 221508 
                 1087 
               
               
                   
               
               
                 533906 
                 TTGCTTATTTACCTGGGTAA 
                 Intron 3 
                 58 
                 225565 
                 225584 
                 1088 
               
               
                   
               
               
                 533907 
                 TTTGCTTATTTACCTGGGTA 
                 Intron 3 
                 64 
                 225566 
                 225585 
                 1089 
               
               
                   
               
               
                 533908 
                 TTTTGCTTATTTACCTGGGT 
                 Intron 3 
                 77 
                 225567 
                 225586 
                 1090 
               
               
                   
               
               
                 533909 
                 CCTTTTGCTTATTTACCTGG 
                 Intron 3 
                 69 
                 225569 
                 225588 
                 1091 
               
               
                   
               
               
                 533910 
                 GCCTTTTGCTTATTTACCTG 
                 Intron 3 
                 69 
                 225570 
                 225589 
                 1092 
               
               
                   
               
               
                 533911 
                 TGCCTTTTGCTTATTTACCT 
                 Intron 3 
                 55 
                 225571 
                 225590 
                 1093 
               
               
                   
               
               
                 533912 
                 ATGATGTTACTACTACTCAA 
                 Intron 3 
                 60 
                 229615 
                 229634 
                 1094 
               
               
                   
               
               
                 533913 
                 AATGATGTTACTACTACTCA 
                 Intron 3 
                 48 
                 229616 
                 229635 
                 1095 
               
               
                   
               
               
                 533914 
                 CAATGATGTTACTACTACTC 
                 Intron 3 
                 57 
                 229617 
                 229636 
                 1096 
               
               
                   
               
               
                 533915 
                 TCCAATGATGTTACTACTAC 
                 Intron 3 
                 69 
                 229619 
                 229638 
                 1097 
               
               
                   
               
               
                 533916 
                 TTCCAATGATGTTACTACTA 
                 Intron 3 
                 74 
                 229620 
                 229639 
                 1098 
               
               
                   
               
               
                 533917 
                 ATTCCAATGATGTTACTACT 
                 Intron 3 
                 74 
                 229621 
                 229640 
                 1099 
               
               
                   
               
               
                 533918 
                 CCCCTAGAGCAATGGTCTAG 
                 Intron 3 
                 71 
                 232823 
                 232842 
                 1100 
               
               
                   
               
               
                 533919 
                 CCCCCTAGAGCAATGGTCTA 
                 Intron 3 
                 44 
                 232824 
                 232843 
                 1101 
               
               
                   
               
               
                 533920 
                 TCCCCCTAGAGCAATGGTCT 
                 Intron 3 
                 54 
                 232825 
                 232844 
                 1102 
               
               
                   
               
               
                 533921 
                 TATCCCCCTAGAGCAATGGT 
                 Intron 3 
                 62 
                 232827 
                 232846 
                 1103 
               
               
                   
               
               
                 533922 
                 ATATCCCCCTAGAGCAATGG 
                 Intron 3 
                 50 
                 232828 
                 232847 
                 1104 
               
               
                   
               
               
                 533923 
                 AATATCCCCCTAGAGCAATG 
                 Intron 3 
                 61 
                 232829 
                 232848 
                 1105 
               
               
                   
               
               
                 533924 
                 GCTCACATTTGGAAGACAGT 
                 Intron 3 
                 68 
                 233623 
                 233642 
                 1106 
               
               
                   
               
               
                 533925 
                 GGCTCACATTTGGAAGACAG 
                 Intron 3 
                 74 
                 233624 
                 233643 
                 1107 
               
               
                   
               
               
                 533926 
                 AGGCTCACATTTGGAAGACA 
                 Intron 3 
                 56 
                 233625 
                 233644 
                 1108 
               
               
                   
               
               
                 533927 
                 AGAGGCTCACATTTGGAAGA 
                 Intron 3 
                 34 
                 233627 
                 233646 
                 1109 
               
               
                   
               
               
                 533928 
                 TAGAGGCTCACATTTGGAAG 
                 Intron 3 
                 18 
                 233628 
                 233647 
                 1110 
               
               
                   
               
               
                 533929 
                 TTAGAGGCTCACATTTGGAA 
                 Intron 3 
                 19 
                 233629 
                 233648 
                 1111 
               
               
                   
               
               
                 533930 
                 CTCAATTGCAGATGCTCTGA 
                 Intron 3 
                 66 
                 237673 
                 237692 
                 1112 
               
               
                   
               
               
                 533931 
                 GCTCAATTGCAGATGCTCTG 
                 Intron 3 
                 72 
                 237674 
                 237693 
                 1113 
               
               
                   
               
               
                 533932 
                 AGCTCAATTGCAGATGCTCT 
                 Intron 3 
                 74 
                 237675 
                 237694 
                 1114 
               
               
                   
               
               
                 533933 
                 AAAGCTCAATTGCAGATGCT 
                 Intron 3 
                 66 
                 237677 
                 237696 
                 1115 
               
               
                   
               
               
                 533934 
                 TAAAGCTCAATTGCAGATGC 
                 Intron 3 
                 59 
                 237678 
                 237697 
                 1116 
               
               
                   
               
               
                 533935 
                 ATAAAGCTCAATTGCAGATG 
                 Intron 3 
                 23 
                 237679 
                 237698 
                 1117 
               
               
                   
               
               
                 533936 
                 GTGAGTCCATTAAACCTCTT 
                 Intron 3 
                 73 
                 244873 
                 244892 
                 1118 
               
               
                   
               
               
                 533937 
                 TGTGAGTCCATTAAACCTCT 
                 Intron 3 
                 73 
                 244874 
                 244893 
                 1119 
               
               
                   
               
               
                 533938 
                 ACTGTGAGTCCATTAAACCT 
                 Intron 3 
                 17 
                 244876 
                 244895 
                 1120 
               
               
                   
               
               
                 533939 
                 AACTGTGAGTCCATTAAACC 
                 Intron 3 
                 19 
                 244877 
                 244896 
                 1121 
               
               
                   
               
               
                 533940 
                 GAACTGTGAGTCCATTAAAC 
                 Intron 3 
                 28 
                 244878 
                 244897 
                 1122 
               
               
                   
               
               
                 533941 
                 ATATTGAAAGGCCCATCAAA 
                 Intron 3 
                 13 
                 246498 
                 246517 
                 1123 
               
               
                   
               
               
                 533942 
                 AATATTGAAAGGCCCATCAA 
                 Intron 3 
                 31 
                 246499 
                 246518 
                 1124 
               
               
                   
               
               
                 533943 
                 AAATATTGAAAGGCCCATCA 
                 Intron 3 
                 51 
                 246500 
                 246519 
                 1125 
               
               
                   
               
               
                 533944 
                 GAAAATATTGAAAGGCCCAT 
                 Intron 3 
                 22 
                 246502 
                 246521 
                 1126 
               
               
                   
               
               
                 533945 
                 GGAAAATATTGAAAGGCCCA 
                 Intron 3 
                 42 
                 246503 
                 246522 
                 1127 
               
               
                   
               
               
                 533946 
                 AGGAAAATATTGAAAGGCCC 
                 Intron 3 
                 28 
                 246504 
                 246523 
                 1128 
               
               
                   
               
               
                 533947 
                 GTATATTCAGTCCAAGGATC 
                 Intron 3 
                 65 
                 248228 
                 248247 
                 1129 
               
               
                   
               
               
                 533948 
                 AGTATATTCAGTCCAAGGAT 
                 Intron 3 
                 63 
                 248229 
                 248248 
                 1130 
               
               
                   
               
               
                 533949 
                 CAGTATATTCAGTCCAAGGA 
                 Intron 3 
                 67 
                 248230 
                 248249 
                 1131 
               
               
                   
               
               
                 533950 
                 AACAGTATATTCAGTCCAAG 
                 Intron 3 
                 56 
                 248232 
                 248251 
                 1132 
               
               
                   
               
               
                 533951 
                 AAACAGTATATTCAGTCCAA 
                 Intron 3 
                 60 
                 248233 
                 248252 
                 1133 
               
               
                   
               
               
                 533952 
                 AAAACAGTATATTCAGTCCA 
                 Intron 3 
                 59 
                 248234 
                 248253 
                 1134 
               
               
                   
               
               
                 533953 
                 TCTATTGTTGCCACCTTTAT 
                 Intron 3 
                 45 
                 252838 
                 252857 
                 1135 
               
               
                   
               
               
                 533954 
                 TTCTATTGTTGCCACCTTTA 
                 Intron 3 
                 52 
                 252839 
                 252858 
                 1136 
               
               
                   
               
               
                 533955 
                 TTTCTATTGTTGCCACCTTT 
                 Intron 3 
                 46 
                 252840 
                 252859 
                 1137 
               
               
                   
               
               
                 533956 
                 AGTTTCTATTGTTGCCACCT 
                 Intron 3 
                 59 
                 252842 
                 252861 
                 1138 
               
               
                   
               
               
                 533957 
                 CAGTTTCTATTGTTGCCACC 
                 Intron 3 
                 41 
                 252843 
                 252862 
                 1139 
               
               
                   
               
               
                 533958 
                 CCAGTTTCTATTGTTGCCAC 
                 Intron 3 
                 48 
                 252844 
                 252863 
                 1140 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 17 
               
             
            
               
                   
               
               
                 Inhibition of GHR mRNA by 5-10-5 MOE gapmers 
               
               
                 targeting intron 3 of SEQ ID NO: 2 
               
            
           
           
               
               
               
               
               
               
            
               
                 ISIS 
                   
                 % 
                 SEQ ID NO: 2 
                 SEQ ID NO: 2 
                 SEQ 
               
               
                 NO 
                 Sequence 
                 inhibition 
                 Start Site 
                 Stop Site 
                 ID NO 
               
               
                   
               
               
                 532454 
                 GCAGAACTGATTGCTTACTT 
                 78 
                 182862 
                 182881 
                 1141 
               
               
                   
               
               
                 532455 
                 AGGTCATAAGATTTTCATTT 
                 48 
                 183533 
                 183552 
                 1142 
               
               
                   
               
               
                 532456 
                 GCCTCTGGCCATAAAGAAAT 
                 54 
                 183578 
                 183597 
                 1143 
               
               
                   
               
               
                 532457 
                 AAAGTTTAAGAGGCACCCCA 
                 31 
                 184508 
                 184527 
                 1144 
               
               
                   
               
               
                 532458 
                 GAATAAGCACAAAAGTTTAA 
                 28 
                 184519 
                 184538 
                 1145 
               
               
                   
               
               
                 532459 
                 GAACCAAATAAACCTCTCTT 
                 52 
                 185452 
                 185471 
                 1146 
               
               
                   
               
               
                 532460 
                 ATGTTGAAATTTGATCCCCA 
                 79 
                 185763 
                 185782 
                 1147 
               
               
                   
               
               
                 532461 
                 TGTGAGAGCTCACTCACTAT 
                 42 
                 186134 
                 186153 
                 1148 
               
               
                   
               
               
                 532462 
                 CTTGTGAGAGCTCACTCACT 
                 72 
                 186136 
                 186155 
                 1149 
               
               
                   
               
               
                 532463 
                 ACATGGTGGCAGGAGAGAGG 
                 42 
                 186206 
                 186225 
                 1150 
               
               
                   
               
               
                 532464 
                 CTAGAAAGAAACTACCTGAG 
                 12 
                 186341 
                 186360 
                 1151 
               
               
                   
               
               
                 532465 
                 AACTTCAGTTGTAAAATAAT 
                 27 
                 187044 
                 187063 
                 1152 
               
               
                   
               
               
                 532466 
                 GAAAAGGATTTTGAGATTTC 
                 43 
                 188897 
                 188916 
                 1153 
               
               
                   
               
               
                 532467 
                 CTTAGCTGTCAAGGCCCTTT 
                 80 
                 189084 
                 189103 
                 1154 
               
               
                   
               
               
                 532468 
                 TGTGCTTCATGTCTTTCTAG 
                 88 
                 189119 
                 189138 
                 1155 
               
               
                   
               
               
                 532469 
                 CCCTTGAACATGCTATCCTT 
                 85 
                 189256 
                 189275 
                 1156 
               
               
                   
               
               
                 532470 
                 CTTGCAGGGATGCATCTCAG 
                 87 
                 189625 
                 189644 
                 1157 
               
               
                   
               
               
                 532471 
                 TCTCTTGCACATCTAATTTC 
                 82 
                 189656 
                 189675 
                 1158 
               
               
                   
               
               
                 532472 
                 CTTCCAGCACAACCCATCAC 
                 77 
                 190109 
                 190128 
                 1159 
               
               
                   
               
               
                 532473 
                 GTAACTACATTCCCTTTATC 
                 52 
                 190860 
                 190879 
                 1160 
               
               
                   
               
               
                 532474 
                 AGTAACTACATTCCCTTTAT 
                 58 
                 190861 
                 190880 
                 1161 
               
               
                   
               
               
                 532475 
                 CAGATAGCACAGGGCTAAAA 
                 84 
                 190979 
                 190998 
                 1162 
               
               
                   
               
               
                 532476 
                 AGAATCAGGAATGTTTGCCT 
                 86 
                 192904 
                 192923 
                 1163 
               
               
                   
               
               
                 532477 
                 TGACTCAATCATTTAGACTT 
                 45 
                 192990 
                 193009 
                 1164 
               
               
                   
               
               
                 532478 
                 TCAACAGTCAATGGACTTGT 
                 71 
                 193042 
                 193061 
                 1165 
               
               
                   
               
               
                 532479 
                 AATTTCTACTGCTATGATGC 
                 75 
                 194806 
                 194825 
                 1166 
               
               
                   
               
               
                 532480 
                 ATGGTTCCAAATTTCTATCT 
                 86 
                 195704 
                 195723 
                 1167 
               
               
                   
               
               
                 532481 
                 CTGTATGGCTTTAAGTATTC 
                 63 
                 196756 
                 196775 
                 1168 
               
               
                   
               
               
                 532482 
                 AACTTATGAACTGTTCACCA 
                 86 
                 198307 
                 198326 
                 1169 
               
               
                   
               
               
                 532483 
                 AATAAGCTTGAAGTCTGAAG 
                 63 
                 199520 
                 199539 
                 1170 
               
               
                   
               
               
                 532484 
                 TAGTTATCTAACTGCCCAAT 
                 77 
                 199544 
                 199563 
                 1171 
               
               
                   
               
               
                 532485 
                 TTCTGCAAAGCTTCCCAGTA 
                 72 
                 200314 
                 200333 
                 1172 
               
               
                   
               
               
                 532486 
                 ACAACTTCAAGCTTCACATA 
                 65 
                 200599 
                 200618 
                 1173 
               
               
                   
               
               
                 532487 
                 GAATCAATGTTCTGGCAAGA 
                 52 
                 201842 
                 201861 
                 1174 
               
               
                   
               
               
                 532488 
                 CAGCCTTTCAGCTGTGAAAG 
                 52 
                 204181 
                 204200 
                 1175 
               
               
                   
               
               
                 532489 
                 AACAATGCCAAGAAATCTAT 
                 74 
                 204369 
                 204388 
                 1176 
               
               
                   
               
               
                 532490 
                 CCCACAGTAACAATGCCAAG 
                 90 
                 204377 
                 204396 
                 1177 
               
               
                   
               
               
                 532491 
                 TTTTACCTCCCAGTGAAACT 
                 34 
                 205896 
                 205915 
                 1178 
               
               
                   
               
               
                 532492 
                 TAATTGTTGATCCATGATGT 
                  5 
                 208856 
                 208875 
                 1179 
               
               
                   
               
               
                 532493 
                 GTTGGAGAGACAAGTTTAAC 
                 29 
                 208975 
                 208994 
                 1180 
               
               
                   
               
               
                 532494 
                 AGTCATAAAATTCAAATTAT 
                 39 
                 209537 
                 209556 
                 1181 
               
               
                   
               
               
                 532495 
                 GGCCTTGGGCACACTTTCTC 
                 82 
                 207510 
                 207529 
                 1182 
               
               
                   
                   
                   
                 210189 
                 210208 
                   
               
               
                   
               
               
                 532496 
                 AAGTTTTTATTGAAGTTAAT 
                  0 
                 212551 
                 212570 
                 1183 
               
               
                   
               
               
                 532497 
                 AAGAAAAATTAGGAAGCTAG 
                 31 
                 212649 
                 212668 
                 1184 
               
               
                   
               
               
                 532498 
                 CAGGGAGATAAGTTTATTCA 
                 61 
                 212797 
                 212816 
                 1185 
               
               
                   
               
               
                 532499 
                 ATTTAATACACATTGGAATA 
                 15 
                 213390 
                 213409 
                 1186 
               
               
                   
               
               
                 532500 
                 GTAGGACTATTTATGATTCC 
                 86 
                 213914 
                 213933 
                 1187 
               
               
                   
               
               
                 532501 
                 CACTCTCTTGGGCTGTTAAG 
                 82 
                 214479 
                 214498 
                 1188 
               
               
                   
               
               
                 532502 
                 GAGTATTTCAGGCTGGAAAA 
                 66 
                 214623 
                 214642 
                 1064 
               
               
                   
               
               
                 532503 
                 TTGTTTGAGTTCCAAAAGAA 
                 39 
                 214932 
                 214951 
                 1189 
               
               
                   
               
               
                 532504 
                 TTTGCCATGAGACACACAAT 
                 77 
                 215932 
                 215951 
                 1190 
               
               
                   
               
               
                 532505 
                 CACCAAACCTCAGAGACATG 
                 80 
                 216468 
                 216487 
                 1191 
               
               
                   
               
               
                 532506 
                 CCACTGTTAAGTGATGCATG 
                 83 
                 217480 
                 217499 
                 1192 
               
               
                   
               
               
                 532507 
                 CTCTCAGGTAATTTCTGGAA 
                 86 
                 219019 
                 219038 
                 1193 
               
               
                   
               
               
                 532508 
                 GCTCCTCACAATGACCCTTT 
                 84 
                 219452 
                 219471 
                 1194 
               
               
                   
               
               
                 532509 
                 GGGACTGGCACTGGTAATTT 
                 56 
                 220062 
                 220081 
                 1195 
               
               
                   
               
               
                 532510 
                 CTAACCATTAGTTACTGTAT 
                 69 
                 220558 
                 220577 
                 1196 
               
               
                   
               
               
                 532511 
                 GGATTTTAGGTTCTTGCTGT 
                 51 
                 221588 
                 221607 
                 1197 
               
               
                   
               
               
                 532512 
                 TGAATCATATACTGATATCA 
                 63 
                 222914 
                 222933 
                 1198 
               
               
                   
               
               
                 532513 
                 TTGAGGTATTAAATTTTAAA 
                  0 
                 223001 
                 223020 
                 1199 
               
               
                   
               
               
                 532514 
                 AGTTTGTAATGTAGTGATTT 
                 19 
                 223156 
                 223175 
                 1200 
               
               
                   
               
               
                 532515 
                 AAATATTTGATAGCTCACAT 
                 18 
                 224409 
                 224428 
                 1201 
               
               
                   
               
               
                 532516 
                 AGAAATATTTGATAGCTCAC 
                 57 
                 224411 
                 224430 
                 1202 
               
               
                   
               
               
                 532517 
                 CCACATTTCAAATGTTCTCT 
                 80 
                 224717 
                 224736 
                 1203 
               
               
                   
               
               
                 532518 
                 GCAGGAAGAGTGGCATGGAC 
                 59 
                 224750 
                 224769 
                 1204 
               
               
                   
               
               
                 532519 
                 CACTTATCCAAATGCAGAGA 
                 82 
                 225742 
                 225761 
                 1205 
               
               
                   
               
               
                 532520 
                 CAAGGTAATGGGAGGCTAGC 
                 47 
                 225903 
                 225922 
                 1206 
               
               
                   
               
               
                 532521 
                 ATAGTCAAAGCTAAGGATAT 
                  4 
                 226177 
                 226196 
                 1207 
               
               
                   
               
               
                 532522 
                 GTAATTTCATTCATGCTTCC 
                 67 
                 226804 
                 226823 
                 1208 
               
               
                   
               
               
                 532523 
                 GTCCACATTCAGCTGTGTGT 
                 72 
                 231912 
                 231931 
                 1209 
               
               
                   
               
               
                 532524 
                 TCATTCAGGAAATTCTGCTA 
                 62 
                 232286 
                 232305 
                 1210 
               
               
                   
               
               
                 532525 
                 AACATGTCTCATTCAGGAAA 
                 71 
                 232294 
                 232313 
                 1211 
               
               
                   
               
               
                 532526 
                 TAACATGTCTCATTCAGGAA 
                 85 
                 232295 
                 232314 
                 1212 
               
               
                   
               
               
                 532527 
                 AGATTCCTCAAATTCAGTGA 
                 66 
                 232389 
                 232408 
                 1213 
               
               
                   
               
               
                 532528 
                 TAAGCGGAAAAGGAGAAAAG 
                  0 
                 233684 
                 233703 
                 1214 
               
               
                   
               
               
                 532529 
                 AAAGCAAGAGAATTCCTAAA 
                 32 
                 234203 
                 234222 
                 1215 
               
               
                   
               
               
                 532530 
                 AATGAACCTTTAACTTAGTA 
                 40 
                 234876 
                 234895 
                 1216 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 18 
               
             
            
               
                   
               
               
                 Inhibition of GHR mRNA by 5-10-5 MOE gapmers targeting 
               
               
                 introns 3-8 and intron-exonic regions of SEQ ID NO: 2 
               
            
           
           
               
               
               
               
               
               
               
            
               
                 ISIS 
                   
                   
                 % 
                 SEQ ID NO: 2 
                 SEQ ID NO: 2 
                 SEQ 
               
               
                 NO 
                 Sequence 
                 Target region 
                 inhibition 
                 Start Site 
                 Stop Site 
                 ID NO 
               
               
                   
               
               
                 523792 
                 AAAGCTTTGTGGATAAAGTT 
                 Intron 3 
                 44 
                 213025 
                 213044 
                 1217 
               
               
                   
               
               
                 523793 
                 GAAGGAAAGGTTCTGTGGAA 
                 Intron 3 
                 38 
                 213825 
                 213844 
                 1218 
               
               
                   
               
               
                 523794 
                 CTGAGTATTTCAGGCTGGAA 
                 Intron 3 
                 84 
                 214625 
                 214644 
                 1219 
               
               
                   
               
               
                 523795 
                 TTGAATTATCCCTTTAAAAA 
                 Intron 3 
                 38 
                 215446 
                 215465 
                 1220 
               
               
                   
               
               
                 523796 
                 TTTAGAATGGTTTGGCATAC 
                 Intron 3 
                 66 
                 216365 
                 216384 
                 1221 
               
               
                   
               
               
                 523797 
                 GATATGTCCACATTGATTAG 
                 Intron 3 
                 65 
                 218132 
                 218151 
                 1222 
               
               
                   
               
               
                 523798 
                 ATTATTTAAGCTTCTACTTT 
                 Intron 3 
                 44 
                 218973 
                 218992 
                 1223 
               
               
                   
               
               
                 523799 
                 ATACATGGCAATTAAAAGAT 
                 Intron 3 
                 26 
                 219886 
                 219905 
                 1224 
               
               
                   
               
               
                 523800 
                 TGAGATAGTGTGGGAAATAT 
                 Intron 3 
                 18 
                 220686 
                 220705 
                 1225 
               
               
                   
               
               
                 523801 
                 TATTTTTGTGTTATGCCTTG 
                 Intron 3 
                 73 
                 221486 
                 221505 
                 1226 
               
               
                   
               
               
                 523802 
                 TTATTAACTAGAATATGCCT 
                 Intron 3 
                 16 
                 223110 
                 223129 
                 1227 
               
               
                   
               
               
                 523803 
                 GATTATTCTATTTTTATTTT 
                 Intron 3 
                 33 
                 223948 
                 223967 
                 1228 
               
               
                   
               
               
                 523804 
                 AGGAAGAGTGGCATGGACAT 
                 Intron 3 
                 43 
                 224748 
                 224767 
                 1229 
               
               
                   
               
               
                 523805 
                 CTTTTGCTTATTTACCTGGG 
                 Intron 3 
                 84 
                 225568 
                 225587 
                 1230 
               
               
                   
               
               
                 523806 
                 TTTATATTATTAATATCATT 
                 Intron 3 
                 31 
                 226371 
                 226390 
                 1231 
               
               
                   
               
               
                 523807 
                 GGTACATGGCTTTTAAGTGG 
                 Intron 3 
                 53 
                 227218 
                 227237 
                 1232 
               
               
                   
               
               
                 523808 
                 AATATTGGTCAGGTTTAAGA 
                 Intron 3 
                 28 
                 228018 
                 228037 
                 1233 
               
               
                   
               
               
                 523809 
                 ATTTCATCTCTTTCTTAGTT 
                 Intron 3 
                 45 
                 228818 
                 228837 
                 1234 
               
               
                   
               
               
                 523810 
                 CCAATGATGTTACTACTACT 
                 Intron 3 
                 89 
                 229618 
                 229637 
                 1235 
               
               
                   
               
               
                 523811 
                 GTTCCCCCAACCCCTTGGAA 
                 Intron 3 
                 28 
                 230418 
                 230437 
                 1236 
               
               
                   
               
               
                 523812 
                 TATAGGAAGTGAGATGTATG 
                 Intron 3 
                 46 
                 231218 
                 231237 
                 1237 
               
               
                   
               
               
                 523813 
                 ATTATTCTAGAAGAAGATTT 
                 Intron 3 
                 12 
                 232018 
                 232037 
                 1238 
               
               
                   
               
               
                 523814 
                 ATCCCCCTAGAGCAATGGTC 
                 Intron 3 
                 79 
                 232826 
                 232845 
                 1239 
               
               
                   
               
               
                 523815 
                 GAGGCTCACATTTGGAAGAC 
                 Intron 3 
                 69 
                 233626 
                 233645 
                 1240 
               
               
                   
               
               
                 523816 
                 TACACAAATCCAAGGCAGAG 
                 Intron 3 
                 57 
                 234447 
                 234466 
                 1241 
               
               
                   
               
               
                 523817 
                 AGGAAGAGTGGGAGTGTTAC 
                 Intron 3 
                 35 
                 235258 
                 235277 
                 1242 
               
               
                   
               
               
                 523818 
                 GTCCCTGACTAGGCATTTTG 
                 Intron 3 
                 43 
                 236071 
                 236090 
                 1243 
               
               
                   
               
               
                 523819 
                 AAGCTCAATTGCAGATGCTC 
                 Intron 3 
                 80 
                 237676 
                 237695 
                 1244 
               
               
                   
               
               
                 523820 
                 CTGTGAGTCCATTAAACCTC 
                 Intron 3 
                 81 
                 244875 
                 244894 
                 1245 
               
               
                   
               
               
                 523821 
                 TGAAATGTGGCTAGTGTGAC 
                 Intron 3 
                 51 
                 245701 
                 245720 
                 1246 
               
               
                   
               
               
                 523822 
                 AAAATATTGAAAGGCCCATC 
                 Intron 3 
                 68 
                 246501 
                 246520 
                 1247 
               
               
                   
               
               
                 523823 
                 AATGTCAATAGTGCCCTATT 
                 Intron 3 
                 48 
                 247431 
                 247450 
                 1248 
               
               
                   
               
               
                 523824 
                 ACAGTATATTCAGTCCAAGG 
                 Intron 3 
                 82 
                 248231 
                 248250 
                 1249 
               
               
                   
               
               
                 523825 
                 TGTCTATTTAAGTTTGTTGC 
                 Intron 3 
                 45 
                 250001 
                 250020 
                 1250 
               
               
                   
               
               
                 523826 
                 TTCAAGTACTGTCATGAATA 
                 Intron 3 
                 47 
                 251214 
                 251233 
                 1251 
               
               
                   
               
               
                 523827 
                 TTTCTTTTTCTTAAACTAAG 
                 Intron 3 
                 11 
                 252041 
                 252060 
                 1252 
               
               
                   
               
               
                 523828 
                 GTTTCTATTGTTGCCACCTT 
                 Intron 3 
                 70 
                 252841 
                 252860 
                 1253 
               
               
                   
               
               
                 523829 
                 AAGGCCACATATTATAGTAT 
                 Intron 3 
                 29 
                 253698 
                 253717 
                 1254 
               
               
                   
               
               
                 523830 
                 ACCTGAACTATTAATTTCTT 
                 Intron 3 
                 19 
                 255397 
                 255416 
                 1255 
               
               
                   
               
               
                 523831 
                 GAATGGGCTGAGTAGTTGAA 
                 Intron 3 
                 47 
                 256197 
                 256216 
                 1256 
               
               
                   
               
               
                 523832 
                 TGATGAACATTGCTAATTTG 
                 Intron 3 
                 26 
                 257018 
                 257037 
                 1257 
               
               
                   
               
               
                 523833 
                 ATCTTGCCTCGATGAAAGTT 
                 Intron 3 
                 17 
                 257818 
                 257837 
                 1258 
               
               
                   
               
               
                 523834 
                 TTAAGTGGCACAGCCATGAT 
                 Intron 3 
                 9 
                 258774 
                 258793 
                 1259 
               
               
                   
               
               
                 523835 
                 AATGAGTTAAGTTGGAACAC 
                 Intron 3 
                 25 
                 261294 
                 261313 
                 1260 
               
               
                   
               
               
                 523836 
                 TCCTTAGTAGAATGCCTGGA 
                 Intron 3 
                 57 
                 263338 
                 263357 
                 1261 
               
               
                   
               
               
                 523837 
                 TATGTAGAAAAATAAGCTGG 
                 Intron 3 
                 0 
                 266514 
                 266533 
                 1262 
               
               
                   
               
               
                 523838 
                 GCCGAGGCAGGCACCTGAGT 
                 Intron 3 
                 43 
                 267375 
                 267394 
                 1263 
               
               
                   
               
               
                 523839 
                 TGGTACCTATATTGAGAGGT 
                 Intron 4 
                 46 
                 269052 
                 269071 
                 1264 
               
               
                   
               
               
                 523840 
                 TTAAGGAAAAATATAGTATA 
                 Intron 4 
                 7 
                 269854 
                 269873 
                 1265 
               
               
                   
               
               
                 523841 
                 TTATTTATGTGTCAGGGATG 
                 Intron 4 
                 28 
                 270668 
                 270687 
                 1266 
               
               
                   
               
               
                 523842 
                 CAAAAGTTAAGTGCTTTAGG 
                 Intron 4 
                 10 
                 271468 
                 271487 
                 1267 
               
               
                   
               
               
                 523843 
                 TTCATAGATGTCTAAGGAAT 
                 Intron 4 
                 32 
                 273341 
                 273360 
                 1268 
               
               
                   
               
               
                 523844 
                 ACCTGTGATTTACCTATTTC 
                 Exon 5-intron 5 
                 18 
                 274185 
                 274204 
                 1269 
               
               
                   
                   
                 junction 
                   
                   
                   
                   
               
               
                   
               
               
                 523845 
                 TGCCTAGAAAACCACATAAA 
                 Intron 5 
                 38 
                 274985 
                 275004 
                 1270 
               
               
                   
               
               
                 523846 
                 AAACATCCTCAAAGGTACCT 
                 Intron 5 
                 64 
                 275808 
                 275827 
                 1271 
               
               
                   
               
               
                 523847 
                 CTTCCCTGAGACACACACAT 
                 Intron 5 
                 35 
                 276617 
                 276636 
                 1272 
               
               
                   
               
               
                 523848 
                 CTTCTTCAATCTTCTCATAC 
                 Intron 5 
                 33 
                 278288 
                 278307 
                 1273 
               
               
                   
               
               
                 523849 
                 TACCATTTTCCATTTAGTTT 
                 Exon 6-intron 6 
                 7 
                 279088 
                 279107 
                 1274 
               
               
                   
                   
                 junction 
                   
                   
                   
                   
               
               
                   
               
               
                 523850 
                 ATTGGCATCTTTTTCAGTGG 
                 Intron 6 
                 34 
                 279902 
                 279921 
                 1275 
               
               
                   
               
               
                 523851 
                 TCAAGCTCACGGTTGGAGAC 
                 Intron 6 
                 36 
                 280799 
                 280818 
                 1276 
               
               
                   
               
               
                 523852 
                 AAATGAAATCAGTATGTTGA 
                 Intron 6 
                 0 
                 281622 
                 281641 
                 1277 
               
               
                   
               
               
                 523853 
                 TGATTTATCACAAAGGTGCT 
                 Intron 6 
                 29 
                 282437 
                 282456 
                 1278 
               
               
                   
               
               
                 523854 
                 AAAACAGTAGAAAAGATTAA 
                 Intron 6 
                 14 
                 284073 
                 284092 
                 1279 
               
               
                   
               
               
                 523855 
                 CTACATCACAGCAGTCAGAA 
                 Intron 6 
                 23 
                 285187 
                 285206 
                 1280 
               
               
                   
               
               
                 523856 
                 AAAAGATGTAAGTGTGACAT 
                 Intron 6 
                 28 
                 286349 
                 286368 
                 1281 
               
               
                   
                   
                   
                   
                 286919 
                 286938 
                   
               
               
                   
               
               
                 523857 
                 TTACAAGAACTGCTAAAGGG 
                 Intron 6 
                 15 
                 287151 
                 287170 
                 1282 
               
               
                   
               
               
                 523858 
                 ATAAAGAAAAAGTTAACTGA 
                 Intron 6 
                 9 
                 287982 
                 288001 
                 1283 
               
               
                   
               
               
                 523859 
                 AGATAATATACTTCTTCTAT 
                 Intron 6 
                 4 
                 288809 
                 288828 
                 1284 
               
               
                   
               
               
                 523860 
                 CCTTCTTCACATGTAAATTG 
                 Exon 7-intron 7 
                 19 
                 290456 
                 290475 
                 1285 
               
               
                   
                   
                 junction 
                   
                   
                   
                   
               
               
                   
               
               
                 523861 
                 TTTCTATGTAGCTTGTGGTT 
                 Intron 7 
                 30 
                 291258 
                 291277 
                 1286 
               
               
                   
               
               
                 523862 
                 AGGCAGAGTTTTTATTGATA 
                 Intron 7 
                 19 
                 292058 
                 292077 
                 1287 
               
               
                   
               
               
                 523863 
                 ATAGTCACCAGCCTAAGCCT 
                 Intron 8 
                 28 
                 292858 
                 292877 
                 1288 
               
               
                   
               
               
                 523864 
                 AGACTTTTAGCATGCTTGAC 
                 Intron 8 
                 56 
                 293658 
                 293677 
                 1289 
               
               
                   
               
               
                 523865 
                 TTTACAGCCCTACAGTTCTA 
                 Intron 8 
                 7 
                 294464 
                 294483 
                 1290 
               
               
                   
               
               
                 523866 
                 CCAGAGAACCTGACTCCAAA 
                 Intron 8 
                 6 
                 295330 
                 295349 
                 1291 
               
               
                   
               
               
                 523867 
                 CAGAAGAAAATATTAGACAG 
                 Intron 8 
                 10 
                 296993 
                 297012 
                 1292 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 19 
               
             
            
               
                   
               
               
                 Inhibition of GHR mRNA by 5-10-5 MOE gapmers 
               
               
                 targeting introns 3-8 of SEQ ID NO: 2 
               
            
           
           
               
               
               
               
               
               
               
            
               
                 ISIS 
                   
                 Target 
                 % 
                 SEQ ID NO: 2 
                 SEQ ID NO: 2 
                 SEQ 
               
               
                 NO 
                 Sequence 
                 Region 
                 inhibition 
                 Start Site 
                 Stop Site 
                 ID NO 
               
               
                   
               
               
                 532531 
                 TATTATACTTCTAAATTCCC 
                 Intron 3 
                 70 
                 236716 
                 236735 
                 1293 
               
               
                   
               
               
                 532532 
                 TAAAAGCAAGAAAAAGGAAC 
                 Intron 3 
                 52 
                 236889 
                 236908 
                 1294 
               
               
                   
               
               
                 532533 
                 CCTAATTTATATGAACAAAC 
                 Intron 3 
                 56 
                 237177 
                 237196 
                 1295 
               
               
                   
               
               
                 532534 
                 TGCAATGCCTTAGCCTAAAA 
                 Intron 3 
                 86 
                 238087 
                 238106 
                 1296 
               
               
                   
               
               
                 532535 
                 CACCACCATTATTACACTAC 
                 Intron 3 
                 75 
                 238186 
                 238205 
                 1297 
               
               
                   
               
               
                 532536 
                 AAATAAATCAGATTATTATA 
                 Intron 3 
                 52 
                 238242 
                 238261 
                 1298 
               
               
                   
               
               
                 532537 
                 CTTAGATCTGTGCTGTCCAA 
                 Intron 3 
                 81 
                 245758 
                 245777 
                 1299 
               
               
                   
               
               
                 532538 
                 GTTAGTGTTAGATTCTTTGA 
                 Intron 3 
                 67 
                 246152 
                 246171 
                 1300 
               
               
                   
               
               
                 532539 
                 CATGCTCACGGCTGTGTTAC 
                 Intron 3 
                 66 
                 246248 
                 246267 
                 1301 
               
               
                   
               
               
                 532540 
                 CCCATCAAATACTGAGTTCT 
                 Intron 3 
                 86 
                 246487 
                 246506 
                 1302 
               
               
                   
               
               
                 532541 
                 GAAAGTAGTGATTAATGAGA 
                 Intron 3 
                 38 
                 247012 
                 247031 
                 1303 
               
               
                   
               
               
                 532542 
                 ATTAATCAACAAGTGGCATT 
                 Intron 3 
                 72 
                 247203 
                 247222 
                 1304 
               
               
                   
               
               
                 532543 
                 TTTAATTTTAGGGTTTAGAG 
                 Intron 3 
                 48 
                 248344 
                 248363 
                 1305 
               
               
                   
               
               
                 532544 
                 CTTGCTACCACTAGAGCCTT 
                 Intron 3 
                 69 
                 248694 
                 248713 
                 1306 
               
               
                   
               
               
                 532545 
                 ACCACTGACTTATATCATTT 
                 Intron 3 
                 58 
                 248743 
                 248762 
                 1307 
               
               
                   
               
               
                 532546 
                 TTCCCCATTGCTAATTTTGT 
                 Intron 3 
                 48 
                 251601 
                 251620 
                 1308 
               
               
                   
               
               
                 532547 
                 TCCTGAAACTTAGTAGCTGG 
                 Intron 3 
                 83 
                 253147 
                 253166 
                 1309 
               
               
                   
               
               
                 532548 
                 TGTCTTAAAAAGGAATAAAA 
                 Intron 3 
                 52 
                 253785 
                 253804 
                 1310 
               
               
                   
               
               
                 532549 
                 CCTATAATAAAGTATTGTCT 
                 Intron 3 
                 70 
                 253800 
                 253819 
                 1311 
               
               
                   
               
               
                 532550 
                 ATGTAAAATGGTATAGCTAC 
                 Intron 3 
                 50 
                 254040 
                 254059 
                 1312 
               
               
                   
               
               
                 532551 
                 AACCCTCACACACTTCTGTT 
                 Intron 3 
                 71 
                 254064 
                 254083 
                 1313 
               
               
                   
               
               
                 532552 
                 ATTCTGCATAAGCAGTGTTT 
                 Intron 3 
                 53 
                 254246 
                 254265 
                 1314 
               
               
                   
               
               
                 532553 
                 TTACTACCCTGAAGAAGAAC 
                 Intron 3 
                 35 
                 254314 
                 254333 
                 1315 
               
               
                   
               
               
                 532554 
                 AAGACCTATAACTTACTACC 
                 Intron 3 
                 49 
                 254326 
                 254345 
                 1316 
               
               
                   
               
               
                 532555 
                 TTTCACAAGATTTACTTGGT 
                 Intron 3 
                 77 
                 254641 
                 254660 
                 1317 
               
               
                   
               
               
                 532556 
                 CAGTTGTGATTGTCAACCTA 
                 Intron 3 
                 77 
                 257073 
                 257092 
                 1318 
               
               
                   
               
               
                 532557 
                 AATCTTGCCTCGATGAAAGT 
                 Intron 3 
                 57 
                 257819 
                 257838 
                 1319 
               
               
                   
               
               
                 532558 
                 TGGCCTAAATGTATCAGTTA 
                 Intron 3 
                 66 
                 259157 
                 259176 
                 1320 
               
               
                   
               
               
                 532559 
                 AGGCTTTGGGTAAAATCTTT 
                 Intron 3 
                 67 
                 259184 
                 259203 
                 1321 
               
               
                   
               
               
                 532560 
                 TATGATTTTTAAAGATTAAA 
                 Intron 3 
                 20 
                 261419 
                 261438 
                 1322 
               
               
                   
               
               
                 532561 
                 GTACAGTGAAAAAGATGTGT 
                 Intron 3 
                 56 
                 263666 
                 263685 
                 1323 
               
               
                   
               
               
                 532562 
                 GACAGGTATGAAGCAAAACA 
                 Intron 3 
                 64 
                 267033 
                 267052 
                 1324 
               
               
                   
               
               
                 532563 
                 TGAGCTGAGGGTCTTTGCCG 
                 Intron 3 
                 61 
                 267391 
                 267410 
                 1325 
               
               
                   
               
               
                 532564 
                 AGGCTGAGTTGTACACAAAC 
                 Intron 4 
                 52 
                 269422 
                 269441 
                 1326 
               
               
                   
               
               
                 532565 
                 ATGAGGAGGCTGAGTTGTAC 
                 Intron 4 
                 43 
                 269428 
                 269447 
                 1327 
               
               
                   
               
               
                 532566 
                 TCATAAAGTGGGCCCAGCTT 
                 Intron 4 
                 70 
                 270044 
                 270063 
                 1328 
               
               
                   
               
               
                 532567 
                 ACTCCTAATCCCTCAGTTTT 
                 Intron 4 
                 62 
                 270492 
                 270511 
                 1329 
               
               
                   
               
               
                 532568 
                 TTTACATGCAAGGAGCTGAG 
                 Intron 4 
                 61 
                 271047 
                 271066 
                 1330 
               
               
                   
               
               
                 532569 
                 TAATGCCCTTTCTCCCTACT 
                 Intron 4 
                 60 
                 271215 
                 271234 
                 1331 
               
               
                   
               
               
                 532570 
                 CCTGTTTAGATTATCCCAAA 
                 Intron 4 
                 62 
                 271763 
                 271782 
                 1332 
               
               
                   
               
               
                 532571 
                 CATGATTCACAGAATTTCTC 
                 Intron 4 
                 56 
                 271831 
                 271850 
                 1333 
               
               
                   
               
               
                 532572 
                 AGTTAGAAAACTCAAAGTAT 
                 Intron 4 
                  2 
                 271915 
                 271934 
                 1334 
               
               
                   
               
               
                 532573 
                 TCAAATGTACTTAGCATAAG 
                 Intron 4 
                  9 
                 271947 
                 271966 
                 1335 
               
               
                   
               
               
                 532574 
                 ATATCAAATGTACTTAGCAT 
                 Intron 4 
                 59 
                 271950 
                 271969 
                 1336 
               
               
                   
               
               
                 532575 
                 AAAGTTCAGAAGAGGGAATG 
                 Intron 4 
                 51 
                 273233 
                 273252 
                 1337 
               
               
                   
               
               
                 532576 
                 AATTCCCATCTGAGTAGTTT 
                 Intron 4 
                 56 
                 273440 
                 273459 
                 1338 
               
               
                   
               
               
                 532577 
                 GTCCCCTAATTTCAGGCTAA 
                 Intron 4 
                 31 
                 273471 
                 273490 
                 1339 
               
               
                   
               
               
                 532578 
                 CTATGTCAAATGAAACAAAA 
                 Intron 5 
                 38 
                 274205 
                 274224 
                 1340 
               
               
                   
               
               
                 532579 
                 TGATTATGCTTTGTGATAAA 
                 Intron 5 
                 42 
                 274624 
                 274643 
                 1341 
               
               
                   
               
               
                 532580 
                 TCCAGCTGACTAGGAGGGCT 
                 Intron 5 
                  7 
                 275732 
                 275751 
                 1342 
               
               
                   
               
               
                 532581 
                 CATACCAGTCTCCTCGCTCA 
                 Intron 5 
                  0 
                 276738 
                 276757 
                 1343 
               
               
                   
               
               
                 532582 
                 ATATAACAGAATCCAACCAT 
                 Intron 5 
                 47 
                 277045 
                 277064 
                 1344 
               
               
                   
                   
                   
                   
                 278361 
                 278380 
                   
               
               
                   
               
               
                 532583 
                 TGCAAAATGGCCAAACTACA 
                 Intron 5 
                 56 
                 277577 
                 277596 
                 1345 
               
               
                   
               
               
                 532584 
                 TCTTCCTAGCCACATGTGAT 
                 Intron 5 
                 32 
                 278227 
                 278246 
                 1346 
               
               
                   
               
               
                 532585 
                 TACCATGCTCTCTAATTGCC 
                 Intron 6 
                 47 
                 279624 
                 279643 
                 1347 
               
               
                   
               
               
                 532586 
                 AGTGATCTGTGCCAGGCTGC 
                 Intron 6 
                 65 
                 279848 
                 279867 
                 1348 
               
               
                   
               
               
                 532587 
                 AAGTTACAGAACAGATATCT 
                 Intron 6 
                 61 
                 280012 
                 280031 
                 1349 
               
               
                   
               
               
                 532588 
                 GTATTGTGAAAATAGTACTG 
                 Intron 6 
                 45 
                 280226 
                 280245 
                 1350 
               
               
                   
               
               
                 532589 
                 AAACACTATCAAGCTCACGG 
                 Intron 6 
                 54 
                 280807 
                 280826 
                 1351 
               
               
                   
               
               
                 532590 
                 TTCAAGAAAAGTCTTCAAAT 
                 Intron 6 
                 24 
                 280831 
                 280850 
                 1352 
               
               
                   
               
               
                 532591 
                 GGATCATTTCCCCATGCATG 
                 Intron 6 
                 52 
                 280982 
                 281001 
                 1353 
               
               
                   
               
               
                 532592 
                 ATATTATATTAAGAAAAATG 
                 Intron 6 
                  4 
                 281422 
                 281441 
                 1354 
               
               
                   
               
               
                 532593 
                 CTCCCATGTTCATTACTTAT 
                 Intron 6 
                 49 
                 281587 
                 281606 
                 1355 
               
               
                   
               
               
                 532594 
                 CATGACATTGGTTTGGGCAA 
                 Intron 6 
                 43 
                 282229 
                 282248 
                 1356 
               
               
                   
               
               
                 532595 
                 AATGTTGTTGGGAAAATTGG 
                 Intron 6 
                 42 
                 282383 
                 282402 
                 1357 
               
               
                   
               
               
                 532596 
                 AGCTGCAGGATACAAAGTCA 
                 Intron 6 
                 49 
                 282986 
                 283005 
                 1358 
               
               
                   
               
               
                 532597 
                 ATATCCTTTCATGATAAAAA 
                 Intron 6 
                 31 
                 283354 
                 283373 
                 1359 
               
               
                   
               
               
                 532598 
                 ATGGGCTAATATCTCTGATA 
                 Intron 6 
                 50 
                 283590 
                 283609 
                 1360 
               
               
                   
               
               
                 532599 
                 ACATTACTAATAATTAGAGA 
                 Intron 6 
                  0 
                 285236 
                 285255 
                 1361 
               
               
                   
               
               
                 532600 
                 ATAAAAACATATGAAAGTAT 
                 Intron 6 
                 12 
                 287093 
                 287112 
                 1362 
               
               
                   
               
               
                 532601 
                 TTCTGAATTAAATCTATTAG 
                 Intron 6 
                 16 
                 287408 
                 287427 
                 1363 
               
               
                   
               
               
                 532602 
                 TTACATTTTTGCAAATTTAT 
                 Intron 6 
                 31 
                 287472 
                 287491 
                 1364 
               
               
                   
               
               
                 532603 
                 TGAACAGTTGATTAACAAAG 
                 Intron 6 
                 15 
                 287887 
                 287906 
                 1365 
               
               
                   
               
               
                 532604 
                 AAGTTATTGGTTTACTAGAT 
                 Intron 6 
                  0 
                 288598 
                 288617 
                 1366 
               
               
                   
               
               
                 532605 
                 TTGGAAAAGGTCCTAGAAAA 
                 Intron 6 
                 24 
                 289808 
                 289827 
                 1367 
               
               
                   
               
               
                 532606 
                 CATGACAGAAACTTCTTAGA 
                 Intron 7 
                 25 
                 292035 
                 292054 
                 1368 
               
               
                   
               
               
                 532607 
                 CCATACTTGCTGACAAATAT 
                 Intron 8 
                 39 
                 294389 
                 294408 
                 1369 
               
               
                   
               
            
           
         
       
     
     Example 2: Dose-Dependent Antisense Inhibition of Human GHR in Hep3B Cells by MOE Gapmers 
     Gapmers from Example 1 exhibiting significant in vitro inhibition of GHR mRNA were selected and tested at various doses in Hep3B cells. The antisense oligonucleotides were tested in a series of experiments that had similar culture conditions. The results for each experiment are presented in separate tables shown below. Cells were plated at a density of 20,000 cells per well and transfected using electroporation with 0.625 μM, 1.25 μM, 2.50 μM, 5.00 μM and 10.00 μM concentrations of antisense oligonucleotide, as specified in the Tables below. After a treatment period of approximately 16 hours, RNA was isolated from the cells and GHR mRNA levels were measured by quantitative real-time PCR. Human primer probe set RTS3437_MGB was used to measure mRNA levels. GHR mRNA levels were adjusted according to total RNA content, as measured by RIBOGREEN©. Results are presented as percent inhibition of GHR, relative to untreated control cells. 
     The half maximal inhibitory concentration (IC 50 ) of each oligonucleotide is also presented. GHR mRNA levels were significantly reduced in a dose-dependent manner in antisense oligonucleotide treated cells. 
     
       
         
           
               
               
               
               
               
               
               
               
             
               
                   
                 TABLE 20 
               
               
                   
                   
               
               
                   
                   
                 0.625 
                 1.250 
                 2.50 
                 5.00 
                 10.00 
                 IC 50   
               
               
                   
                 ISIS No 
                 μM 
                 μM 
                 μM 
                 μM 
                 μM 
                 (μM) 
               
               
                   
                   
               
             
            
               
                   
                 523271 
                 41 
                 61 
                 73 
                 86 
                 92 
                 0.8 
               
               
                   
                 523274 
                 20 
                 36 
                 64 
                 80 
                 92 
                 1.8 
               
               
                   
                 523324 
                 35 
                 45 
                 68 
                 91 
                 90 
                 1.2 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
               
               
               
               
               
               
               
             
               
                   
                 TABLE 21 
               
               
                   
                   
               
               
                   
                   
                 0.625 
                 1.250 
                 2.50 
                 5.00 
                 10.00 
                 IC 50   
               
               
                   
                 ISIS No 
                 μM 
                 μM 
                 μM 
                 μM 
                 μM 
                 (μM) 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                 523604 
                 21 
                 42 
                 68 
                 58 
                 86 
                 2.0 
               
               
                   
                 523577 
                 6 
                 22 
                 56 
                 66 
                 91 
                 2.7 
               
               
                   
                 523614 
                 14 
                 44 
                 61 
                 84 
                 87 
                 1.9 
               
               
                   
                 523564 
                 4 
                 26 
                 48 
                 67 
                 86 
                 2.8 
               
               
                   
                 523633 
                 30 
                 43 
                 71 
                 82 
                 84 
                 1.4 
               
               
                   
                 523571 
                 2 
                 9 
                 38 
                 55 
                 82 
                 3.9 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
               
               
               
               
               
               
               
             
               
                   
                 TABLE 22 
               
               
                   
                   
               
               
                   
                   
                 0.625 
                 1.250 
                 2.50 
                 5.00 
                 10.00 
                 IC 50   
               
               
                   
                 ISIS No 
                 μM 
                 μM 
                 μM 
                 μM 
                 μM 
                 (μM) 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                 523570 
                 25 
                 50 
                 64 
                 77 
                 88 
                 1.5 
               
               
                   
                 523592 
                 27 
                 42 
                 59 
                 79 
                 88 
                 1.7 
               
               
                   
                 523595 
                 21 
                 50 
                 62 
                 76 
                 90 
                 1.6 
               
               
                   
                 523596 
                 36 
                 47 
                 62 
                 75 
                 77 
                 1.4 
               
               
                   
                 523607 
                 49 
                 62 
                 71 
                 82 
                 84 
                 0.5 
               
               
                   
                 523615 
                 20 
                 49 
                 63 
                 83 
                 91 
                 1.6 
               
               
                   
                 523630 
                 4 
                 28 
                 54 
                 79 
                 78 
                 2.6 
               
               
                   
                 523661 
                 4 
                 34 
                 48 
                 73 
                 79 
                 2.7 
               
               
                   
                 523665 
                 4 
                 28 
                 54 
                 73 
                 79 
                 2.7 
               
               
                   
                 523687 
                 30 
                 56 
                 61 
                 78 
                 81 
                 1.4 
               
               
                   
                 523711 
                 42 
                 66 
                 78 
                 94 
                 95 
                 0.7 
               
               
                   
                 523712 
                 6 
                 37 
                 60 
                 72 
                 89 
                 2.3 
               
               
                   
                 523713 
                 4 
                 32 
                 55 
                 72 
                 85 
                 2.5 
               
               
                   
                 523714 
                 59 
                 75 
                 88 
                 95 
                 97 
                 0.2 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
               
               
               
               
               
               
               
             
               
                   
                 TABLE 23 
               
               
                   
                   
               
               
                   
                   
                 0.625 
                 1.250 
                 2.50 
                 5.00 
                 10.00 
                 IC 50   
               
               
                   
                 ISIS No 
                 μM 
                 μM 
                 μM 
                 μM 
                 μM 
                 (μM) 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                 523655 
                 26 
                 33 
                 60 
                 67 
                 78 
                 2.1 
               
               
                   
                 523656 
                 19 
                 33 
                 45 
                 69 
                 87 
                 2.4 
               
               
                   
                 523658 
                 0 
                 42 
                 62 
                 67 
                 79 
                 3.1 
               
               
                   
                 523715 
                 78 
                 90 
                 92 
                 93 
                 95 
                 &lt;0.6 
               
               
                   
                 523718 
                 30 
                 46 
                 67 
                 84 
                 92 
                 1.4 
               
               
                   
                 523723 
                 56 
                 69 
                 83 
                 92 
                 94 
                 0.3 
               
               
                   
                 523725 
                 45 
                 64 
                 79 
                 89 
                 95 
                 0.6 
               
               
                   
                 523726 
                 32 
                 48 
                 77 
                 88 
                 89 
                 1.2 
               
               
                   
                 523736 
                 0 
                 64 
                 75 
                 90 
                 96 
                 1.5 
               
               
                   
                 523747 
                 48 
                 64 
                 80 
                 91 
                 92 
                 0.6 
               
               
                   
                 523758 
                 25 
                 39 
                 61 
                 74 
                 84 
                 1.9 
               
               
                   
                 523766 
                 7 
                 37 
                 66 
                 81 
                 93 
                 2.0 
               
               
                   
                 523776 
                 26 
                 54 
                 72 
                 78 
                 83 
                 1.3 
               
               
                   
                 523789 
                 62 
                 68 
                 81 
                 85 
                 90 
                 0.2 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
               
               
               
               
               
               
               
             
               
                   
                 TABLE 24 
               
               
                   
                   
               
               
                   
                   
                 0.625 
                 1.250 
                 2.50 
                 5.00 
                 10.00 
                 IC 50   
               
               
                   
                 ISIS No 
                 μM 
                 μM 
                 μM 
                 μM 
                 μM 
                 (μM) 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                 523719 
                 24 
                 46 
                 65 
                 84 
                 93 
                 1.5 
               
               
                   
                 523720 
                 18 
                 49 
                 72 
                 85 
                 93 
                 1.5 
               
               
                   
                 523724 
                 43 
                 61 
                 77 
                 91 
                 91 
                 0.7 
               
               
                   
                 523735 
                 8 
                 42 
                 63 
                 81 
                 93 
                 2.0 
               
               
                   
                 523740 
                 37 
                 58 
                 72 
                 83 
                 88 
                 1.0 
               
               
                   
                 523752 
                 9 
                 29 
                 52 
                 72 
                 86 
                 2.5 
               
               
                   
                 523763 
                 8 
                 32 
                 57 
                 70 
                 80 
                 2.6 
               
               
                   
                 523764 
                 43 
                 52 
                 67 
                 77 
                 79 
                 0.9 
               
               
                   
                 523765 
                 24 
                 48 
                 62 
                 88 
                 4 
                 1.5 
               
               
                   
                 523767 
                 49 
                 62 
                 67 
                 72 
                 82 
                 0.6 
               
               
                   
                 523772 
                 29 
                 39 
                 54 
                 62 
                 61 
                 2.7 
               
               
                   
                 523774 
                 28 
                 59 
                 63 
                 88 
                 91 
                 1.2 
               
               
                   
                 523778 
                 25 
                 32 
                 63 
                 78 
                 84 
                 1.9 
               
               
                   
                 523783 
                 0 
                 22 
                 53 
                 72 
                 88 
                 2.8 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
               
               
               
               
               
               
               
             
               
                   
                 TABLE 25 
               
               
                   
                   
               
               
                   
                   
                 0.625 
                 1.250 
                 2.50 
                 5.00 
                 10.00 
                 IC 50   
               
               
                   
                 ISIS No 
                 μM 
                 μM 
                 μM 
                 μM 
                 μM 
                 (μM) 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                 532151 
                 57 
                 69 
                 76 
                 85 
                 88 
                 &lt;0.6 
               
               
                   
                 532153 
                 23 
                 43 
                 54 
                 80 
                 86 
                 1.8 
               
               
                   
                 532158 
                 46 
                 58 
                 81 
                 87 
                 87 
                 0.6 
               
               
                   
                 532160 
                 17 
                 26 
                 55 
                 76 
                 92 
                 2.2 
               
               
                   
                 532162 
                 14 
                 46 
                 71 
                 83 
                 93 
                 1.7 
               
               
                   
                 532164 
                 37 
                 76 
                 82 
                 90 
                 93 
                 0.6 
               
               
                   
                 532171 
                 41 
                 81 
                 67 
                 81 
                 83 
                 &lt;0.6 
               
               
                   
                 532181 
                 56 
                 81 
                 84 
                 89 
                 93 
                 0.2 
               
               
                   
                 532186 
                 26 
                 65 
                 75 
                 83 
                 91 
                 1.1 
               
               
                   
                 532188 
                 51 
                 68 
                 80 
                 89 
                 93 
                 &lt;0.6 
               
               
                   
                 532189 
                 24 
                 31 
                 52 
                 75 
                 86 
                 2.1 
               
               
                   
                 532197 
                 0 
                 40 
                 66 
                 85 
                 93 
                 2.1 
               
               
                   
                 532199 
                 24 
                 37 
                 50 
                 73 
                 87 
                 2.1 
               
               
                   
                 532222 
                 12 
                 41 
                 67 
                 84 
                 94 
                 1.8 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
               
               
               
               
               
               
               
             
               
                   
                 TABLE 26 
               
               
                   
                   
               
               
                   
                   
                 0.625 
                 1.250 
                 2.50 
                 5.00 
                 10.00 
                 IC 50   
               
               
                   
                 ISIS No 
                 μM 
                 μM 
                 μM 
                 μM 
                 μM 
                 (μM) 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                 532175 
                 41 
                 54 
                 76 
                 84 
                 89 
                 0.9 
               
               
                   
                 532223 
                 53 
                 69 
                 75 
                 88 
                 94 
                 &lt;0.6 
               
               
                   
                 532235 
                 43 
                 58 
                 67 
                 77 
                 82 
                 0.8 
               
               
                   
                 532241 
                 39 
                 53 
                 62 
                 73 
                 87 
                 1.2 
               
               
                   
                 532248 
                 49 
                 65 
                 72 
                 85 
                 93 
                 0.6 
               
               
                   
                 532254 
                 52 
                 62 
                 85 
                 87 
                 92 
                 &lt;0.6 
               
               
                   
                 532300 
                 20 
                 29 
                 49 
                 66 
                 78 
                 2.7 
               
               
                   
                 532304 
                 26 
                 39 
                 66 
                 78 
                 90 
                 1.7 
               
               
                   
                 532316 
                 41 
                 66 
                 76 
                 86 
                 94 
                 0.7 
               
               
                   
                 532395 
                 32 
                 56 
                 84 
                 93 
                 97 
                 1.0 
               
               
                   
                 532401 
                 47 
                 80 
                 92 
                 96 
                 98 
                 &lt;0.6 
               
               
                   
                 532411 
                 73 
                 90 
                 94 
                 97 
                 98 
                 &lt;0.6 
               
               
                   
                 532420 
                 38 
                 49 
                 82 
                 85 
                 97 
                 1.0 
               
               
                   
                 532436 
                 37 
                 58 
                 75 
                 90 
                 96 
                 0.9 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
               
               
               
               
               
               
               
             
               
                   
                 TABLE 27 
               
               
                   
                   
               
               
                   
                   
                 0.625 
                 1.250 
                 2.50 
                 5.00 
                 10.00 
                 IC 50   
               
               
                   
                 ISIS No 
                 μM 
                 μM 
                 μM 
                 μM 
                 μM 
                 (μM) 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                 532410 
                 66 
                 83 
                 92 
                 94 
                 97 
                 &lt;0.6 
               
               
                   
                 532468 
                 45 
                 68 
                 78 
                 93 
                 94 
                 0.6 
               
               
                   
                 532469 
                 0 
                 17 
                 56 
                 76 
                 92 
                 2.8 
               
               
                   
                 532470 
                 10 
                 34 
                 62 
                 84 
                 94 
                 2.0 
               
               
                   
                 532475 
                 13 
                 36 
                 52 
                 64 
                 87 
                 2.5 
               
               
                   
                 532476 
                 34 
                 64 
                 73 
                 79 
                 93 
                 0.9 
               
               
                   
                 532480 
                 28 
                 54 
                 67 
                 78 
                 87 
                 1.4 
               
               
                   
                 532482 
                 21 
                 39 
                 69 
                 83 
                 92 
                 1.7 
               
               
                   
                 532490 
                 42 
                 60 
                 68 
                 84 
                 93 
                 0.9 
               
               
                   
                 532500 
                 37 
                 50 
                 63 
                 81 
                 87 
                 1.2 
               
               
                   
                 532506 
                 13 
                 41 
                 66 
                 75 
                 89 
                 1.9 
               
               
                   
                 532507 
                 47 
                 59 
                 71 
                 86 
                 89 
                 0.7 
               
               
                   
                 532508 
                 0 
                 31 
                 73 
                 83 
                 89 
                 2.2 
               
               
                   
                 532526 
                 31 
                 56 
                 78 
                 79 
                 88 
                 1.1 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
               
               
               
               
               
               
               
             
               
                   
                 TABLE 28 
               
               
                   
                   
               
               
                   
                   
                 0.625 
                 1.250 
                 2.50 
                 5.00 
                 10.00 
                 IC 50   
               
               
                   
                 ISIS No 
                 μM 
                 μM 
                 μM 
                 μM 
                 μM 
                 (μM) 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                 532495 
                 59 
                 74 
                 81 
                 87 
                 95 
                 &lt;0.6 
               
               
                   
                 532501 
                 49 
                 53 
                 71 
                 83 
                 84 
                 0.7 
               
               
                   
                 532534 
                 53 
                 75 
                 85 
                 91 
                 97 
                 &lt;0.6 
               
               
                   
                 532535 
                 0 
                 34 
                 61 
                 84 
                 92 
                 2.6 
               
               
                   
                 532537 
                 49 
                 67 
                 80 
                 90 
                 94 
                 &lt;0.6 
               
               
                   
                 532540 
                 59 
                 70 
                 87 
                 93 
                 95 
                 &lt;0.6 
               
               
                   
                 532547 
                 57 
                 71 
                 81 
                 91 
                 92 
                 &lt;0.6 
               
               
                   
                 532555 
                 48 
                 36 
                 61 
                 72 
                 85 
                 1.3 
               
               
                   
                 532556 
                 33 
                 57 
                 67 
                 86 
                 90 
                 1.1 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
               
               
               
               
               
               
               
             
               
                   
                 TABLE 29 
               
               
                   
                   
               
               
                   
                   
                 0.625 
                 1.250 
                 2.50 
                 5.00 
                 10.00 
                 IC 50   
               
               
                   
                 ISIS No 
                 μM 
                 μM 
                 μM 
                 μM 
                 μM 
                 (μM) 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                 523421 
                 32 
                 57 
                 81 
                 82 
                 88 
                 1.0 
               
               
                   
                 533006 
                 46 
                 43 
                 69 
                 83 
                 91 
                 1.0 
               
               
                   
                 533121 
                 53 
                 75 
                 75 
                 88 
                 93 
                 &lt;0.6 
               
               
                   
                 533122 
                 65 
                 77 
                 82 
                 90 
                 93 
                 &lt;0.6 
               
               
                   
                 533123 
                 39 
                 71 
                 84 
                 91 
                 95 
                 0.6 
               
               
                   
                 533125 
                 49 
                 61 
                 81 
                 85 
                 91 
                 0.6 
               
               
                   
                 533131 
                 3 
                 57 
                 59 
                 82 
                 90 
                 1.9 
               
               
                   
                 533136 
                 32 
                 65 
                 62 
                 81 
                 88 
                 1.1 
               
               
                   
                 533139 
                 13 
                 51 
                 72 
                 90 
                 94 
                 1.5 
               
               
                   
                 533140 
                 36 
                 66 
                 39 
                 87 
                 92 
                 1.2 
               
               
                   
                 533153 
                 50 
                 65 
                 83 
                 89 
                 90 
                 &lt;0.6 
               
               
                   
                 533156 
                 43 
                 64 
                 74 
                 85 
                 90 
                 0.7 
               
               
                   
                 533160 
                 57 
                 80 
                 87 
                 91 
                 95 
                 &lt;0.6 
               
               
                   
                 533161 
                 54 
                 62 
                 81 
                 89 
                 92 
                 &lt;0.6 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
               
               
               
               
               
               
               
             
               
                   
                 TABLE 30 
               
               
                   
                   
               
               
                   
                   
                 0.625 
                 1.250 
                 2.50 
                 5.00 
                 10.00 
                 IC 50   
               
               
                   
                 ISIS No 
                 μM 
                 μM 
                 μM 
                 μM 
                 μM 
                 (μM) 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                 533234 
                 50 
                 70 
                 86 
                 93 
                 95 
                 &lt;0.6 
               
               
                   
                 533237 
                 5 
                 45 
                 63 
                 84 
                 93 
                 1.9 
               
               
                   
                 533233 
                 43 
                 55 
                 76 
                 90 
                 95 
                 0.8 
               
               
                   
                 533179 
                 31 
                 63 
                 75 
                 87 
                 87 
                 1.0 
               
               
                   
                 533178 
                 53 
                 67 
                 76 
                 89 
                 94 
                 &lt;0.6 
               
               
                   
                 533187 
                 5 
                 15 
                 53 
                 79 
                 86 
                 2.7 
               
               
                   
                 533188 
                 49 
                 68 
                 83 
                 89 
                 94 
                 &lt;0.6 
               
               
                   
                 533271 
                 45 
                 66 
                 85 
                 92 
                 94 
                 0.6 
               
               
                   
                 533134 
                 22 
                 45 
                 64 
                 81 
                 89 
                 1.6 
               
               
                   
                 533258 
                 52 
                 72 
                 88 
                 93 
                 95 
                 &lt;0.6 
               
               
                   
                 533235 
                 50 
                 54 
                 75 
                 82 
                 90 
                 0.7 
               
               
                   
                 533262 
                 23 
                 54 
                 78 
                 91 
                 96 
                 1.2 
               
               
                   
                 533189 
                 48 
                 66 
                 78 
                 82 
                 88 
                 &lt;0.6 
               
               
                   
                 533193 
                 38 
                 53 
                 72 
                 77 
                 91 
                 1.0 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
               
               
               
               
               
               
               
             
               
                   
                 TABLE 31 
               
               
                   
                   
               
               
                   
                   
                 0.625 
                 1.250 
                 2.50 
                 5.00 
                 10.00 
                 IC 50   
               
               
                   
                 ISIS No 
                 μM 
                 μM 
                 μM 
                 μM 
                 μM 
                 (μM) 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                 533259 
                 63 
                 78 
                 84 
                 90 
                 92 
                 &lt;0.6 
               
               
                   
                 533291 
                 25 
                 57 
                 75 
                 86 
                 96 
                 1.2 
               
               
                   
                 533256 
                 67 
                 76 
                 90 
                 95 
                 95 
                 &lt;0.6 
               
               
                   
                 533269 
                 42 
                 75 
                 82 
                 94 
                 97 
                 0.6 
               
               
                   
                 533265 
                 67 
                 78 
                 91 
                 95 
                 97 
                 &lt;0.6 
               
               
                   
                 533318 
                 16 
                 45 
                 77 
                 87 
                 95 
                 1.5 
               
               
                   
                 533257 
                 55 
                 84 
                 91 
                 96 
                 96 
                 &lt;0.6 
               
               
                   
                 533280 
                 34 
                 62 
                 80 
                 91 
                 91 
                 0.9 
               
               
                   
                 533301 
                 52 
                 77 
                 84 
                 93 
                 96 
                 &lt;0.6 
               
               
                   
                 533316 
                 41 
                 50 
                 79 
                 93 
                 94 
                 0.9 
               
               
                   
                 533270 
                 62 
                 71 
                 88 
                 94 
                 97 
                 &lt;0.6 
               
               
                   
                 533330 
                 46 
                 76 
                 93 
                 97 
                 98 
                 &lt;0.6 
               
               
                   
                 533317 
                 55 
                 60 
                 82 
                 87 
                 96 
                 &lt;0.6 
               
               
                   
                 533315 
                 39 
                 56 
                 82 
                 87 
                 93 
                 0.9 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
               
               
               
               
               
               
               
             
               
                   
                 TABLE 32 
               
               
                   
                   
               
               
                   
                   
                 0.625 
                 1.250 
                 2.50 
                 5.00 
                 10.00 
                 IC 50   
               
               
                   
                 ISIS No 
                 μM 
                 μM 
                 μM 
                 μM 
                 μM 
                 (μM) 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                 533364 
                 71 
                 77 
                 92 
                 90 
                 94 
                 &lt;0.6 
               
               
                   
                 533925 
                 26 
                 55 
                 61 
                 85 
                 91 
                 1.4 
               
               
                   
                 533326 
                 54 
                 77 
                 80 
                 93 
                 95 
                 &lt;0.6 
               
               
                   
                 533916 
                 18 
                 62 
                 69 
                 83 
                 93 
                 1.4 
               
               
                   
                 533328 
                 52 
                 68 
                 89 
                 94 
                 98 
                 &lt;0.6 
               
               
                   
                 533932 
                 42 
                 49 
                 80 
                 86 
                 92 
                 0.9 
               
               
                   
                 533352 
                 42 
                 82 
                 88 
                 93 
                 94 
                 &lt;0.6 
               
               
                   
                 533917 
                 20 
                 37 
                 57 
                 78 
                 84 
                 2.0 
               
               
                   
                 533331 
                 54 
                 83 
                 89 
                 93 
                 96 
                 &lt;0.6 
               
               
                   
                 533936 
                 21 
                 46 
                 73 
                 84 
                 88 
                 1.5 
               
               
                   
                 533329 
                 56 
                 73 
                 84 
                 92 
                 98 
                 &lt;0.6 
               
               
                   
                 533937 
                 26 
                 32 
                 79 
                 86 
                 94 
                 1.5 
               
               
                   
                 533908 
                 58 
                 66 
                 81 
                 88 
                 94 
                 &lt;0.6 
               
               
                   
                 533898 
                 61 
                 64 
                 84 
                 90 
                 92 
                 &lt;0.6 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
               
               
               
               
               
               
               
             
               
                   
                 TABLE 33 
               
               
                   
                   
               
               
                   
                   
                 0.625 
                 1.250 
                 2.50 
                 5.00 
                 10.00 
                 IC 50   
               
               
                   
                 ISIS No 
                 μM 
                 μM 
                 μM 
                 μM 
                 μM 
                 (μM) 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                 539371 
                 32 
                 41 
                 82 
                 92 
                 98 
                 1.2 
               
               
                   
                 539382 
                 18 
                 58 
                 74 
                 91 
                 97 
                 1.3 
               
               
                   
                 539392 
                 34 
                 59 
                 79 
                 94 
                 96 
                 0.9 
               
               
                   
                 539398 
                 31 
                 53 
                 89 
                 94 
                 98 
                 1.0 
               
               
                   
                 539399 
                 31 
                 72 
                 87 
                 95 
                 97 
                 0.8 
               
               
                   
                 539400 
                 36 
                 60 
                 79 
                 93 
                 97 
                 0.9 
               
               
                   
                 539405 
                 33 
                 58 
                 74 
                 91 
                 94 
                 1.0 
               
               
                   
                 539412 
                 23 
                 61 
                 80 
                 93 
                 95 
                 1.1 
               
               
                   
                 539413 
                 53 
                 75 
                 86 
                 92 
                 96 
                 &lt;0.6 
               
               
                   
                 539415 
                 47 
                 62 
                 84 
                 91 
                 96 
                 0.6 
               
               
                   
                 539416 
                 61 
                 85 
                 94 
                 97 
                 96 
                 &lt;0.6 
               
               
                   
                 539430 
                 24 
                 48 
                 68 
                 80 
                 93 
                 1.5 
               
               
                   
                 539431 
                 14 
                 40 
                 71 
                 89 
                 95 
                 1.7 
               
               
                   
                 539433 
                 46 
                 67 
                 74 
                 92 
                 95 
                 0.6 
               
               
                   
                   
               
            
           
         
       
     
     Example 3: Dose-Dependent Antisense Inhibition of Human GHR in Hep3B Cells by MOE Gapmers 
     Gapmers from the studies described above exhibiting significant in vitro inhibition of GHR mRNA were selected and tested at various doses in Hep3B cells. The antisense oligonucleotides were tested in a series of experiments that had similar culture conditions. The results for each experiment are presented in separate tables shown below. Cells were plated at a density of 20,000 cells per well and transfected using electroporation with 0.3125 μM, 0.625 μM, 1.25 μM, 2.50 μM, 5.00 μM and 10.00 μM concentrations of antisense oligonucleotide, as specified in the Tables below. After a treatment period of approximately 16 hours, RNA was isolated from the cells and GHR mRNA levels were measured by quantitative real-time PCR. Human primer probe set RTS3437_MGB was used to measure mRNA levels. GHR mRNA levels were adjusted according to total RNA content, as measured by RIBOGREEN®. Results are presented as percent inhibition of GHR, relative to untreated control cells. 
     The half maximal inhibitory concentration (IC 50 ) of each oligonucleotide is also presented. GHR mRNA levels were significantly reduced in a dose-dependent manner in antisense oligonucleotide treated cells. 
     
       
         
           
               
               
               
               
               
               
               
               
             
               
                 TABLE 34 
               
               
                   
               
               
                   
                 0.3125 
                 0.625 
                 1.250 
                 2.50 
                 5.00 
                 10.00 
                 IC 50   
               
               
                 ISIS No 
                 μM 
                 μM 
                 μM 
                 μM 
                 μM 
                 μM 
                 (μM) 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 523814 
                 0 
                 24 
                 48 
                 52 
                 68 
                 82 
                 2.2 
               
               
                 523805 
                 13 
                 29 
                 55 
                 0 
                 79 
                 85 
                 1.5 
               
               
                 523822 
                 0 
                 19 
                 26 
                 41 
                 65 
                 85 
                 2.8 
               
               
                 523820 
                 0 
                 19 
                 29 
                 58 
                 74 
                 86 
                 2.3 
               
               
                 523815 
                 3 
                 6 
                 19 
                 37 
                 45 
                 71 
                 4.8 
               
               
                 523828 
                 12 
                 19 
                 32 
                 51 
                 64 
                 74 
                 2.7 
               
               
                 523801 
                 3 
                 9 
                 31 
                 43 
                 59 
                 76 
                 3.3 
               
               
                 523824 
                 12 
                 28 
                 44 
                 63 
                 77 
                 85 
                 1.7 
               
               
                 523794 
                 13 
                 21 
                 30 
                 51 
                 66 
                 78 
                 2.5 
               
               
                 523810 
                 15 
                 34 
                 55 
                 72 
                 78 
                 86 
                 1.3 
               
               
                 523819 
                 0 
                 24 
                 40 
                 60 
                 66 
                 75 
                 2.4 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
               
               
               
               
               
               
               
             
               
                 TABLE 35 
               
               
                   
               
               
                   
                 0.3125 
                 0.625 
                 1.250 
                 2.50 
                 5.00 
                 10.00 
                 IC 50   
               
               
                 ISIS No 
                 μM 
                 μM 
                 μM 
                 μM 
                 μM 
                 μM 
                 (μM) 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 539302 
                 31 
                 56 
                 80 
                 92 
                 97 
                 98 
                 0.5 
               
               
                 539314 
                 16 
                 28 
                 49 
                 69 
                 85 
                 95 
                 1.3 
               
               
                 539319 
                 8 
                 30 
                 45 
                 71 
                 90 
                 94 
                 1.4 
               
               
                 539320 
                 11 
                 42 
                 64 
                 83 
                 92 
                 95 
                 1.0 
               
               
                 539321 
                 25 
                 48 
                 64 
                 82 
                 95 
                 97 
                 0.8 
               
               
                 539322 
                 19 
                 34 
                 58 
                 72 
                 90 
                 96 
                 1.1 
               
               
                 539331 
                 7 
                 14 
                 46 
                 69 
                 88 
                 96 
                 1.6 
               
               
                 539355 
                 28 
                 35 
                 67 
                 89 
                 96 
                 98 
                 0.8 
               
               
                 539358 
                 12 
                 39 
                 56 
                 80 
                 93 
                 98 
                 1.1 
               
               
                 539359 
                 15 
                 23 
                 58 
                 77 
                 93 
                 98 
                 1.2 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
               
               
               
               
               
               
               
             
               
                 TABLE 36 
               
               
                   
               
               
                   
                 0.3125 
                 0.625 
                 1.250 
                 2.50 
                 5.00 
                 10.00 
                 IC 50   
               
               
                 ISIS No 
                 μM 
                 μM 
                 μM 
                 μM 
                 μM 
                 μM 
                 (μM) 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 539318 
                 23 
                 21 
                 56 
                 73 
                 88 
                 94 
                 1.2 
               
               
                 539325 
                 14 
                 26 
                 38 
                 74 
                 92 
                 98 
                 1.4 
               
               
                 539339 
                 18 
                 23 
                 58 
                 83 
                 92 
                 98 
                 1.1 
               
               
                 539341 
                 17 
                 29 
                 62 
                 84 
                 94 
                 95 
                 1.0 
               
               
                 539342 
                 20 
                 31 
                 43 
                 71 
                 90 
                 95 
                 1.2 
               
               
                 539352 
                 15 
                 23 
                 41 
                 61 
                 89 
                 95 
                 1.5 
               
               
                 539356 
                 24 
                 46 
                 62 
                 83 
                 90 
                 97 
                 0.8 
               
               
                 539361 
                 37 
                 42 
                 73 
                 88 
                 96 
                 98 
                 0.6 
               
               
                 539379 
                 53 
                 66 
                 83 
                 96 
                 96 
                 98 
                 0.2 
               
               
                 539380 
                 52 
                 77 
                 91 
                 97 
                 97 
                 99 
                 0.1 
               
               
                 539383 
                 34 
                 61 
                 71 
                 89 
                 98 
                 98 
                 0.5 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
               
               
               
               
               
               
               
             
               
                 TABLE 37 
               
               
                   
               
               
                   
                 0.3125 
                 0.625 
                 1.250 
                 2.50 
                 5.00 
                 10.00 
                 IC 50   
               
               
                 ISIS No 
                 μM 
                 μM 
                 μM 
                 μM 
                 μM 
                 μM 
                 (μM) 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 539360 
                 45 
                 60 
                 81 
                 94 
                 97 
                 98 
                 0.3 
               
               
                 539362 
                 21 
                 36 
                 72 
                 90 
                 98 
                 99 
                 0.8 
               
               
                 539375 
                 23 
                 36 
                 66 
                 85 
                 95 
                 99 
                 0.9 
               
               
                 539376 
                 26 
                 35 
                 58 
                 82 
                 95 
                 99 
                 0.9 
               
               
                 539377 
                 29 
                 31 
                 43 
                 64 
                 85 
                 89 
                 1.3 
               
               
                 539378 
                 37 
                 59 
                 81 
                 93 
                 97 
                 98 
                 0.4 
               
               
                 539389 
                 34 
                 61 
                 61 
                 87 
                 95 
                 97 
                 0.5 
               
               
                 539401 
                 34 
                 52 
                 63 
                 84 
                 92 
                 95 
                 0.6 
               
               
                 539403 
                 52 
                 73 
                 83 
                 94 
                 97 
                 98 
                 0.1 
               
               
                 539404 
                 22 
                 55 
                 74 
                 88 
                 94 
                 96 
                 0.6 
               
               
                 539432 
                 32 
                 50 
                 75 
                 86 
                 94 
                 96 
                 0.6 
               
               
                   
               
            
           
         
       
     
     Example 4: Dose-Dependent Antisense Inhibition of Human GHR in Hep3B Cells by MOE Gapmers 
     Gapmers from studies described above exhibiting significant in vitro inhibition of GHR mRNA were selected and tested at various doses in Hep3B cells. The antisense oligonucleotides were tested in a series of experiments that had similar culture conditions. The results for each experiment are presented in separate tables shown below. Cells were plated at a density of 20,000 cells per well and transfected using electroporation with 0.625 μM, 1.25 μM, 2.50 μM, 5.00 μM and 10.00 μM concentrations of antisense oligonucleotide, as specified in the Tables below. After a treatment period of approximately 16 hours, RNA was isolated from the cells and GHR mRNA levels were measured by quantitative real-time PCR. Human primer probe set RTS3437_MGB was used to measure mRNA levels. GHR mRNA levels were adjusted according to total RNA content, as measured by RIBOGREEN®. Results are presented as percent inhibition of GHR, relative to untreated control cells. 
     The half maximal inhibitory concentration (IC 50 ) of each oligonucleotide is also presented. GHR mRNA levels were significantly reduced in a dose-dependent manner in antisense oligonucleotide treated cells. 
     
       
         
           
               
               
               
               
               
               
               
               
             
               
                   
                 TABLE 38 
               
               
                   
                   
               
               
                   
                   
                 0.625 
                 1.250 
                 2.50 
                 5.00 
                 10.00 
                 IC 50   
               
               
                   
                 ISIS No 
                 μM 
                 μM 
                 μM 
                 μM 
                 μM 
                 (μM) 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                 523271 
                 26 
                 41 
                 80 
                 89 
                 94 
                 1.4 
               
               
                   
                 523274 
                 13 
                 35 
                 63 
                 85 
                 95 
                 1.9 
               
               
                   
                 523324 
                 26 
                 40 
                 64 
                 88 
                 95 
                 1.6 
               
               
                   
                 523577 
                 27 
                 50 
                 72 
                 87 
                 95 
                 1.3 
               
               
                   
                 523604 
                 49 
                 66 
                 74 
                 81 
                 87 
                 0.5 
               
               
                   
                 523614 
                 43 
                 54 
                 82 
                 92 
                 89 
                 0.8 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
               
               
               
               
               
               
               
             
               
                   
                 TABLE 39 
               
               
                   
                   
               
               
                   
                   
                 0.625 
                 1.250 
                 2.50 
                 5.00 
                 10.00 
                 IC 50   
               
               
                   
                 ISIS No 
                 μM 
                 μM 
                 μM 
                 μM 
                 μM 
                 (μM) 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                 523564 
                 16 
                 48 
                 69 
                 75 
                 91 
                 1.7 
               
               
                   
                 523570 
                 24 
                 52 
                 65 
                 71 
                 88 
                 1.6 
               
               
                   
                 523592 
                 6 
                 31 
                 52 
                 65 
                 81 
                 2.8 
               
               
                   
                 523595 
                 13 
                 49 
                 60 
                 79 
                 92 
                 1.8 
               
               
                   
                 523596 
                 20 
                 49 
                 62 
                 71 
                 75 
                 1.9 
               
               
                   
                 523607 
                 38 
                 63 
                 66 
                 74 
                 76 
                 0.8 
               
               
                   
                 523615 
                 17 
                 48 
                 60 
                 80 
                 92 
                 1.8 
               
               
                   
                 523630 
                 19 
                 42 
                 42 
                 67 
                 80 
                 2.5 
               
               
                   
                 523633 
                 41 
                 69 
                 78 
                 79 
                 80 
                 0.6 
               
               
                   
                 523665 
                 16 
                 45 
                 56 
                 71 
                 80 
                 2.1 
               
               
                   
                 523687 
                 37 
                 59 
                 73 
                 75 
                 78 
                 0.9 
               
               
                   
                 523711 
                 33 
                 63 
                 78 
                 91 
                 93 
                 0.9 
               
               
                   
                 523712 
                 13 
                 36 
                 61 
                 78 
                 87 
                 2.1 
               
               
                   
                 523714 
                 63 
                 85 
                 91 
                 96 
                 96 
                 &lt;0.6 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
               
               
               
               
               
               
               
             
               
                   
                 TABLE 40 
               
               
                   
                   
               
               
                   
                   
                 0.625 
                 1.250 
                 2.50 
                 5.00 
                 10.00 
                 IC 50   
               
               
                   
                 ISIS No 
                 μM 
                 μM 
                 μM 
                 μM 
                 μM 
                 (μM) 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                 523655 
                 28 
                 42 
                 57 
                 74 
                 76 
                 1.9 
               
               
                   
                 523656 
                 33 
                 43 
                 53 
                 74 
                 88 
                 1.7 
               
               
                   
                 523661 
                 29 
                 29 
                 66 
                 79 
                 82 
                 1.9 
               
               
                   
                 523713 
                 35 
                 45 
                 64 
                 83 
                 87 
                 1.3 
               
               
                   
                 523715 
                 83 
                 86 
                 92 
                 93 
                 94 
                 &lt;0.6 
               
               
                   
                 523718 
                 27 
                 52 
                 69 
                 84 
                 95 
                 1.3 
               
               
                   
                 523723 
                 65 
                 74 
                 86 
                 85 
                 94 
                 &lt;0.6 
               
               
                   
                 523725 
                 37 
                 63 
                 78 
                 78 
                 92 
                 0.8 
               
               
                   
                 523726 
                 43 
                 57 
                 72 
                 86 
                 89 
                 0.8 
               
               
                   
                 523736 
                 39 
                 65 
                 80 
                 88 
                 95 
                 0.8 
               
               
                   
                 523747 
                 51 
                 71 
                 83 
                 86 
                 93 
                 &lt;0.6 
               
               
                   
                 523766 
                 30 
                 50 
                 70 
                 82 
                 89 
                 1.3 
               
               
                   
                 523776 
                 45 
                 59 
                 67 
                 79 
                 84 
                 0.7 
               
               
                   
                 523789 
                 63 
                 75 
                 76 
                 83 
                 83 
                 &lt;0.6 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
               
               
               
               
               
               
               
             
               
                   
                 TABLE 41 
               
               
                   
                   
               
               
                   
                   
                 0.625 
                 1.250 
                 2.50 
                 5.00 
                 10.00 
                 IC 50   
               
               
                   
                 ISIS No 
                 μM 
                 μM 
                 μM 
                 μM 
                 μM 
                 (μM) 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                 523719 
                 18 
                 40 
                 56 
                 73 
                 83 
                 2.1 
               
               
                   
                 523720 
                 36 
                 46 
                 59 
                 64 
                 89 
                 1.5 
               
               
                   
                 523724 
                 44 
                 60 
                 75 
                 81 
                 87 
                 0.7 
               
               
                   
                 523735 
                 11 
                 40 
                 60 
                 78 
                 84 
                 2.1 
               
               
                   
                 523740 
                 17 
                 47 
                 61 
                 80 
                 81 
                 1.8 
               
               
                   
                 523752 
                 25 
                 31 
                 38 
                 70 
                 84 
                 2.5 
               
               
                   
                 523758 
                 23 
                 48 
                 58 
                 72 
                 80 
                 1.8 
               
               
                   
                 523763 
                 2 
                 24 
                 48 
                 64 
                 75 
                 3.3 
               
               
                   
                 523764 
                 22 
                 49 
                 45 
                 73 
                 75 
                 2.1 
               
               
                   
                 523765 
                 42 
                 40 
                 57 
                 79 
                 87 
                 1.4 
               
               
                   
                 523767 
                 43 
                 53 
                 56 
                 69 
                 79 
                 1.2 
               
               
                   
                 523774 
                 36 
                 52 
                 71 
                 81 
                 89 
                 1.1 
               
               
                   
                 523778 
                 15 
                 45 
                 59 
                 75 
                 79 
                 2.0 
               
               
                   
                 523783 
                 5 
                 30 
                 48 
                 66 
                 83 
                 2.9 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
               
               
               
               
               
               
               
             
               
                   
                 TABLE 42 
               
               
                   
                   
               
               
                   
                   
                 0.625 
                 1.250 
                 2.50 
                 5.00 
                 10.00 
                 IC 50   
               
               
                   
                 ISIS No 
                 μM 
                 μM 
                 μM 
                 μM 
                 μM 
                 (μM) 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                 532151 
                 40 
                 45 
                 64 
                 71 
                 82 
                 1.3 
               
               
                   
                 532158 
                 28 
                 47 
                 63 
                 70 
                 87 
                 1.6 
               
               
                   
                 532164 
                 36 
                 47 
                 64 
                 75 
                 89 
                 1.3 
               
               
                   
                 532171 
                 35 
                 47 
                 50 
                 69 
                 89 
                 1.6 
               
               
                   
                 532175 
                 27 
                 38 
                 43 
                 75 
                 87 
                 2.1 
               
               
                   
                 532181 
                 21 
                 56 
                 63 
                 69 
                 80 
                 1.7 
               
               
                   
                 532186 
                 28 
                 49 
                 62 
                 73 
                 91 
                 1.5 
               
               
                   
                 532188 
                 40 
                 52 
                 73 
                 75 
                 90 
                 1.0 
               
               
                   
                 532223 
                 22 
                 34 
                 53 
                 71 
                 90 
                 2.2 
               
               
                   
                 532235 
                 35 
                 31 
                 48 
                 68 
                 73 
                 2.3 
               
               
                   
                 532241 
                 6 
                 24 
                 29 
                 51 
                 72 
                 4.5 
               
               
                   
                 532248 
                 19 
                 37 
                 47 
                 73 
                 84 
                 2.3 
               
               
                   
                 532254 
                 56 
                 56 
                 72 
                 85 
                 90 
                 0.5 
               
               
                   
                 532316 
                 32 
                 55 
                 50 
                 78 
                 90 
                 1.5 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
               
               
               
               
               
               
               
             
               
                   
                 TABLE 43 
               
               
                   
                   
               
               
                   
                   
                 0.625 
                 1.250 
                 2.50 
                 5.00 
                 10.00 
                 IC 50   
               
               
                   
                 ISIS No 
                 μM 
                 μM 
                 μM 
                 μM 
                 μM 
                 (μM) 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                 532304 
                 44 
                 57 
                 68 
                 78 
                 73 
                 0.7 
               
               
                   
                 532395 
                 47 
                 62 
                 82 
                 91 
                 96 
                 0.6 
               
               
                   
                 532401 
                 70 
                 83 
                 91 
                 94 
                 96 
                 &lt;0.6 
               
               
                   
                 532410 
                 56 
                 71 
                 85 
                 90 
                 96 
                 &lt;0.6 
               
               
                   
                 532411 
                 88 
                 93 
                 96 
                 97 
                 98 
                 &lt;0.6 
               
               
                   
                 532420 
                 61 
                 67 
                 82 
                 85 
                 96 
                 &lt;0.6 
               
               
                   
                 532436 
                 48 
                 49 
                 77 
                 90 
                 97 
                 0.8 
               
               
                   
                 532468 
                 42 
                 67 
                 82 
                 89 
                 94 
                 0.6 
               
               
                   
                 532476 
                 32 
                 58 
                 75 
                 84 
                 90 
                 1.1 
               
               
                   
                 532482 
                 5 
                 26 
                 56 
                 71 
                 87 
                 2.6 
               
               
                   
                 532490 
                 18 
                 47 
                 55 
                 69 
                 86 
                 2.0 
               
               
                   
                 532501 
                 4 
                 22 
                 43 
                 59 
                 77 
                 3.5 
               
               
                   
                 532507 
                 39 
                 63 
                 66 
                 83 
                 89 
                 0.9 
               
               
                   
                 532526 
                 30 
                 48 
                 67 
                 82 
                 88 
                 1.4 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
               
               
               
               
               
               
               
             
               
                   
                 TABLE 44 
               
               
                   
                   
               
               
                   
                   
                 0.625 
                 1.250 
                 2.50 
                 5.00 
                 10.00 
                 IC 50   
               
               
                   
                 ISIS No 
                 μM 
                 μM 
                 μM 
                 μM 
                 μM 
                 (μM) 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                 533121 
                 59 
                 67 
                 78 
                 83 
                 87 
                 0.2 
               
               
                   
                 533122 
                 48 
                 73 
                 78 
                 84 
                 90 
                 0.4 
               
               
                   
                 533125 
                 47 
                 61 
                 74 
                 89 
                 89 
                 0.6 
               
               
                   
                 533136 
                 5 
                 25 
                 58 
                 79 
                 90 
                 2.4 
               
               
                   
                 533156 
                 37 
                 48 
                 69 
                 77 
                 87 
                 1.2 
               
               
                   
                 533161 
                 28 
                 67 
                 77 
                 89 
                 90 
                 1.0 
               
               
                   
                 533178 
                 30 
                 60 
                 72 
                 90 
                 92 
                 1.1 
               
               
                   
                 533179 
                 37 
                 66 
                 76 
                 76 
                 87 
                 0.8 
               
               
                   
                 533188 
                 32 
                 64 
                 74 
                 80 
                 90 
                 1.0 
               
               
                   
                 533189 
                 49 
                 66 
                 77 
                 81 
                 81 
                 0.4 
               
               
                   
                 533193 
                 26 
                 48 
                 69 
                 75 
                 85 
                 1.5 
               
               
                   
                 533233 
                 39 
                 60 
                 59 
                 84 
                 93 
                 1.0 
               
               
                   
                 533234 
                 45 
                 69 
                 84 
                 91 
                 94 
                 0.5 
               
               
                   
                 533235 
                 28 
                 49 
                 69 
                 82 
                 90 
                 1.4 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
               
               
               
               
               
               
               
             
               
                   
                 TABLE 45 
               
               
                   
                   
               
               
                   
                   
                 0.625 
                 1.250 
                 2.50 
                 5.00 
                 10.00 
                 IC 50   
               
               
                   
                 ISIS No 
                 μM 
                 μM 
                 μM 
                 μM 
                 μM 
                 (μM) 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                 533256 
                 47 
                 72 
                 86 
                 90 
                 94 
                 &lt;0.6 
               
               
                   
                 533257 
                 63 
                 77 
                 88 
                 91 
                 96 
                 &lt;0.6 
               
               
                   
                 533258 
                 66 
                 81 
                 88 
                 95 
                 95 
                 &lt;0.6 
               
               
                   
                 533259 
                 48 
                 70 
                 84 
                 90 
                 93 
                 &lt;0.6 
               
               
                   
                 533262 
                 44 
                 66 
                 79 
                 90 
                 96 
                 0.7 
               
               
                   
                 533265 
                 59 
                 74 
                 85 
                 93 
                 96 
                 &lt;0.6 
               
               
                   
                 533269 
                 25 
                 55 
                 74 
                 86 
                 87 
                 1.2 
               
               
                   
                 533270 
                 34 
                 59 
                 73 
                 86 
                 95 
                 1.0 
               
               
                   
                 533271 
                 63 
                 82 
                 88 
                 92 
                 92 
                 &lt;0.6 
               
               
                   
                 533291 
                 14 
                 46 
                 64 
                 84 
                 89 
                 1.8 
               
               
                   
                 533301 
                 49 
                 61 
                 75 
                 83 
                 91 
                 0.6 
               
               
                   
                 533315 
                 22 
                 39 
                 73 
                 76 
                 91 
                 1.7 
               
               
                   
                 533317 
                 26 
                 53 
                 68 
                 85 
                 94 
                 1.3 
               
               
                   
                 533318 
                 29 
                 40 
                 46 
                 77 
                 91 
                 1.9 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
               
               
               
               
               
               
               
             
               
                   
                 TABLE 46 
               
               
                   
                   
               
               
                   
                   
                 0.625 
                 1.250 
                 2.50 
                 5.00 
                 10.00 
                 IC 50   
               
               
                   
                 ISIS No 
                 μM 
                 μM 
                 μM 
                 μM 
                 μM 
                 (μM) 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                 533280 
                 58 
                 64 
                 77 
                 82 
                 87 
                 0.3 
               
               
                   
                 533316 
                 35 
                 55 
                 68 
                 87 
                 91 
                 1.1 
               
               
                   
                 533326 
                 34 
                 68 
                 76 
                 89 
                 96 
                 0.8 
               
               
                   
                 533328 
                 54 
                 55 
                 79 
                 83 
                 92 
                 0.5 
               
               
                   
                 533329 
                 46 
                 62 
                 72 
                 83 
                 95 
                 0.7 
               
               
                   
                 533330 
                 56 
                 75 
                 83 
                 91 
                 94 
                 0.3 
               
               
                   
                 533331 
                 54 
                 61 
                 80 
                 86 
                 89 
                 0.4 
               
               
                   
                 533352 
                 54 
                 62 
                 79 
                 83 
                 89 
                 0.4 
               
               
                   
                 533364 
                 52 
                 73 
                 83 
                 91 
                 94 
                 0.4 
               
               
                   
                 533898 
                 17 
                 47 
                 63 
                 78 
                 87 
                 1.8 
               
               
                   
                 533908 
                 35 
                 58 
                 74 
                 82 
                 87 
                 1 
               
               
                   
                 533916 
                 22 
                 46 
                 72 
                 78 
                 88 
                 1.6 
               
               
                   
                 533932 
                 51 
                 62 
                 70 
                 79 
                 80 
                 0.5 
               
               
                   
                 533937 
                 20 
                 40 
                 61 
                 79 
                 85 
                 1.9 
               
               
                   
                   
               
            
           
         
       
     
     Example 5: Dose-Dependent Antisense Inhibition of Human GHR in Hep3B Cells by MOE Gapmers 
     Gapmers from studies described above exhibiting significant in vitro inhibition of GHR mRNA were selected and tested at various doses in Hep3B cells. The antisense oligonucleotides were tested in a series of experiments that had similar culture conditions. The results for each experiment are presented in separate tables shown below. Cells were plated at a density of 20,000 cells per well and transfected using electroporation with 0.3125 μM, 0.625 μM, 1.25 μM, 2.50 μM, 5.00 μM and 10.00 μM concentrations of antisense oligonucleotide, as specified in the Tables below. After a treatment period of approximately 16 hours, RNA was isolated from the cells and GHR mRNA levels were measured by quantitative real-time PCR. Human primer probe set RTS3437_MGB was used to measure mRNA levels. GHR mRNA levels were adjusted according to total RNA content, as measured by RIBOGREEN®. Results are presented as percent inhibition of GHR, relative to untreated control cells. 
     The half maximal inhibitory concentration (IC 50 ) of each oligonucleotide is also presented. GHR mRNA levels were significantly reduced in a dose-dependent manner in antisense oligonucleotide treated cells. 
     
       
         
           
               
               
               
               
               
               
               
               
             
               
                 TABLE 47 
               
               
                   
               
               
                   
                 0.3125  
                 0.625  
                 1.250  
                 2.50  
                 5.00  
                 10.00  
                 IC 50    
               
               
                 ISIS No  
                 μM  
                 μM  
                 μM  
                 μM  
                 μM  
                 μM  
                 (μM) 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 523577  
                 0  
                 16  
                 33  
                 59  
                 72  
                 94  
                 2.2  
               
               
                 523633  
                 15  
                 33  
                 66  
                 73  
                 82  
                 86  
                 1.1  
               
               
                 523764  
                 11  
                 33  
                 50  
                 68  
                 78  
                 83  
                 1.5  
               
               
                 523794  
                 12  
                 30  
                 33  
                 56  
                 76  
                 82  
                 1.9  
               
               
                 523805  
                 21  
                 48  
                 66  
                 78  
                 85  
                 92  
                 0.8  
               
               
                 523810  
                 18  
                 36  
                 61  
                 80  
                 89  
                 90  
                 1.0  
               
               
                 523814  
                 13  
                 35  
                 52  
                 67  
                 81  
                 88  
                 1.3  
               
               
                 523819  
                 11  
                 30  
                 57  
                 72  
                 81  
                 89  
                 1.3  
               
               
                 523820  
                 0  
                 15  
                 43  
                 61  
                 84  
                 92  
                 1.8  
               
               
                 523824  
                 21  
                 27  
                 59  
                 72  
                 84  
                 90  
                 1.2 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
               
               
               
               
               
               
               
             
               
                 TABLE 48 
               
               
                   
               
               
                   
                 0.3125  
                 0.625  
                 1.250  
                 2.50  
                 5.00  
                 10.00  
                 IC 50    
               
               
                 ISIS No  
                 μM  
                 μM  
                 μM  
                 μM  
                 μM  
                 μM  
                 (μM) 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 539302  
                 34  
                 41  
                 56  
                 83  
                 83  
                 96  
                 0.8  
               
               
                 539321  
                 30  
                 32  
                 76  
                 73  
                 80  
                 94  
                 0.8  
               
               
                 539322  
                 22  
                 36  
                 57  
                 72  
                 78  
                 94  
                 1.1  
               
               
                 539355  
                 23  
                 42  
                 48  
                 72  
                 71  
                 88  
                 1.2  
               
               
                 539359  
                 21  
                 38  
                 48  
                 73  
                 78  
                 92  
                 1.2  
               
               
                 539320  
                 14  
                 32  
                 53  
                 72  
                 82  
                 91  
                 1.3  
               
               
                 539341  
                 3  
                 19  
                 35  
                 56  
                 78  
                 89  
                 2.0  
               
               
                 539342  
                 6  
                 18  
                 33  
                 51  
                 70  
                 83  
                 2.3  
               
               
                 539356  
                 0  
                 0  
                 21  
                 45  
                 73  
                 94  
                 2.7  
               
               
                 539358  
                 0  
                 15  
                 23  
                 50  
                 52  
                 91  
                 2.9 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
               
               
               
               
               
               
               
             
               
                 TABLE 49 
               
               
                   
               
               
                   
                 0.3125  
                 0.625  
                 1.250  
                 2.50  
                 5.00  
                 10.00  
                 IC 50    
               
               
                 ISIS No  
                 μM  
                 μM  
                 μM  
                 μM  
                 μM  
                 μM  
                 (μM) 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 539339  
                 22  
                 37  
                 52  
                 77  
                 90  
                 92  
                 1.0  
               
               
                 539360  
                 28  
                 49  
                 72  
                 82  
                 95  
                 97  
                 0.7  
               
               
                 539361  
                 36  
                 56  
                 75  
                 86  
                 95  
                 98  
                 0.5  
               
               
                 539362  
                 24  
                 26  
                 63  
                 77  
                 91  
                 97  
                 1.0  
               
               
                 539375  
                 21  
                 29  
                 39  
                 63  
                 77  
                 91  
                 1.5  
               
               
                 539378  
                 8  
                 42  
                 64  
                 85  
                 92  
                 97  
                 1.0  
               
               
                 539379  
                 43  
                 59  
                 80  
                 89  
                 96  
                 98  
                 0.3  
               
               
                 539380  
                 61  
                 73  
                 90  
                 95  
                 98  
                 98  
                 0.1  
               
               
                 539383  
                 30  
                 49  
                 75  
                 87  
                 97  
                 98  
                 0.6  
               
               
                 539403  
                 48  
                 55  
                 75  
                 85  
                 94  
                 96  
                 0.3  
               
               
                 539432  
                 36  
                 42  
                 69  
                 79  
                 88  
                 95  
                 0.7 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
               
               
               
               
               
               
               
             
               
                 TABLE 50 
               
               
                   
               
               
                   
                 0.3125  
                 0.625  
                 1.250  
                 2.50  
                 5.00  
                 10.00  
                 IC 50    
               
               
                 ISIS No  
                 μM  
                 μM  
                 μM  
                 μM  
                 μM  
                 μM  
                 (μM) 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 539376  
                 34  
                 46  
                 62  
                 82  
                 94  
                 98  
                 0.7  
               
               
                 539389  
                 53  
                 58  
                 78  
                 86  
                 94  
                 97  
                 0.2  
               
               
                 539392  
                 1  
                 19  
                 26  
                 68  
                 81  
                 94  
                 1.9  
               
               
                 539399  
                 27  
                 52  
                 65  
                 78  
                 92  
                 98  
                 0.7  
               
               
                 539400  
                 7  
                 26  
                 43  
                 59  
                 88  
                 95  
                 1.6  
               
               
                 539401  
                 32  
                 39  
                 77  
                 90  
                 92  
                 95  
                 0.6  
               
               
                 539404  
                 22  
                 59  
                 77  
                 87  
                 93  
                 95  
                 0.6  
               
               
                 539413  
                 16  
                 33  
                 53  
                 82  
                 86  
                 96  
                 1.1  
               
               
                 539415  
                 4  
                 44  
                 56  
                 74  
                 81  
                 94  
                 1.2  
               
               
                 539416  
                 37  
                 61  
                 70  
                 85  
                 92  
                 95  
                 0.4  
               
               
                 539433  
                 31  
                 52  
                 70  
                 85  
                 87  
                 94  
                 0.6 
               
               
                   
               
            
           
         
       
     
     Example 6: Antisense Inhibition of Human Growth Hormone Receptor in Hep3B Cells by Deoxy, MOE and cEt Gapmers 
     Additional antisense oligonucleotides were designed targeting a growth hormone receptor (GHR) nucleic acid and were tested for their effects on GHR mRNA in vitro. The antisense oligonucleotides were tested in a series of experiments that had similar culture conditions. The results for each experiment are presented in separate tables shown below. Cultured Hep3B cells at a density of 20,000 cells per well were transfected using electroporation with 5,000 nM antisense oligonucleotide. After a treatment period of approximately 24 hours, RNA was isolated from the cells and GHR mRNA levels were measured by quantitative real-time PCR. Human primer probe set RTS3437_MGB was used to measure mRNA levels. GHR mRNA levels were adjusted according to total RNA content, as measured by RIBOGREEN®. Results are presented as percent inhibition of GHR, relative to untreated control cells. 
     The newly designed chimeric antisense oligonucleotides in the Tables below were designed as deoxy, MOE, and cEt gapmers. The deoxy, MOE and cEt oligonucleotides are 16 nucleosides in length wherein the nucleoside have either a MOE sugar modification, an cEt sugar modification, or a deoxy modification. The ‘Chemistry’ column describes the sugar modifications of each oligonucleotide. ‘k’ indicates a cEt sugar modification; ‘d’ indicates deoxyribose; and ‘e’ indicates a MOE modification. The internucleoside linkages throughout each gapmer are phosphorothioate (P═S) linkages. All cytosine residues throughout each gapmer are 5-methylcytosines. “Start site” indicates the 5′-most nucleoside to which the gapmer is targeted in the human gene sequence. “Stop site” indicates the 3′-most nucleoside to which the gapmer is targeted human gene sequence. Each gapmer listed in the Tables below is targeted to either the human GHR mRNA, designated herein as SEQ ID NO: 1 (GENBANK Accession No. NM_000163.4) or the human GHR genomic sequence, designated herein as SEQ ID NO: 2 (GENBANK Accession No. NT_006576.16 truncated from nucleotides 42411001 to 42714000). ‘n/a’ indicates that the antisense oligonucleotide does not target that particular gene sequence with 100% complementarity. In case the sequence alignment for a target gene in a particular table is not shown, it is understood that none of the oligonucleotides presented in that table align with 100% complementarity with that target gene. 
     
       
         
           
               
             
               
                 TABLE 51 
               
             
            
               
                   
               
               
                 Inhibition of GHR mRNA by deoxy, MOE and cEt gapmers targeting 
               
               
                 intronic and exonic regions of SEQ ID NO: 1 and 2 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 ISIS 
                   
                   
                   
                   
                 % 
                   
                 SEQ 
               
               
                 NO 
                 Start Site 
                 Target Region 
                 Sequence 
                 Chemistry 
                 inhibition 
                 Start Site 
                 ID NO 
               
               
                   
               
               
                 541262 
                 n/a 
                 Intron 2 
                 TTGGTTTGTCAATCCT 
                 eekddddddddddkke 
                 84 
                 156891 
                 1370 
               
               
                   
               
               
                 541263 
                  164 
                 Intron 1 
                 CCGAGCTTCGCCTCTG 
                 eekddddddddddkke 
                 89 
                   3040 
                 1371 
               
               
                   
               
               
                 541264 
                  167 
                 Intron 1 
                 CCTCCGAGCTTCGCCT 
                 eekddddddddddkke 
                 90 
                   3043 
                 1372 
               
               
                   
               
               
                 541265 
                  170 
                 Junction 
                 GGACCTCCGAGCTTCG 
                 eekddddddddddkke 
                 89 
                 n/a 
                 1373 
               
               
                   
                   
                 spanning two 
                   
                   
                   
                   
                   
               
               
                   
                   
                 exons 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 541266 
                  176 
                 Junction 
                 CCTGTAGGACCTCCGA 
                 eekddddddddddkke 
                 83 
                 n/a 
                 1374 
               
               
                   
                   
                 spanning two 
                   
                   
                   
                   
                   
               
               
                   
                   
                 exons 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 541268 
                  214 
                 Exon 2 
                 CCAGTGCCAAGGTCAA 
                 eekddddddddddkke 
                 87 
                 144998 
                 1375 
               
               
                   
               
               
                 541269 
                  226 
                 Exon 2 
                 CACTTGATCCTGCCAG 
                 eekddddddddddkke 
                 67 
                 145010 
                 1376 
               
               
                   
               
               
                 541270 
                  244 
                 Exon 2 
                 CACTTCCAGAAAAAGC 
                 eekddddddddddkke 
                 34 
                 145028 
                 1377 
               
               
                   
               
               
                 541278 
                  365 
                 Exon 4/Intron 3 
                 GTCTCTCGCTCAGGTG 
                 eekddddddddddkke 
                 77 
                 268028 
                 1378 
               
               
                   
               
               
                 541279 
                  368 
                 Exon 4/Intron 3 
                 AAAGTCTCTCGCTCAG 
                 eekddddddddddkke 
                 76 
                 268031 
                 1379 
               
               
                   
               
               
                 541280 
                  373 
                 Exon 4/Intron 3 
                 ATGAAAAAGTCTCTCG 
                 eekddddddddddkke 
                 66 
                 268036 
                 1380 
               
               
                   
               
               
                 541283 
                  445 
                 exon 2-exon 3 
                 TCCTTCTGGTATAGAA 
                 eekddddddddddkke 
                 37 
                 n/a 
                 1381 
               
               
                   
                   
                 junction 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 541288 
                  554 
                 Exon 5 
                 CAATAAGGTATCCAGA 
                 eekddddddddddkke 
                 49 
                 274114 
                 1382 
               
               
                   
               
               
                 541289 
                  561 
                 Exon 5 
                 CTTGATACAATAAGGT 
                 eekddddddddddkke 
                 66 
                 274121 
                 1383 
               
               
                   
               
               
                 541290 
                  569 
                 Exon 5 
                 CTAGTTAGCTTGATAC 
                 eekddddddddddkke 
                 61 
                 274129 
                 1384 
               
               
                   
               
               
                 541293 
                  628 
                 exon 3-exon 4 
                 GATCTGGTTGCACTAT 
                 eekddddddddddkke 
                 57 
                 n/a 
                 1385 
               
               
                   
                   
                 junction 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 541294 
                  639 
                 Exon 6 
                 GGCAATGGGTGGATCT 
                 eekddddddddddkke 
                 38 
                 278933 
                 1386 
               
               
                   
               
               
                 541295 
                  648 
                 Exon 6 
                 CCAGTTGAGGGCAATG 
                 eekddddddddddkke 
                 67 
                 278942 
                 1387 
               
               
                   
               
               
                 541296 
                  654 
                 Exon 6 
                 TAAAGTCCAGTTGAGG 
                 eekddddddddddkke 
                 43 
                 278948 
                 1388 
               
               
                   
               
               
                 541301 
                  924 
                 Exon 7 
                 TACATAGAGCACCTCA 
                 eekddddddddddkke 
                 86 
                 290422 
                 1389 
               
               
                   
               
               
                 541302 
                  927 
                 Exon 7 
                 TGTTACATAGAGCACC 
                 eekddddddddddkke 
                 78 
                 290425 
                 1390 
               
               
                   
               
               
                 541303 
                  930 
                 Exon 7 
                 AAGTGTTACATAGAGC 
                 eekddddddddddkke 
                 59 
                 290428 
                 1391 
               
               
                   
               
               
                 541304 
                  958 
                 Exon 7 
                 CTTCACATGTAAATTG 
                 eekddddddddddkke 
                 26 
                 290456 
                 1392 
               
               
                   
               
               
                 541305 
                  981 
                 Exon 8 
                 GAGCCATGGAAAGTAG 
                 eekddddddddddkke 
                 66 
                 292535 
                 1393 
               
               
                   
               
               
                 541310 
                 1127 
                 Exon 7-exon 8 
                 CCTTCCTTGAGGAGAT 
                 eekddddddddddkke 
                 26 
                 n/a 
                 1394 
               
               
                   
                   
                 junction 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 541320 
                 1317 
                 Exon 10 
                 CTTCACCCCTAGGTTA 
                 eekddddddddddkke 
                 38 
                 297734 
                 1395 
               
               
                   
               
               
                 541321 
                 1322 
                 Exon 10 
                 CCATCCTTCACCCCTA 
                 eekddddddddddkke 
                 81 
                 297739 
                 1396 
               
               
                   
               
               
                 541322 
                 1326 
                 Exon 10 
                 GTCGCCATCCTTCACC 
                 eekddddddddddkke 
                 79 
                 297743 
                 1397 
               
               
                   
               
               
                 541323 
                 1331 
                 Exon 10 
                 CCAGAGTCGCCATCCT 
                 eekddddddddddkke 
                 64 
                 297748 
                 1398 
               
               
                   
               
               
                 541325 
                 1420 
                 Exon 10 
                 GTGGCTGAGCAACCTC 
                 eekddddddddddkke 
                 79 
                 297837 
                 1399 
               
               
                   
               
               
                 541326 
                 1434 
                 Exon 10 
                 CCCTTTTAACCTCTGT 
                 eekddddddddddkke 
                 67 
                 297851 
                 1400 
               
               
                   
               
               
                 541331 
                 1492 
                 Exon 10 
                 CATCATGATAAGGTGA 
                 eekddddddddddkke 
                 16 
                 297909 
                 1401 
               
               
                   
               
               
                 541332 
                 1526 
                 Exon 10 
                 TGGATAACACTGGGCT 
                 eekddddddddddkke 
                 30 
                 297943 
                 1402 
               
               
                   
               
               
                 541333 
                 1532 
                 Exon 10 
                 TCTGCTTGGATAACAC 
                 eekddddddddddkke 
                 63 
                 297949 
                 1403 
               
               
                   
               
               
                 541335 
                 1597 
                 Exon 10 
                 GAATATGGGCAGCTTG 
                 eekddddddddddkke 
                 33 
                 298014 
                 1404 
               
               
                   
               
               
                 541336 
                 1601 
                 Exon 10 
                 AGCTGAATATGGGCAG 
                 eekddddddddddkke 
                 34 
                 298018 
                 1405 
               
               
                   
               
               
                 541337 
                 1607 
                 Exon 10 
                 TTGCTTAGCTGAATAT 
                 eekddddddddddkke 
                 39 
                 298024 
                 1406 
               
               
                   
               
               
                 541338 
                 1611 
                 Exon 10 
                 TGGATTGCTTAGCTGA 
                 eekddddddddddkke 
                 79 
                 298028 
                 1407 
               
               
                   
               
               
                 541339 
                 1614 
                 Exon 10 
                 ACTTGGATTGCTTAGC 
                 eekddddddddddkke 
                 73 
                 298031 
                 1408 
               
               
                   
               
            
           
         
       
     
     Example 7: Antisense Inhibition of Human Growth Hormone Receptor in Hep3B Cells by Deoxy, MOE and cEt Gapmers 
     Additional antisense oligonucleotides were designed targeting a growth hormone receptor (GHR) nucleic acid and were tested for their effects on GHR mRNA in vitro. The antisense oligonucleotides were tested in a series of experiments that had similar culture conditions. The results for each experiment are presented in separate tables shown below. Cultured Hep3B cells at a density of 20,000 cells per well were transfected using electroporation with 4,500 nM antisense oligonucleotide. After a treatment period of approximately 24 hours, RNA was isolated from the cells and GHR mRNA levels were measured by quantitative real-time PCR. Human primer probe set RTS3437_MGB was used to measure mRNA levels. GHR mRNA levels were adjusted according to total RNA content, as measured by RIBOGREEN®. Results are presented as percent inhibition of GHR, relative to untreated control cells. 
     The newly designed chimeric antisense oligonucleotides in the Tables below were designed as deoxy, MOE, and cEt gapmers. The deoxy, MOE and cEt oligonucleotides are 16 nucleosides in length wherein the nucleoside have either a MOE sugar modification, a cEt sugar modification, or a deoxy modification. The ‘Chemistry’ column describes the sugar modifications of each oligonucleotide. ‘k’ indicates a cEt sugar modification; ‘d’ indicates deoxyribose; and ‘e’ indicates a MOE modification. The internucleoside linkages throughout each gapmer are phosphorothioate (P═S) linkages. All cytosine residues throughout each gapmer are 5-methylcytosines. “Start site” indicates the 5′-most nucleoside to which the gapmer is targeted in the human gene sequence. “Stop site” indicates the 3′-most nucleoside to which the gapmer is targeted human gene sequence. Each gapmer listed in the Tables below is targeted to either the human GHR mRNA, designated herein as SEQ ID NO: 1 (GENBANK Accession No. NM_000163.4) or the human GHR genomic sequence, designated herein as SEQ ID NO: 2 (GENBANK Accession No. NT_006576.16 truncated from nucleotides 42411001 to 42714000). ‘n/a’ indicates that the antisense oligonucleotide does not target that particular gene sequence with 100% complementarity. In case the sequence alignment for a target gene in a particular table is not shown, it is understood that none of the oligonucleotides presented in that table align with 100% complementarity with that target gene. The oligonucleotides of Table 54 do not target SEQ ID NOs: 1 or 2, but instead target variant gene sequences SEQ ID NO: 4 (GENBANK Accession No. DR006395.1) or SEQ ID NO: 7 (the complement of GENBANK Accession No. AA398260.1). 
     
       
         
           
               
             
               
                 TABLE 52 
               
             
            
               
                   
               
               
                 Inhibition of GHR mRNA by deoxy, MOE and cEt gapmers targeting 
               
               
                 intronic and exonic regions of SEQ ID NO: 1 and 2 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 ISIS 
                 Start 
                 Target 
                   
                   
                 % 
                 Start 
                 SEQ 
               
               
                 NO 
                 Site 
                 Region 
                 Sequence 
                 Chemistry 
                 inhibition 
                 Site 
                 ID NO 
               
               
                   
               
               
                 541262 
                 n/a 
                 Intron 2 
                 TTGGTTTGTCAATCCT 
                 eekddddddddddkke 
                 86 
                 156891 
                 1370 
               
               
                   
               
               
                 541340 
                 1619 
                 Exon 10 
                 AGTGAACTTGGATTGC 
                 eekddddddddddkke 
                 73 
                 298036 
                 1409 
               
               
                   
               
               
                 541341 
                 1641 
                 Exon 10 
                 GGCATAAAAGTCGATG 
                 eekddddddddddkke 
                 41 
                 298058 
                 1410 
               
               
                   
               
               
                 541342 
                 1644 
                 Exon 10 
                 CTGGGCATAAAAGTCG 
                 eekddddddddddkke 
                 33 
                 298061 
                 1411 
               
               
                   
               
               
                 541343 
                 1683 
                 Exon 10 
                 GGAAAGGACCACACTA 
                 eekddddddddddkke 
                 34 
                 298100 
                 1412 
               
               
                   
               
               
                 541344 
                 1746 
                 Exon 10 
                 GAGTGAGACCATTTCC 
                 eekddddddddddkke 
                 65 
                 298163 
                 1413 
               
               
                   
               
               
                 541345 
                 1827 
                 Exon 10 
                 GATGTGAGGAGCCACA 
                 eekddddddddddkke 
                 54 
                 298244 
                 1414 
               
               
                   
               
               
                 541346 
                 1830 
                 Exon 10 
                 CTTGATGTGAGGAGCC 
                 eekddddddddddkke 
                 70 
                 298247 
                 1415 
               
               
                   
               
               
                 541347 
                 1835 
                 Exon 10 
                 TCAACCTTGATGTGAG 
                 eekddddddddddkke 
                 38 
                 298252 
                 1416 
               
               
                   
               
               
                 541348 
                 1839 
                 Exon 10 
                 TGATTCAACCTTGATG 
                 eekddddddddddkke 
                 39 
                 298256 
                 1417 
               
               
                   
               
               
                 541349 
                 1842 
                 Exon 10 
                 GTGTGATTCAACCTTG 
                 eekddddddddddkke 
                 74 
                 298259 
                 1418 
               
               
                   
               
               
                 541350 
                 1845 
                 Exon 10 
                 TATGTGTGATTCAACC 
                 eekddddddddddkke 
                 58 
                 298262 
                 1419 
               
               
                   
               
               
                 541351 
                 1949 
                 Exon 10 
                 GGCATCTCAGAACCTG 
                 eekddddddddddkke 
                 41 
                 298366 
                 1420 
               
               
                   
               
               
                 541352 
                 1965 
                 Exon 10 
                 GGTATAGTCTGGGACA 
                 eekddddddddddkke 
                 18 
                 298382 
                 1421 
               
               
                   
               
               
                 541353 
                 1969 
                 Exon 10 
                 TGGAGGTATAGTCTGG 
                 eekddddddddddkke 
                 17 
                 298386 
                 1422 
               
               
                   
               
               
                 541354 
                 1972 
                 Exon 10 
                 GAATGGAGGTATAGTC 
                 eekddddddddddkke 
                  0 
                 298389 
                 1423 
               
               
                   
               
               
                 541355 
                 1975 
                 Exon 10 
                 TATGAATGGAGGTATA 
                 eekddddddddddkke 
                  0 
                 298392 
                 1424 
               
               
                   
               
               
                 541356 
                 1978 
                 Exon 10 
                 CTATATGAATGGAGGT 
                 eekddddddddddkke 
                 30 
                 298395 
                 1425 
               
               
                   
               
               
                 541357 
                 1981 
                 Exon 10 
                 GTACTATATGAATGGA 
                 eekddddddddddkke 
                 43 
                 298398 
                 1426 
               
               
                   
               
               
                 541358 
                 1987 
                 Exon 10 
                 GGGACTGTACTATATG 
                 eekddddddddddkke 
                 12 
                 298404 
                 1427 
               
               
                   
               
               
                 541369 
                 2306 
                 Exon 10 
                 TTACATTGCACAATAG 
                 eekddddddddddkke 
                 21 
                 298723 
                 1428 
               
               
                   
               
               
                 541373 
                 2667 
                 Exon 10 
                 TAGCCATGCTTGAAGT 
                 eekddddddddddkke 
                 34 
                 299084 
                 1429 
               
               
                   
               
               
                 541374 
                 2686 
                 Exon 10 
                 TGTGTAGTGTAATATA 
                 eekddddddddddkke 
                 10 
                 299103 
                 1430 
               
               
                   
               
               
                 541375 
                 2690 
                 Exon 10 
                 ACAGTGTGTAGTGTAA 
                 eekddddddddddkke 
                 82 
                 299107 
                 1431 
               
               
                   
               
               
                 541376 
                 2697 
                 Exon 10 
                 GCAGTACACAGTGTGT 
                 eekddddddddddkke 
                 46 
                 299114 
                 1432 
               
               
                   
               
               
                 541377 
                 2700 
                 Exon 10 
                 ACTGCAGTACACAGTG 
                 eekddddddddddkke 
                 32 
                 299117 
                 1433 
               
               
                   
               
               
                 541378 
                 2740 
                 Exon 10 
                 TTAGACTGTAGTTGCT 
                 eekddddddddddkke 
                 25 
                 299157 
                 1434 
               
               
                   
               
               
                 541379 
                 2746 
                 Exon 10 
                 CCAGCTTTAGACTGTA 
                 eekddddddddddkke 
                 69 
                 299163 
                 1435 
               
               
                   
               
               
                 541380 
                 2750 
                 Exon 10 
                 TAAACCAGCTTTAGAC 
                 eekddddddddddkke 
                 20 
                 299167 
                 1436 
               
               
                   
               
               
                 541381 
                 2755 
                 Exon 10 
                 AACATTAAACCAGCTT 
                 eekddddddddddkke 
                 64 
                 299172 
                 1437 
               
               
                   
               
               
                 541382 
                 2849 
                 Exon 10 
                 ACTACAATCATTTTAG 
                 eekddddddddddkke 
                  0 
                 299266 
                 1438 
               
               
                   
               
               
                 541383 
                 2853 
                 Exon 10 
                 GATTACTACAATCATT 
                 eekddddddddddkke 
                  0 
                 299270 
                 1439 
               
               
                   
               
               
                 541384 
                 2859 
                 Exon 10 
                 AATGCAGATTACTACA 
                 eekddddddddddkke 
                 46 
                 299276 
                 1440 
               
               
                   
               
               
                 541385 
                 2865 
                 Exon 10 
                 TCCAATAATGCAGATT 
                 eekddddddddddkke 
                 52 
                 299282 
                 1441 
               
               
                   
               
               
                 541386 
                 2941 
                 Exon 10 
                 GTTGATCTGTGCAAAC 
                 eekddddddddddkke 
                 74 
                 299358 
                 1442 
               
               
                   
               
               
                 541389 
                 3037 
                 Exon 10 
                 TCTACTTCTCTTAGCA 
                 eekddddddddddkke 
                 50 
                 299454 
                 1443 
               
               
                   
               
               
                 541393 
                 3215 
                 Exon 10 
                 GCTTCTTGTACCTTAT 
                 eekddddddddddkke 
                 84 
                 299632 
                 1444 
               
               
                   
               
               
                 541394 
                 3237 
                 Exon 10 
                 GATTTGCTTCAACTTA 
                 eekddddddddddkke 
                 47 
                 299654 
                 1445 
               
               
                   
               
               
                 541395 
                 3305 
                 Exon 10 
                 GGTTATAGGCTGTGAA 
                 eekddddddddddkke 
                  0 
                 299722 
                 1446 
               
               
                   
               
               
                 541396 
                 3308 
                 Exon 10 
                 TCTGGTTATAGGCTGT 
                 eekddddddddddkke 
                 88 
                 299725 
                 1447 
               
               
                   
               
               
                 541397 
                 3311 
                 Exon 10 
                 GTGTCTGGTTATAGGC 
                 eekddddddddddkke 
                 56 
                 299728 
                 1448 
               
               
                   
               
               
                 541398 
                 3316 
                 Exon 10 
                 AGTATGTGTCTGGTTA 
                 eekddddddddddkke 
                 76 
                 299733 
                 1449 
               
               
                   
               
               
                 541399 
                 3371 
                 Exon 10 
                 GGGACTGAAAACCTTG 
                 eekddddddddddkke 
                 50 
                 299788 
                 1450 
               
               
                   
               
               
                 541400 
                 3975 
                 Exon 10 
                 AGTATTCTTCACTGAG 
                 eekddddddddddkke 
                 36 
                 300392 
                 1451 
               
               
                   
               
               
                 541401 
                 4044 
                 Exon 10 
                 GCGATAAATGGGAAAT 
                 eekddddddddddkke 
                 36 
                 300461 
                 1452 
               
               
                   
               
               
                 541402 
                 4048 
                 Exon 10 
                 GTCTGCGATAAATGGG 
                 eekddddddddddkke 
                 52 
                 300465 
                 1453 
               
               
                   
               
               
                 541403 
                 4058 
                 Exon 10 
                 CCTAAAAAAGGTCTGC 
                 eekddddddddddkke 
                 51 
                 300475 
                 1454 
               
               
                   
               
               
                 541404 
                 4072 
                 Exon 10 
                 CATTAAGCTTGCTTCC 
                 eekddddddddddkke 
                 53 
                 300489 
                 1455 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 53 
               
             
            
               
                   
               
               
                 Inhibition of GHR mRNA by deoxy, MOE and cEt gapmers targeting 
               
               
                 intronic and exonic regions of SEQ ID NO: 1 and 2 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 ISIS 
                 Start 
                   
                   
                   
                 % 
                 Start 
                 SEQ 
               
               
                 NO 
                 Site 
                 Target Region 
                 Sequence 
                 Chemistry 
                 inhibition 
                 Site 
                 ID NO 
               
               
                   
               
               
                 541262 
                 n/a 
                 Intron 2 
                 TTGGTTTGTCAATCCT 
                 eekddddddddddkke 
                 85 
                 156891 
                 1370 
               
               
                   
               
               
                 541421 
                 4418 
                 Exon 10 
                 CACAACTAGTCATACT 
                 eekddddddddddkke 
                 42 
                 300835 
                 1456 
               
               
                   
               
               
                 541422 
                 4428 
                 Exon 10 
                 AACTGCCAGACACAAC 
                 eekddddddddddkke 
                 68 
                 300845 
                 1457 
               
               
                   
               
               
                 541423 
                 4431 
                 Exon 10 
                 ATAAACTGCCAGACAC 
                 eekddddddddddkke 
                 86 
                 300848 
                 1458 
               
               
                   
               
               
                 541424 
                 4503 
                 Exon 10 
                 TATCAGGAATCCAAGA 
                 eekddddddddddkke 
                 11 
                 300920 
                 1459 
               
               
                   
               
               
                 541425 
                 4521 
                 Exon 10 
                 TTGATAACAGAAGCAC 
                 eekddddddddddkke 
                 16 
                 300938 
                 1460 
               
               
                   
               
               
                 541426 
                 4528 
                 Exon 10 
                 TTGGTGTTTGATAACA 
                 eekddddddddddkke 
                 31 
                 300945 
                 1461 
               
               
                   
               
               
                 541427 
                 4531 
                 Exon 10 
                 ATGTTGGTGTTTGATA 
                 eekddddddddddkke 
                 32 
                 300948 
                 1462 
               
               
                   
               
               
                 541429 
                   30 
                 Exon 1 
                 CCGCCACTGTAGCAGC 
                 eekddddddddddkke 
                 77 
                   2906 
                 1463 
               
               
                   
               
               
                 541430 
                   35 
                 Exon 1 
                 CGCCACCGCCACTGTA 
                 eekddddddddddkke 
                 88 
                   2911 
                 1464 
               
               
                   
               
               
                 541431 
                   63 
                 Exon 1 
                 GCCGCCCGGGCTCAGC 
                 eekddddddddddkke 
                 86 
                   2939 
                 1465 
               
               
                   
               
               
                 541432 
                   67 
                 Exon 1 
                 CGCCGCCGCCCGGGCT 
                 eekddddddddddkke 
                 61 
                   2943 
                 1466 
               
               
                   
               
               
                 541433 
                  144 
                 Exon 1 
                 GAGAGCGCGGGTTCGC 
                 eekddddddddddkke 
                 57 
                   3020 
                 1467 
               
               
                   
               
               
                 541434 
                 n/a 
                 Exon 1/Intron 1 
                 CTACTGACCCCAGTTC 
                 eekddddddddddkke 
                 80 
                   3655 
                 1468 
               
               
                   
               
               
                 541435 
                 n/a 
                 Exon 1/Intron 1 
                 TCACTCTACTGACCCC 
                 eekddddddddddkke 
                 90 
                   3660 
                 1469 
               
               
                   
               
               
                 541436 
                 n/a 
                 Exon 1/Intron 1 
                 TCATGCGGACTGGTGG 
                 eekddddddddddkke 
                 56 
                   3679 
                 1470 
               
               
                   
               
               
                 541437 
                 n/a 
                 Exon 3/Intron 3 
                 ATGTGAGCATGGACCC 
                 eekddddddddddkke 
                 82 
                 225438 
                 1471 
               
               
                   
               
               
                 541438 
                 n/a 
                 Exon 3/Intron 3 
                 TCTTGATATGTGAGCA 
                 eekddddddddddkke 
                 93 
                 225445 
                 1472 
               
               
                   
               
               
                 541439 
                 n/a 
                 Exon 3/Intron 3 
                 TTCAAGTTGGTGAGCT 
                 eekddddddddddkke 
                 72 
                 226788 
                 1473 
               
               
                   
               
               
                 541440 
                 n/a 
                 Exon 3/Intron 3 
                 TGCTTCCTTCAAGTTG 
                 eekddddddddddkke 
                 68 
                 226795 
                 1474 
               
               
                   
               
               
                 541441 
                 n/a 
                 Exon 3/Intron 3 
                 TGTAATTTCATTCATG 
                 eekddddddddddkke 
                 62 
                 226809 
                 1475 
               
               
                   
               
               
                 541442 
                 n/a 
                 Exon 3/Intron 3 
                 CCTTTTGCCAAGAGCA 
                 eekddddddddddkke 
                 85 
                 226876 
                 1476 
               
               
                   
               
               
                 541443 
                 n/a 
                 Exon 3/Intron 3 
                 GATCCTTTTGCCAAGA 
                 eekddddddddddkke 
                 77 
                 226879 
                 1477 
               
               
                   
               
               
                 541444 
                 n/a 
                 Exon 3/Intron 3 
                 GCTAGTAATGTTACAT 
                 eekddddddddddkke 
                 68 
                 238331 
                 1478 
               
               
                   
               
               
                 541445 
                 n/a 
                 Exon 3/Intron 3 
                 GCAACTTGCTAGTAAT 
                 eekddddddddddkke 
                 65 
                 238338 
                 1479 
               
               
                   
               
               
                 541446 
                 n/a 
                 Exon 3/Intron 3 
                 TGTGCAACTTGCTAGT 
                 eekddddddddddkke 
                 44 
                 238341 
                 1480 
               
               
                   
               
               
                 541447 
                 n/a 
                 Exon 3/Intron 3 
                 GGATTTCAGTTTGAAT 
                 eekddddddddddkke 
                  0 
                 238363 
                 1481 
               
               
                   
               
               
                 541448 
                 n/a 
                 Exon 3/Intron 3 
                 CTCAGAGCCTTGGTAG 
                 eekddddddddddkke 
                 65 
                 238428 
                 1482 
               
               
                   
               
               
                 541449 
                 n/a 
                 Exon 1/Intron 1 
                 CAAACGCGCAAAAGAC 
                 eekddddddddddkke 
                  1 
                   3608 
                 1483 
               
               
                   
               
               
                 541450 
                 n/a 
                 Exon 1/Intron 1 
                 GCCCGCACAAACGCGC 
                 eekddddddddddkke 
                 11 
                   3615 
                 1484 
               
               
                   
               
               
                 541451 
                 n/a 
                 Exon 1/Intron 1 
                 GGTTAAAGAAGTTGCT 
                 eekddddddddddkke 
                 60 
                  93190 
                 1485 
               
               
                   
               
               
                 541452 
                 n/a 
                 Exon 1/Intron 1 
                 CCCAGTGAATTCAGCA 
                 eekddddddddddkke 
                 85 
                  93245 
                 1486 
               
               
                   
               
               
                 541453 
                 n/a 
                 Exon 1/Intron 1 
                 GCGCCCAGTGAATTCA 
                 eekddddddddddkke 
                 74 
                  93248 
                 1487 
               
               
                   
               
               
                 541454 
                 n/a 
                 Exon 1/Intron 1 
                 AAGATGCGCCCAGTGA 
                 eekddddddddddkke 
                 71 
                  93253 
                 1488 
               
               
                   
               
               
                 541455 
                 n/a 
                 Exon 1/Intron 1 
                 TGTAAGATGCGCCCAG 
                 eekddddddddddkke 
                 75 
                  93256 
                 1489 
               
               
                   
               
               
                 541456 
                 n/a 
                 Exon 1/Intron 1 
                 AATTACTTGTAAGATG 
                 eekddddddddddkke 
                 15 
                  93263 
                 1490 
               
               
                   
               
               
                 541457 
                 n/a 
                 Exon 1/Intron 1 
                 CCCAGAAGGCACTTGT 
                 eekddddddddddkke 
                 61 
                  93302 
                 1491 
               
               
                   
               
               
                 541458 
                 n/a 
                 Exon 1/Intron 1 
                 TTGCAGAACAAATCTT 
                 eekddddddddddkke 
                  3 
                  93333 
                 1492 
               
               
                   
               
               
                 541459 
                 n/a 
                 Exon 1/Intron 1 
                 CATGGAAGATTTGCAG 
                 eekddddddddddkke 
                 17 
                  93343 
                 1493 
               
               
                   
               
               
                 541460 
                 n/a 
                 Exon 1/Intron 1 
                 GGTCATGGAAGATTTG 
                 eekddddddddddkke 
                 57 
                  93346 
                 1494 
               
               
                   
               
               
                 541461 
                 n/a 
                 Exon 1/Intron 1 
                 GACCTTGGTCATGGAA 
                 eekddddddddddkke 
                 51 
                  93352 
                 1495 
               
               
                   
               
               
                 541462 
                 n/a 
                 Exon 1/Intron 1 
                 TGCCAATCCAAAGAGG 
                 eekddddddddddkke 
                 34 
                  93369 
                 1496 
               
               
                   
               
               
                 541463 
                 n/a 
                 Exon 1/Intron 1 
                 GGGTCTGCCAATCCAA 
                 eekddddddddddkke 
                 67 
                  93374 
                 1497 
               
               
                   
               
               
                 541464 
                 n/a 
                 Exon 1/Intron 1 
                 TCCCTGGGTCTGCCAA 
                 eekddddddddddkke 
                 82 
                  93379 
                 1498 
               
               
                   
               
               
                 541465 
                 n/a 
                 Exon 1/Intron 1 
                 AAGTGTGAATTTATCT 
                 eekddddddddddkke 
                 16 
                  93408 
                 1499 
               
               
                   
               
               
                 541466 
                 n/a 
                 Exon 1/Intron 1 
                 GGAGATCTCAACAAGG 
                 eekddddddddddkke 
                 38 
                  93428 
                 1500 
               
               
                   
               
               
                 541468 
                 n/a 
                 Exon 1/Intron 1 
                 TCGCCCATCACTCTTC 
                 eekddddddddddkke 
                 43 
                  93989 
                 1501 
               
               
                   
               
               
                 541469 
                 n/a 
                 Exon 1/Intron 1 
                 CCTGTCGCCCATCACT 
                 eekddddddddddkke 
                 61 
                  93993 
                 1502 
               
               
                   
               
               
                 541470 
                 n/a 
                 Exon 1/Intron 1 
                 TCACCTGTCGCCCATC 
                 eekddddddddddkke 
                 70 
                  93996 
                 1503 
               
               
                   
               
               
                 541471 
                 n/a 
                 Exon 1/Intron 1 
                 CCATCACCTGTCGCCC 
                 eekddddddddddkke 
                 89 
                  93999 
                 1504 
               
               
                   
               
               
                 541472 
                 n/a 
                 Exon 1/Intron 1 
                 TCACCATCACCTGTCG 
                 eekddddddddddkke 
                 72 
                  94002 
                 1505 
               
               
                   
               
               
                 541473 
                 n/a 
                 Exon 1/Intron 1 
                 TAATAGTTGTCACCAT 
                 eekddddddddddkke 
                 42 
                  94011 
                 1506 
               
               
                   
               
               
                 541474 
                 n/a 
                 Exon 1/Intron 1 
                 TTCAGATCTTATTAAT 
                 eekddddddddddkke 
                  0 
                  94023 
                 1507 
               
               
                   
               
               
                 541475 
                 n/a 
                 Exon 1/Intron 1 
                 TTGCAAATTCAGTCTG 
                 eekddddddddddkke 
                 32 
                  94096 
                 1508 
               
               
                   
               
               
                 541477 
                 n/a 
                 Exon 2/Intron 2 
                 CGTTCTCTTGGAAGTA 
                 eekddddddddddkke 
                 78 
                 198766 
                 1509 
               
               
                   
               
               
                 541478 
                 n/a 
                 Exon 2/Intron 2 
                 TCTTGAATAAATTTCG 
                 eekddddddddddkke 
                 25 
                 198780 
                 1510 
               
               
                   
               
               
                 541479 
                 n/a 
                 Exon 2/Intron 2 
                 AAGCTCACTCTTCAAT 
                 eekddddddddddkke 
                 60 
                 198810 
                 1511 
               
               
                   
               
               
                 541480 
                 n/a 
                 Exon 2/Intron 2 
                 TCCAAGCTCACTCTTC 
                 eekddddddddddkke 
                 49 
                 198813 
                 1512 
               
               
                   
               
               
                 541481 
                 n/a 
                 Exon 2/Intron 2 
                 GCTCCTGCCACTCTGT 
                 eekddddddddddkke 
                 75 
                 198837 
                 1513 
               
               
                   
               
               
                 541482 
                 n/a 
                 Exon 2/Intron 2 
                 ATGGGCAAAGGCATCT 
                 eekddddddddddkke 
                 60 
                 198874 
                 1514 
               
               
                   
               
               
                 541483 
                 n/a 
                 5′UTR 
                 AGTCTTCCCGGCGAGG 
                 eekddddddddddkke 
                 32 
                   2571 
                 1515 
               
               
                   
               
               
                 541484 
                 n/a 
                 5′ and overlappig 
                 CCGCCGCTCCCTAGCC 
                 eekddddddddddkke 
                 73 
                   2867 
                 1516 
               
               
                   
                   
                 with exon 1 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 541485 
                 n/a 
                 Intron 1 
                 GCCCGCAACTCCCTGC 
                 eekddddddddddkke 
                 37 
                   3341 
                 1517 
               
               
                   
               
               
                 541486 
                 n/a 
                 Intron 1 
                 CGCCTCCCCAGGCGCA 
                 eekddddddddddkke 
                 34 
                   4024 
                 1518 
               
               
                   
               
               
                 541487 
                 n/a 
                 Intron 1 
                 GAGTGTCTTCCCAGGC 
                 eekddddddddddkke 
                 86 
                   4446 
                 1519 
               
               
                   
               
               
                 541488 
                 n/a 
                 Intron 1 
                 CTGAAGACTCCTTGAA 
                 eekddddddddddkke 
                 39 
                   4721 
                 1520 
               
               
                   
               
               
                 541489 
                 n/a 
                 Intron 1 
                 GGCTAGCCAAGTTGGA 
                 eekddddddddddkke 
                 54 
                   5392 
                 1521 
               
               
                   
               
               
                 541490 
                 n/a 
                 Intron 1 
                 TGACTCCAGTCTTACC 
                 eekddddddddddkke 
                 76 
                   5802 
                 1522 
               
               
                   
               
               
                 541491 
                 n/a 
                 Intron 1 
                 ATTCATTGTGGTCAGC 
                 eekddddddddddkke 
                 91 
                   6128 
                 1523 
               
               
                   
               
               
                 541492 
                 n/a 
                 Intron 1 
                 GAAGTGGGTTTTTCCC 
                 eekddddddddddkke 
                 86 
                   6543 
                 1524 
               
               
                   
               
               
                 541493 
                 n/a 
                 Intron 1 
                 GCCTTGGTTCAGGTGA 
                 eekddddddddddkke 
                 79 
                   6786 
                 1525 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 54 
               
             
            
               
                   
               
               
                 Inhibition of GHR mRNA by deoxy, MOE and cEt 
               
               
                 gapmers targeting SEQ ID NO: 3 and 4 
               
            
           
           
               
               
               
               
               
               
               
            
               
                 ISIS 
                 Target 
                 Targe 
                   
                   
                 % 
                 SEQ 
               
               
                 NO 
                 Start Site 
                 SEQ ID NO 
                 Sequence 
                 Chemistry 
                 inhibition 
                 ID NO 
               
               
                   
               
               
                 541428 
                  66 
                 3 
                 CCACTGTAGCAGCCGC 
                 eekddddddddddkke 
                 92 
                 1526 
               
               
                   
               
               
                 541476 
                 263 
                 4 
                 TAGGTATTTCAGAGCC 
                 eekddddddddddkke 
                 80 
                 1527 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
            
               
                   
               
               
                 Inhibition of GHR mRNA by deoxy, MOE and cEt gapmers targeting intronic regions of SEQ ID NO: 2 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                 SEQ ID 
                 SEQ ID 
                   
                   
                   
                   
                   
               
               
                 ISIS 
                 NO: 1 
                 NO: 1 
                 Target 
                   
                   
                 % 
                 SEQ 
               
               
                 NO 
                 Start Site 
                 Target Region 
                 Region 
                 Sequence 
                 Chemistry 
                 inhibition 
                 ID NO 
               
               
                   
               
               
                 541262 
                 156891 
                 541277 
                 Intron 2 
                 TTGGTTTGTCAATCCT 
                 eekddddddddddkke 
                 80 
                 1370 
               
               
                   
               
               
                 541494 
                   7231 
                 541509 
                 Intron 1 
                 GTCCAGGCAGAGTTGT 
                 eekddddddddddkke 
                 30 
                 1528 
               
               
                   
               
               
                 541495 
                   7570 
                 541510 
                 Intron 1 
                 AGCCAAATGTTGGTCA 
                 eekddddddddddkke 
                 19 
                 1529 
               
               
                   
               
               
                 541496 
                   8395 
                 541511 
                 Intron 1 
                 GAGGGCGAGTTTTTCC 
                 eekddddddddddkke 
                 71 
                 1530 
               
               
                   
               
               
                 541497 
                   9153 
                 541512 
                 Intron 1 
                 GTGGCATTGGCAAGCC 
                 eekddddddddddkke 
                 81 
                 1531 
               
               
                   
               
               
                 541498 
                   9554 
                 541513 
                 Intron 1 
                 ACCCCACTGCACCAAG 
                 eekddddddddddkke 
                 67 
                 1532 
               
               
                   
               
               
                 541499 
                   9931 
                 541514 
                 Intron 1 
                 TCCAAGTACTTGCCAA 
                 eekddddddddddkke 
                 83 
                 1533 
               
               
                   
               
               
                 541500 
                 10549 
                 541515 
                 Intron 1 
                 AGTGCCTGGCCTAAGG 
                 eekddddddddddkke 
                 75 
                 1534 
               
               
                   
               
               
                 541501 
                 11020 
                 541516 
                 Intron 1 
                 GCGCTTCTTCCCTAGG 
                 eekddddddddddkke 
                 71 
                 1535 
               
               
                   
               
               
                 541502 
                 11793 
                 541517 
                 Intron 1 
                 CATCTTGCCCAGGGAT 
                 eekddddddddddkke 
                 84 
                 1536 
               
               
                   
               
               
                 541503 
                 12214 
                 541518 
                 Intron 1 
                 CCATCTTGCTCCAAGT 
                 eekddddddddddkke 
                 93 
                 1537 
               
               
                   
               
               
                 541504 
                 12474 
                 541519 
                 Intron 1 
                 CTTACATCCTGTAGGC 
                 eekddddddddddkke 
                 71 
                 1538 
               
               
                   
               
               
                 541505 
                 12905 
                 541520 
                 Intron 1 
                 CGCCTCCTGGTCCTCA 
                 eekddddddddddkke 
                 97 
                 1539 
               
               
                   
               
               
                 541506 
                 13400 
                 541521 
                 Intron 1 
                 CCCTATGCACTACCTA 
                 eekddddddddddkke 
                 49 
                 1540 
               
               
                   
               
               
                 541507 
                 13717 
                 541522 
                 Intron 1 
                 GAGGGACTGTGGTGCT 
                 eekddddddddddkke 
                 65 
                 1541 
               
               
                   
               
               
                 541508 
                 14149 
                 541523 
                 Intron 1 
                 GCCCAATATGTGCCAG 
                 eekddddddddddkke 
                 60 
                 1542 
               
               
                   
               
               
                 541509 
                 14540 
                 541524 
                 Intron 1 
                 GCTCTCTCATCGCTGG 
                 eekddddddddddkke 
                 90 
                 1543 
               
               
                   
               
               
                 541510 
                 15264 
                 541525 
                 Intron 1 
                 CTCAAGGCTATGTGCC 
                 eekddddddddddkke 
                 67 
                 1544 
               
               
                   
               
               
                 541511 
                 15849 
                 541526 
                 Intron 1 
                 TCCACATCCCTCATGT 
                 eekddddddddddkke 
                 68 
                 1545 
               
               
                   
               
               
                 541512 
                 16530 
                 541527 
                 Intron 1 
                 AGGACTGAAGGCCCAT 
                 eekddddddddddkke 
                 49 
                 1546 
               
               
                   
               
               
                 541513 
                 17377 
                 541528 
                 Intron 1 
                 GTGCGACTTACCAGCT 
                 eekddddddddddkke 
                 85 
                 1547 
               
               
                   
               
               
                 541514 
                 17581 
                 541529 
                 Intron 1 
                 TCGCTAAAGCCACACA 
                 eekddddddddddkke 
                 89 
                 1548 
               
               
                   
               
               
                 541515 
                 17943 
                 541530 
                 Intron 1 
                 GCTCTGGCTGATGGTC 
                 eekddddddddddkke 
                 92 
                 1549 
               
               
                   
               
               
                 541516 
                 18353 
                 541531 
                 Intron 1 
                 TTCCCATGAGGATTTC 
                 eekddddddddddkke 
                 70 
                 1550 
               
               
                   
               
               
                 541517 
                 18636 
                 541532 
                 Intron 1 
                 TTGGGCTTAAGCACTA 
                 eekddddddddddkke 
                 71 
                 1551 
               
               
                   
               
               
                 541518 
                 19256 
                 541533 
                 Intron 1 
                 GCTAGCACCTAGTCCA 
                 eekddddddddddkke 
                 71 
                 1552 
               
               
                   
               
               
                 541519 
                 19814 
                 541534 
                 Intron 1 
                 CCTCTGGCCTACAACA 
                 eekddddddddddkke 
                 64 
                 1553 
               
               
                   
               
               
                 541520 
                 20365 
                 541535 
                 Intron 1 
                 ACCCCTCATCAGCACC 
                 eekddddddddddkke 
                 93 
                 1554 
               
               
                   
               
               
                 541521 
                 20979 
                 541536 
                 Intron 1 
                 GGCCACCCCTGATCCT 
                 eekddddddddddkke 
                 66 
                 1555 
               
               
                   
               
               
                 541522 
                 21566 
                 541537 
                 Intron 1 
                 GAAGCTCCCTTGCCCA 
                 eekddddddddddkke 
                 96 
                 1556 
               
               
                   
               
               
                 541523 
                 22150 
                 541538 
                 Intron 1 
                 AGTGTTGCCCCTCCAA 
                 eekddddddddddkke 
                 83 
                 1557 
               
               
                   
               
               
                 541524 
                 22803 
                 541539 
                 Intron 1 
                 GGGTCTCCAACCTACT 
                 eekddddddddddkke 
                 70 
                 1558 
               
               
                   
               
               
                 541525 
                 29049 
                 541540 
                 Intron 1 
                 GGGATGTAGGTTTACC 
                 eekddddddddddkke 
                 74 
                 1559 
               
               
                   
               
               
                 541526 
                 29554 
                 541541 
                 Intron 1 
                 GCAACCGATATCACAG 
                 eekddddddddddkke 
                 60 
                 1560 
               
               
                   
               
               
                 541527 
                 30245 
                 541542 
                 Intron 1 
                 TGCCCTGGAACAAATT 
                 eekddddddddddkke 
                 13 
                 1561 
               
               
                   
               
               
                 541528 
                 30550 
                 541543 
                 Intron 1 
                 AGTCTAGGAGTAGCTA 
                 eekddddddddddkke 
                 50 
                 1562 
               
               
                   
               
               
                 541529 
                 30915 
                 541544 
                 Intron 1 
                 GCTGTTGTCAAGAGAC 
                 eekddddddddddkke 
                 55 
                 1563 
               
               
                   
               
               
                 541530 
                 31468 
                 541545 
                 Intron 1 
                 CACCTAGACACTCAGT 
                 eekddddddddddkke 
                 47 
                 1564 
               
               
                   
               
               
                 541531 
                 32366 
                 541546 
                 Intron 1 
                 GTCAAGGGATCCCTGC 
                 eekddddddddddkke 
                 34 
                 1565 
               
               
                   
               
               
                 541532 
                 32897 
                 541547 
                 Intron 1 
                 TCCCCCTGGCACTCCA 
                 eekddddddddddkke 
                 79 
                 1566 
               
               
                   
               
               
                 541533 
                 33187 
                 541548 
                 Intron 1 
                 GCCTGGTAACTCCATT 
                 eekddddddddddkke 
                 56 
                 1567 
               
               
                   
               
               
                 541534 
                 33780 
                 541549 
                 Intron 1 
                 GGGCTCACCAACTGTG 
                 eekddddddddddkke 
                 39 
                 1568 
               
               
                   
               
               
                 541535 
                 34407 
                 541550 
                 Intron 1 
                 CCACAGGATCATATCA 
                 eekddddddddddkke 
                 37 
                 1569 
               
               
                   
               
               
                 541536 
                 34846 
                 541551 
                 Intron 1 
                 CTCCAGCAGAAGTGTC 
                 eekddddddddddkke 
                 10 
                 1570 
               
               
                   
               
               
                 541537 
                 35669 
                 541552 
                 Intron 1 
                 AGCCCAACTGTTGCCT 
                 eekddddddddddkke 
                 79 
                 1571 
               
               
                   
               
               
                 541538 
                 36312 
                 541553 
                 Intron 1 
                 TGCCAGGCAGTTGCCA 
                 eekddddddddddkke 
                 75 
                 1572 
               
               
                   
               
               
                 541539 
                 36812 
                 541554 
                 Intron 1 
                 GCCAGTAAGCACCTTG 
                 eekddddddddddkke 
                 93 
                 1573 
               
               
                   
               
               
                 541540 
                 37504 
                 541555 
                 Intron 1 
                 CTAGCTTCCCAGCCCC 
                 eekddddddddddkke 
                 46 
                 1574 
               
               
                   
               
               
                 541541 
                 38841 
                 541556 
                 Intron 1 
                 TCAAGCCCAGCTAGCA 
                 eekddddddddddkke 
                 39 
                 1575 
               
               
                   
               
               
                 541542 
                 39108 
                 541557 
                 Intron 1 
                 CCTCACAGGCCCTAAT 
                 eekddddddddddkke 
                  4 
                 1576 
               
               
                   
               
               
                 541543 
                 39408 
                 541558 
                 Intron 1 
                 ACCTGCTTACATGGTA 
                 eekddddddddddkke 
                 21 
                 1577 
               
               
                   
               
               
                 541544 
                 40250 
                 541559 
                 Intron 1 
                 CCTTTGCTAGGACCCA 
                 eekddddddddddkke 
                 52 
                 1578 
               
               
                   
               
               
                 541545 
                 40706 
                 541560 
                 Intron 1 
                 GGGACTGCCACCAAGG 
                 eekddddddddddkke 
                 27 
                 1579 
               
               
                   
               
               
                 541546 
                 40922 
                 541561 
                 Intron 1 
                 GCTAGATGTTCAGGCC 
                 eekddddddddddkke 
                 34 
                 1580 
               
               
                   
               
               
                 541547 
                 41424 
                 541562 
                 Intron 1 
                 CCTATGGCCATGCTGA 
                 eekddddddddddkke 
                 32 
                 1581 
               
               
                   
               
               
                 541548 
                 41999 
                 541563 
                 Intron 1 
                 GTATGCTAGTTCCCAT 
                 eekddddddddddkke 
                 83 
                 1582 
               
               
                   
               
               
                 541549 
                 42481 
                 541564 
                 Intron 1 
                 CCCTCATAATCTTGGG 
                 eekddddddddddkke 
                 13 
                 1583 
               
               
                   
               
               
                 541550 
                 42700 
                 541565 
                 Intron 1 
                 GTCCAACCACTACCAC 
                 eekddddddddddkke 
                 74 
                 1584 
               
               
                   
               
               
                 541551 
                 43291 
                 541566 
                 Intron 1 
                 ACTTGCAGATAGCTGA 
                 eekddddddddddkke 
                 73 
                 1585 
               
               
                   
               
               
                 541552 
                 43500 
                 541567 
                 Intron 1 
                 GCATGACCCCACTGCC 
                 eekddddddddddkke 
                 72 
                 1586 
               
               
                   
               
               
                 541553 
                 43947 
                 541568 
                 Intron 1 
                 GAGGGTCACATTCCCT 
                 eekddddddddddkke 
                 23 
                 1587 
               
               
                   
               
               
                 541554 
                 44448 
                 541569 
                 Intron 1 
                 TCTCTTACTGGTGGGT 
                 eekddddddddddkke 
                 90 
                 1588 
               
               
                   
               
               
                 541555 
                 45162 
                 541570 
                 Intron 1 
                 GCCCCCTTCCTGGATA 
                 eekddddddddddkke 
                 28 
                 1589 
               
               
                   
               
               
                 541556 
                 46010 
                 541571 
                 Intron 1 
                 CCTCATGCGACACCAC 
                 eekddddddddddkke 
                 71 
                 1590 
               
               
                   
               
               
                 541557 
                 46476 
                 541572 
                 Intron 1 
                 AGCCCTCTGCCTGTAA 
                 eekddddddddddkke 
                 67 
                 1591 
               
               
                   
               
               
                 541558 
                 47447 
                 541573 
                 Intron 1 
                 CTCCCAGCTATAGGCG 
                 eekddddddddddkke 
                 38 
                 1592 
               
               
                   
               
               
                 541559 
                 47752 
                 541574 
                 Intron 1 
                 GCTAGCTGCGCAAGGA 
                 eekddddddddddkke 
                  5 
                 1593 
               
               
                   
               
               
                 541560 
                 48001 
                 541575 
                 Intron 1 
                 GCGCAGCCCGCTGCAA 
                 eekddddddddddkke 
                 18 
                 1594 
               
               
                   
               
               
                 541561 
                 48423 
                 541576 
                 Intron 1 
                 TGCATGATCCACCCCA 
                 eekddddddddddkke 
                 65 
                 1595 
               
               
                   
               
               
                 541562 
                 50195 
                 541577 
                 Intron 1 
                 GCTTAGTGCTGGCCCA 
                 eekddddddddddkke 
                 72 
                 1596 
               
               
                   
               
               
                 541563 
                 50470 
                 541578 
                 Intron 1 
                 CCTTCCAGTCCTCATA 
                 eekddddddddddkke 
                 81 
                 1597 
               
               
                   
               
               
                 541564 
                 51104 
                 541579 
                 Intron 1 
                 ATAGTGTCAAGGCCCA 
                 eekddddddddddkke 
                 91 
                 1598 
               
               
                   
               
               
                 541565 
                 51756 
                 541580 
                 Intron 1 
                 AGGCCTTAGTCACCCA 
                 eekddddddddddkke 
                 88 
                 1599 
               
               
                   
               
               
                 541566 
                 52015 
                 541581 
                 Intron 1 
                 TAACCAACCTAAGGGA 
                 eekddddddddddkke 
                 11 
                 1600 
               
               
                   
               
               
                 541567 
                 52230 
                 541582 
                 Intron 1 
                 ATTCTGGTGATGCCCT 
                 eekddddddddddkke 
                 66 
                 1601 
               
               
                   
               
               
                 541568 
                 52588 
                 541583 
                 Intron 1 
                 GTGTTCACTGCCATGA 
                 eekddddddddddkke 
                 67 
                 1602 
               
               
                   
               
               
                 541569 
                 53532 
                 541584 
                 Intron 1 
                 GGTAGAGCACACTGCC 
                 eekddddddddddkke 
                 47 
                 1603 
               
               
                   
               
               
                 541570 
                 54645 
                 541585 
                 Intron 1 
                 CCACTTTAATGCCACC 
                 eekddddddddddkke 
                 76 
                 1604 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 56 
               
             
            
               
                   
               
               
                 Inhibition of GHR mRNA by deoxy, MOE and cEt gapmers targeting intronic regions of SEQ ID NO: 2 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                 SEQ ID 
                 SEQ ID 
                   
                   
                   
                   
                   
               
               
                 ISIS 
                 NO: 2 
                 NO: 2 
                 Target 
                   
                   
                 % 
                 SEQ 
               
               
                 NO 
                 Start Site 
                 Target Region 
                 Region 
                 Sequence 
                 Chemistry 
                 inhibition 
                 ID NO 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 541262 
                 156891 
                 156906 
                 Intron 2 
                 TTGGTTTGTCAATCCT 
                 eekddddddddddkke 
                 88 
                 1370 
               
               
                   
               
               
                 541571 
                  54886 
                  54901 
                 Intron 1 
                 GTCAAATGCTGTTGGG 
                 eekddddddddddkke 
                 91 
                 1605 
               
               
                   
               
               
                 541572 
                  55900 
                  55915 
                 Intron 1 
                 CATCCCCTATCAGGGT 
                 eekddddddddddkke 
                 53 
                 1606 
               
               
                   
               
               
                 541573 
                  62266 
                  62281 
                 Intron 1 
                 CTCGAATCCCTTGAGC 
                 eekddddddddddkke 
                 73 
                 1607 
               
               
                   
               
               
                 541574 
                  62733 
                  62748 
                 Intron 1 
                 GATTCCCTCCCCTAAC 
                 eekddddddddddkke 
                 27 
                 1608 
               
               
                   
               
               
                 541575 
                  63173 
                  63188 
                 Intron 1 
                 ATCCATCCATGTGCTG 
                 eekddddddddddkke 
                 92 
                 1609 
               
               
                   
               
               
                 541576 
                  63751 
                  63766 
                 Intron 1 
                 GAGCATGCCTCAGTGG 
                 eekddddddddddkke 
                 81 
                 1610 
               
               
                   
               
               
                 541577 
                  63964 
                  63979 
                 Intron 1 
                 CAGAAGGACTGCCTCT 
                 eekddddddddddkke 
                 50 
                 1611 
               
               
                   
               
               
                 541578 
                  64213 
                  64228 
                 Intron 1 
                 ACAATGCTCAACAGCC 
                 eekddddddddddkke 
                 75 
                 1612 
               
               
                   
               
               
                 541579 
                  64576 
                  64591 
                 Intron 1 
                 GTTGGATCTGGCATGC 
                 eekddddddddddkke 
                 80 
                 1613 
               
               
                   
               
               
                 541580 
                  65027 
                  65042 
                 Intron 1 
                 CGGCTGAGAGCAAGGG 
                 eekddddddddddkke 
                 88 
                 1614 
               
               
                   
               
               
                 541581 
                  65363 
                  65378 
                 Intron 1 
                 GAGAGGGTTCAGCCTG 
                 eekddddddddddkke 
                 62 
                 1615 
               
               
                   
               
               
                 541582 
                  65600 
                  65615 
                 Intron 1 
                 ACTTAGTTCCTAGCCA 
                 eekddddddddddkke 
                 91 
                 1616 
               
               
                   
               
               
                 541583 
                  66087 
                  66102 
                 Intron 1 
                 GTGAACCAGATGTGCT 
                 eekddddddddddkke 
                 86 
                 1617 
               
               
                   
               
               
                 541584 
                  66566 
                  66581 
                 Intron 1 
                 GGAGTGACAGCTAAGT 
                 eekddddddddddkke 
                 98 
                 1618 
               
               
                   
               
               
                 541585 
                  66978 
                  66993 
                 Intron 1 
                 AAGTGTTCAGAGCCAC 
                 eekddddddddddkke 
                 97 
                 1619 
               
               
                   
               
               
                 541586 
                  67662 
                  67677 
                 Intron 1 
                 AACCCTGCCAAGGTAC 
                 eekddddddddddkke 
                 45 
                 1620 
               
               
                   
               
               
                 541587 
                  67914 
                  67929 
                 Intron 1 
                 GATGGTGAGCACTACC 
                 eekddddddddddkke 
                 78 
                 1621 
               
               
                   
               
               
                 541588 
                  68278 
                  68293 
                 Intron 1 
                 GGCAGGATAGGACAGA 
                 eekddddddddddkke 
                 11 
                 1622 
               
               
                   
               
               
                 541589 
                  68727 
                  68742 
                 Intron 1 
                 GCAAAGTGATGAGCCT 
                 eekddddddddddkke 
                 81 
                 1623 
               
               
                   
               
               
                 541590 
                  69207 
                  69222 
                 Intron 1 
                 CTATCCACACCATTCC 
                 eekddddddddddkke 
                 93 
                 1624 
               
               
                   
               
               
                 541591 
                  69605 
                  69620 
                 Intron 1 
                 GGATCATGGGCCCCTA 
                 eekddddddddddkke 
                 70 
                 1625 
               
               
                   
               
               
                 541592 
                  70130 
                  70145 
                 Intron 1 
                 GTGAATTTGCTGGGCC 
                 eekddddddddddkke 
                 94 
                 1626 
               
               
                   
               
               
                 541593 
                  70569 
                  70584 
                 Intron 1 
                 GTGATGGGCCCAAGGC 
                 eekddddddddddkke 
                 67 
                 1627 
               
               
                   
               
               
                 541594 
                  71056 
                  71071 
                 Intron 1 
                 TCCTCAGTCGGCTTGC 
                 eekddddddddddkke 
                 69 
                 1628 
               
               
                   
               
               
                 541595 
                  71314 
                  71329 
                 Intron 1 
                 CAGCCTTTTGCCAGAT 
                 eekddddddddddkke 
                 93 
                 1629 
               
               
                   
               
               
                 541596 
                  71620 
                  71635 
                 Intron 1 
                 CCTCCCTAGGATTACC 
                 eekddddddddddkke 
                 42 
                 1630 
               
               
                   
               
               
                 541597 
                  72226 
                  72241 
                 Intron 1 
                 ACGCCCCAATCACTCA 
                 eekddddddddddkke 
                 79 
                 1631 
               
               
                   
               
               
                 541598 
                  72655 
                  72670 
                 Intron 1 
                 GCATGACCCATTATGT 
                 eekddddddddddkke 
                 94 
                 1632 
               
               
                   
               
               
                 541599 
                  73061 
                  73076 
                 Intron 1 
                 TCCCTCCAAGAGCTCA 
                 eekddddddddddkke 
                 83 
                 1633 
               
               
                   
               
               
                 541600 
                  73708 
                  73723 
                 Intron 1 
                 GATGCCTGTGGCTGAC 
                 eekddddddddddkke 
                 84 
                 1634 
               
               
                   
               
               
                 541601 
                  74107 
                  74122 
                 Intron 1 
                 GGCTAGCATGTTGCCT 
                 eekddddddddddkke 
                 19 
                 1635 
               
               
                   
               
               
                 541602 
                  74542 
                  74557 
                 Intron 1 
                 TAACCCACTAGGCTGG 
                 eekddddddddddkke 
                 84 
                 1636 
               
               
                   
               
               
                 541603 
                  74947 
                  74962 
                 Intron 1 
                 TGGCCCAAAACTAATC 
                 eekddddddddddkke 
                 34 
                 1637 
               
               
                   
               
               
                 541604 
                  75192 
                  75207 
                 Intron 1 
                 GGAGCAGTCTGGCACC 
                 eekddddddddddkke 
                 85 
                 1638 
               
               
                   
               
               
                 541605 
                  75699 
                  75714 
                 Intron 1 
                 TATTCTGTGGGACAAG 
                 eekddddddddddkke 
                 51 
                 1639 
               
               
                   
               
               
                 541606 
                  75979 
                  75994 
                 Intron 1 
                 GTGTCTAGTTCCAGCC 
                 eekddddddddddkke 
                 86 
                 1640 
               
               
                   
               
               
                 541607 
                  76410 
                  76425 
                 Intron 1 
                 TACTATCATGTAGCGC 
                 eekddddddddddkke 
                 87 
                 1641 
               
               
                   
               
               
                 541608 
                  76701 
                  76716 
                 Intron 1 
                 TGCCCTTGTAGTGAGA 
                 eekddddddddddkke 
                 31 
                 1642 
               
               
                   
               
               
                 541609 
                  76980 
                  76995 
                 Intron 1 
                 TCCCCAACCTACAAGC 
                 eekddddddddddkke 
                 41 
                 1643 
               
               
                   
               
               
                 541610 
                  77292 
                  77307 
                 Intron 1 
                 GCTCTAGGCATATGAA 
                 eekddddddddddkke 
                 63 
                 1644 
               
               
                   
               
               
                 541611 
                  77555 
                  77570 
                 Intron 1 
                 TACCTCCCTTGTAGGG 
                 eekddddddddddkke 
                 27 
                 1645 
               
               
                   
               
               
                 541612 
                  77854 
                  77869 
                 Intron 1 
                 GGTTCCCTTGCAGAGA 
                 eekddddddddddkke 
                 62 
                 1646 
               
               
                   
               
               
                 541613 
                  78311 
                  78326 
                 Intron 1 
                 GTGCCCTCTTCATGCC 
                 eekddddddddddkke 
                 68 
                 1647 
               
               
                   
               
               
                 541614 
                  79006 
                  79021 
                 Intron 1 
                 CCTGTGTGCAACTGGC 
                 eekddddddddddkke 
                 85 
                 1648 
               
               
                   
               
               
                 541615 
                  79490 
                  79505 
                 Intron 1 
                 CTGAGTCATTTGCCTG 
                 eekddddddddddkke 
                 93 
                 1649 
               
               
                   
               
               
                 541616 
                  79829 
                  79844 
                 Intron 1 
                 GGCCTTAGTAGGCCAG 
                 eekddddddddddkke 
                  0 
                 1650 
               
               
                   
               
               
                 541617 
                  80277 
                  80292 
                 Intron 1 
                 GTCCTTGCAGTCAACC 
                 eekddddddddddkke 
                 77 
                 1651 
               
               
                   
               
               
                 541618 
                  80575 
                  80590 
                 Intron 1 
                 GCTGGGCCAAGTCCAT 
                 eekddddddddddkke 
                 77 
                 1652 
               
               
                   
               
               
                 541619 
                  80895 
                  80910 
                 Intron 1 
                 TAGGGCACTTTTTGCC 
                 eekddddddddddkke 
                 31 
                 1653 
               
               
                   
               
               
                 541620 
                  81207 
                  81222 
                 Intron 1 
                 GCTGAGGTCCCTCTCT 
                 eekddddddddddkke 
                 34 
                 1654 
               
               
                   
               
               
                 541621 
                  81761 
                  81776 
                 Intron 1 
                 CTTTGGTCCCATTGCC 
                 eekddddddddddkke 
                 83 
                 1655 
               
               
                   
               
               
                 541622 
                  82233 
                  82248 
                 Intron 1 
                 GGAACATGCCAAGGGC 
                 eekddddddddddkke 
                 91 
                 1656 
               
               
                   
               
               
                 541623 
                  82738 
                  82753 
                 Intron 1 
                 AGGTGGTCTCCCTTCA 
                 eekddddddddddkke 
                 74 
                 1657 
               
               
                   
               
               
                 541624 
                  83056 
                  83071 
                 Intron 1 
                 TCCCAAAGCTCCCCTC 
                 eekddddddddddkke 
                 53 
                 1658 
               
               
                   
               
               
                 541625 
                  83401 
                  83416 
                 Intron 1 
                 CCTGGCCTAGCAAGCT 
                 eekddddddddddkke 
                 47 
                 1659 
               
               
                   
               
               
                 541626 
                  84048 
                  84063 
                 Intron 1 
                 TCTTAGCCCTGGGCTA 
                 eekddddddddddkke 
                 12 
                 1660 
               
               
                   
               
               
                 541627 
                  84388 
                  84403 
                 Intron 1 
                 GACTTGGACTGGGCTC 
                 eekddddddddddkke 
                 81 
                 1661 
               
               
                   
               
               
                 541628 
                  85261 
                  85276 
                 Intron 1 
                 GGCCTAGGATCTAGGA 
                 eekddddddddddkke 
                  0 
                 1662 
               
               
                   
               
               
                 541629 
                  85714 
                  85729 
                 Intron 1 
                 GTCAGGCTAGAGGGAC 
                 eekddddddddddkke 
                 41 
                 1663 
               
               
                   
               
               
                 541630 
                  86220 
                  86235 
                 Intron 1 
                 GGAAGTTCTCCCAGCC 
                 eekddddddddddkke 
                 47 
                 1664 
               
               
                   
               
               
                 541631 
                  86640 
                  86655 
                 Intron 1 
                 CCTGACTGATGTACAC 
                 eekddddddddddkke 
                 35 
                 1665 
               
               
                   
               
               
                 541632 
                  86903 
                  86918 
                 Intron 1 
                 CTCTGGCCTAGCCTAT 
                 eekddddddddddkke 
                 54 
                 1666 
               
               
                   
               
               
                 541633 
                  87247 
                  87262 
                 Intron 1 
                 GGCTGCTGTCAGATGC 
                 eekddddddddddkke 
                 79 
                 1667 
               
               
                   
               
               
                 541634 
                  88293 
                  88308 
                 Intron 1 
                 TCTCAGGTGTAGGCAG 
                 eekddddddddddkke 
                 59 
                 1668 
               
               
                   
               
               
                 541635 
                  88605 
                  88620 
                 Intron 1 
                 GGTCACTGAGACTGGG 
                 eekddddddddddkke 
                 88 
                 1669 
               
               
                   
               
               
                 541636 
                  88952 
                  88967 
                 Intron 1 
                 ACCCACTAGCAGCTAG 
                 eekddddddddddkke 
                 61 
                 1670 
               
               
                   
               
               
                 541637 
                  89160 
                  89175 
                 Intron 1 
                 CGGATGAGGCAGTTAG 
                 eekddddddddddkke 
                 42 
                 1671 
               
               
                   
               
               
                 541638 
                  89855 
                  89870 
                 Intron 1 
                 TGGTAGGCCCTCTGGC 
                 eekddddddddddkke 
                 28 
                 1672 
               
               
                   
               
               
                 541639 
                  90240 
                  90255 
                 Intron 1 
                 GTCACAAGGTGGGTGC 
                 eekddddddddddkke 
                 28 
                 1673 
               
               
                   
               
               
                 541640 
                  90513 
                  90528 
                 Intron 1 
                 GTCTTGCCCTCACGGA 
                 eekddddddddddkke 
                 73 
                 1674 
               
               
                   
               
               
                 541641 
                  91073 
                  91088 
                 Intron 1 
                 GCAGTCTGTGGACTTA 
                 eekddddddddddkke 
                 93 
                 1675 
               
               
                   
               
               
                 541642 
                  91647 
                  91662 
                 Intron 1 
                 TGCTCTCTGGTCACAC 
                 eekddddddddddkke 
                 75 
                 1676 
               
               
                   
               
               
                 541643 
                  92069 
                  92084 
                 Intron 1 
                 TATCCCCCAGAGCCAT 
                 eekddddddddddkke 
                 68 
                 1677 
               
               
                   
               
               
                 541644 
                  92356 
                  92371 
                 Intron 1 
                 AAGGTGAGAGGGCACT 
                 eekddddddddddkke 
                 75 
                 1678 
               
               
                   
               
               
                 541645 
                  92904 
                  92919 
                 Intron 1 
                 GTTTTAACCTCACCCT 
                 eekddddddddddkke 
                  0 
                 1679 
               
               
                   
               
               
                 541646 
                  93846 
                  93861 
                 Intron 1 
                 CCTTCCACTGACCTTC 
                 eekddddddddddkke 
                 56 
                 1680 
               
               
                   
               
               
                 541647 
                  94374 
                  94389 
                 Intron 1 
                 GACACTAGCCTAAGCC 
                 eekddddddddddkke 
                 37 
                 1681 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 57 
               
             
            
               
                   
               
               
                 Inhibition of GHR mRNA by deoxy, MOE and cEt gapmers targeting intronic regions of SEQ ID NO: 2 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                 SEQ ID 
                 SEQ ID 
                   
                   
                   
                   
                   
               
               
                   
                 NO: 2 
                 NO: 2 
                   
                   
                   
                   
                   
               
               
                 ISIS 
                 Start 
                 Stop 
                 Target 
                   
                   
                 % 
                 SEQ 
               
               
                 NO 
                 Site 
                 Site 
                 Region 
                 Sequence 
                 Chemistry 
                 inhibition 
                 ID NO 
               
               
                   
               
               
                 541262 
                 156891 
                 156906 
                 Intron 2 
                 TTGGTTTGTCAATCCT 
                 eekddddddddddkke 
                 94 
                 1370 
               
               
                   
               
               
                 541648 
                  94638 
                  94653 
                 Intron 1 
                 GGTTAGCCCTCAGCCT 
                 eekddddddddddkke 
                 61 
                 1682 
               
               
                   
               
               
                 541649 
                  94839 
                  94854 
                 Intron 1 
                 TATGAAGGTTGGACCA 
                 eekddddddddddkke 
                 69 
                 1683 
               
               
                   
               
               
                 541650 
                  95509 
                  95524 
                 Intron 1 
                 CAACCAGCTCACCTGA 
                 eekddddddddddkke 
                 37 
                 1684 
               
               
                   
               
               
                 541651 
                  95829 
                  95844 
                 Intron 1 
                 GGGCTCCAAGGCTCTC 
                 eekddddddddddkke 
                 75 
                 1685 
               
               
                   
               
               
                 541652 
                  96158 
                  96173 
                 Intron 1 
                 AGCTGTTACATGCCAA 
                 eekddddddddddkke 
                 93 
                 1686 
               
               
                   
               
               
                 541653 
                  96488 
                  96503 
                 Intron 1 
                 GGCCCAGAGGTTATAG 
                 eekddddddddddkke 
                 30 
                 1687 
               
               
                   
               
               
                 541654 
                  96991 
                  97006 
                 Intron 1 
                 GTCCTTAGACCCCTCA 
                 eekddddddddddkke 
                 70 
                 1688 
               
               
                   
               
               
                 541655 
                  97539 
                  97554 
                 Intron 1 
                 GCCCTGGCTAGAGACA 
                 eekddddddddddkke 
                 39 
                 1689 
               
               
                   
               
               
                 541656 
                  98132 
                  98147 
                 Intron 1 
                 CATCCAGCAGCTGGAC 
                 eekddddddddddkke 
                 35 
                 1690 
               
               
                   
               
               
                 541657 
                  98833 
                  98848 
                 Intron 1 
                 GACTGAGGTCATCACA 
                 eekddddddddddkke 
                 60 
                 1691 
               
               
                   
               
               
                 541658 
                  99258 
                  99273 
                 Intron 1 
                 GGCCAGGCACATCATG 
                 eekddddddddddkke 
                 45 
                 1692 
               
               
                   
               
               
                 541659 
                  99843 
                  99858 
                 Intron 1 
                 GGAGCTCATTGAGCCA 
                 eekddddddddddkke 
                 36 
                 1693 
               
               
                   
               
               
                 541660 
                 100406 
                 100421 
                 Intron 1 
                 GTGCCCATTGCTGTGT 
                 eekddddddddddkke 
                 70 
                 1694 
               
               
                   
               
               
                 541661 
                 100742 
                 100757 
                 Intron 1 
                 CCAAGTGTGGCTTCAG 
                 eekddddddddddkke 
                 54 
                 1695 
               
               
                   
               
               
                 541662 
                 101305 
                 101320 
                 Intron 1 
                 CCACCCTTTATACGCA 
                 eekddddddddddkke 
                 87 
                 1696 
               
               
                   
               
               
                 541663 
                 101788 
                 101803 
                 Intron 1 
                 CAGTAACCCCAAGGGA 
                 eekddddddddddkke 
                 12 
                 1697 
               
               
                   
               
               
                 541664 
                 102649 
                 102664 
                 Intron 1 
                 CCCCACCTTATATGGG 
                 eekddddddddddkke 
                  9 
                 1698 
               
               
                   
               
               
                 541665 
                 103034 
                 103049 
                 Intron 1 
                 AGGCCCTTTTTACATG 
                 eekddddddddddkke 
                  9 
                 1699 
               
               
                   
               
               
                 541666 
                 103316 
                 103331 
                 Intron 1 
                 TCAATAAGTCCCTAGG 
                 eekddddddddddkke 
                 20 
                 1700 
               
               
                   
               
               
                 541667 
                 104277 
                 104292 
                 Intron 1 
                 GGCATTGAGTGACTGC 
                 eekddddddddddkke 
                 51 
                 1701 
               
               
                   
               
               
                 541668 
                 104679 
                 104694 
                 Intron 1 
                 ATAATGCCTTCTCAGC 
                 eekddddddddddkke 
                 62 
                 1702 
               
               
                   
               
               
                 541669 
                 106349 
                 106364 
                 Intron 1 
                 GTGAGGCATTTAGCCC 
                 eekddddddddddkke 
                 35 
                 1703 
               
               
                   
               
               
                 541670 
                 106632 
                 106647 
                 Intron 1 
                 GCTCTTGTGTTGGGTA 
                 eekddddddddddkke 
                 89 
                 1704 
               
               
                   
               
               
                 541671 
                 107084 
                 107099 
                 Intron 1 
                 TGTGCAGGAGGTCTCA 
                 eekddddddddddkke 
                 60 
                 1705 
               
               
                   
               
               
                 541672 
                 107949 
                 107964 
                 Intron 1 
                 TGGAGAGTCTTGTCTC 
                 eekddddddddddkke 
                 17 
                 1706 
               
               
                   
               
               
                 541673 
                 108773 
                 108788 
                 Intron 1 
                 GTGACCCACCCAAGAG 
                 eekddddddddddkke 
                 34 
                 1707 
               
               
                   
               
               
                 541674 
                 109336 
                 109351 
                 Intron 1 
                 GTTGTAGCTAGTGTTC 
                 eekddddddddddkke 
                 74 
                 1708 
               
               
                   
               
               
                 541675 
                 109849 
                 109864 
                 Intron 1 
                 GCCTTAGTTTGTGCCA 
                 eekddddddddddkke 
                 78 
                 1709 
               
               
                   
               
               
                 541676 
                 110427 
                 110442 
                 Intron 1 
                 GCCCCAGCTGAGAATT 
                 eekddddddddddkke 
                 29 
                 1710 
               
               
                   
               
               
                 541677 
                 110701 
                 110716 
                 Intron 1 
                 ACAACAATCCAGGGTG 
                 eekddddddddddkke 
                 61 
                 1711 
               
               
                   
               
               
                 541678 
                 110959 
                 110974 
                 Intron 1 
                 CTCCCCTGGAAGTCAC 
                 eekddddddddddkke 
                 59 
                 1712 
               
               
                   
               
               
                 541679 
                 111307 
                 111322 
                 Intron 1 
                 GCCCTCATGGCTCAAG 
                 eekddddddddddkke 
                 60 
                 1713 
               
               
                   
               
               
                 541680 
                 112499 
                 112514 
                 Intron 1 
                 TCAGCAGATAGGGAGC 
                 eekddddddddddkke 
                 61 
                 1714 
               
               
                   
               
               
                 541681 
                 113896 
                 113911 
                 Intron 1 
                 GAATGCGGTGATCAGG 
                 eekddddddddddkke 
                 29 
                 1715 
               
               
                   
               
               
                 541682 
                 117477 
                 117492 
                 Intron 1 
                 CTGAGAGAATTGGCCC 
                 eekddddddddddkke 
                  5 
                 1716 
               
               
                   
               
               
                 541683 
                 117740 
                 117755 
                 Intron 1 
                 AGGCACATTGTTACCA 
                 eekddddddddddkke 
                 26 
                 1717 
               
               
                   
               
               
                 541684 
                 118229 
                 118244 
                 Intron 1 
                 GGGAGGCACTAGAGAA 
                 eekddddddddddkke 
                 13 
                 1718 
               
               
                   
               
               
                 541685 
                 119269 
                 119284 
                 Intron 1 
                 TACAGTAACACATCCC 
                 eekddddddddddkke 
                 78 
                 1719 
               
               
                   
               
               
                 541686 
                 119688 
                 119703 
                 Intron 1 
                 GAAGCTCAGCCTGATC 
                 eekddddddddddkke 
                 45 
                 1720 
               
               
                   
               
               
                 541687 
                 120376 
                 120391 
                 Intron 1 
                 CTTGCCTGACAACCTA 
                 eekddddddddddkke 
                 53 
                 1721 
               
               
                   
               
               
                 541688 
                 120738 
                 120753 
                 Intron 1 
                 GCCTACCTGCTTTTGC 
                 eekddddddddddkke 
                 10 
                 1722 
               
               
                   
               
               
                 541689 
                 121242 
                 121257 
                 Intron 1 
                 TTTCCCAACCACTTAG 
                 eekddddddddddkke 
                  7 
                 1723 
               
               
                   
               
               
                 541690 
                 121615 
                 121630 
                 Intron 1 
                 TCTCCTATTTCAGTTA 
                 eekddddddddddkke 
                 23 
                 1724 
               
               
                   
               
               
                 541691 
                 121823 
                 121838 
                 Intron 1 
                 GGGTGATGGATGAACT 
                 eekddddddddddkke 
                 40 
                 1725 
               
               
                   
               
               
                 541692 
                 122345 
                 122360 
                 Intron 1 
                 ACACTGCTGGTAGTGA 
                 eekddddddddddkke 
                  0 
                 1726 
               
               
                   
               
               
                 541693 
                 122588 
                 122603 
                 Intron 1 
                 ACCCAACTAGCCTGTC 
                 eekddddddddddkke 
                 35 
                 1727 
               
               
                   
               
               
                 541694 
                 123152 
                 123167 
                 Intron 1 
                 GAGACCTGCTGCCTGA 
                 eekddddddddddkke 
                 80 
                 1728 
               
               
                   
               
               
                 541695 
                 123671 
                 123686 
                 Intron 1 
                 ACATCTCTTGGGAGGT 
                 eekddddddddddkke 
                 78 
                 1729 
               
               
                   
               
               
                 541696 
                 124040 
                 124055 
                 Intron 1 
                 ACATAGTACCCCTCCA 
                 eekddddddddddkke 
                 35 
                 1730 
               
               
                   
               
               
                 541697 
                 124430 
                 124445 
                 Intron 1 
                 CTCTCAAGTACCTGCC 
                 eekddddddddddkke 
                 72 
                 1731 
               
               
                   
               
               
                 541698 
                 124824 
                 124839 
                 Intron 1 
                 TTTGTACCCAACCCCC 
                 eekddddddddddkke 
                 15 
                 1732 
               
               
                   
               
               
                 541699 
                 125032 
                 125047 
                 Intron 1 
                 AGGCCCACATAAATGC 
                 eekddddddddddkke 
                 21 
                 1733 
               
               
                   
               
               
                 541700 
                 125533 
                 125548 
                 Intron 1 
                 GAGCATCCCCTACACT 
                 eekddddddddddkke 
                 12 
                 1734 
               
               
                   
               
               
                 541701 
                 126357 
                 126372 
                 Intron 1 
                 GCTGGGCCTTTAGCTG 
                 eekddddddddddkke 
                 66 
                 1735 
               
               
                   
               
               
                 541702 
                 126736 
                 126751 
                 Intron 1 
                 TTGGTCAATTGGGCAG 
                 eekddddddddddkke 
                 79 
                 1736 
               
               
                   
               
               
                 541703 
                 127179 
                 127194 
                 Intron 1 
                 GTCTCATGAGGCCTAT 
                 eekddddddddddkke 
                 60 
                 1737 
               
               
                   
               
               
                 541704 
                 127454 
                 127469 
                 Intron 1 
                 GGAGGTGGGATCCCAC 
                 eekddddddddddkke 
                 35 
                 1738 
               
               
                   
               
               
                 541705 
                 128467 
                 128482 
                 Intron 1 
                 GCCCACTACCTAGCAC 
                 eekddddddddddkke 
                 30 
                 1739 
               
               
                   
               
               
                 541706 
                 129096 
                 129111 
                 Intron 1 
                 CCCAGCTGGCTGGTCG 
                 eekddddddddddkke 
                 50 
                 1740 
               
               
                   
               
               
                 541707 
                 129312 
                 129327 
                 Intron 1 
                 GCACCAGGTCTCCTGT 
                 eekddddddddddkke 
                  7 
                 1741 
               
               
                   
               
               
                 541708 
                 129516 
                 129531 
                 Intron 1 
                 GTCTAGAAGCCTAGGG 
                 eekddddddddddkke 
                 23 
                 1742 
               
               
                   
               
               
                 541709 
                 129976 
                 129991 
                 Intron 1 
                 GCCGGGTGTTGGTGCA 
                 eekddddddddddkke 
                 50 
                 1743 
               
               
                   
               
               
                 541710 
                 130308 
                 130323 
                 Intron 1 
                 TTGGTGCCTGTGTTGC 
                 eekddddddddddkke 
                 49 
                 1744 
               
               
                   
               
               
                 541711 
                 130767 
                 130782 
                 Intron 1 
                 TGCTTCTGATCCCTAC 
                 eekddddddddddkke 
                 18 
                 1745 
               
               
                   
               
               
                 541712 
                 131286 
                 131301 
                 Intron 1 
                 GTTCCCAGGAGGCTTA 
                 eekddddddddddkke 
                 56 
                 1746 
               
               
                   
               
               
                 541713 
                 131676 
                 131691 
                 Intron 1 
                 AGGCCCCTAGAGTCTA 
                 eekddddddddddkke 
                 41 
                 1747 
               
               
                   
               
               
                 541714 
                 132292 
                 132307 
                 Intron 1 
                 TGGTGTGCCCAGACTT 
                 eekddddddddddkke 
                 60 
                 1748 
               
               
                   
               
               
                 541715 
                 132730 
                 132745 
                 Intron 1 
                 GATGGCTAACCCACTG 
                 eekddddddddddkke 
                 14 
                 1749 
               
               
                   
               
               
                 541716 
                 133101 
                 133116 
                 Intron 1 
                 CCCCCAAAAGTTGCCC 
                 eekddddddddddkke 
                 12 
                 1750 
               
               
                   
               
               
                 541717 
                 133522 
                 133537 
                 Intron 1 
                 TAGGGTGTTCCAGATC 
                 eekddddddddddkke 
                 44 
                 1751 
               
               
                   
               
               
                 541718 
                 133724 
                 133739 
                 Intron 1 
                 GTACCATGAAGCTCTG 
                 eekddddddddddkke 
                 67 
                 1752 
               
               
                   
               
               
                 541719 
                 134086 
                 134101 
                 Intron 1 
                 CTTGGACTTGGACCAT 
                 eekddddddddddkke 
                 42 
                 1753 
               
               
                   
               
               
                 541720 
                 134441 
                 134456 
                 Intron 1 
                 GTGCATAGGGCCTGTC 
                 eekddddddddddkke 
                 42 
                 1754 
               
               
                   
               
               
                 541721 
                 135015 
                 135030 
                 Intron 1 
                 CCTCACCTGAACACCC 
                 eekddddddddddkke 
                 23 
                 1755 
               
               
                   
               
               
                 541722 
                 135859 
                 135874 
                 Intron 1 
                 ATGCCTCCCCGCAACT 
                 eekddddddddddkke 
                 27 
                 1756 
               
               
                   
               
               
                 541723 
                 136287 
                 136302 
                 Intron 1 
                 TTGTGCTTGGGTGTAC 
                 eekddddddddddkke 
                 39 
                 1757 
               
               
                   
               
               
                 541724 
                 137000 
                 137015 
                 Intron 1 
                 AGGCTTCATGTGAGGT 
                 eekddddddddddkke 
                 86 
                 1758 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 58 
               
             
            
               
                   
               
               
                 Inhibition of GHR mRNA by deoxy, MOE and cEt gapmers targeting introns 1 and 2 of SEQ ID NO: 2 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                 SEQ 
                 SEQ 
                   
                   
                   
                   
                   
               
               
                   
                 ID NO: 
                 ID NO: 
                   
                   
                   
                   
                   
               
               
                 ISIS 
                 2 Start 
                 2 Stop 
                 Target 
                   
                   
                 % 
                 SEQ 
               
               
                 NO 
                 Site 
                 Site 
                 Region 
                 Sequence 
                 Chemistry 
                 inhibition 
                 ID NO 
               
               
                   
               
               
                 541262 
                 156891 
                 156906 
                 Intron 2 
                 TTGGTTTGTCAATCCT 
                 eekddddddddddkke 
                 95 
                 1370 
               
               
                   
               
               
                 541725 
                 137372 
                 137387 
                 Intron 1 
                 TGTAAAAGGTCCTCCC 
                 eekddddddddddkke 
                 53 
                 1759 
               
               
                   
               
               
                 541726 
                 137750 
                 137765 
                 Intron 1 
                 GACCTGTGCAGCAGGT 
                 eekddddddddddkke 
                 32 
                 1760 
               
               
                   
               
               
                 541727 
                 138783 
                 138798 
                 Intron 1 
                 TCCTCTTGGAGATCCA 
                 eekddddddddddkke 
                 44 
                 1761 
               
               
                   
               
               
                 541728 
                 139825 
                 139840 
                 Intron 1 
                 AGGTCATAGGACTGCT 
                 eekddddddddddkke 
                 73 
                 1762 
               
               
                   
               
               
                 541729 
                 140343 
                 140358 
                 Intron 1 
                 GAAGGTCAGACTAGGG 
                 eekddddddddddkke 
                 53 
                 1763 
               
               
                   
               
               
                 541730 
                 140686 
                 140701 
                 Intron 1 
                 TCTGTAGACTGCCCAG 
                 eekddddddddddkke 
                 87 
                 1764 
               
               
                   
               
               
                 541731 
                 141116 
                 141131 
                 Intron 1 
                 GTCCCTCTATTCCCCT 
                 eekddddddddddkke 
                 57 
                 1765 
               
               
                   
               
               
                 541732 
                 141591 
                 141606 
                 Intron 1 
                 AATTGCCATGCTCCCA 
                 eekddddddddddkke 
                 56 
                 1766 
               
               
                   
               
               
                 541733 
                 142113 
                 142128 
                 Intron 1 
                 GATGACCTTCCTCCAA 
                 eekddddddddddkke 
                 15 
                 1767 
               
               
                   
               
               
                 541734 
                 142327 
                 142342 
                 Intron 1 
                 GTTTCCAGTAGCACCT 
                 eekddddddddddkke 
                 82 
                 1768 
               
               
                   
               
               
                 541735 
                 143118 
                 143133 
                 Intron 1 
                 GGCCTTGAGCTGATGG 
                 eekddddddddddkke 
                 11 
                 1769 
               
               
                   
               
               
                 541736 
                 143836 
                 143851 
                 Intron 1 
                 TATCCCTAATCAGGCT 
                 eekddddddddddkke 
                 40 
                 1770 
               
               
                   
               
               
                 541737 
                 144094 
                 144109 
                 Intron 1 
                 GGTGTCCACATCCCGG 
                 eekddddddddddkke 
                 58 
                 1771 
               
               
                   
               
               
                 541738 
                 144558 
                 144573 
                 Intron 1 
                 AGCTGGACAGGCCATA 
                 eekddddddddddkke 
                 27 
                 1772 
               
               
                   
               
               
                 541740 
                 145510 
                 145525 
                 Intron 2 
                 GGTAATCACCCAGAGA 
                 eekddddddddddkke 
                 90 
                 1773 
               
               
                   
               
               
                 541741 
                 145937 
                 145952 
                 Intron 2 
                 GCGCTAAGTCTGCTGT 
                 eekddddddddddkke 
                 92 
                 1774 
               
               
                   
               
               
                 541742 
                 146320 
                 146335 
                 Intron 2 
                 CCTCAAATCTTGCCCA 
                 eekddddddddddkke 
                 96 
                 1775 
               
               
                   
               
               
                 541743 
                 147028 
                 147043 
                 Intron 2 
                 ATCCAGACCTGGCAGA 
                 eekddddddddddkke 
                 84 
                 1776 
               
               
                   
               
               
                 541744 
                 147262 
                 147277 
                 Intron 2 
                 ATCCCTGCTCAAGTGC 
                 eekddddddddddkke 
                 89 
                 1777 
               
               
                   
               
               
                 541745 
                 147671 
                 147686 
                 Intron 2 
                 CAGGCACTCCTTGGAA 
                 eekddddddddddkke 
                 93 
                 1778 
               
               
                   
               
               
                 541746 
                 148139 
                 148154 
                 Intron 2 
                 AGCTGAGGTATCCCTC 
                 eekddddddddddkke 
                 94 
                 1779 
               
               
                   
               
               
                 541747 
                 148564 
                 148579 
                 Intron 2 
                 GGGCCCAGCAAGTCTT 
                 eekddddddddddkke 
                 33 
                 1780 
               
               
                   
               
               
                 541748 
                 149069 
                 149084 
                 Intron 2 
                 GTTTTGTCAGTGTGCA 
                 eekddddddddddkke 
                 98 
                 1781 
               
               
                   
               
               
                 541749 
                 149491 
                 149506 
                 Intron 2 
                 GTGACCTGCTGAACTC 
                 eekddddddddddkke 
                 95 
                 1782 
               
               
                   
               
               
                 541750 
                 150236 
                 150251 
                 Intron 2 
                 GGCTGAACTGTGCACC 
                 eekddddddddddkke 
                 95 
                 1783 
               
               
                   
               
               
                 541751 
                 150748 
                 150763 
                 Intron 2 
                 GGGTGGTCCCACTCCT 
                 eekddddddddddkke 
                 91 
                 1784 
               
               
                   
               
               
                 541752 
                 151124 
                 151139 
                 Intron 2 
                 GAGGAATCCTGGGCCC 
                 eekddddddddddkke 
                 94 
                 1785 
               
               
                   
               
               
                 541753 
                 151373 
                 151388 
                 Intron 2 
                 ATGACAAGCTAGGTGC 
                 eekddddddddddkke 
                 81 
                 1786 
               
               
                   
               
               
                 541754 
                 151644 
                 151659 
                 Intron 2 
                 TTGCCAGACAGGGCAC 
                 eekddddddddddkke 
                 18 
                 1787 
               
               
                   
               
               
                 541755 
                 152373 
                 152388 
                 Intron 2 
                 AGACCCCTCCCACTAT 
                 eekddddddddddkke 
                 43 
                 1788 
               
               
                   
               
               
                 541756 
                 152617 
                 152632 
                 Intron 2 
                 GGTGCTGGGTGACCGG 
                 eekddddddddddkke 
                 91 
                 1789 
               
               
                   
               
               
                 541757 
                 153349 
                 153364 
                 Intron 2 
                 GGCCAAACGGTGCCCT 
                 eekddddddddddkke 
                 23 
                 1790 
               
               
                   
               
               
                 541758 
                 153918 
                 153933 
                 Intron 2 
                 TGGGTGAATAGCAACC 
                 eekddddddddddkke 
                 85 
                 1791 
               
               
                   
               
               
                 541759 
                 154171 
                 154186 
                 Intron 2 
                 GCCCCCAAGGAAGTGA 
                 eekddddddddddkke 
                 76 
                 1792 
               
               
                   
               
               
                 541760 
                 154813 
                 154828 
                 Intron 2 
                 CAGGCTTCATGTGTGG 
                 eekddddddddddkke 
                 92 
                 1793 
               
               
                   
               
               
                 541761 
                 155289 
                 155304 
                 Intron 2 
                 CTGTCAGTGCTTTGGT 
                 eekddddddddddkke 
                 52 
                 1794 
               
               
                   
               
               
                 541762 
                 156233 
                 156248 
                 Intron 2 
                 GAGTACCCTGGCAGGT 
                 eekddddddddddkke 
                 58 
                 1795 
               
               
                   
               
               
                 541763 
                 156847 
                 156862 
                 Intron 2 
                 TAGCTAGCACCTGGGT 
                 eekddddddddddkke 
                 90 
                 1796 
               
               
                   
               
               
                 541764 
                 157552 
                 157567 
                 Intron 2 
                 GGCAAACCTTTGAGCC 
                 eekddddddddddkke 
                 27 
                 1797 
               
               
                   
               
               
                 541765 
                 157927 
                 157942 
                 Intron 2 
                 GCTATCATTGGAGCAG 
                 eekddddddddddkke 
                 94 
                 1798 
               
               
                   
               
               
                 541766 
                 158542 
                 158557 
                 Intron 2 
                 CCTCTGAGTACTCCCT 
                 eekddddddddddkke 
                 96 
                 1799 
               
               
                   
               
               
                 541767 
                 159252 
                 159267 
                 Intron 2 
                 AGCTGAAGGCAACCAG 
                 eekddddddddddkke 
                 97 
                 1800 
               
               
                   
               
               
                 541768 
                 159539 
                 159554 
                 Intron 2 
                 GGGCAGTTTTCCATAG 
                 eekddddddddddkke 
                 89 
                 1801 
               
               
                   
               
               
                 541769 
                 159778 
                 159793 
                 Intron 2 
                 GGTCCTACCTCTGACA 
                 eekddddddddddkke 
                 82 
                 1802 
               
               
                   
               
               
                 541770 
                 160352 
                 160367 
                 Intron 2 
                 GGCTGCCTTAGGGTGG 
                 eekddddddddddkke 
                 90 
                 1803 
               
               
                   
               
               
                 541771 
                 160812 
                 160827 
                 Intron 2 
                 CGCACCTCCCCCACTA 
                 eekddddddddddkke 
                 15 
                 1804 
               
               
                   
               
               
                 541772 
                 161461 
                 161476 
                 Intron 2 
                 GCTTATTGGTCCATGG 
                 eekddddddddddkke 
                 93 
                 1805 
               
               
                   
               
               
                 541773 
                 161821 
                 161836 
                 Intron 2 
                 AACCGCAGAGCCCCCA 
                 eekddddddddddkke 
                 76 
                 1806 
               
               
                   
               
               
                 541774 
                 162132 
                 162147 
                 Intron 2 
                 GGGCTTGTTCTGCCAA 
                 eekddddddddddkke 
                 33 
                 1807 
               
               
                   
               
               
                 541775 
                 162639 
                 162654 
                 Intron 2 
                 GGGACCTGCGCTGACT 
                 eekddddddddddkke 
                 86 
                 1808 
               
               
                   
               
               
                 541776 
                 163024 
                 163039 
                 Intron 2 
                 CTTTCACCTGGTGACT 
                 eekddddddddddkke 
                 83 
                 1809 
               
               
                   
               
               
                 541777 
                 163542 
                 163557 
                 Intron 2 
                 AGCTTGAGGGAGTATA 
                 eekddddddddddkke 
                 52 
                 1810 
               
               
                   
               
               
                 541778 
                 164144 
                 164159 
                 Intron 2 
                 GCCTGCTCAATTGAGG 
                 eekddddddddddkke 
                 32 
                 1811 
               
               
                   
               
               
                 541779 
                 164570 
                 164585 
                 Intron 2 
                 ATAGCAGCTGGCTGCC 
                 eekddddddddddkke 
                 24 
                 1812 
               
               
                   
               
               
                 541780 
                 165419 
                 165434 
                 Intron 2 
                 AAAAGCTTGGCACCCC 
                 eekddddddddddkke 
                 91 
                 1813 
               
               
                   
               
               
                 541781 
                 165859 
                 165874 
                 Intron 2 
                 CCTGGCAAGAAGGGCC 
                 eekddddddddddkke 
                 65 
                 1814 
               
               
                   
               
               
                 541782 
                 166435 
                 166450 
                 Intron 2 
                 TTAGCCCATCTATCCC 
                 eekddddddddddkke 
                 82 
                 1815 
               
               
                   
               
               
                 541783 
                 166837 
                 166852 
                 Intron 2 
                 GTGGTCTCCCTGTGCC 
                 eekddddddddddkke 
                 90 
                 1816 
               
               
                   
               
               
                 541784 
                 167107 
                 167122 
                 Intron 2 
                 AGCCCTCTCTGGCAAA 
                 eekddddddddddkke 
                 38 
                 1817 
               
               
                   
               
               
                 541785 
                 168004 
                 168019 
                 Intron 2 
                 TTACTGTGGCCCGAGT 
                 eekddddddddddkke 
                 94 
                 1818 
               
               
                   
               
               
                 541786 
                 169062 
                 169077 
                 Intron 2 
                 GTAGACTCCTAGGGTC 
                 eekddddddddddkke 
                 90 
                 1819 
               
               
                   
               
               
                 541787 
                 169696 
                 169711 
                 Intron 2 
                 CCTCCAGTTAGTGTGC 
                 eekddddddddddkke 
                 91 
                 1820 
               
               
                   
               
               
                 541788 
                 170081 
                 170096 
                 Intron 2 
                 GTGGGTGGCCAACAGG 
                 eekddddddddddkke 
                 91 
                 1821 
               
               
                   
               
               
                 541789 
                 170799 
                 170814 
                 Intron 2 
                 GGGATTCCCTGGTAGC 
                 eekddddddddddkke 
                 77 
                 1822 
               
               
                   
               
               
                 541790 
                 171021 
                 171036 
                 Intron 2 
                 GTGAGACCGGCCTTTG 
                 eekddddddddddkke 
                 23 
                 1823 
               
               
                   
               
               
                 541791 
                 171530 
                 171545 
                 Intron 2 
                 ACTGGCACCCACTTGG 
                 eekddddddddddkke 
                 54 
                 1824 
               
               
                   
               
               
                 541792 
                 172447 
                 172462 
                 Intron 2 
                 ATTGGCCTAATGCCCC 
                 eekddddddddddkke 
                 76 
                 1825 
               
               
                   
               
               
                 541793 
                 172733 
                 172748 
                 Intron 2 
                 AGGCTATACATTCCAG 
                 eekddddddddddkke 
                 94 
                 1826 
               
               
                   
               
               
                 541794 
                 173045 
                 173060 
                 Intron 2 
                 GGTGGCAGCTAGGTGG 
                 eekddddddddddkke 
                 80 
                 1827 
               
               
                   
               
               
                 541795 
                 173677 
                 173692 
                 Intron 2 
                 TCCACAGTTGGCACTG 
                 eekddddddddddkke 
                 77 
                 1828 
               
               
                   
               
               
                 541796 
                 174128 
                 174143 
                 Intron 2 
                 TGGGCCTTAGATTGTA 
                 eekddddddddddkke 
                 69 
                 1829 
               
               
                   
               
               
                 541797 
                 174521 
                 174536 
                 Intron 2 
                 TGTCTTCCTGGTGGCC 
                 eekddddddddddkke 
                 97 
                 1830 
               
               
                   
               
               
                 541798 
                 174870 
                 174885 
                 Intron 2 
                 CCCGCCTCTCCAGCAA 
                 eekddddddddddkke 
                 89 
                 1831 
               
               
                   
               
               
                 541799 
                 175275 
                 175290 
                 Intron 2 
                 GCAGCAGCCAATAAGT 
                 eekddddddddddkke 
                 76 
                 1832 
               
               
                   
               
               
                 541800 
                 175691 
                 175706 
                 Intron 2 
                 TTGTATCCTGGCCCCT 
                 eekddddddddddkke 
                 80 
                 1833 
               
               
                   
               
               
                 541801 
                 176038 
                 176053 
                 Intron 2 
                 GCCTCATGGGCCTTAC 
                 eekddddddddddkke 
                 66 
                 1834 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 59 
               
             
            
               
                   
               
               
                 Inhibition of GHR mRNA by deoxy, MOE and cEt gapmers targeting introns 2 and 3 of SEQ ID NO: 2 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                 SEQ 
                 SEQ ID 
                   
                   
                   
                   
                   
               
               
                   
                 ID NO: 
                 NO: 2 
                   
                   
                   
                   
                 SEQ 
               
               
                 ISIS 
                 2 Start 
                 Stop 
                 Target 
                   
                   
                 % 
                 ID 
               
               
                 NO 
                 Site 
                 Site 
                 Region 
                 Sequence 
                 Chemistry 
                 inhibition 
                 NO 
               
               
                   
               
               
                 541262 
                 156891 
                 156906 
                 Intron 2 
                 TTGGTTTGTCAATCCT 
                 eekddddddddddkke 
                 97 
                 1370 
               
               
                   
               
               
                 541802 
                 176619 
                 176634 
                 Intron 2 
                 GGATGCCAGTCTTGGC 
                 eekddddddddddkke 
                 48 
                 1835 
               
               
                   
               
               
                 541803 
                 176835 
                 176850 
                 Intron 2 
                 CTGCTCTCAGTACCTC 
                 eekddddddddddkke 
                 87 
                 1836 
               
               
                   
               
               
                 541804 
                 177300 
                 177315 
                 Intron 2 
                 ACCCAAGAAGTCACCT 
                 eekddddddddddkke 
                 93 
                 1837 
               
               
                   
               
               
                 541805 
                 177551 
                 177566 
                 Intron 2 
                 GCCTCAAGCCCTACCC 
                 eekddddddddddkke 
                 73 
                 1838 
               
               
                   
               
               
                 541806 
                 178066 
                 178081 
                 Intron 2 
                 AGCTCCAGCCTATAGA 
                 eekddddddddddkke 
                 81 
                 1839 
               
               
                   
               
               
                 541807 
                 178361 
                 178376 
                 Intron 2 
                 GGTCCACATGGCCCTA 
                 eekddddddddddkke 
                 90 
                 1840 
               
               
                   
               
               
                 541808 
                 178895 
                 178910 
                 Intron 2 
                 CAGGCCCAGGATTGTC 
                 eekddddddddddkke 
                 81 
                 1841 
               
               
                   
               
               
                 541809 
                 179444 
                 179459 
                 Intron 2 
                 GGGCCTGCTTTGCAGC 
                 eekddddddddddkke 
                 81 
                 1842 
               
               
                   
               
               
                 541810 
                 179863 
                 179878 
                 Intron 2 
                 ACTCCTCTCTTTAGGC 
                 eekddddddddddkke 
                 87 
                 1843 
               
               
                   
               
               
                 541811 
                 180524 
                 180539 
                 Intron 2 
                 CTGGGTAACAGTCCTC 
                 eekddddddddddkke 
                 98 
                 1844 
               
               
                   
               
               
                 541812 
                 181528 
                 181543 
                 Intron 2 
                 ACTGTATGGTTTCCAC 
                 eekddddddddddkke 
                 83 
                 1845 
               
               
                   
               
               
                 541813 
                 182103 
                 182118 
                 Intron 2 
                 GCCAAAGATAGCTCTT 
                 eekddddddddddkke 
                 94 
                 1846 
               
               
                   
               
               
                 541814 
                 182978 
                 182993 
                 Intron 2 
                 GGCATTGGAAGTTGGT 
                 eekddddddddddkke 
                 87 
                 1847 
               
               
                   
               
               
                 541815 
                 183193 
                 183208 
                 Intron 2 
                 CCCTTCCTGACCTTAC 
                 eekddddddddddkke 
                 55 
                 1848 
               
               
                   
               
               
                 541816 
                 183658 
                 183673 
                 Intron 2 
                 TTACCCTCTATTCACC 
                 eekddddddddddkke 
                 65 
                 1849 
               
               
                   
               
               
                 541818 
                 184501 
                 184516 
                 Intron 2 
                 GGCACCCCAGGCCGGG 
                 eekddddddddddkke 
                 25 
                 1850 
               
               
                   
               
               
                 541819 
                 185080 
                 185095 
                 Intron 2 
                 CAGCAGCTAGTTCCCC 
                 eekddddddddddkke 
                 96 
                 1851 
               
               
                   
               
               
                 541820 
                 185327 
                 185342 
                 Intron 2 
                 GTGGGCACTAGTGTGT 
                 eekddddddddddkke 
                 75 
                 1852 
               
               
                   
               
               
                 541821 
                 185682 
                 185697 
                 Intron 2 
                 TGCCCTTGTCAGGGCA 
                 eekddddddddddkke 
                 20 
                 1853 
               
               
                   
               
               
                 541822 
                 186025 
                 186040 
                 Intron 2 
                 GCAGATAGGCTCAGCA 
                 eekddddddddddkke 
                 98 
                 1854 
               
               
                   
               
               
                 541823 
                 186570 
                 186585 
                 Intron 2 
                 CCCTAGCCCTTAGCAC 
                 eekddddddddddkke 
                 44 
                 1855 
               
               
                   
               
               
                 541824 
                 186841 
                 186856 
                 Intron 2 
                 ACTGGAATGGCCCTCT 
                 eekddddddddddkke 
                 86 
                 1856 
               
               
                   
               
               
                 541825 
                 187176 
                 187191 
                 Intron 2 
                 TTTGCTCATGCTCACA 
                 eekddddddddddkke 
                 96 
                 1857 
               
               
                   
               
               
                 541826 
                 187629 
                 187644 
                 Intron 2 
                 GCCTTTGTGTGTCACT 
                 eekddddddddddkke 
                 99 
                 1858 
               
               
                   
               
               
                 541827 
                 187857 
                 187872 
                 Intron 2 
                 TATGTGGTAGCATGTC 
                 eekddddddddddkke 
                 96 
                 1859 
               
               
                   
               
               
                 541828 
                 188442 
                 188457 
                 Intron 2 
                 CCCCAGGAAGTTGGCC 
                 eekddddddddddkke 
                 68 
                 1860 
               
               
                   
               
               
                 541829 
                 189086 
                 189101 
                 Intron 2 
                 TAGCTGTCAAGGCCCT 
                 eekddddddddddkke 
                 90 
                 1861 
               
               
                   
               
               
                 541830 
                 189534 
                 189549 
                 Intron 2 
                 CCTAGTCAGCCACTAG 
                 eekddddddddddkke 
                 20 
                 1862 
               
               
                   
               
               
                 541831 
                 189889 
                 189904 
                 Intron 2 
                 AGACTCCCCATCAGCC 
                 eekddddddddddkke 
                 74 
                 1863 
               
               
                   
               
               
                 541832 
                 190172 
                 190187 
                 Intron 2 
                 GTGAAGGGCCTTCATC 
                 eekddddddddddkke 
                 68 
                 1864 
               
               
                   
               
               
                 541833 
                 190961 
                 190976 
                 Intron 2 
                 GGTTGAGAGTCCAATG 
                 eekddddddddddkke 
                 95 
                 1865 
               
               
                   
               
               
                 541834 
                 191404 
                 191419 
                 Intron 2 
                 CAGCTAATTCCCTCAT 
                 eekddddddddddkke 
                 79 
                 1866 
               
               
                   
               
               
                 541835 
                 191614 
                 191629 
                 Intron 2 
                 TTGTGTCTCAACCCAC 
                 eekddddddddddkke 
                 95 
                 1867 
               
               
                   
               
               
                 541836 
                 191999 
                 192014 
                 Intron 2 
                 GGCTATGCTGCATGCT 
                 eekddddddddddkke 
                 91 
                 1868 
               
               
                   
               
               
                 541837 
                 192860 
                 192875 
                 Intron 2 
                 CCCCATACCCAGTGGA 
                 eekddddddddddkke 
                 71 
                 1869 
               
               
                   
               
               
                 541838 
                 193460 
                 193475 
                 Intron 2 
                 GGTGGTTTTCCTCCCT 
                 eekddddddddddkke 
                 95 
                 1870 
               
               
                   
               
               
                 541839 
                 194144 
                 194159 
                 Intron 2 
                 GAGCCTGCCCAACTTT 
                 eekddddddddddkke 
                 90 
                 1871 
               
               
                   
               
               
                 541840 
                 194425 
                 194440 
                 Intron 2 
                 TGATGCCCAAGAGTGA 
                 eekddddddddddkke 
                 85 
                 1872 
               
               
                   
               
               
                 541841 
                 194953 
                 194968 
                 Intron 2 
                 TTCCCTCTGCGAACAT 
                 eekddddddddddkke 
                 96 
                 1873 
               
               
                   
               
               
                 541842 
                 195428 
                 195443 
                 Intron 2 
                 GTTCCATCTCAATCCA 
                 eekddddddddddkke 
                 94 
                 1874 
               
               
                   
               
               
                 541843 
                 196858 
                 196873 
                 Intron 2 
                 ACGGCCACTCCACTGG 
                 eekddddddddddkke 
                 44 
                 1875 
               
               
                   
               
               
                 541844 
                 197326 
                 197341 
                 Intron 2 
                 TGGAAGTGGTTCCAGA 
                 eekddddddddddkke 
                 90 
                 1876 
               
               
                   
               
               
                 541845 
                 197946 
                 197961 
                 Intron 2 
                 TTGCCCCAGACCAACA 
                 eekddddddddddkke 
                 47 
                 1877 
               
               
                   
               
               
                 541846 
                 198366 
                 198381 
                 Intron 2 
                 GAGGTTGTGGAGGTGC 
                 eekddddddddddkke 
                 26 
                 1878 
               
               
                   
               
               
                 541847 
                 198715 
                 198730 
                 Intron 2 
                 GAGTTGCTGTGTGTGA 
                 eekddddddddddkke 
                 83 
                 1879 
               
               
                   
               
               
                 541848 
                 198939 
                 198954 
                 Intron 2 
                 CATGTCAGAGGTGTCC 
                 eekddddddddddkke 
                 93 
                 1880 
               
               
                   
               
               
                 541849 
                 199506 
                 199521 
                 Intron 2 
                 AGGTAAGGATCATGGC 
                 eekddddddddddkke 
                 87 
                 1881 
               
               
                   
               
               
                 541850 
                 199816 
                 199831 
                 Intron 2 
                 GTTCAGTTGCATCACG 
                 eekddddddddddkke 
                 90 
                 1882 
               
               
                   
               
               
                 541851 
                 200249 
                 200264 
                 Intron 2 
                 GCCCAGCTAGCCACCC 
                 eekddddddddddkke 
                 68 
                 1883 
               
               
                   
               
               
                 541852 
                 201258 
                 201273 
                 Intron 2 
                 CCTTAGCAGCCAGGCC 
                 eekddddddddddkke 
                 86 
                 1884 
               
               
                   
               
               
                 541853 
                 202079 
                 202094 
                 Intron 2 
                 GCACTTAGGGTTTTGC 
                 eekddddddddddkke 
                 94 
                 1885 
               
               
                   
               
               
                 541854 
                 202382 
                 202397 
                 Intron 2 
                 GTTGAACTTTCCCTAC 
                 eekddddddddddkke 
                 53 
                 1886 
               
               
                   
               
               
                 541855 
                 202702 
                 202717 
                 Intron 2 
                 TGACTCCTTGAGACAG 
                 eekddddddddddkke 
                 83 
                 1887 
               
               
                   
               
               
                 541856 
                 203098 
                 203113 
                 Intron 2 
                 TGCGCTGGCTTAGCAA 
                 eekddddddddddkke 
                 59 
                 1888 
               
               
                   
               
               
                 541857 
                 203464 
                 203479 
                 Intron 2 
                 GGCCTAACATCAGCAG 
                 eekddddddddddkke 
                 88 
                 1889 
               
               
                   
               
               
                 541858 
                 204212 
                 204227 
                 Intron 2 
                 ACTCCTCCCAGTTAGC 
                 eekddddddddddkke 
                 70 
                 1890 
               
               
                   
               
               
                 541859 
                 205630 
                 205645 
                 Intron 2 
                 ACCAGTGGCCAATGTC 
                 eekddddddddddkke 
                 92 
                 1891 
               
               
                   
               
               
                 541861 
                 206422 
                 206437 
                 Intron 2 
                 GCCTAGACACAGTAGG 
                 eekddddddddddkke 
                 70 
                 1892 
               
               
                   
               
               
                 541862 
                 206749 
                 206764 
                 Intron 2 
                 TATTCTCCCCCTAGGG 
                 eekddddddddddkke 
                 42 
                 1893 
               
               
                   
               
               
                 541863 
                 207517 
                 207532 
                 Intron 2 
                 GACGGCCTTGGGCACA 
                 eekddddddddddkke 
                 96 
                 1894 
               
               
                   
                 210196 
                 210211 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 541865 
                 208659 
                 208674 
                 Intron 3 
                 GCAGGCTGTATTAGCA 
                 eekddddddddddkke 
                 15 
                 1895 
               
               
                   
               
               
                 541867 
                 209999 
                 210014 
                 Intron 3 
                 ACCCCCTATCCTGCAC 
                 eekddddddddddkke 
                 58 
                 1896 
               
               
                   
               
               
                 541868 
                 210281 
                 210296 
                 Intron 3 
                 TCCTCCATACCTAGAG 
                 eekddddddddddkke 
                 61 
                 1897 
               
               
                   
                 211033 
                 211048 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 541869 
                 210502 
                 210517 
                 Intron 3 
                 GATAGGTGCCCACTGT 
                 eekddddddddddkke 
                 80 
                 1898 
               
               
                   
               
               
                 541870 
                 210920 
                 210935 
                 Intron 3 
                 GTCAGTTCTGGCTAGG 
                 eekddddddddddkke 
                 97 
                 1899 
               
               
                   
               
               
                 541871 
                 211269 
                 211284 
                 Intron 3 
                 GCCTGAACTTACAAGC 
                 eekddddddddddkke 
                 68 
                 1900 
               
               
                   
               
               
                 541872 
                 211836 
                 211851 
                 Intron 3 
                 ACCCTGGGCTGACCTT 
                 eekddddddddddkke 
                 92 
                 1901 
               
               
                   
               
               
                 541873 
                 212606 
                 212621 
                 Intron 3 
                 GGACCTGGACAAGCAA 
                 eekddddddddddkke 
                 97 
                 1902 
               
               
                   
               
               
                 541874 
                 213099 
                 213114 
                 Intron 3 
                 CTCCTTGCGAGAGAGG 
                 eekddddddddddkke 
                  7 
                 1903 
               
               
                   
               
               
                 541875 
                 213425 
                 213440 
                 Intron 3 
                 AGAGTTGACATGGGCA 
                 eekddddddddddkke 
                 96 
                 1904 
               
               
                   
               
               
                 541876 
                 213846 
                 213861 
                 Intron 3 
                 CACTAGGTCCCTGACC 
                 eekddddddddddkke 
                 37 
                 1905 
               
               
                   
               
               
                 541877 
                 214483 
                 214498 
                 Intron 3 
                 CACTCTCTTGGGCTGT 
                 eekddddddddddkke 
                 94 
                 1906 
               
               
                   
               
               
                 541878 
                 214884 
                 214899 
                 Intron 3 
                 AGGGACCTGCATTCCA 
                 eekddddddddddkke 
                 72 
                 1907 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 60 
               
             
            
               
                   
               
               
                 Inhibition of GHR mRNA by deoxy, MOE and cEt gapmers targeting introns 2 and 3 of SEQ ID NO: 2 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                 SEQ ID 
                 SEQ 
                   
                   
                   
                   
                   
               
               
                   
                 NO: 2 
                 ID NO: 
                   
                   
                   
                   
                   
               
               
                 ISIS 
                 Start 
                 2 Stop 
                 Target 
                   
                   
                 % 
                 SEQ ID 
               
               
                 NO 
                 Site 
                 Site 
                 Region 
                 Sequence 
                 Chemistry 
                 inhibition 
                 NO 
               
               
                   
               
               
                 541262 
                 156891 
                 156906 
                 Intron 2 
                 TTGGTTTGTCAATCCT 
                 eekddddddddddkke 
                 91 
                 1370 
               
               
                   
               
               
                 541879 
                 215493 
                 215508 
                 Intron 3 
                 TTCACCACCCATTGGG 
                 eekddddddddddkke 
                 63 
                 1908 
               
               
                   
               
               
                 541880 
                 216192 
                 216207 
                 Intron 3 
                 ATCTGGTCTGAGGGCC 
                 eekddddddddddkke 
                 92 
                 1909 
               
               
                   
               
               
                 541881 
                 216458 
                 216473 
                 Intron 3 
                 GACATGCAATTGACCC 
                 eekddddddddddkke 
                 98 
                 1910 
               
               
                   
               
               
                 541882 
                 217580 
                 217595 
                 Intron 3 
                 GTGTGCAGCAGACTGT 
                 eekddddddddddkke 
                 92 
                 1911 
               
               
                   
               
               
                 541883 
                 218233 
                 218248 
                 Intron 3 
                 GACAGTCCAGCTGCAA 
                 eekddddddddddkke 
                 84 
                 1912 
               
               
                   
               
               
                 541884 
                 218526 
                 218541 
                 Intron 3 
                 CCTGCGGCAGTGAAGA 
                 eekddddddddddkke 
                 85 
                 1913 
               
               
                   
               
               
                 541885 
                 218734 
                 218749 
                 Intron 3 
                 CTCTGAGGATAACCCT 
                 eekddddddddddkke 
                 76 
                 1914 
               
               
                   
               
               
                 541886 
                 219342 
                 219357 
                 Intron 3 
                 GTTCCCAGCTCCCCAA 
                 eekddddddddddkke 
                 68 
                 1915 
               
               
                   
               
               
                 541887 
                 219618 
                 219633 
                 Intron 3 
                 TAGGGTCAGTGTCCCA 
                 eekddddddddddkke 
                 79 
                 1916 
               
               
                   
               
               
                 541888 
                 220039 
                 220054 
                 Intron 3 
                 GGCGAGCCTCTCAGCC 
                 eekddddddddddkke 
                 52 
                 1917 
               
               
                   
               
               
                 541889 
                 220393 
                 220408 
                 Intron 3 
                 GACTCATCCAGGCAGT 
                 eekddddddddddkke 
                 91 
                 1918 
               
               
                   
               
               
                 541890 
                 220665 
                 220680 
                 Intron 3 
                 TCCCTCCCTTAGGCAC 
                 eekddddddddddkke 
                 71 
                 1919 
               
               
                   
               
               
                 541891 
                 221044 
                 221059 
                 Intron 3 
                 GAGGAGCCAGGCATAT 
                 eekddddddddddkke 
                 80 
                 1920 
               
               
                   
               
               
                 541892 
                 221562 
                 221577 
                 Intron 3 
                 CACCAACGAAGTCCCC 
                 eekddddddddddkke 
                 89 
                 1921 
               
               
                   
               
               
                 541893 
                 221947 
                 221962 
                 Intron 3 
                 GCTGGCAGTCACCAAA 
                 eekddddddddddkke 
                 90 
                 1922 
               
               
                   
               
               
                 541894 
                 222569 
                 222584 
                 Intron 3 
                 GCCCACACCATTGAGC 
                 eekddddddddddkke 
                 70 
                 1923 
               
               
                   
               
               
                 541895 
                 222983 
                 222998 
                 Intron 3 
                 AGTGAGATGCCCTGGT 
                 eekddddddddddkke 
                 92 
                 1924 
               
               
                   
               
               
                 541896 
                 223436 
                 223451 
                 Intron 3 
                 CACTGGCAGTTAGACC 
                 eekddddddddddkke 
                 88 
                 1925 
               
               
                   
               
               
                 541897 
                 224107 
                 224122 
                 Intron 3 
                 ACTCTGGCCACTAGTA 
                 eekddddddddddkke 
                 80 
                 1926 
               
               
                   
               
               
                 541898 
                 224731 
                 224746 
                 Intron 3 
                 GGTAGGGTGGCCACAT 
                 eekddddddddddkke 
                 78 
                 1927 
               
               
                   
               
               
                 541899 
                 225133 
                 225148 
                 Intron 3 
                 GAGCCATGTCTAGGCA 
                 eekddddddddddkke 
                 18 
                 1928 
               
               
                   
               
               
                 541900 
                 225465 
                 225480 
                 Intron 3 
                 CAGACTGAAACCCACC 
                 eekddddddddddkke 
                 86 
                 1929 
               
               
                   
               
               
                 541901 
                 225671 
                 225686 
                 Intron 3 
                 TATGGTCCAGCCACCA 
                 eekddddddddddkke 
                 76 
                 1930 
               
               
                   
               
               
                 541902 
                 226110 
                 226125 
                 Intron 3 
                 TACCTCCTCTGTTGGT 
                 eekddddddddddkke 
                 36 
                 1931 
               
               
                   
               
               
                 541903 
                 227025 
                 227040 
                 Intron 3 
                 ACACCTCAGTCATGAT 
                 eekddddddddddkke 
                 92 
                 1932 
               
               
                   
               
               
                 541904 
                 227236 
                 227251 
                 Intron 3 
                 AACAGGCTTCAAGAGG 
                 eekddddddddddkke 
                 91 
                 1933 
               
               
                   
               
               
                 541905 
                 227485 
                 227500 
                 Intron 3 
                 GTACTACTGGCCATGT 
                 eekddddddddddkke 
                 73 
                 1934 
               
               
                   
               
               
                 541906 
                 227914 
                 227929 
                 Intron 3 
                 CTGCAGGCGGTTGCTA 
                 eekddddddddddkke 
                 60 
                 1935 
               
               
                   
               
               
                 541907 
                 228718 
                 228733 
                 Intron 3 
                 GTCTGTTGCCAAGAGC 
                 eekddddddddddkke 
                 95 
                 1936 
               
               
                   
               
               
                 541908 
                 229174 
                 229189 
                 Intron 3 
                 CCCTGGGTCACTTAAG 
                 eekddddddddddkke 
                 44 
                 1937 
               
               
                   
               
               
                 541909 
                 229423 
                 229438 
                 Intron 3 
                 CCTGTCCTTGCTTGCA 
                 eekddddddddddkke 
                 96 
                 1938 
               
               
                   
               
               
                 541910 
                 230042 
                 230057 
                 Intron 3 
                 GCCCAGCTTATCCTAA 
                 eekddddddddddkke 
                 78 
                 1939 
               
               
                   
               
               
                 541911 
                 230313 
                 230328 
                 Intron 3 
                 AGTAGAGCCTTTGCCT 
                 eekddddddddddkke 
                 75 
                 1940 
               
               
                   
               
               
                 541912 
                 230580 
                 230595 
                 Intron 3 
                 CTGTCTCTTGGCCCAT 
                 eekddddddddddkke 
                 80 
                 1941 
               
               
                   
               
               
                 541913 
                 231330 
                 231345 
                 Intron 3 
                 GGCCCAAATCTTGAGT 
                 eekddddddddddkke 
                 67 
                 1942 
               
               
                   
               
               
                 541914 
                 231817 
                 231832 
                 Intron 3 
                 GCTTGTTACAGCACTA 
                 eekddddddddddkke 
                 92 
                 1943 
               
               
                   
               
               
                 541915 
                 232088 
                 232103 
                 Intron 3 
                 ACTTTGGCCCAGAGAT 
                 eekddddddddddkke 
                 51 
                 1944 
               
               
                   
               
               
                 541916 
                 232884 
                 232899 
                 Intron 3 
                 GCAGTCAGGTCAGCTG 
                 eekddddddddddkke 
                 75 
                 1945 
               
               
                   
               
               
                 541917 
                 233210 
                 233225 
                 Intron 3 
                 GCCTTGTCCTACTACC 
                 eekddddddddddkke 
                 65 
                 1946 
               
               
                   
               
               
                 541918 
                 233657 
                 233672 
                 Intron 3 
                 GGCTCTGCTATTGGCC 
                 eekddddddddddkke 
                 59 
                 1947 
               
               
                   
               
               
                 541919 
                 233998 
                 234013 
                 Intron 3 
                 CTTATAGAGCCTTGCC 
                 eekddddddddddkke 
                 59 
                 1948 
               
               
                   
               
               
                 541920 
                 234296 
                 234311 
                 Intron 3 
                 GGAAGGGCCCAAATAT 
                 eekddddddddddkke 
                 15 
                 1949 
               
               
                   
               
               
                 541921 
                 234903 
                 234918 
                 Intron 3 
                 GATCTACTCCTACTGC 
                 eekddddddddddkke 
                 65 
                 1950 
               
               
                   
               
               
                 541922 
                 235313 
                 235328 
                 Intron 3 
                 GTCAGCCTGTGTCTGA 
                 eekddddddddddkke 
                 45 
                 1951 
               
               
                   
               
               
                 541923 
                 235770 
                 235785 
                 Intron 3 
                 AGCTTCCTCCTTACAC 
                 eekddddddddddkke 
                 54 
                 1952 
               
               
                   
               
               
                 541924 
                 236198 
                 236213 
                 Intron 3 
                 CTGCTAAGCCCCTACC 
                 eekddddddddddkke 
                 59 
                 1953 
               
               
                   
               
               
                 541925 
                 236684 
                 236699 
                 Intron 3 
                 AGAGGTCAGGTGCATA 
                 eekddddddddddkke 
                 77 
                 1954 
               
               
                   
               
               
                 541926 
                 237055 
                 237070 
                 Intron 3 
                 TTCAGCCTGGTTGGGA 
                 eekddddddddddkke 
                 71 
                 1955 
               
               
                   
               
               
                 541927 
                 237585 
                 237600 
                 Intron 3 
                 GATTGATTGAGCTCCT 
                 eekddddddddddkke 
                 86 
                 1956 
               
               
                   
               
               
                 541928 
                 237949 
                 237964 
                 Intron 3 
                 ATGGACTCCCTAGGCT 
                 eekddddddddddkke 
                 61 
                 1957 
               
               
                   
               
               
                 541929 
                 238542 
                 238557 
                 Intron 3 
                 TACTCAAGGGCCCCTC 
                 eekddddddddddkke 
                 67 
                 1958 
               
               
                   
               
               
                 541930 
                 245319 
                 245334 
                 Intron 3 
                 GGCATATGTAGCTTGC 
                 eekddddddddddkke 
                 91 
                 1959 
               
               
                   
               
               
                 541931 
                 245765 
                 245780 
                 Intron 3 
                 GAGCTTAGATCTGTGC 
                 eekddddddddddkke 
                 73 
                 1960 
               
               
                   
               
               
                 541932 
                 246251 
                 246266 
                 Intron 3 
                 ATGCTCACGGCTGTGT 
                 eekddddddddddkke 
                 81 
                 1961 
               
               
                   
               
               
                 541933 
                 246500 
                 246515 
                 Intron 3 
                 ATTGAAAGGCCCATCA 
                 eekddddddddddkke 
                 45 
                 1962 
               
               
                   
               
               
                 541934 
                 246936 
                 246951 
                 Intron 3 
                 CAACCCAGTTTGCCGG 
                 eekddddddddddkke 
                 71 
                 1963 
               
               
                   
               
               
                 541935 
                 247225 
                 247240 
                 Intron 3 
                 CAGCTATTCCCTGTTT 
                 eekddddddddddkke 
                 53 
                 1964 
               
               
                   
               
               
                 541936 
                 247644 
                 247659 
                 Intron 3 
                 GCTGTGTCACACTTCC 
                 eekddddddddddkke 
                 98 
                 1965 
               
               
                   
               
               
                 541937 
                 248223 
                 248238 
                 Intron 3 
                 GTCCAAGGATCACAGC 
                 eekddddddddddkke 
                 86 
                 1966 
               
               
                   
               
               
                 541938 
                 248695 
                 248710 
                 Intron 3 
                 GCTACCACTAGAGCCT 
                 eekddddddddddkke 
                 81 
                 1967 
               
               
                   
               
               
                 541939 
                 249494 
                 249509 
                 Intron 3 
                 GTTTCAGGGCTTATGT 
                 eekddddddddddkke 
                 63 
                 1968 
               
               
                   
               
               
                 541940 
                 250693 
                 250708 
                 Intron 3 
                 TCCCACACCTATTGAA 
                 eekddddddddddkke 
                 51 
                 1969 
               
               
                   
               
               
                 541941 
                 251622 
                 251637 
                 Intron 3 
                 ACTGACTAGAGAGTCC 
                 eekddddddddddkke 
                 81 
                 1970 
               
               
                   
               
               
                 541942 
                 251950 
                 251965 
                 Intron 3 
                 TCCAAGGCTGATGTCC 
                 eekddddddddddkke 
                 85 
                 1971 
               
               
                   
               
               
                 541943 
                 252665 
                 252680 
                 Intron 3 
                 TCCCATGGTGGACATG 
                 eekddddddddddkke 
                 39 
                 1972 
               
               
                   
               
               
                 541944 
                 253140 
                 253155 
                 Intron 3 
                 AGTAGCTGGCAGAAGG 
                 eekddddddddddkke 
                 85 
                 1973 
               
               
                   
               
               
                 541945 
                 253594 
                 253609 
                 Intron 3 
                 CTGGGAGTGACTACTA 
                 eekddddddddddkke 
                 77 
                 1974 
               
               
                   
               
               
                 541946 
                 254036 
                 254051 
                 Intron 3 
                 TGGTATAGCTACTGGG 
                 eekddddddddddkke 
                 84 
                 1975 
               
               
                   
               
               
                 541947 
                 254905 
                 254920 
                 Intron 3 
                 CTGTGGTTTGGCAGGT 
                 eekddddddddddkke 
                 90 
                 1976 
               
               
                   
               
               
                 541948 
                 255407 
                 255422 
                 Intron 3 
                 GTTCTCACCTGAACTA 
                 eekddddddddddkke 
                 65 
                 1977 
               
               
                   
               
               
                 541949 
                 255618 
                 255633 
                 Intron 3 
                 ATAGGCTACTGGCAGG 
                 eekddddddddddkke 
                 89 
                 1978 
               
               
                   
               
               
                 541950 
                 255992 
                 256007 
                 Intron 3 
                 CCCAGCTAGCTGGAGT 
                 eekddddddddddkke 
                 50 
                 1979 
               
               
                   
               
               
                 541951 
                 256428 
                 256443 
                 Intron 3 
                 GGCTGGCTCTCAAAGG 
                 eekddddddddddkke 
                 61 
                 1980 
               
               
                   
               
               
                 541952 
                 256689 
                 256704 
                 Intron 3 
                 TGGTGATACTGTGGCA 
                 eekddddddddddkke 
                 94 
                 1981 
               
               
                   
               
               
                 541953 
                 257317 
                 257332 
                 Intron 3 
                 GCTGATTTTGGTGCCA 
                 eekddddddddddkke 
                 92 
                 1982 
               
               
                   
               
               
                 541954 
                 257826 
                 257841 
                 Intron 3 
                 GCTAATCTTGCCTCGA 
                 eekddddddddddkke 
                 52 
                 1983 
               
               
                   
               
               
                 541955 
                 258407 
                 258422 
                 Intron 3 
                 CACTGGTGGCTTTCAA 
                 eekddddddddddkke 
                 31 
                 1984 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 61 
               
             
            
               
                   
               
               
                 Inhibition of GHR mRNA by deoxy, MOE and cEt gapmers targeting intronic and exonic regions 
               
               
                 of SEQ ID NOs: 1 and 2 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                 SEQ 
                   
                   
                   
                   
                 SEQ ID 
                   
               
               
                   
                 ID NO: 
                   
                   
                   
                   
                 NO: 2 
                 SEQ 
               
               
                 ISIS 
                 1 Start 
                 Target 
                   
                   
                 % 
                 Start 
                 ID 
               
               
                 NO 
                 Site 
                 Region 
                 Sequence 
                 Chemistry 
                 inhibition 
                 Site 
                 NO 
               
               
                   
               
               
                 541262 
                 n/a 
                 Intron 2 
                 TTGGTTTGTCAATCCT 
                 eekddddddddddkke 
                 93 
                 156891 
                 1370 
               
               
                   
               
               
                 541956 
                 n/a 
                 Intron 3 
                 GTCCCCTTCTTAAGCA 
                 eekddddddddddkke 
                 56 
                 258980 
                 1985 
               
               
                   
               
               
                 541957 
                 n/a 
                 Intron 3 
                 GCCAGGCCAACTGTGG 
                 eekddddddddddkke 
                 53 
                 259290 
                 1986 
               
               
                   
               
               
                 541958 
                 n/a 
                 Intron 3 
                 GGCCCGTTATGGTGGA 
                 eekddddddddddkke 
                 72 
                 259500 
                 1987 
               
               
                   
               
               
                 541959 
                 n/a 
                 Intron 3 
                 CCTAAAGTCCAACTCC 
                 eekddddddddddkke 
                 76 
                 261641 
                 1988 
               
               
                   
               
               
                 541960 
                 n/a 
                 Intron 3 
                 CCCTATCCAGCCTTCA 
                 eekddddddddddkke 
                 77 
                 262021 
                 1989 
               
               
                   
               
               
                 541961 
                 n/a 
                 Intron 3 
                 AAGCATGGCCTCTGGC 
                 eekddddddddddkke 
                 23 
                 262453 
                 1990 
               
               
                   
               
               
                 541962 
                 n/a 
                 Intron 3 
                 TACCCTGCACCCTCCT 
                 eekddddddddddkke 
                 71 
                 262764 
                 1991 
               
               
                   
               
               
                 541963 
                 n/a 
                 Intron 3 
                 TCCTTAGTAGAATGCC 
                 eekddddddddddkke 
                 82 
                 263342 
                 1992 
               
               
                   
               
               
                 541964 
                 n/a 
                 Intron 3 
                 TTAGCCCTGGGAGCAC 
                 eekddddddddddkke 
                 78 
                 263913 
                 1993 
               
               
                   
               
               
                 541965 
                 n/a 
                 Intron 3 
                 GCTGGGTCAGGTAGCG 
                 eekddddddddddkke 
                 71 
                 266503 
                 1994 
               
               
                   
               
               
                 541966 
                 n/a 
                 Intron 3 
                 GGGAGGCTCTCAATCT 
                 eekddddddddddkke 
                 75 
                 266861 
                 1995 
               
               
                   
               
               
                 541967 
                 n/a 
                 Intron 3 
                 GTAAGTGCAGAATGCC 
                 eekddddddddddkke 
                 87 
                 267116 
                 1996 
               
               
                   
               
               
                 541968 
                 n/a 
                 Intron 3 
                 TGCCGAGGCAGGCACC 
                 eekddddddddddkke 
                 33 
                 267380 
                 1997 
               
               
                   
               
               
                 541969 
                 n/a 
                 Intron 3 
                 TCCGTGTCTAGGAGGT 
                 eekddddddddddkke 
                 84 
                 267865 
                 1998 
               
               
                   
               
               
                 541970 
                 n/a 
                 Intron 4 
                 GTCTCCCTGCATTGGA 
                 eekddddddddddkke 
                 31 
                 268366 
                 1999 
               
               
                   
               
               
                 541971 
                 n/a 
                 Intron 4 
                 CCATATCACTCTCCTC 
                 eekddddddddddkke 
                 79 
                 268786 
                 2000 
               
               
                   
               
               
                 541972 
                 n/a 
                 Intron 4 
                 CGAACACCTTGAGCCA 
                 eekddddddddddkke 
                 90 
                 269252 
                 2001 
               
               
                   
               
               
                 541973 
                 n/a 
                 Intron 4 
                 GGCCCAGCTTAAGAGG 
                 eekddddddddddkke 
                 59 
                 270038 
                 2002 
               
               
                   
               
               
                 541974 
                 n/a 
                 Intron 4 
                 CTGATACTCCTAATCC 
                 eekddddddddddkke 
                 70 
                 270501 
                 2003 
               
               
                   
               
               
                 541975 
                 n/a 
                 Intron 4 
                 GCCTGTAGGGCTGTGC 
                 eekddddddddddkke 
                 82 
                 270817 
                 2004 
               
               
                   
               
               
                 541976 
                 n/a 
                 Intron 4 
                 TGCCCTTTCTCCCTAC 
                 eekddddddddddkke 
                 87 
                 271216 
                 2005 
               
               
                   
               
               
                 541977 
                 n/a 
                 Intron 4 
                 AGTGCATGTCAGTACC 
                 eekddddddddddkke 
                 75 
                 271812 
                 2006 
               
               
                   
               
               
                 541978 
                 n/a 
                 Intron 4 
                 TGCTCCTCAGCTGTTG 
                 eekddddddddddkke 
                 44 
                 272631 
                 2007 
               
               
                   
               
               
                 541979 
                 n/a 
                 Intron 4 
                 GTTTGGGACCATCCCT 
                 eekddddddddddkke 
                 41 
                 272834 
                 2008 
               
               
                   
               
               
                 541980 
                 n/a 
                 Intron 4 
                 AGTGCTCTCTAGGGTC 
                 eekddddddddddkke 
                 87 
                 273257 
                 2009 
               
               
                   
               
               
                 541981 
                 n/a 
                 Intron 4 
                 TACAGAGAATCACCCC 
                 eekddddddddddkke 
                 82 
                 273651 
                 2010 
               
               
                   
               
               
                 541982 
                 n/a 
                 Intron 4 
                 GTCCAAGTAAGGTGCT 
                 eekddddddddddkke 
                 57 
                 273947 
                 2011 
               
               
                   
               
               
                 541983 
                 n/a 
                 Intron 5 
                 GACCTTGCAGGCTTCC 
                 eekddddddddddkke 
                 87 
                 274244 
                 2012 
               
               
                   
               
               
                 541984 
                 n/a 
                 Intron 5 
                 GGGCAAAGGATCCTCT 
                 eekddddddddddkke 
                 71 
                 274758 
                 2013 
               
               
                   
               
               
                 541985 
                 n/a 
                 Intron 5 
                 CCCATTCTGCTATCCC 
                 eekddddddddddkke 
                 92 
                 275198 
                 2014 
               
               
                   
               
               
                 541986 
                 n/a 
                 Intron 5 
                 GCTGACTAGGAGGGCT 
                 eekddddddddddkke 
                 62 
                 275732 
                 2015 
               
               
                   
               
               
                 541987 
                 n/a 
                 Intron 5 
                 CCTGTGAGGTAGTACC 
                 eekddddddddddkke 
                 83 
                 276309 
                 2016 
               
               
                   
               
               
                 541988 
                 n/a 
                 Intron 5 
                 GTCCCCCTCCAGTCTA 
                 eekddddddddddkke 
                 50 
                 276932 
                 2017 
               
               
                   
               
               
                 541989 
                 n/a 
                 Intron 5 
                 GAGGACTCAATTCCTC 
                 eekddddddddddkke 
                  0 
                 277149 
                 2018 
               
               
                   
               
               
                 541990 
                 n/a 
                 Intron 5 
                 GACAAGGTCCTTTTGG 
                 eekddddddddddkke 
                 43 
                 277391 
                 2019 
               
               
                   
               
               
                 541991 
                 n/a 
                 Intron 5 
                 GCTCTTGTGTGCACCC 
                 eekddddddddddkke 
                 90 
                 277730 
                 2020 
               
               
                   
               
               
                 541992 
                 n/a 
                 Intron 5 
                 TCACCGCCTGCACCAC 
                 eekddddddddddkke 
                 75 
                 278342 
                 2021 
               
               
                   
               
               
                 541993 
                 n/a 
                 Intron 5 
                 GGTTGCACTGTGCAAT 
                 eekddddddddddkke 
                 26 
                 278917 
                 2022 
               
               
                   
               
               
                 541994 
                 n/a 
                 Intron 6 
                 TTCCACAGGCCTCCAT 
                 eekddddddddddkke 
                 64 
                 279303 
                 2023 
               
               
                   
               
               
                 541995 
                 n/a 
                 Intron 6 
                 GCTGAGTTCCATATGC 
                 eekddddddddddkke 
                 72 
                 279679 
                 2024 
               
               
                   
               
               
                 541996 
                 n/a 
                 Intron 6 
                 GAACCGCCACCTCAGG 
                 eekddddddddddkke 
                 38 
                 280157 
                 2025 
               
               
                   
               
               
                 541997 
                 n/a 
                 Intron 6 
                 GCTCACGGTTGGAGAC 
                 eekddddddddddkke 
                 42 
                 280799 
                 2026 
               
               
                   
               
               
                 541998 
                 n/a 
                 Intron 6 
                 TGGGCTCCCATGTTCA 
                 eekddddddddddkke 
                 45 
                 281595 
                 2027 
               
               
                   
               
               
                 541999 
                 n/a 
                 Intron 6 
                 TCACTCTACCAACCTC 
                 eekddddddddddkke 
                 33 
                 282572 
                 2028 
               
               
                   
               
               
                 542000 
                 n/a 
                 Intron 6 
                 TCCTTGCTTACAGATG 
                 eekddddddddddkke 
                 33 
                 283079 
                 2029 
               
               
                   
               
               
                 542001 
                 n/a 
                 Intron 6 
                 TGATGCTAGCATTACC 
                 eekddddddddddkke 
                 37 
                 283653 
                 2030 
               
               
                   
               
               
                 542002 
                 n/a 
                 Intron 6 
                 TGGGTAACTGGCTAGT 
                 eekddddddddddkke 
                 47 
                 285711 
                 2031 
               
               
                   
               
               
                 542003 
                 n/a 
                 Intron 6 
                 AACCATTCCTCACCAA 
                 eekddddddddddkke 
                 53 
                 287181 
                 2032 
               
               
                   
               
               
                 542004 
                 n/a 
                 Intron 6 
                 GCCCTGAACAGTTGAT 
                 eekddddddddddkke 
                 37 
                 287895 
                 2033 
               
               
                   
               
               
                 542005 
                 n/a 
                 Intron 6 
                 GGCTCCTATCATACCT 
                 eekddddddddddkke 
                 38 
                 288943 
                 2034 
               
               
                   
               
               
                 542006 
                 n/a 
                 Intron 6 
                 TAGGTCTCACAACCCT 
                 eekddddddddddkke 
                 10 
                 289638 
                 2035 
               
               
                   
               
               
                 542007 
                 n/a 
                 Intron 6 
                 GTGCATTAGTCTTCCA 
                 eekddddddddddkke 
                 74 
                 290035 
                 2036 
               
               
                   
               
               
                 542008 
                 n/a 
                 Intron 7 
                 CAAAAGCCAGGTTAGC 
                 eekddddddddddkke 
                 13 
                 290503 
                 2037 
               
               
                   
               
               
                 542009 
                 n/a 
                 Intron 7 
                 CTGCTGTTGACTACCT 
                 eekddddddddddkke 
                 50 
                 290924 
                 2038 
               
               
                   
               
               
                 542010 
                 n/a 
                 Intron 7 
                 GTACCTGCCAGCTACT 
                 eekddddddddddkke 
                 35 
                 291807 
                 2039 
               
               
                   
               
               
                 542011 
                 n/a 
                 Exon 8- 
                 CCTACCTTTGCTGTTT 
                 eekddddddddddkke 
                 12 
                 292611 
                 2040 
               
               
                   
                   
                 intron 8 
                   
                   
                   
                   
                   
               
               
                   
                   
                 junction 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 542012 
                 n/a 
                 Intron 8 
                 AGTCACCAGCCTAAGC 
                 eekddddddddddkke 
                 47 
                 292860 
                 2041 
               
               
                   
               
               
                 542013 
                 n/a 
                 Intron 8 
                 AGGCAACCTGGGAGTG 
                 eekddddddddddkke 
                 52 
                 293377 
                 2042 
               
               
                   
               
               
                 542014 
                 n/a 
                 Intron 8 
                 TGGCCTTCACAATGGC 
                 eekddddddddddkke 
                 33 
                 294052 
                 2043 
               
               
                   
               
               
                 542015 
                 n/a 
                 Intron 8 
                 GGTGAAGTGGGTTGGA 
                 eekddddddddddkke 
                 27 
                 294536 
                 2044 
               
               
                   
               
               
                 542016 
                 n/a 
                 Intron 8 
                 GCTGGTTGTCTGCTGC 
                 eekddddddddddkke 
                 60 
                 294931 
                 2045 
               
               
                   
               
               
                 542017 
                 n/a 
                 Intron 8 
                 AGTTTGTGACCCCTGC 
                 eekddddddddddkke 
                 81 
                 295475 
                 2046 
               
               
                   
               
               
                 542018 
                 n/a 
                 Intron 8 
                 CCACTCAGTGTGAATG 
                 eekddddddddddkke 
                 85 
                 295955 
                 2047 
               
               
                   
               
               
                 542019 
                 n/a 
                 Intron 8 
                 CTGGCCTCAGGGCAAT 
                 eekddddddddddkke 
                 51 
                 296186 
                 2048 
               
               
                   
               
               
                 542020 
                 n/a 
                 Intron 8 
                 GTAGACTTGGGTAGGT 
                 eekddddddddddkke 
                 53 
                 296680 
                 2049 
               
               
                   
               
               
                 542022 
                 n/a 
                 3&#39;UTR 
                 TGGTGCTAAGCTCTCC 
                 eekddddddddddkke 
                 67 
                 301009 
                 2050 
               
               
                   
               
               
                 542023 
                 n/a 
                 3&#39;UTR 
                 CATGCTCAAGCTGGAA 
                 eekddddddddddkke 
                 47 
                 301280 
                 2051 
               
               
                   
               
               
                 542024 
                 206 
                 Exon 2 
                 AAGGTCAACAGCAGCT 
                 eekddddddddddkke 
                 93 
                 144990 
                 2052 
               
               
                   
               
               
                 542025 
                 207 
                 Exon 2 
                 CAAGGTCAACAGCAGC 
                 eekddddddddddkke 
                 85 
                 144991 
                 2053 
               
               
                   
               
               
                 542026 
                 208 
                 Exon 2 
                 CCAAGGTCAACAGCAG 
                 eekddddddddddkke 
                 82 
                 144992 
                 2054 
               
               
                   
               
               
                 542027 
                 209 
                 Exon 2 
                 GCCAAGGTCAACAGCA 
                 eekddddddddddkke 
                 84 
                 144993 
                 2055 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 62 
               
             
            
               
                   
               
               
                 Inhibition of GHR mRNA by deoxy, MOE and cEt gapmers targeting intronic and exonic regions 
               
               
                 of SEQ ID NOs: 1 and 2 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                 SEQ 
                   
                   
                   
                   
                 SEQ ID 
                   
               
               
                   
                 ID NO: 
                   
                   
                   
                   
                 NO: 2 
                   
               
               
                 ISIS 
                 1 Start 
                 Target 
                   
                   
                 % 
                 Start 
                 SEQ 
               
               
                 NO 
                 Site 
                 Region 
                 Sequence 
                 Chemistry 
                 inhibition 
                 Site 
                 ID NO 
               
               
                   
               
               
                 541262 
                 n/a 
                 Intron 2 
                 TTGGTTTGTCAATCCT 
                 eekddddddddddkke 
                 86 
                 156891 
                 1370 
               
               
                   
               
               
                 542034 
                 870 
                 Exon 7 
                 TCTCACACGCACTTCA 
                 eekddddddddddkke 
                 49 
                 290368 
                 2056 
               
               
                   
               
               
                 542035 
                 871 
                 Exon 7 
                 ATCTCACACGCACTTC 
                 eekddddddddddkke 
                 39 
                 290369 
                 2057 
               
               
                   
               
               
                 542036 
                 872 
                 Exon 7 
                 GATCTCACACGCACTT 
                 eekddddddddddkke 
                 50 
                 290370 
                 2058 
               
               
                   
               
               
                 542049 
                 n/a 
                 Intron 1 
                 CTTTCATGAATCAAGC 
                 eekddddddddddkke 
                 85 
                 17928 
                 2059 
               
               
                   
               
               
                 542050 
                 n/a 
                 Intron 1 
                 TCTTTCATGAATCAAG 
                 eekddddddddddkke 
                 54 
                 17929 
                 2060 
               
               
                   
               
               
                 542051 
                 n/a 
                 Intron 1 
                 GTCTTTCATGAATCAA 
                 eekddddddddddkke 
                 96 
                 17930 
                 2061 
               
               
                   
               
               
                 542052 
                 n/a 
                 Intron 1 
                 GGTCTTTCATGAATCA 
                 eekddddddddddkke 
                 98 
                 17931 
                 2062 
               
               
                   
               
               
                 542053 
                 n/a 
                 Intron 1 
                 ATGGTCTTTCATGAAT 
                 eekddddddddddkke 
                 94 
                 17933 
                 2063 
               
               
                   
               
               
                 542054 
                 n/a 
                 Intron 1 
                 GATGGTCTTTCATGAA 
                 eekddddddddddkke 
                 73 
                 17934 
                 2064 
               
               
                   
               
               
                 542055 
                 n/a 
                 Intron 1 
                 TGATGGTCTTTCATGA 
                 eekddddddddddkke 
                 83 
                 17935 
                 2065 
               
               
                   
               
               
                 542056 
                 n/a 
                 Intron 1 
                 TATATCAATATTCTCC 
                 eekddddddddddkke 
                 75 
                 21821 
                 2066 
               
               
                   
               
               
                 542057 
                 n/a 
                 Intron 1 
                 TTATATCAATATTCTC 
                 eekddddddddddkke 
                 23 
                 21822 
                 2067 
               
               
                   
               
               
                 542058 
                 n/a 
                 Intron 1 
                 GTTATATCAATATTCT 
                 eekddddddddddkke 
                 87 
                 21823 
                 2068 
               
               
                   
               
               
                 542059 
                 n/a 
                 Intron 1 
                 TTTCTTTAGCAATAGT 
                 eekddddddddddkke 
                 85 
                 22519 
                 2069 
               
               
                   
               
               
                 542060 
                 n/a 
                 Intron 1 
                 CTTTCTTTAGCAATAG 
                 eekddddddddddkke 
                 81 
                 22520 
                 2070 
               
               
                   
               
               
                 542061 
                 n/a 
                 Intron 1 
                 GCTTTCTTTAGCAATA 
                 eekddddddddddkke 
                 68 
                 22521 
                 2071 
               
               
                   
               
               
                 542062 
                 n/a 
                 Intron 1 
                 CTCCATTAGGGTTCTG 
                 eekddddddddddkke 
                 91 
                 50948 
                 2072 
               
               
                   
               
               
                 542063 
                 n/a 
                 Intron 1 
                 TCTCCATTAGGGTTCT 
                 eekddddddddddkke 
                 88 
                 50949 
                 2073 
               
               
                   
               
               
                 542064 
                 n/a 
                 Intron 1 
                 TTCTCCATTAGGGTTC 
                 eekddddddddddkke 
                 85 
                 50950 
                 2074 
               
               
                   
               
               
                 542065 
                 n/a 
                 Intron 1 
                 GTTCTCCATTAGGGTT 
                 eekddddddddddkke 
                 84 
                 50951 
                 2075 
               
               
                   
               
               
                 542066 
                 n/a 
                 Intron 1 
                 AGGTTGGCAGACAGAC 
                 eekddddddddddkke 
                 92 
                 53467 
                 2076 
               
               
                   
               
               
                 542067 
                 n/a 
                 Intron 1 
                 CAGGTTGGCAGACAGA 
                 eekddddddddddkke 
                 93 
                 53468 
                 2077 
               
               
                   
               
               
                 542068 
                 n/a 
                 Intron 1 
                 GCAGGTTGGCAGACAG 
                 eekddddddddddkke 
                 91 
                 53469 
                 2078 
               
               
                   
               
               
                 542069 
                 n/a 
                 Intron 1 
                 CTTCTTGTGAGCTGGC 
                 eekddddddddddkke 
                 95 
                 64885 
                 2079 
               
               
                   
               
               
                 542070 
                 n/a 
                 Intron 1 
                 TCTTCTTGTGAGCTGG 
                 eekddddddddddkke 
                 89 
                 64886 
                 2080 
               
               
                   
               
               
                 542071 
                 n/a 
                 Intron 1 
                 GTCTTCTTGTGAGCTG 
                 eekddddddddddkke 
                 96 
                 64887 
                 2081 
               
               
                   
               
               
                 542072 
                 n/a 
                 Intron 1 
                 AGTCTTCTTGTGAGCT 
                 eekddddddddddkke 
                 81 
                 64888 
                 2082 
               
               
                   
               
               
                 542073 
                 n/a 
                 Intron 1 
                 TCTTCCACTCACATCC 
                 eekddddddddddkke 
                 89 
                 65991 
                 2083 
               
               
                   
               
               
                 542074 
                 n/a 
                 Intron 1 
                 CTCTTCCACTCACATC 
                 eekddddddddddkke 
                 79 
                 65992 
                 2084 
               
               
                   
               
               
                 542075 
                 n/a 
                 Intron 1 
                 TCTCTTCCACTCACAT 
                 eekddddddddddkke 
                 86 
                 65993 
                 2085 
               
               
                   
               
               
                 542076 
                 n/a 
                 Intron 1 
                 GTCTCTTCCACTCACA 
                 eekddddddddddkke 
                 92 
                 65994 
                 2086 
               
               
                   
               
               
                 542077 
                 n/a 
                 Intron 1 
                 ATAGATTTTGACTTCC 
                 eekddddddddddkke 
                 86 
                 72108 
                 2087 
               
               
                   
               
               
                 542078 
                 n/a 
                 Intron 1 
                 CATAGATTTTGACTTC 
                 eekddddddddddkke 
                 42 
                 72109 
                 2088 
               
               
                   
               
               
                 542079 
                 n/a 
                 Intron 1 
                 GCATAGATTTTGACTT 
                 eekddddddddddkke 
                 66 
                 72110 
                 2089 
               
               
                   
               
               
                 542080 
                 n/a 
                 Intron 1 
                 AAATGTCAACAGTGCA 
                 eekddddddddddkke 
                 97 
                 80639 
                 2090 
               
               
                   
               
               
                 542081 
                 n/a 
                 Intron 1 
                 CATGACTATGTTCTGG 
                 eekddddddddddkke 
                 68 
                 125595 
                 2091 
               
               
                   
               
               
                 542082 
                 n/a 
                 Intron 1 
                 ACATGACTATGTTCTG 
                 eekddddddddddkke 
                 66 
                 125596 
                 2092 
               
               
                   
               
               
                 542083 
                 n/a 
                 Intron 1 
                 CACATGACTATGTTCT 
                 eekddddddddddkke 
                 74 
                 125597 
                 2093 
               
               
                   
               
               
                 542084 
                 n/a 
                 Intron 2 
                 GAATTCTGAGCTCTGG 
                 eekddddddddddkke 
                 91 
                 145430 
                 2094 
               
               
                   
               
               
                 542085 
                 n/a 
                 Intron 2 
                 TGAATTCTGAGCTCTG 
                 eekddddddddddkke 
                 94 
                 145431 
                 2095 
               
               
                   
               
               
                 542086 
                 n/a 
                 Intron 2 
                 CTGAATTCTGAGCTCT 
                 eekddddddddddkke 
                 94 
                 145432 
                 2096 
               
               
                   
               
               
                 542087 
                 n/a 
                 Intron 2 
                 CCTGAATTCTGAGCTC 
                 eekddddddddddkke 
                 93 
                 145433 
                 2097 
               
               
                   
               
               
                 542088 
                 n/a 
                 Intron 2 
                 GCCTGAATTCTGAGCT 
                 eekddddddddddkke 
                 87 
                 145434 
                 2098 
               
               
                   
               
               
                 542089 
                 n/a 
                 Intron 2 
                 AGCCTGAATTCTGAGC 
                 eekddddddddddkke 
                 84 
                 145435 
                 2099 
               
               
                   
               
               
                 542090 
                 n/a 
                 Intron 2 
                 ATATTGTAATTCTTGG 
                 eekddddddddddkke 
                 47 
                 148060 
                 2100 
               
               
                   
               
               
                 542091 
                 n/a 
                 Intron 2 
                 GATATTGTAATTCTTG 
                 eekddddddddddkke 
                 61 
                 148061 
                 2101 
               
               
                   
               
               
                 542092 
                 n/a 
                 Intron 2 
                 TGATATTGTAATTCTT 
                 eekddddddddddkke 
                  0 
                 148062 
                 2102 
               
               
                   
               
               
                 542093 
                 n/a 
                 Intron 2 
                 CTGATATTGTAATTCT 
                 eekddddddddddkke 
                 58 
                 148063 
                 2103 
               
               
                   
               
               
                 542094 
                 n/a 
                 Intron 2 
                 CCTGATATTGTAATTC 
                 eekddddddddddkke 
                 95 
                 148064 
                 2104 
               
               
                   
               
               
                 542095 
                 n/a 
                 Intron 2 
                 GCCTGATATTGTAATT 
                 eekddddddddddkke 
                 85 
                 148065 
                 2105 
               
               
                   
               
               
                 542096 
                 n/a 
                 Intron 2 
                 TGCCTGATATTGTAAT 
                 eekddddddddddkke 
                 86 
                 148066 
                 2106 
               
               
                   
               
               
                 542097 
                 n/a 
                 Intron 2 
                 ATTATGTGCTTTGCCT 
                 eekddddddddddkke 
                 86 
                 148907 
                 2107 
               
               
                   
               
               
                 542098 
                 n/a 
                 Intron 2 
                 AATTATGTGCTTTGCC 
                 eekddddddddddkke 
                 75 
                 148908 
                 2108 
               
               
                   
               
               
                 542099 
                 n/a 
                 Intron 2 
                 CAATTATGTGCTTTGC 
                 eekddddddddddkke 
                 88 
                 148909 
                 2109 
               
               
                   
               
               
                 542100 
                 n/a 
                 Intron 2 
                 TCAATTATGTGCTTTG 
                 eekddddddddddkke 
                 78 
                 148910 
                 2110 
               
               
                   
               
               
                 542101 
                 n/a 
                 Intron 2 
                 GTCAATTATGTGCTTT 
                 eekddddddddddkke 
                 97 
                 148911 
                 2111 
               
               
                   
               
               
                 542102 
                 n/a 
                 Intron 2 
                 GCCATCACCAAACACC 
                 eekddddddddddkke 
                 97 
                 150973 
                 2112 
               
               
                   
               
               
                 542103 
                 n/a 
                 Intron 2 
                 TGCCATCACCAAACAC 
                 eekddddddddddkke 
                 90 
                 150974 
                 2113 
               
               
                   
               
               
                 542104 
                 n/a 
                 Intron 2 
                 TTGCCATCACCAAACA 
                 eekddddddddddkke 
                 89 
                 150975 
                 2114 
               
               
                   
               
               
                 542105 
                 n/a 
                 Intron 2 
                 TGGTGACTCTGCCTGA 
                 eekddddddddddkke 
                 98 
                 151388 
                 2115 
               
               
                   
               
               
                 542106 
                 n/a 
                 Intron 2 
                 CTGGTGACTCTGCCTG 
                 eekddddddddddkke 
                 96 
                 151389 
                 2116 
               
               
                   
               
               
                 542107 
                 n/a 
                 Intron 2 
                 GCTGGTGACTCTGCCT 
                 eekddddddddddkke 
                 98 
                 151390 
                 2117 
               
               
                   
               
               
                 542108 
                 n/a 
                 Intron 2 
                 TGCTGGTGACTCTGCC 
                 eekddddddddddkke 
                 97 
                 151391 
                 2118 
               
               
                   
               
               
                 542109 
                 n/a 
                 Intron 2 
                 CTGCTGGTGACTCTGC 
                 eekddddddddddkke 
                 93 
                 151392 
                 2119 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 63 
               
             
            
               
                   
               
               
                 Inhibition of GHR mRNA by deoxy, MOE and cEt gapmers targeting introns 2 and 3 of SEQ ID NO: 2 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                 SEQ 
                   
                   
                   
                   
                   
                   
               
               
                   
                 ID 
                 SEQ ID 
                   
                   
                   
                   
                   
               
               
                   
                 NO: 2 
                 NO: 2 
                   
                   
                   
                   
                   
               
               
                 ISIS 
                 Start 
                 Stop 
                 Target 
                   
                   
                 % 
                 SEQ 
               
               
                 NO 
                 Site 
                 Site 
                 Region 
                 Sequence 
                 Chemistry 
                 inhibition 
                 ID NO 
               
               
                   
               
               
                 541262 
                 156891 
                 156906 
                 Intron 2 
                 TTGGTTTGTCAATCCT 
                 eekddddddddddkke 
                 95 
                 1370 
               
               
                   
               
               
                 542110 
                 153002 
                 153017 
                 Intron 2 
                 AGTAGTCAATATTATT 
                 eekddddddddddkke 
                 74 
                 2120 
               
               
                   
               
               
                 542111 
                 153003 
                 153018 
                 Intron 2 
                 CAGTAGTCAATATTAT 
                 eekddddddddddkke 
                 55 
                 2121 
               
               
                   
               
               
                 542112 
                 153004 
                 153019 
                 Intron 2 
                 CCAGTAGTCAATATTA 
                 eekddddddddddkke 
                 97 
                 2122 
               
               
                   
               
               
                 542113 
                 153922 
                 153937 
                 Intron 2 
                 CCTTTGGGTGAATAGC 
                 eekddddddddddkke 
                 90 
                 2123 
               
               
                   
               
               
                 542114 
                 153923 
                 153938 
                 Intron 2 
                 ACCTTTGGGTGAATAG 
                 eekddddddddddkke 
                 71 
                 2124 
               
               
                   
               
               
                 542115 
                 153924 
                 153939 
                 Intron 2 
                 CACCTTTGGGTGAATA 
                 eekddddddddddkke 
                 78 
                 2125 
               
               
                   
               
               
                 542116 
                 155595 
                 155610 
                 Intron 2 
                 CAACTTGAGGACAATA 
                 eekddddddddddkke 
                 89 
                 2126 
               
               
                   
               
               
                 542118 
                 155597 
                 155612 
                 Intron 2 
                 CTCAACTTGAGGACAA 
                 eekddddddddddkke 
                 98 
                 2127 
               
               
                   
               
               
                 542119 
                 156395 
                 156410 
                 Intron 2 
                 CAGGAAGAAAGGAACC 
                 eekddddddddddkke 
                 95 
                 2128 
               
               
                   
               
               
                 542120 
                 156396 
                 156411 
                 Intron 2 
                 CCAGGAAGAAAGGAAC 
                 eekddddddddddkke 
                 83 
                 2129 
               
               
                   
               
               
                 542121 
                 156397 
                 156412 
                 Intron 2 
                 ACCAGGAAGAAAGGAA 
                 eekddddddddddkke 
                 90 
                 2130 
               
               
                   
               
               
                 542122 
                 156595 
                 156610 
                 Intron 2 
                 TGCAGTCATGTACACA 
                 eekddddddddddkke 
                 97 
                 2131 
               
               
                   
               
               
                 542123 
                 156596 
                 156611 
                 Intron 2 
                 CTGCAGTCATGTACAC 
                 eekddddddddddkke 
                 90 
                 2132 
               
               
                   
               
               
                 542124 
                 156597 
                 156612 
                 Intron 2 
                 TCTGCAGTCATGTACA 
                 eekddddddddddkke 
                 81 
                 2133 
               
               
                   
               
               
                 542125 
                 156890 
                 156905 
                 Intron 2 
                 TGGTTTGTCAATCCTT 
                 eekddddddddddkke 
                 97 
                 2134 
               
               
                   
               
               
                 542126 
                 156892 
                 156907 
                 Intron 2 
                 CTTGGTTTGTCAATCC 
                 eekddddddddddkke 
                 99 
                 2135 
               
               
                   
               
               
                 542127 
                 157204 
                 157219 
                 Intron 2 
                 GCTACAATGCACAGGA 
                 eekddddddddddkke 
                 98 
                 2136 
               
               
                   
               
               
                 542128 
                 157205 
                 157220 
                 Intron 2 
                 TGCTACAATGCACAGG 
                 eekddddddddddkke 
                 98 
                 2137 
               
               
                   
               
               
                 542129 
                 158008 
                 158023 
                 Intron 2 
                 GATATTTATTGCTGTA 
                 eekddddddddddkke 
                 61 
                 2138 
               
               
                   
               
               
                 542130 
                 158009 
                 158024 
                 Intron 2 
                 TGATATTTATTGCTGT 
                 eekddddddddddkke 
                 41 
                 2139 
               
               
                   
               
               
                 542131 
                 158010 
                 158025 
                 Intron 2 
                 CTGATATTTATTGCTG 
                 eekddddddddddkke 
                 86 
                 2140 
               
               
                   
               
               
                 542132 
                 162752 
                 162767 
                 Intron 2 
                 AGGGTCTTTACAAAGT 
                 eekddddddddddkke 
                 69 
                 2141 
               
               
                   
               
               
                 542133 
                 162753 
                 162768 
                 Intron 2 
                 CAGGGTCTTTACAAAG 
                 eekddddddddddkke 
                 71 
                 2142 
               
               
                   
               
               
                 542134 
                 162754 
                 162769 
                 Intron 2 
                 CCAGGGTCTTTACAAA 
                 eekddddddddddkke 
                 93 
                 2143 
               
               
                   
               
               
                 542135 
                 166353 
                 166368 
                 Intron 2 
                 TTCTGCAGTATCCTAG 
                 eekddddddddddkke 
                 84 
                 2144 
               
               
                   
               
               
                 542136 
                 166354 
                 166369 
                 Intron 2 
                 TTTCTGCAGTATCCTA 
                 eekddddddddddkke 
                 88 
                 2145 
               
               
                   
               
               
                 542137 
                 166355 
                 166370 
                 Intron 2 
                 GTTTCTGCAGTATCCT 
                 eekddddddddddkke 
                 95 
                 2146 
               
               
                   
               
               
                 542138 
                 166356 
                 166371 
                 Intron 2 
                 AGTTTCTGCAGTATCC 
                 eekddddddddddkke 
                 92 
                 2147 
               
               
                   
               
               
                 542139 
                 166357 
                 166372 
                 Intron 2 
                 CAGTTTCTGCAGTATC 
                 eekddddddddddkke 
                 93 
                 2148 
               
               
                   
               
               
                 542140 
                 172747 
                 172762 
                 Intron 2 
                 CAAATTCCAGTCCTAG 
                 eekddddddddddkke 
                 73 
                 2149 
               
               
                   
               
               
                 542141 
                 172748 
                 172763 
                 Intron 2 
                 CCAAATTCCAGTCCTA 
                 eekddddddddddkke 
                 91 
                 2150 
               
               
                   
               
               
                 542142 
                 172749 
                 172764 
                 Intron 2 
                 TCCAAATTCCAGTCCT 
                 eekddddddddddkke 
                 90 
                 2151 
               
               
                   
               
               
                 542143 
                 175372 
                 175387 
                 Intron 2 
                 ACCCATTTCATCCATT 
                 eekddddddddddkke 
                 94 
                 2152 
               
               
                   
               
               
                 542144 
                 175373 
                 175388 
                 Intron 2 
                 AACCCATTTCATCCAT 
                 eekddddddddddkke 
                 93 
                 2153 
               
               
                   
               
               
                 542145 
                 175374 
                 175389 
                 Intron 2 
                 GAACCCATTTCATCCA 
                 eekddddddddddkke 
                 97 
                 2154 
               
               
                   
               
               
                 542146 
                 175375 
                 175390 
                 Intron 2 
                 GGAACCCATTTCATCC 
                 eekddddddddddkke 
                 96 
                 2155 
               
               
                   
               
               
                 542147 
                 175376 
                 175391 
                 Intron 2 
                 AGGAACCCATTTCATC 
                 eekddddddddddkke 
                 68 
                 2156 
               
               
                   
               
               
                 542148 
                 189120 
                 189135 
                 Intron 2 
                 GCTTCATGTCTTTCTA 
                 eekddddddddddkke 
                 90 
                 2157 
               
               
                   
               
               
                 542149 
                 189121 
                 189136 
                 Intron 2 
                 TGCTTCATGTCTTTCT 
                 eekddddddddddkke 
                 96 
                 2158 
               
               
                   
               
               
                 542150 
                 189122 
                 189137 
                 Intron 2 
                 GTGCTTCATGTCTTTC 
                 eekddddddddddkke 
                 97 
                 2159 
               
               
                   
               
               
                 542151 
                 189485 
                 189500 
                 Intron 2 
                 TGAGCTTAGCAGTCAC 
                 eekddddddddddkke 
                 92 
                 2160 
               
               
                   
               
               
                 542152 
                 189486 
                 189501 
                 Intron 2 
                 ATGAGCTTAGCAGTCA 
                 eekddddddddddkke 
                 95 
                 2161 
               
               
                   
               
               
                 542153 
                 189487 
                 189502 
                 Intron 2 
                 CATGAGCTTAGCAGTC 
                 eekddddddddddkke 
                 95 
                 2162 
               
               
                   
               
               
                 542154 
                 191143 
                 191158 
                 Intron 2 
                 TACAGACATAGCTCTA 
                 eekddddddddddkke 
                 91 
                 2163 
               
               
                   
               
               
                 542155 
                 191144 
                 191159 
                 Intron 2 
                 ATACAGACATAGCTCT 
                 eekddddddddddkke 
                 74 
                 2164 
               
               
                   
               
               
                 542156 
                 191145 
                 191160 
                 Intron 2 
                 GATACAGACATAGCTC 
                 eekddddddddddkke 
                 91 
                 2165 
               
               
                   
               
               
                 542157 
                 191146 
                 191161 
                 Intron 2 
                 GGATACAGACATAGCT 
                 eekddddddddddkke 
                 94 
                 2166 
               
               
                   
               
               
                 542158 
                 198149 
                 198164 
                 Intron 2 
                 TGTGGCTTTAATTCAC 
                 eekddddddddddkke 
                 71 
                 2167 
               
               
                   
               
               
                 542159 
                 198150 
                 198165 
                 Intron 2 
                 ATGTGGCTTTAATTCA 
                 eekddddddddddkke 
                 81 
                 2168 
               
               
                   
               
               
                 542160 
                 198151 
                 198166 
                 Intron 2 
                 TATGTGGCTTTAATTC 
                 eekddddddddddkke 
                 78 
                 2169 
               
               
                   
               
               
                 542161 
                 199817 
                 199832 
                 Intron 2 
                 TGTTCAGTTGCATCAC 
                 eekddddddddddkke 
                 91 
                 2170 
               
               
                   
               
               
                 542162 
                 199818 
                 199833 
                 Intron 2 
                 GTGTTCAGTTGCATCA 
                 eekddddddddddkke 
                 89 
                 2171 
               
               
                   
               
               
                 542163 
                 199819 
                 199834 
                 Intron 2 
                 TGTGTTCAGTTGCATC 
                 eekddddddddddkke 
                 90 
                 2172 
               
               
                   
               
               
                 542164 
                 210562 
                 210577 
                 Intron 3 
                 CATCTGGATGTGAGGC 
                 eekddddddddddkke 
                 90 
                 2173 
               
               
                   
               
               
                 542165 
                 210563 
                 210578 
                 Intron 3 
                 ACATCTGGATGTGAGG 
                 eekddddddddddkke 
                 78 
                 2174 
               
               
                   
               
               
                 542166 
                 210564 
                 210579 
                 Intron 3 
                 CACATCTGGATGTGAG 
                 eekddddddddddkke 
                 55 
                 2175 
               
               
                   
               
               
                 542167 
                 219020 
                 219035 
                 Intron 3 
                 TCAGGTAATTTCTGGA 
                 eekddddddddddkke 
                 82 
                 2176 
               
               
                   
               
               
                 542168 
                 219021 
                 219036 
                 Intron 3 
                 CTCAGGTAATTTCTGG 
                 eekddddddddddkke 
                 73 
                 2177 
               
               
                   
               
               
                 542169 
                 219022 
                 219037 
                 Intron 3 
                 TCTCAGGTAATTTCTG 
                 eekddddddddddkke 
                 40 
                 2178 
               
               
                   
               
               
                 542170 
                 225568 
                 225583 
                 Intron 3 
                 TGCTTATTTACCTGGG 
                 eekddddddddddkke 
                 90 
                 2179 
               
               
                   
               
               
                 542171 
                 225569 
                 225584 
                 Intron 3 
                 TTGCTTATTTACCTGG 
                 eekddddddddddkke 
                 90 
                 2180 
               
               
                   
               
               
                 542172 
                 225570 
                 225585 
                 Intron 3 
                 TTTGCTTATTTACCTG 
                 eekddddddddddkke 
                 79 
                 2181 
               
               
                   
               
               
                 542173 
                 225571 
                 225586 
                 Intron 3 
                 TTTTGCTTATTTACCT 
                 eekddddddddddkke 
                 32 
                 2182 
               
               
                   
               
               
                 542174 
                 229619 
                 229634 
                 Intron 3 
                 ATGATGTTACTACTAC 
                 eekddddddddddkke 
                 63 
                 2183 
               
               
                   
               
               
                 542175 
                 229620 
                 229635 
                 Intron 3 
                 AATGATGTTACTACTA 
                 eekddddddddddkke 
                 53 
                 2184 
               
               
                   
               
               
                 542176 
                 229621 
                 229636 
                 Intron 3 
                 CAATGATGTTACTACT 
                 eekddddddddddkke 
                 12 
                 2185 
               
               
                   
               
               
                 542177 
                 232827 
                 232842 
                 Intron 3 
                 CCCCTAGAGCAATGGT 
                 eekddddddddddkke 
                 76 
                 2186 
               
               
                   
               
               
                 542178 
                 232828 
                 232843 
                 Intron 3 
                 CCCCCTAGAGCAATGG 
                 eekddddddddddkke 
                 83 
                 2187 
               
               
                   
               
               
                 542179 
                 232829 
                 232844 
                 Intron 3 
                 TCCCCCTAGAGCAATG 
                 eekddddddddddkke 
                 49 
                 2188 
               
               
                   
               
               
                 542180 
                 237676 
                 237691 
                 Intron 3 
                 TCAATTGCAGATGCTC 
                 eekddddddddddkke 
                 88 
                 2189 
               
               
                   
               
               
                 542181 
                 237677 
                 237692 
                 Intron 3 
                 CTCAATTGCAGATGCT 
                 eekddddddddddkke 
                 90 
                 2190 
               
               
                   
               
               
                 542182 
                 237678 
                 237693 
                 Intron 3 
                 GCTCAATTGCAGATGC 
                 eekddddddddddkke 
                 81 
                 2191 
               
               
                   
               
               
                 542183 
                 237679 
                 237694 
                 Intron 3 
                 AGCTCAATTGCAGATG 
                 eekddddddddddkke 
                 85 
                 2192 
               
               
                   
               
               
                 542184 
                 248232 
                 248247 
                 Intron 3 
                 GTATATTCAGTCCAAG 
                 eekddddddddddkke 
                 90 
                 2193 
               
               
                   
               
               
                 542185 
                 248233 
                 248248 
                 Intron 3 
                 AGTATATTCAGTCCAA 
                 eekddddddddddkke 
                 94 
                 2194 
               
               
                   
               
               
                 542186 
                 248234 
                 248249 
                 Intron 3 
                 CAGTATATTCAGTCCA 
                 eekddddddddddkke 
                 97 
                 2195 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 64 
               
             
            
               
                   
               
               
                 Inhibition of GHR mRNA by deoxy, MOE and cEt gapmers targeting intronic and exonic regions 
               
               
                 of SEQ ID NOs: 1 and 2 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                 SEQ 
                   
                   
                   
                   
                   
                   
               
               
                   
                 ID 
                   
                   
                   
                   
                 SEQ ID 
                   
               
               
                   
                 NO: 1 
                   
                   
                   
                   
                 NO: 2 
                   
               
               
                 ISIS 
                 Start 
                   
                   
                   
                 % 
                 Start 
                 SEQ ID 
               
               
                 NO 
                 Site 
                 Target Region 
                 Sequence 
                 Chemistry 
                 inhibition 
                 Site 
                 NO 
               
               
                   
               
               
                 541262 
                 n/a 
                 Intron 2 
                 TTGGTTTGTCAATCCT 
                 eekddddddddddkke 
                 93 
                 156891 
                 1370 
               
               
                   
               
               
                 545316 
                  168 
                 exon 1-intron 1 
                 ACCTCCGAGCTTCGCC 
                 eekddddddddddkke 
                 80 
                   3044 
                 2196 
               
               
                   
                   
                 junction 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 545317 
                  173 
                 exon-exon 
                 GTAGGACCTCCGAGCT 
                 eekddddddddddkke 
                 74 
                 n/a 
                 2197 
               
               
                   
                   
                 junction 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 545318 
                  177 
                 exon-exon 
                 ACCTGTAGGACCTCCG 
                 eekddddddddddkke 
                 70 
                 n/a 
                 2198 
               
               
                   
                   
                 junction 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 545321 
                  213 
                 Exon 2 
                 CAGTGCCAAGGTCAAC 
                 eekddddddddddkke 
                 77 
                 144997 
                 2199 
               
               
                   
               
               
                 545322 
                  225 
                 Exon 2 
                 ACTTGATCCTGCCAGT 
                 eekddddddddddkke 
                 36 
                 145009 
                 2200 
               
               
                   
               
               
                 545332 
                  361 
                 Exon 4/Intron 3 
                 CTCGCTCAGGTGAACG 
                 eekddddddddddkke 
                 57 
                 268024 
                 2201 
               
               
                   
               
               
                 545333 
                  366 
                 Exon 4/Intron 3 
                 AGTCTCTCGCTCAGGT 
                 eekddddddddddkke 
                 88 
                 268029 
                 2202 
               
               
                   
               
               
                 545337 
                  444 
                 Exon 4-intron 4 
                 CCTTCTGGTATAGAAC 
                 eekddddddddddkke 
                 21 
                 268107 
                 2203 
               
               
                   
                   
                 junction 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 545340 
                  570 
                 Exon 5 
                 GCTAGTTAGCTTGATA 
                 eekddddddddddkke 
                 39 
                 274130 
                 2204 
               
               
                   
               
               
                 545343 
                  626 
                 exon 3-exon 4 
                 TCTGGTTGCACTATTT 
                 eekddddddddddkke 
                 34 
                 n/a 
                 2205 
               
               
                   
                   
                 junction 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 545344 
                  629 
                 exon 3-exon 4 
                 GGATCTGGTTGCACTA 
                 eekddddddddddkke 
                 30 
                 n/a 
                 2206 
               
               
                   
                   
                 junction 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 545345 
                  632 
                 Exon 6 
                 GGTGGATCTGGTTGCA 
                 eekddddddddddkke 
                 18 
                 278926 
                 2207 
               
               
                   
               
               
                 545346 
                  638 
                 Exon 6 
                 GCAATGGGTGGATCTG 
                 eekddddddddddkke 
                 50 
                 278932 
                 2208 
               
               
                   
               
               
                 545347 
                  647 
                 Exon 6 
                 CAGTTGAGGGCAATGG 
                 eekddddddddddkke 
                 71 
                 278941 
                 2209 
               
               
                   
               
               
                 545348 
                  651 
                 Exon 6 
                 AGTCCAGTTGAGGGCA 
                 eekddddddddddkke 
                 58 
                 278945 
                 2210 
               
               
                   
               
               
                 545349 
                  655 
                 Exon 6 
                 GTAAAGTCCAGTTGAG 
                 eekddddddddddkke 
                 34 
                 278949 
                 2211 
               
               
                   
               
               
                 545350 
                  660 
                 Exon 6 
                 GTTCAGTAAAGTCCAG 
                 eekddddddddddkke 
                 52 
                 278954 
                 2212 
               
               
                   
               
               
                 545351 
                  685 
                 Exon 6 
                 CTGCATGAATCCCAGT 
                 eekddddddddddkke 
                 77 
                 278979 
                 2213 
               
               
                   
               
               
                 545355 
                  923 
                 Exon 7 
                 ACATAGAGCACCTCAC 
                 eekddddddddddkke 
                 38 
                 290421 
                 2214 
               
               
                   
               
               
                 545356 
                  926 
                 Exon 7 
                 GTTACATAGAGCACCT 
                 eekddddddddddkke 
                 79 
                 290424 
                 2215 
               
               
                   
               
               
                 545357 
                  929 
                 Exon 7 
                 AGTGTTACATAGAGCA 
                 eekddddddddddkke 
                 70 
                 290427 
                 2216 
               
               
                   
               
               
                 545362 
                 1124 
                 Exon 7-exon 8 
                 TCCTTGAGGAGATCTG 
                 eekddddddddddkke 
                  3 
                 n/a 
                 2217 
               
               
                   
                   
                 junction 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 545363 
                 1170 
                 Exon 10 
                 GCTATCATGAATGGCT 
                 eekddddddddddkke 
                 69 
                 297587 
                 2218 
               
               
                   
               
               
                 545364 
                 1180 
                 Exon 10 
                 CGGGTTTATAGCTATC 
                 eekddddddddddkke 
                 58 
                 297597 
                 2219 
               
               
                   
               
               
                 545369 
                 1320 
                 Exon 10 
                 ATCCTTCACCCCTAGG 
                 eekddddddddddkke 
                 46 
                 297737 
                 2220 
               
               
                   
               
               
                 545370 
                 1328 
                 Exon 10 
                 GAGTCGCCATCCTTCA 
                 eekddddddddddkke 
                 60 
                 297745 
                 2221 
               
               
                   
               
               
                 545371 
                 1332 
                 Exon 10 
                 TCCAGAGTCGCCATCC 
                 eekddddddddddkke 
                 51 
                 297749 
                 2222 
               
               
                   
               
               
                 545373 
                 1418 
                 Exon 10 
                 GGCTGAGCAACCTCTG 
                 eekddddddddddkke 
                 80 
                 297835 
                 2223 
               
               
                   
               
               
                 545374 
                 1422 
                 Exon 10 
                 CTGTGGCTGAGCAACC 
                 eekddddddddddkke 
                 63 
                 297839 
                 2224 
               
               
                   
               
               
                 545380 
                 1524 
                 Exon 10 
                 GATAACACTGGGCTGC 
                 eekddddddddddkke 
                 60 
                 297941 
                 2225 
               
               
                   
               
               
                 545381 
                 1530 
                 Exon 10 
                 TGCTTGGATAACACTG 
                 eekddddddddddkke 
                 76 
                 297947 
                 2226 
               
               
                   
               
               
                 545382 
                 1533 
                 Exon 10 
                 CTCTGCTTGGATAACA 
                 eekddddddddddkke 
                 60 
                 297950 
                 2227 
               
               
                   
               
               
                 545386 
                 1600 
                 Exon 10 
                 GCTGAATATGGGCAGC 
                 eekddddddddddkke 
                 29 
                 298017 
                 2228 
               
               
                   
               
               
                 545387 
                 1613 
                 Exon 10 
                 CTTGGATTGCTTAGCT 
                 eekddddddddddkke 
                 59 
                 298030 
                 2229 
               
               
                   
               
               
                 545388 
                 1645 
                 Exon 10 
                 CCTGGGCATAAAAGTC 
                 eekddddddddddkke 
                 47 
                 298062 
                 2230 
               
               
                   
               
               
                 545392 
                 1832 
                 Exon 10 
                 ACCTTGATGTGAGGAG 
                 eekddddddddddkke 
                 44 
                 298249 
                 2231 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 65 
               
             
            
               
                   
               
               
                 Inhibition of GHR mRNA by deoxy, MOE and cEt gapmers targeting intronic and exonic regions 
               
               
                 of SEQ ID NOs: 1 and 2 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                 SEQ 
                   
                   
                   
                   
                 SEQ 
                   
               
               
                   
                 ID 
                   
                   
                   
                   
                 ID 
                   
               
               
                   
                 NO: 1 
                   
                   
                   
                   
                 NO: 2 
                   
               
               
                 ISIS 
                 Start 
                 Target 
                   
                   
                 % 
                 Start 
                 SEQ ID 
               
               
                 NO 
                 Site 
                 Region 
                 Sequence 
                 Chemistry 
                 inhibition 
                 Site 
                 NO 
               
               
                   
               
               
                 541262 
                 n/a 
                 Intron 2 
                 TTGGTTTGTCAATCCT 
                 eekddddddddddkke 
                 89 
                 156891 
                 1370 
               
               
                   
               
               
                 545393 
                 1838 
                 Exon 10 
                 GATTCAACCTTGATGT 
                 eekddddddddddkke 
                 40 
                 298255 
                 2232 
               
               
                   
               
               
                 545394 
                 1844 
                 Exon 10 
                 ATGTGTGATTCAACCT 
                 eekddddddddddkke 
                 80 
                 298261 
                 2233 
               
               
                   
               
               
                 545395 
                 1956 
                 Exon 10 
                 TGGGACAGGCATCTCA 
                 eekddddddddddkke 
                 29 
                 298373 
                 2234 
               
               
                   
               
               
                 545396 
                 1961 
                 Exon 10 
                 TAGTCTGGGACAGGCA 
                 eekddddddddddkke 
                 48 
                 298378 
                 2235 
               
               
                   
               
               
                 545397 
                 1968 
                 Exon 10 
                 GGAGGTATAGTCTGGG 
                 eekddddddddddkke 
                 61 
                 298385 
                 2236 
               
               
                   
               
               
                 545398 
                 1986 
                 Exon 10 
                 GGACTGTACTATATGA 
                 eekddddddddddkke 
                 48 
                 298403 
                 2237 
               
               
                   
               
               
                 545401 
                 2077 
                 Exon 10 
                 TCAGTTGGTCTGTGCT 
                 eekddddddddddkke 
                 60 
                 298494 
                 2238 
               
               
                   
               
               
                 545402 
                 2095 
                 Exon 10 
                 GCTAAGGCATGATTTT 
                 eekddddddddddkke 
                 53 
                 298512 
                 2239 
               
               
                   
               
               
                 545406 
                 2665 
                 Exon 10 
                 GCCATGCTTGAAGTCT 
                 eekddddddddddkke 
                 87 
                 299082 
                 2240 
               
               
                   
               
               
                 545407 
                 2668 
                 Exon 10 
                 ATAGCCATGCTTGAAG 
                 eekddddddddddkke 
                 70 
                 299085 
                 2241 
               
               
                   
               
               
                 545408 
                 2692 
                 Exon 10 
                 ACACAGTGTGTAGTGT 
                 eekddddddddddkke 
                 60 
                 299109 
                 2242 
               
               
                   
               
               
                 545409 
                 2699 
                 Exon 10 
                 CTGCAGTACACAGTGT 
                 eekddddddddddkke 
                 31 
                 299116 
                 2243 
               
               
                   
               
               
                 545410 
                 2704 
                 Exon 10 
                 ACCAACTGCAGTACAC 
                 eekddddddddddkke 
                 57 
                 299121 
                 2244 
               
               
                   
               
               
                 545411 
                 2739 
                 Exon 10 
                 TAGACTGTAGTTGCTA 
                 eekddddddddddkke 
                 53 
                 299156 
                 2245 
               
               
                   
               
               
                 545412 
                 2747 
                 Exon 10 
                 ACCAGCTTTAGACTGT 
                 eekddddddddddkke 
                 56 
                 299164 
                 2246 
               
               
                   
               
               
                 545413 
                 2945 
                 Exon 10 
                 GTAAGTTGATCTGTGC 
                 eekddddddddddkke 
                 79 
                 299362 
                 2247 
               
               
                   
               
               
                 545414 
                 2963 
                 Exon 10 
                 TACTTCTTTTGGTGCC 
                 eekddddddddddkke 
                 82 
                 299380 
                 2248 
               
               
                   
               
               
                 545416 
                 3212 
                 Exon 10 
                 TCTTGTACCTTATTCC 
                 eekddddddddddkke 
                 73 
                 299629 
                 2249 
               
               
                   
               
               
                 545417 
                 3306 
                 Exon 10 
                 TGGTTATAGGCTGTGA 
                 eekddddddddddkke 
                 90 
                 299723 
                 2250 
               
               
                   
               
               
                 545418 
                 3309 
                 Exon 10 
                 GTCTGGTTATAGGCTG 
                 eekddddddddddkke 
                 88 
                 299726 
                 2251 
               
               
                   
               
               
                 545419 
                 3313 
                 Exon 10 
                 ATGTGTCTGGTTATAG 
                 eekddddddddddkke 
                 68 
                 299730 
                 2252 
               
               
                   
               
               
                 545420 
                 3317 
                 Exon 10 
                 GAGTATGTGTCTGGTT 
                 eekddddddddddkke 
                 84 
                 299734 
                 2253 
               
               
                   
               
               
                 545421 
                 4049 
                 Exon 10 
                 GGTCTGCGATAAATGG 
                 eekddddddddddkke 
                 69 
                 300466 
                 2254 
               
               
                   
               
               
                 545429 
                 4424 
                 Exon 10 
                 GCCAGACACAACTAGT 
                 eekddddddddddkke 
                 59 
                 300841 
                 2255 
               
               
                   
               
               
                 545430 
                   31 
                 Exon 1 
                 ACCGCCACTGTAGCAG 
                 eekddddddddddkke 
                 76 
                   2907 
                 2256 
               
               
                   
               
               
                 545431 
                   36 
                 Exon 1 
                 CCGCCACCGCCACTGT 
                 eekddddddddddkke 
                 94 
                   2912 
                 2257 
               
               
                   
               
               
                 545432 
                  103 
                 Exon 1 
                 GGGCCTCCGGCCCGCG 
                 eekddddddddddkke 
                 22 
                   2979 
                 2258 
               
               
                   
               
               
                 545433 
                  143 
                 Exon 1 
                 AGAGCGCGGGTTCGCG 
                 eekddddddddddkke 
                 61 
                   3019 
                 2259 
               
               
                   
               
               
                 545434 
                 n/a 
                 Intron 
                 TACTGACCCCAGTTCC 
                 eekddddddddddkke 
                 68 
                   3654 
                 2260 
               
               
                   
                   
                 1/Exon 1 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 545435 
                 n/a 
                 Intron 
                 ACTCTACTGACCCCAG 
                 eekddddddddddkke 
                 70 
                   3658 
                 2261 
               
               
                   
                   
                 1/Exon 1 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 545436 
                 n/a 
                 Intron 
                 GTCACTCTACTGACCC 
                 eekddddddddddkke 
                 83 
                   3661 
                 2262 
               
               
                   
                   
                 1/Exon 1 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 545437 
                 n/a 
                 Intron 
                 TTCATGCGGACTGGTG 
                 eekddddddddddkke 
                 68 
                   3680 
                 2263 
               
               
                   
                   
                 1/Exon 1 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 545438 
                 n/a 
                 Intron 
                 GTGAGCATGGACCCCA 
                 eekddddddddddkke 
                 94 
                 225436 
                 2264 
               
               
                   
                   
                 3/Exon 3 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 545439 
                 n/a 
                 Intron 
                 TGATATGTGAGCATGG 
                 eekddddddddddkke 
                 88 
                 225442 
                 2265 
               
               
                   
                   
                 3/Exon 3 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 545440 
                 n/a 
                 Intron 
                 AAGTTGGTGAGCTTCT 
                 eekddddddddddkke 
                 85 
                 226785 
                 2266 
               
               
                   
                   
                 3/Exon 3 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 545441 
                 n/a 
                 Intron 
                 CCTTCAAGTTGGTGAG 
                 eekddddddddddkke 
                 88 
                 226790 
                 2267 
               
               
                   
                   
                 3/Exon 3 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 545442 
                 n/a 
                 Intron 
                 GTAAGATCCTTTTGCC 
                 eekddddddddddkke 
                 70 
                 226883 
                 2268 
               
               
                   
                   
                 3/Exon 3 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 545443 
                 n/a 
                 Intron 
                 CAGCTGTGCAACTTGC 
                 eekddddddddddkke 
                 50 
                 238345 
                 2269 
               
               
                   
                   
                 3/Exon 3 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 545444 
                 n/a 
                 Intron 
                 GCCTTGGTAGGTAGGG 
                 eekddddddddddkke 
                 68 
                 238422 
                 2270 
               
               
                   
                   
                 3/Exon 3 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 545445 
                 n/a 
                 Intron 
                 AGAGCCTTGGTAGGTA 
                 eekddddddddddkke 
                 85 
                 238425 
                 2271 
               
               
                   
                   
                 3/Exon 3 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 545446 
                 n/a 
                 Intron 
                 CCCGCACAAACGCGCA 
                 eekddddddddddkke 
                 10 
                   3614 
                 2272 
               
               
                   
                   
                 1/Exon 1 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 545447 
                 n/a 
                 Intron 
                 GTCTTCAAGGTCAGTT 
                 eekddddddddddkke 
                 92 
                  93208 
                 2273 
               
               
                   
                   
                 1/Exon 1 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 545448 
                 n/a 
                 Intron 
                 GCCCAGTGAATTCAGC 
                 eekddddddddddkke 
                 76 
                  93246 
                 2274 
               
               
                   
                   
                 1/Exon 1 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 545449 
                 n/a 
                 Intron 
                 AGATGCGCCCAGTGAA 
                 eekddddddddddkke 
                 60 
                  93252 
                 2275 
               
               
                   
                   
                 1/Exon 1 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 545450 
                 n/a 
                 Intron 
                 GTAAGATGCGCCCAGT 
                 eekddddddddddkke 
                 78 
                  93255 
                 2276 
               
               
                   
                   
                 1/Exon 1 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 545451 
                 n/a 
                 Intron 
                 CCAGAAGGCACTTGTA 
                 eekddddddddddkke 
                 42 
                  93301 
                 2277 
               
               
                   
                   
                 1/Exon 1 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 545452 
                 n/a 
                 Intron 
                 GGAAGATTTGCAGAAC 
                 eekddddddddddkke 
                 15 
                  93340 
                 2278 
               
               
                   
                   
                 1/Exon 1 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 545453 
                 n/a 
                 Intron 
                 CCTTGGTCATGGAAGA 
                 eekddddddddddkke 
                 35 
                  93350 
                 2279 
               
               
                   
                   
                 1/Exon 1 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 545454 
                 n/a 
                 Intron 
                 TGACCTTGGTCATGGA 
                 eekddddddddddkke 
                 55 
                  93353 
                 2280 
               
               
                   
                   
                 1/Exon 1 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 545455 
                 n/a 
                 Intron 
                 GAGGTGACCTTGGTCA 
                 eekddddddddddkke 
                 70 
                  93357 
                 2281 
               
               
                   
                   
                 1/Exon 1 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 545456 
                 n/a 
                 Intron 
                 ATCCAAAGAGGTGACC 
                 eekddddddddddkke 
                 41 
                  93364 
                 2282 
               
               
                   
                   
                 1/Exon 1 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 545457 
                 n/a 
                 Intron 
                 GCCAATCCAAAGAGGT 
                 eekddddddddddkke 
                 56 
                  93368 
                 2283 
               
               
                   
                   
                 1/Exon 1 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 545458 
                 n/a 
                 Intron 
                 GGTCTGCCAATCCAAA 
                 eekddddddddddkke 
                 79 
                  93373 
                 2284 
               
               
                   
                   
                 1/Exon 1 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 545459 
                 n/a 
                 Intron 
                 CCCTGGGTCTGCCAAT 
                 eekddddddddddkke 
                 68 
                  93378 
                 2285 
               
               
                   
                   
                 1/Exon 1 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 545460 
                 n/a 
                 Intron 
                 GAGATCTCAACAAGGG 
                 eekddddddddddkke 
                 52 
                  93427 
                 2286 
               
               
                   
                   
                 1/Exon 1 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 545461 
                 n/a 
                 Intron 
                 CGCCCATCACTCTTCC 
                 eekddddddddddkke 
                 68 
                  93988 
                 2287 
               
               
                   
                   
                 1/Exon 1 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 545462 
                 n/a 
                 Intron 
                 CACCTGTCGCCCATCA 
                 eekddddddddddkke 
                 67 
                  93995 
                 2288 
               
               
                   
                   
                 1/Exon 1 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 545463 
                 n/a 
                 Intron 
                 CATCACCTGTCGCCCA 
                 eekddddddddddkke 
                 78 
                  93998 
                 2289 
               
               
                   
                   
                 1/Exon 1 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 545464 
                 n/a 
                 Intron 
                 CACCATCACCTGTCGC 
                 eekddddddddddkke 
                 74 
                  94001 
                 2290 
               
               
                   
                   
                 1/Exon 1 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 545465 
                 n/a 
                 Intron 
                 AATAGTTGTCACCATC 
                 eekddddddddddkke 
                 76 
                  94010 
                 2291 
               
               
                   
                   
                 1/Exon 1 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 545466 
                 n/a 
                 Intron 
                 GCCACCTTTCATGAGA 
                 eekddddddddddkke 
                 58 
                  94048 
                 2292 
               
               
                   
                   
                 1/Exon 1 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 545467 
                 n/a 
                 Intron 
                 CTCTTGGAAGTAGGTA 
                 eekddddddddddkke 
                 89 
                 198762 
                 2293 
               
               
                   
                   
                 2/Exon 2 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 545468 
                 n/a 
                 Intron 
                 GTTCTCTTGGAAGTAG 
                 eekddddddddddkke 
                 80 
                 198765 
                 2294 
               
               
                   
                   
                 2/Exon 2 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 545469 
                 n/a 
                 Intron 
                 TAAACAGGTTGGTCTG 
                 eekddddddddddkke 
                 68 
                 198854 
                 2295 
               
               
                   
                   
                 2/Exon 2 
               
               
                   
               
            
           
         
       
     
     Example 8: Dose-Dependent Antisense Inhibition of Human GHR in Hep3B Cells by Deoxy, MOE and cEt Gapmers 
     Gapmers from studies described above exhibiting significant in vitro inhibition of GHR mRNA were selected and tested at various doses in Hep3B cells. The antisense oligonucleotides were tested in a series of experiments that had similar culture conditions. The results for each experiment are presented in separate tables shown below. Cells were plated at a density of 20,000 cells per well and transfected using electroporation with 0.625 μM, 1.25 μM, 2.50 μM, 5.00 μM and 10.00 μM concentrations of antisense oligonucleotide. After a treatment period of approximately 16 hours, RNA was isolated from the cells and GHR mRNA levels were measured by quantitative real-time PCR. Human primer probe set RTS3437_MGB was used to measure mRNA levels. GHR mRNA levels were adjusted according to total RNA content, as measured by RIBOGREEN®. Results are presented as percent inhibition of GHR, relative to untreated control cells. 
     The half maximal inhibitory concentration (IC 50 ) of each oligonucleotide is also presented. GHR mRNA levels were significantly reduced in a dose-dependent manner in antisense oligonucleotide treated cells. 
     
       
         
           
               
               
               
               
               
               
               
               
             
               
                   
                 TABLE 66 
               
               
                   
                   
               
               
                   
                   
                 0.625  
                 1.250  
                 2.50  
                 5.00  
                 10.00  
                 IC 50    
               
               
                   
                 ISIS No  
                 μM  
                 μM  
                 μM  
                 μM  
                 μM  
                 (μM) 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                 541396  
                 30  
                 51  
                 68  
                 74  
                 67  
                 1.4  
               
               
                   
                 541262  
                 55  
                 87  
                 90  
                 94  
                 97  
                 0.2  
               
               
                   
                 541393  
                 30  
                 38  
                 52  
                 66  
                 81  
                 2.1  
               
               
                   
                 541375  
                 41  
                 45  
                 54  
                 64  
                 79  
                 1.6  
               
               
                   
                 541438  
                 44  
                 49  
                 75  
                 80  
                 91  
                 0.9  
               
               
                   
                 541428  
                 35  
                 32  
                 56  
                 78  
                 88  
                 1.8  
               
               
                   
                 541491  
                 13  
                 46  
                 67  
                 55  
                 95  
                 2.0  
               
               
                   
                 541435  
                 21  
                 46  
                 55  
                 72  
                 94  
                 1.9  
               
               
                   
                 541471  
                 11  
                 49  
                 50  
                 77  
                 89  
                 2.0  
               
               
                   
                 541430  
                 24  
                 44  
                 56  
                 57  
                 79  
                 2.2  
               
               
                   
                 541492  
                 32  
                 40  
                 65  
                 80  
                 85  
                 1.5  
               
               
                   
                 541431  
                 22  
                 46  
                 73  
                 84  
                 92  
                 1.5 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
               
               
               
               
               
               
               
             
               
                   
                 TABLE 67 
               
               
                   
                   
               
               
                   
                   
                 0.625  
                 1.250  
                 2.50  
                 5.00  
                 10.00  
                 IC 50    
               
               
                   
                 ISIS No  
                 μM  
                 μM  
                 μM  
                 μM  
                 μM  
                 (μM) 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                 541487  
                 36  
                 46  
                 66  
                 85  
                 92  
                 1.3  
               
               
                   
                 541423  
                 33  
                 55  
                 64  
                 80  
                 93  
                 1.2  
               
               
                   
                 541452  
                 37  
                 60  
                 79  
                 87  
                 94  
                 0.9  
               
               
                   
                 541505  
                 51  
                 75  
                 86  
                 92  
                 97  
                 0.4  
               
               
                   
                 541522  
                 54  
                 76  
                 81  
                 90  
                 95  
                 0.3  
               
               
                   
                 541539  
                 65  
                 76  
                 85  
                 94  
                 98  
                 0.2  
               
               
                   
                 541503  
                 54  
                 65  
                 80  
                 93  
                 97  
                 0.5  
               
               
                   
                 541520  
                 43  
                 61  
                 86  
                 94  
                 96  
                 0.7  
               
               
                   
                 541515  
                 57  
                 72  
                 85  
                 92  
                 94  
                 0.3  
               
               
                   
                 541564  
                 57  
                 72  
                 88  
                 90  
                 97  
                 0.3  
               
               
                   
                 541554  
                 43  
                 65  
                 81  
                 89  
                 93  
                 0.7  
               
               
                   
                 541509  
                 11  
                 8  
                 19  
                 6  
                 8  
                 &gt;10  
               
               
                   
                 541584  
                 59  
                 65  
                 84  
                 91  
                 96  
                 0.3  
               
               
                   
                 541585  
                 70  
                 80  
                 93  
                 92  
                 98  
                 0.1 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
               
               
               
               
               
               
               
             
               
                   
                 TABLE 68 
               
               
                   
                   
               
               
                   
                   
                 0.625  
                 1.250  
                 2.50  
                 5.00  
                 10.00  
                 IC 50    
               
               
                   
                 ISIS No  
                 μM  
                 μM  
                 μM  
                 μM  
                 μM  
                 (μM) 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                 541598  
                 26  
                 43  
                 75  
                 80  
                 76  
                 1.5  
               
               
                   
                 541592  
                 35  
                 48  
                 67  
                 85  
                 95  
                 1.2  
               
               
                   
                 541641  
                 22  
                 63  
                 70  
                 91  
                 93  
                 1.2  
               
               
                   
                 541590  
                 27  
                 59  
                 70  
                 94  
                 95  
                 1.2  
               
               
                   
                 541615  
                 40  
                 65  
                 84  
                 88  
                 94  
                 0.7  
               
               
                   
                 541595  
                 35  
                 57  
                 73  
                 84  
                 95  
                 1.0  
               
               
                   
                 541575  
                 49  
                 60  
                 79  
                 84  
                 95  
                 0.6  
               
               
                   
                 541571  
                 41  
                 50  
                 76  
                 80  
                 94  
                 1.0  
               
               
                   
                 541582  
                 0  
                 10  
                 25  
                 50  
                 82  
                 4.4  
               
               
                   
                 541262  
                 66  
                 79  
                 93  
                 94  
                 99  
                 &lt;0.6  
               
               
                   
                 541652  
                 1  
                 44  
                 80  
                 82  
                 87  
                 1.9  
               
               
                   
                 541670  
                 29  
                 40  
                 63  
                 79  
                 89  
                 1.6  
               
               
                   
                 541662  
                 17  
                 13  
                 45  
                 62  
                 84  
                 3.1  
               
               
                   
                 541724  
                 37  
                 47  
                 72  
                 85  
                 95  
                 1.2 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
               
               
               
               
               
               
               
             
               
                   
                 TABLE 69 
               
               
                   
                   
               
               
                   
                   
                 0.625  
                 1.250  
                 2.50  
                 5.00  
                 10.00  
                 IC 50    
               
               
                   
                 ISIS No  
                 μM  
                 μM  
                 μM  
                 μM  
                 μM  
                 (μM) 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                 541748  
                 86  
                 94  
                 96  
                 98  
                 98  
                 &lt;0.6  
               
               
                   
                 541767  
                 83  
                 91  
                 95  
                 96  
                 98  
                 &lt;0.6  
               
               
                   
                 541797  
                 78  
                 89  
                 93  
                 97  
                 99  
                 &lt;0.6  
               
               
                   
                 541766  
                 59  
                 82  
                 92  
                 97  
                 99  
                 &lt;0.6  
               
               
                   
                 541742  
                 65  
                 87  
                 93  
                 95  
                 99  
                 &lt;0.6  
               
               
                   
                 541750  
                 80  
                 86  
                 96  
                 96  
                 99  
                 &lt;0.6  
               
               
                   
                 541262  
                 79  
                 88  
                 93  
                 97  
                 97  
                 &lt;0.6  
               
               
                   
                 541749  
                 71  
                 84  
                 93  
                 95  
                 98  
                 &lt;0.6  
               
               
                   
                 541793  
                 71  
                 88  
                 94  
                 97  
                 98  
                 &lt;0.6  
               
               
                   
                 541785  
                 56  
                 79  
                 89  
                 93  
                 98  
                 &lt;0.6  
               
               
                   
                 541746  
                 34  
                 61  
                 85  
                 94  
                 97  
                 0.9  
               
               
                   
                 541752  
                 49  
                 72  
                 88  
                 93  
                 93  
                 &lt;0.6  
               
               
                   
                 541826  
                 86  
                 94  
                 95  
                 99  
                 98  
                 &lt;0.6  
               
               
                   
                 541811  
                 66  
                 87  
                 93  
                 97  
                 98  
                 &lt;0.6 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
               
               
               
               
               
               
               
             
               
                   
                 TABLE 70 
               
               
                   
                   
               
               
                   
                   
                 0.625  
                 1.250  
                 2.50  
                 5.00  
                 10.00  
                 IC 50    
               
               
                   
                 ISIS No  
                 μM  
                 μM  
                 μM  
                 μM  
                 μM  
                 (μM) 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                 541822  
                 83  
                 88  
                 95  
                 96  
                 96  
                 &lt;0.6  
               
               
                   
                 541870  
                 77  
                 87  
                 95  
                 97  
                 98  
                 &lt;0.6  
               
               
                   
                 541262  
                 85  
                 93  
                 96  
                 97  
                 98  
                 &lt;0.6  
               
               
                   
                 541873  
                 32  
                 77  
                 93  
                 94  
                 97  
                 0.7  
               
               
                   
                 541819  
                 60  
                 91  
                 97  
                 97  
                 99  
                 &lt;0.6  
               
               
                   
                 541841  
                 86  
                 91  
                 95  
                 96  
                 97  
                 &lt;0.6  
               
               
                   
                 541825  
                 78  
                 88  
                 95  
                 98  
                 98  
                 &lt;0.6  
               
               
                   
                 541863  
                 63  
                 77  
                 87  
                 93  
                 97  
                 &lt;0.6  
               
               
                   
                 541827  
                 42  
                 80  
                 87  
                 94  
                 97  
                 &lt;0.6  
               
               
                   
                 541875  
                 77  
                 84  
                 93  
                 96  
                 97  
                 &lt;0.6  
               
               
                   
                 541835  
                 56  
                 73  
                 90  
                 95  
                 98  
                 &lt;0.6  
               
               
                   
                 541838  
                 72  
                 90  
                 93  
                 98  
                 97  
                 &lt;0.6  
               
               
                   
                 541833  
                 52  
                 69  
                 83  
                 92  
                 97  
                 &lt;0.6  
               
               
                   
                 541813  
                 47  
                 75  
                 86  
                 95  
                 97  
                 &lt;0.6 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
               
               
               
               
               
               
               
             
               
                   
                 TABLE 71 
               
               
                   
                   
               
               
                   
                   
                 0.625  
                 1.250  
                 2.50  
                 5.00  
                 10.00  
                 IC 50    
               
               
                   
                 ISIS No  
                 μM  
                 μM  
                 μM  
                 μM  
                 μM  
                 (μM) 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                 541853  
                 74  
                 79  
                 88  
                 93  
                 91  
                 &lt;0.6  
               
               
                   
                 541842  
                 69  
                 85  
                 91  
                 97  
                 99  
                 &lt;0.6  
               
               
                   
                 541877  
                 79  
                 91  
                 93  
                 98  
                 97  
                 &lt;0.6  
               
               
                   
                 541848  
                 58  
                 90  
                 96  
                 98  
                 98  
                 0.7  
               
               
                   
                 541804  
                 23  
                 81  
                 89  
                 95  
                 95  
                 0.8  
               
               
                   
                 541881  
                 87  
                 94  
                 98  
                 98  
                 99  
                 &lt;0.6  
               
               
                   
                 541936  
                 91  
                 96  
                 98  
                 99  
                 98  
                 &lt;0.6  
               
               
                   
                 541909  
                 56  
                 80  
                 89  
                 95  
                 97  
                 &lt;0.6  
               
               
                   
                 541907  
                 75  
                 91  
                 95  
                 97  
                 98  
                 &lt;0.6  
               
               
                   
                 541952  
                 68  
                 81  
                 93  
                 97  
                 98  
                 &lt;0.6  
               
               
                   
                 541953  
                 68  
                 80  
                 94  
                 97  
                 98  
                 &lt;0.6  
               
               
                   
                 541914  
                 60  
                 78  
                 94  
                 97  
                 97  
                 &lt;0.6  
               
               
                   
                 541880  
                 56  
                 74  
                 89  
                 94  
                 95  
                 &lt;0.6  
               
               
                   
                 541903  
                 37  
                 74  
                 87  
                 96  
                 98  
                 0.6 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
               
               
               
               
               
               
               
             
               
                   
                 TABLE 72 
               
               
                   
                   
               
               
                   
                   
                 0.625  
                 1.250  
                 2.50  
                 5.00  
                 10.00  
                 IC 50    
               
               
                   
                 ISIS No  
                 μM  
                 μM  
                 μM  
                 μM  
                 μM  
                 (μM) 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                 541895  
                 47  
                 72  
                 85  
                 93  
                 94  
                 &lt;0.6  
               
               
                   
                 541882  
                 60  
                 67  
                 89  
                 93  
                 97  
                 &lt;0.6  
               
               
                   
                 541889  
                 63  
                 80  
                 87  
                 94  
                 97  
                 &lt;0.6  
               
               
                   
                 541904  
                 26  
                 78  
                 23  
                 89  
                 93  
                 1.4  
               
               
                   
                 545418  
                 0  
                 81  
                 91  
                 94  
                 95  
                 1.7  
               
               
                   
                 541930  
                 58  
                 71  
                 82  
                 88  
                 92  
                 &lt;0.6  
               
               
                   
                 545439  
                 67  
                 87  
                 93  
                 96  
                 98  
                 &lt;0.6  
               
               
                   
                 542024  
                 15  
                 58  
                 78  
                 87  
                 90  
                 1.4  
               
               
                   
                 541985  
                 59  
                 81  
                 88  
                 93  
                 97  
                 &lt;0.6  
               
               
                   
                 541972  
                 47  
                 58  
                 83  
                 90  
                 92  
                 0.6  
               
               
                   
                 541991  
                 57  
                 64  
                 88  
                 92  
                 83  
                 &lt;0.6  
               
               
                   
                 541980  
                 33  
                 50  
                 76  
                 72  
                 93  
                 1.2 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
               
               
               
               
               
               
               
             
               
                   
                 TABLE 73 
               
               
                   
                   
               
               
                   
                   
                 0.625  
                 1.250  
                 2.50  
                 5.00  
                 10.00  
                 IC 50    
               
               
                   
                 ISIS No  
                 μM  
                 μM  
                 μM  
                 μM  
                 μM  
                 (μM) 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                 541264  
                 26  
                 44  
                 64  
                 79  
                 89  
                 1.6  
               
               
                   
                 541265  
                 29  
                 32  
                 62  
                 79  
                 91  
                 1.8  
               
               
                   
                 541263  
                 25  
                 40  
                 62  
                 78  
                 93  
                 1.7  
               
               
                   
                 541268  
                 57  
                 73  
                 85  
                 90  
                 95  
                 0.3  
               
               
                   
                 541266  
                 15  
                 33  
                 46  
                 66  
                 90  
                 2.5  
               
               
                   
                 542107  
                 93  
                 97  
                 98  
                 98  
                 98  
                 &lt;0.6  
               
               
                   
                 542052  
                 93  
                 96  
                 97  
                 96  
                 98  
                 &lt;0.6  
               
               
                   
                 542105  
                 80  
                 92  
                 96  
                 98  
                 97  
                 &lt;0.6  
               
               
                   
                 542102  
                 94  
                 96  
                 96  
                 97  
                 98  
                 &lt;0.6  
               
               
                   
                 542108  
                 90  
                 92  
                 94  
                 97  
                 99  
                 &lt;0.6  
               
               
                   
                 542080  
                 87  
                 93  
                 95  
                 95  
                 97  
                 &lt;0.6 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
               
               
               
               
               
               
               
             
               
                   
                 TABLE 74 
               
               
                   
                   
               
               
                   
                   
                 0.625  
                 1.250  
                 2.50  
                 5.00  
                 10.00  
                 IC 50    
               
               
                   
                 ISIS No  
                 μM  
                 μM  
                 μM  
                 μM  
                 μM  
                 (μM) 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                 542101  
                 90  
                 97  
                 97  
                 97  
                 95  
                 &lt;0.6  
               
               
                   
                 542051  
                 89  
                 96  
                 95  
                 98  
                 97  
                 &lt;0.6  
               
               
                   
                 542106  
                 83  
                 93  
                 96  
                 96  
                 98  
                 &lt;0.6  
               
               
                   
                 542071  
                 84  
                 91  
                 94  
                 97  
                 97  
                 &lt;0.6  
               
               
                   
                 542094  
                 85  
                 92  
                 94  
                 97  
                 98  
                 &lt;0.6  
               
               
                   
                 542069  
                 89  
                 94  
                 97  
                 95  
                 98  
                 &lt;0.6  
               
               
                   
                 542086  
                 83  
                 94  
                 96  
                 97  
                 98  
                 &lt;0.6  
               
               
                   
                 542085  
                 85  
                 92  
                 96  
                 97  
                 97  
                 &lt;0.6  
               
               
                   
                 542053  
                 64  
                 83  
                 94  
                 98  
                 97  
                 &lt;0.6  
               
               
                   
                 542087  
                 69  
                 84  
                 99  
                 95  
                 98  
                 &lt;0.6  
               
               
                   
                 542109  
                 87  
                 94  
                 96  
                 98  
                 98  
                 &lt;0.6  
               
               
                   
                 542126  
                 96  
                 98  
                 99  
                 98  
                 98  
                 &lt;0.6  
               
               
                   
                 542127  
                 94  
                 96  
                 97  
                 98  
                 97  
                 &lt;0.6  
               
               
                   
                 542128  
                 90  
                 96  
                 98  
                 98  
                 97  
                 &lt;0.6 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
               
               
               
               
               
               
               
             
               
                   
                 TABLE 75 
               
               
                   
                   
               
               
                   
                   
                 0.625  
                 1.250  
                 2.50  
                 5.00  
                 10.00  
                 IC 50    
               
               
                   
                 ISIS No  
                 μM  
                 μM  
                 μM  
                 μM  
                 μM  
                 (μM) 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                 542118  
                 97  
                 97  
                 98  
                 95  
                 43  
                 &lt;0.6  
               
               
                   
                 542186  
                 93  
                 96  
                 98  
                 99  
                 98  
                 &lt;0.6  
               
               
                   
                 542150  
                 95  
                 97  
                 98  
                 99  
                 99  
                 &lt;0.6  
               
               
                   
                 542122  
                 90  
                 94  
                 98  
                 98  
                 99  
                 &lt;0.6  
               
               
                   
                 542125  
                 88  
                 97  
                 98  
                 98  
                 99  
                 &lt;0.6  
               
               
                   
                 542145  
                 90  
                 96  
                 98  
                 99  
                 99  
                 &lt;0.6  
               
               
                   
                 542112  
                 86  
                 94  
                 99  
                 99  
                 99  
                 &lt;0.6  
               
               
                   
                 542149  
                 88  
                 93  
                 99  
                 98  
                 99  
                 &lt;0.6  
               
               
                   
                 542146  
                 79  
                 93  
                 96  
                 97  
                 98  
                 &lt;0.6  
               
               
                   
                 542153  
                 87  
                 94  
                 97  
                 98  
                 99  
                 &lt;0.6  
               
               
                   
                 542119  
                 64  
                 84  
                 93  
                 97  
                 98  
                 &lt;0.6  
               
               
                   
                 542137  
                 76  
                 91  
                 97  
                 97  
                 98  
                 &lt;0.6  
               
               
                   
                 542152  
                 84  
                 94  
                 96  
                 96  
                 97  
                 &lt;0.6  
               
               
                   
                 542157  
                 83  
                 95  
                 98  
                 99  
                 98  
                 &lt;0.6 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
               
               
               
               
               
               
               
             
               
                   
                 TABLE 76 
               
               
                   
                   
               
               
                   
                   
                 0.625  
                 1.250  
                 2.50  
                 5.00  
                 10.00  
                 IC 50    
               
               
                   
                 ISIS No  
                 μM  
                 μM  
                 μM  
                 μM  
                 μM  
                 (μM) 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                 542185  
                 82  
                 93  
                 96  
                 96  
                 94  
                 &lt;0.6  
               
               
                   
                 542143  
                 81  
                 91  
                 96  
                 98  
                 98  
                 &lt;0.6  
               
               
                   
                 542144  
                 77  
                 93  
                 95  
                 96  
                 99  
                 &lt;0.6  
               
               
                   
                 542139  
                 87  
                 93  
                 98  
                 98  
                 98  
                 &lt;0.6  
               
               
                   
                 542134  
                 83  
                 90  
                 90  
                 95  
                 96  
                 &lt;0.6  
               
               
                   
                 545333  
                 68  
                 85  
                 91  
                 96  
                 98  
                 &lt;0.6  
               
               
                   
                 545373  
                 57  
                 73  
                 86  
                 92  
                 97  
                 &lt;0.6  
               
               
                   
                 545438  
                 84  
                 96  
                 98  
                 97  
                 99  
                 &lt;0.6  
               
               
                   
                 545431  
                 77  
                 91  
                 93  
                 97  
                 98  
                 &lt;0.6  
               
               
                   
                 545447  
                 70  
                 85  
                 96  
                 96  
                 97  
                 &lt;0.6  
               
               
                   
                 545417  
                 62  
                 82  
                 90  
                 93  
                 95  
                 &lt;0.6  
               
               
                   
                 545467  
                 77  
                 88  
                 91  
                 94  
                 95  
                 &lt;0.6  
               
               
                   
                 545441  
                 63  
                 82  
                 92  
                 94  
                 96  
                 &lt;0.6 
               
               
                   
                   
               
            
           
         
       
     
     Example 9: Dose-Dependent Antisense Inhibition of Human GHR in Hep3B Cells by Deoxy, MOE and cEt Gapmers 
     Gapmers from studies described above exhibiting significant in vitro inhibition of GHR mRNA were selected and tested at various doses in Hep3B cells. The antisense oligonucleotides were tested in a series of experiments that had similar culture conditions. The results for each experiment are presented in separate tables shown below. Cells were plated at a density of 20,000 cells per well and transfected using electroporation with 0.04 μM, 0.11 μM, 0.33 μM, 1.00 μM, and 3.00 μM concentrations of antisense oligonucleotide. After a treatment period of approximately 16 hours, RNA was isolated from the cells and GHR mRNA levels were measured by quantitative real-time PCR. Human primer probe set RTS3437_MGB was used to measure mRNA levels. GHR mRNA levels were adjusted according to total RNA content, as measured by RIBOGREEN®. Results are presented as percent inhibition of GHR, relative to untreated control cells. 
     The half maximal inhibitory concentration (IC 50 ) of each oligonucleotide is also presented. GHR mRNA levels were significantly reduced in a dose-dependent manner in antisense oligonucleotide treated cells. 
     
       
         
           
               
               
               
               
               
               
               
               
             
               
                   
                 TABLE 77 
               
               
                   
                   
               
               
                   
                   
                 0.04  
                 0.11  
                 0.33  
                 1.00  
                 3.00  
                 IC 50    
               
               
                   
                 ISIS No  
                 μM  
                 μM  
                 μM  
                 μM  
                 μM  
                 (μM) 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                 539380  
                 11  
                 16  
                 57  
                 93  
                 98  
                 0.2  
               
               
                   
                 541724  
                 0  
                 27  
                 71  
                 66  
                 83  
                 0.3  
               
               
                   
                 541748  
                 28  
                 40  
                 71  
                 90  
                 97  
                 0.1  
               
               
                   
                 541767  
                 19  
                 38  
                 54  
                 87  
                 98  
                 0.2  
               
               
                   
                 541797  
                 23  
                 46  
                 70  
                 88  
                 97  
                 0.1  
               
               
                   
                 541766  
                 15  
                 26  
                 49  
                 82  
                 96  
                 0.3  
               
               
                   
                 541742  
                 17  
                 28  
                 41  
                 80  
                 95  
                 0.3  
               
               
                   
                 541750  
                 33  
                 27  
                 60  
                 89  
                 98  
                 0.2  
               
               
                   
                 541749  
                 27  
                 16  
                 62  
                 84  
                 82  
                 0.2  
               
               
                   
                 541793  
                 0  
                 14  
                 44  
                 77  
                 96  
                 0.4  
               
               
                   
                 541785  
                 4  
                 11  
                 39  
                 75  
                 95  
                 0.4  
               
               
                   
                 541752  
                 14  
                 6  
                 45  
                 70  
                 94  
                 0.4  
               
               
                   
                 541826  
                 8  
                 34  
                 74  
                 94  
                 99  
                 0.2  
               
               
                   
                 541811  
                 6  
                 4  
                 45  
                 79  
                 97  
                 0.4  
               
               
                   
                 541822  
                 9  
                 29  
                 67  
                 89  
                 97  
                 0.2 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
               
               
               
               
               
               
               
             
               
                   
                 TABLE 78 
               
               
                   
                   
               
               
                   
                   
                 0.04  
                 0.11  
                 0.33  
                 1.00  
                 3.00  
                 IC 50    
               
               
                   
                 ISIS No  
                 μM  
                 μM  
                 μM  
                 μM  
                 μM  
                 (μM) 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                 539380  
                 0  
                 16  
                 47  
                 82  
                 98  
                 0.4  
               
               
                   
                 541819  
                 3  
                 12  
                 50  
                 76  
                 94  
                 0.3  
               
               
                   
                 541841  
                 0  
                 19  
                 47  
                 80  
                 95  
                 0.3  
               
               
                   
                 541825  
                 0  
                 6  
                 40  
                 74  
                 96  
                 0.4  
               
               
                   
                 541827  
                 5  
                 26  
                 48  
                 76  
                 95  
                 0.3  
               
               
                   
                 541835  
                 7  
                 11  
                 33  
                 74  
                 93  
                 0.4  
               
               
                   
                 541838  
                 21  
                 26  
                 61  
                 90  
                 97  
                 0.2  
               
               
                   
                 541833  
                 0  
                 9  
                 41  
                 63  
                 89  
                 0.5  
               
               
                   
                 541813  
                 0  
                 17  
                 28  
                 65  
                 92  
                 0.5  
               
               
                   
                 541842  
                 5  
                 15  
                 30  
                 72  
                 90  
                 0.4  
               
               
                   
                 541804  
                 0  
                 12  
                 3  
                 49  
                 79  
                 1.1  
               
               
                   
                 542024  
                 0  
                 0  
                 26  
                 54  
                 76  
                 1.0  
               
               
                   
                 542107  
                 15  
                 45  
                 78  
                 92  
                 99  
                 0.1  
               
               
                   
                 542105  
                 2  
                 14  
                 55  
                 88  
                 98  
                 0.3  
               
               
                   
                 542102  
                 10  
                 16  
                 73  
                 88  
                 98  
                 0.2 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
               
               
               
               
               
               
               
             
               
                   
                 TABLE 79 
               
               
                   
                   
               
               
                   
                   
                 0.04  
                 0.11  
                 0.33  
                 1.00  
                 3.00  
                 IC 50    
               
               
                   
                 ISIS No  
                 μM  
                 μM  
                 μM  
                 μM  
                 μM  
                 (μM) 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                 539380  
                 4  
                 18  
                 50  
                 86  
                 95  
                 0.3  
               
               
                   
                 542108  
                 15  
                 13  
                 65  
                 86  
                 97  
                 0.2  
               
               
                   
                 542101  
                 17  
                 40  
                 68  
                 92  
                 98  
                 0.2  
               
               
                   
                 542106  
                 4  
                 23  
                 56  
                 88  
                 98  
                 0.3  
               
               
                   
                 542094  
                 0  
                 30  
                 51  
                 86  
                 96  
                 0.3  
               
               
                   
                 542086  
                 13  
                 38  
                 50  
                 84  
                 97  
                 0.2  
               
               
                   
                 542085  
                 0  
                 27  
                 57  
                 90  
                 98  
                 0.3  
               
               
                   
                 542087  
                 7  
                 3  
                 49  
                 80  
                 92  
                 0.4  
               
               
                   
                 542109  
                 17  
                 10  
                 56  
                 88  
                 98  
                 0.3  
               
               
                   
                 542126  
                 40  
                 63  
                 91  
                 96  
                 99  
                 &lt;0.03  
               
               
                   
                 542127  
                 27  
                 47  
                 69  
                 93  
                 97  
                 0.1  
               
               
                   
                 542128  
                 11  
                 30  
                 66  
                 90  
                 98  
                 0.2  
               
               
                   
                 542118  
                 14  
                 42  
                 77  
                 95  
                 98  
                 0.1  
               
               
                   
                 542150  
                 31  
                 46  
                 72  
                 94  
                 98  
                 0.1  
               
               
                   
                 542122  
                 13  
                 14  
                 59  
                 90  
                 97  
                 0.3 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
               
               
               
               
               
               
               
             
               
                   
                 TABLE 80 
               
               
                   
                   
               
               
                   
                   
                 0.04  
                 0.11  
                 0.33  
                 1.00  
                 3.00  
                 IC 50    
               
               
                   
                 ISIS No  
                 μM  
                 μM  
                 μM  
                 μM  
                 μM  
                 (μM) 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                 539380  
                 0  
                 2  
                 50  
                 86  
                 97  
                 0.4  
               
               
                   
                 542125  
                 31  
                 32  
                 69  
                 89  
                 96  
                 0.1  
               
               
                   
                 542145  
                 15  
                 29  
                 64  
                 91  
                 97  
                 0.2  
               
               
                   
                 542112  
                 14  
                 38  
                 61  
                 87  
                 96  
                 0.2  
               
               
                   
                 542149  
                 9  
                 37  
                 63  
                 90  
                 97  
                 0.2  
               
               
                   
                 542146  
                 13  
                 33  
                 59  
                 82  
                 95  
                 0.2  
               
               
                   
                 542153  
                 22  
                 26  
                 63  
                 86  
                 96  
                 0.2  
               
               
                   
                 542119  
                 10  
                 20  
                 34  
                 70  
                 87  
                 0.4  
               
               
                   
                 542137  
                 3  
                 19  
                 47  
                 77  
                 95  
                 0.3  
               
               
                   
                 542152  
                 0  
                 9  
                 47  
                 82  
                 96  
                 0.4  
               
               
                   
                 542157  
                 0  
                 26  
                 56  
                 84  
                 96  
                 0.3  
               
               
                   
                 542143  
                 8  
                 12  
                 44  
                 81  
                 95  
                 0.3  
               
               
                   
                 542144  
                 0  
                 21  
                 42  
                 75  
                 95  
                 0.4  
               
               
                   
                 542139  
                 0  
                 14  
                 46  
                 82  
                 97  
                 0.4  
               
               
                   
                 542134  
                 3  
                 23  
                 43  
                 72  
                 92  
                 0.4 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
               
               
               
               
               
               
               
             
               
                   
                 TABLE 81 
               
               
                   
                   
               
               
                   
                   
                 0.04  
                 0.11  
                 0.33  
                 1.00  
                 3.00  
                 IC 50    
               
               
                   
                 ISIS No  
                 μM  
                 μM  
                 μM  
                 μM  
                 μM  
                 (μM) 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                 539380  
                 0  
                 9  
                 64  
                 85  
                 97  
                 0.3  
               
               
                   
                 541870  
                 7  
                 15  
                 48  
                 80  
                 92  
                 0.3  
               
               
                   
                 541262  
                 0  
                 29  
                 63  
                 90  
                 98  
                 0.2  
               
               
                   
                 541863  
                 0  
                 26  
                 40  
                 82  
                 93  
                 0.4  
               
               
                   
                 541875  
                 6  
                 30  
                 71  
                 84  
                 91  
                 0.2  
               
               
                   
                 541853  
                 0  
                 13  
                 39  
                 67  
                 91  
                 0.5  
               
               
                   
                 541877  
                 0  
                 26  
                 41  
                 79  
                 94  
                 0.4  
               
               
                   
                 541881  
                 0  
                 30  
                 54  
                 87  
                 94  
                 0.3  
               
               
                   
                 541936  
                 20  
                 41  
                 73  
                 93  
                 98  
                 0.1  
               
               
                   
                 541909  
                 0  
                 16  
                 34  
                 64  
                 90  
                 0.5  
               
               
                   
                 541907  
                 6  
                 31  
                 59  
                 84  
                 96  
                 0.2  
               
               
                   
                 541952  
                 0  
                 0  
                 50  
                 72  
                 92  
                 0.5  
               
               
                   
                 541953  
                 0  
                 22  
                 50  
                 80  
                 92  
                 0.4  
               
               
                   
                 541914  
                 0  
                 0  
                 46  
                 76  
                 93  
                 0.4  
               
               
                   
                 541880  
                 0  
                 13  
                 48  
                 79  
                 89  
                 0.4 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
               
               
               
               
               
               
               
             
               
                   
                 TABLE 82 
               
               
                   
                   
               
               
                   
                   
                 0.04  
                 0.11  
                 0.33  
                 1.00  
                 3.00  
                 IC 50    
               
               
                   
                 ISIS No  
                 μM  
                 μM  
                 μM  
                 μM  
                 μM  
                 (μM) 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                 539380  
                 0  
                 5  
                 53  
                 78  
                 94  
                 0.4  
               
               
                   
                 541903  
                 12  
                 20  
                 26  
                 62  
                 88  
                 0.5  
               
               
                   
                 541895  
                 3  
                 12  
                 29  
                 66  
                 92  
                 0.5  
               
               
                   
                 541882  
                 2  
                 0  
                 27  
                 65  
                 86  
                 0.7  
               
               
                   
                 541889  
                 12  
                 12  
                 47  
                 68  
                 87  
                 0.4  
               
               
                   
                 541930  
                 0  
                 6  
                 40  
                 59  
                 85  
                 0.6  
               
               
                   
                 541985  
                 0  
                 16  
                 41  
                 66  
                 93  
                 0.4  
               
               
                   
                 542031  
                 1  
                 0  
                 22  
                 55  
                 80  
                 0.8  
               
               
                   
                 541972  
                 0  
                 1  
                 23  
                 46  
                 83  
                 0.9  
               
               
                   
                 541991  
                 4  
                 35  
                 42  
                 67  
                 89  
                 0.4  
               
               
                   
                 542052  
                 5  
                 28  
                 70  
                 92  
                 98  
                 0.2  
               
               
                   
                 542080  
                 0  
                 18  
                 54  
                 87  
                 96  
                 0.3  
               
               
                   
                 542051  
                 0  
                 18  
                 52  
                 86  
                 97  
                 0.3  
               
               
                   
                 542071  
                 5  
                 3  
                 51  
                 74  
                 95  
                 0.4  
               
               
                   
                 542069  
                 0  
                 7  
                 56  
                 85  
                 94  
                 0.3 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
               
               
               
               
               
               
               
             
               
                   
                 TABLE 83 
               
               
                   
                   
               
               
                   
                   
                 0.04  
                 0.11  
                 0.33  
                 1.00  
                 3.00  
                 IC 50    
               
               
                   
                 ISIS No  
                 μM  
                 μM  
                 μM  
                 μM  
                 μM  
                 (μM) 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                 539380  
                 11  
                 20  
                 54  
                 89  
                 92  
                 0.3  
               
               
                   
                 542053  
                 6  
                 14  
                 38  
                 69  
                 74  
                 0.6  
               
               
                   
                 542186  
                 14  
                 43  
                 70  
                 90  
                 98  
                 0.2  
               
               
                   
                 542185  
                 0  
                 26  
                 48  
                 80  
                 96  
                 0.3  
               
               
                   
                 545333  
                 0  
                 4  
                 27  
                 65  
                 90  
                 0.6  
               
               
                   
                 545336  
                 0  
                 15  
                 24  
                 43  
                 79  
                 0.9  
               
               
                   
                 545373  
                 0  
                 2  
                 9  
                 42  
                 86  
                 1.0  
               
               
                   
                 545438  
                 0  
                 24  
                 56  
                 81  
                 92  
                 0.3  
               
               
                   
                 545431  
                 0  
                 18  
                 50  
                 73  
                 91  
                 0.4  
               
               
                   
                 545447  
                 0  
                 15  
                 34  
                 78  
                 93  
                 0.4  
               
               
                   
                 545417  
                 0  
                 11  
                 39  
                 66  
                 87  
                 0.5  
               
               
                   
                 545467  
                 12  
                 16  
                 37  
                 76  
                 93  
                 0.4  
               
               
                   
                 545441  
                 21  
                 15  
                 20  
                 60  
                 87  
                 0.6  
               
               
                   
                 545439  
                 17  
                 24  
                 49  
                 82  
                 91  
                 0.3 
               
               
                   
                   
               
            
           
         
       
     
     Example 10: Dose-Dependent Antisense Inhibition of Rhesus Monkey GHR in LLC-MK2 Cells 
     Gapmers from studies described above exhibiting significant in vitro inhibition of GHR mRNA were selected and tested for their potency for rhesus GHR mRNA in LLC-MK2 cells. Cells were plated at a density of 20,000 cells per well and transfected using electroporation with 0.12 μM, 0.37 μM, 1.11 μM, 3.33 μM, and 10.00 μM concentrations of antisense oligonucleotide. After a treatment period of approximately 16 hours, RNA was isolated from the cells and GHR mRNA levels were measured by quantitative real-time PCR. Primer probe set RTS3437_MGB was used to measure mRNA levels. GHR mRNA levels were adjusted according to total RNA content, as measured by RIBOGREEN®. Results are presented as percent inhibition of GHR, relative to untreated control cells. 
     The half maximal inhibitory concentration (IC 50 ) of each oligonucleotide is also presented. GHR mRNA levels were significantly reduced in a dose-dependent manner in antisense oligonucleotide treated cells. 
     
       
         
           
               
               
               
               
               
               
               
               
             
               
                 TABLE 84 
               
               
                   
               
               
                   
                   
                 0.12  
                 0.37  
                 1.11  
                 3.33  
                 10.00  
                 IC 50    
               
               
                 ISIS No  
                 Chemistry  
                 μM  
                 μM  
                 μM  
                 μM  
                 μM  
                 (μM) 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 541262  
                 Deoxy, MOE and  
                 9  
                 25  
                 42  
                 85  
                 91  
                 1.1  
               
               
                   
                 cEt  
                   
                   
                   
                   
                   
                   
               
               
                 541742  
                 Deoxy, MOE and  
                 0  
                 24  
                 19  
                 58  
                 77  
                 3.2  
               
               
                   
                 cEt  
                   
                   
                   
                   
                   
                   
               
               
                 541767  
                 Deoxy, MOE and  
                 6  
                 10  
                 30  
                 68  
                 88  
                 2.0  
               
               
                   
                 cEt  
                   
                   
                   
                   
                   
                   
               
               
                 541875  
                 Deoxy, MOE and  
                 7  
                 19  
                 64  
                 84  
                 96  
                 0.9  
               
               
                   
                 cEt  
                   
                   
                   
                   
                   
                   
               
               
                 541881  
                 Deoxy, MOE and  
                 6  
                 24  
                 59  
                 79  
                 91  
                 1.0  
               
               
                   
                 cEt  
                   
                   
                   
                   
                   
                   
               
               
                 542101  
                 Deoxy, MOE and  
                 0  
                 5  
                 38  
                 71  
                 81  
                 2.0  
               
               
                   
                 cEt  
                   
                   
                   
                   
                   
                   
               
               
                 542112  
                 Deoxy, MOE and  
                 5  
                 17  
                 33  
                 67  
                 76  
                 2.0  
               
               
                   
                 cEt  
                   
                   
                   
                   
                   
                   
               
               
                 542118  
                 Deoxy, MOE and  
                 1  
                 6  
                 35  
                 68  
                 86  
                 2.0  
               
               
                   
                 cEt  
                   
                   
                   
                   
                   
                   
               
               
                 542125  
                 Deoxy, MOE and  
                 0  
                 12  
                 57  
                 83  
                 93  
                 1.0  
               
               
                   
                 cEt  
                   
                   
                   
                   
                   
                   
               
               
                 542127  
                 Deoxy, MOE and  
                 1  
                 0  
                 30  
                 68  
                 84  
                 2.4  
               
               
                   
                 cEt  
                   
                   
                   
                   
                   
                   
               
               
                 542128  
                 Deoxy, MOE and  
                 12  
                 0  
                 26  
                 58  
                 83  
                 2.7  
               
               
                   
                 cEt  
                   
                   
                   
                   
                   
                   
               
               
                 542153  
                 Deoxy, MOE and  
                 4  
                 0  
                 0  
                 36  
                 59  
                 6.6  
               
               
                   
                 cEt  
                   
                   
                   
                   
                   
                   
               
               
                 542185  
                 Deoxy, MOE and  
                 4  
                 0  
                 25  
                 56  
                 87  
                 2.5  
               
               
                   
                 cEt  
                   
                   
                   
                   
                   
                   
               
               
                 542186  
                 Deoxy, MOE and  
                 15  
                 23  
                 51  
                 73  
                 90  
                 1.1  
               
               
                   
                 cEt  
                   
                   
                   
                   
                   
                   
               
               
                 542051  
                 Deoxy, MOE and  
                 5  
                 19  
                 40  
                 81  
                 94  
                 1.2  
               
               
                   
                 cEt 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
               
               
               
               
               
               
               
             
               
                 TABLE 85 
               
               
                   
               
               
                   
                   
                 0.12  
                 0.37  
                 1.11  
                 3.33  
                 10.00  
                 IC 50    
               
               
                 ISIS No  
                 Chemistry  
                 μM  
                 μM  
                 μM  
                 μM  
                 μM  
                 (μM) 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 523723  
                 5-10-5 MOE  
                 23  
                 14  
                 31  
                 43  
                 71  
                 3.5  
               
               
                 532254  
                 5-10-5 MOE  
                 29  
                 35  
                 42  
                 69  
                 87  
                 0.8  
               
               
                 532401  
                 5-10-5 MOE  
                 27  
                 28  
                 46  
                 73  
                 88  
                 1.2  
               
               
                 533932  
                 5-10-5 MOE  
                 10  
                 24  
                 48  
                 70  
                 92  
                 1.2  
               
               
                 539376  
                 3-10-4 MOE  
                 21  
                 8  
                 8  
                 35  
                 81  
                 4.3  
               
               
                 539399  
                 3-10-4 MOE  
                 2  
                 10  
                 14  
                 18  
                 57  
                 8.3  
               
               
                 539404  
                 3-10-4 MOE  
                 39  
                 12  
                 25  
                 27  
                 57  
                 7.7  
               
               
                 539416  
                 3-10-4 MOE  
                 24  
                 35  
                 44  
                 79  
                 89  
                 1.0  
               
               
                 539432  
                 3-10-4 MOE  
                 9  
                 29  
                 42  
                 73  
                 89  
                 1.2  
               
               
                 541262  
                 Deoxy, MOE  
                 0  
                 43  
                 63  
                 88  
                 94  
                 0.8  
               
               
                   
                 and cEt  
                   
                   
                   
                   
                   
                   
               
               
                 541742  
                 Deoxy, MOE  
                 3  
                 19  
                 35  
                 56  
                 85  
                 1.9  
               
               
                   
                 and cEt  
                   
                   
                   
                   
                   
                   
               
               
                 541767  
                 Deoxy, MOE  
                 3  
                 24  
                 39  
                 64  
                 86  
                 1.6  
               
               
                   
                 and cEt  
                   
                   
                   
                   
                   
                   
               
               
                 545439  
                 Deoxy, MOE  
                 19  
                 15  
                 43  
                 74  
                 80  
                 1.7  
               
               
                   
                 and cEt  
                   
                   
                   
                   
                   
                   
               
               
                 545447  
                 Deoxy, MOE  
                 25  
                 34  
                 58  
                 80  
                 90  
                 0.6  
               
               
                   
                 and cEt 
               
               
                   
               
            
           
         
       
     
     Example 11: Dose-Dependent Antisense Inhibition of GHR in Cynomolgus Primary Hepatocytes 
     Gapmers from studies described above exhibiting significant in vitro inhibition of GHR mRNA were selected and tested for their potency for GHR mRNA in cynomolgus monkey primary hepatocytes. Cells were plated at a density of 20,000 cells per well and transfected using electroporation with 0.12 μM, 0.37 μM, 1.11 μM, 3.33 μM, and 10.00 μM concentrations of antisense oligonucleotide. After a treatment period of approximately 16 hours, RNA was isolated from the cells and GHR mRNA levels were measured by quantitative real-time PCR. Primer probe set RTS3437_MGB was used to measure mRNA levels. GHR mRNA levels were adjusted according to total RNA content, as measured by RIBOGREEN®. Results are presented as percent inhibition of GHR, relative to untreated control cells. 
     The half maximal inhibitory concentration (IC 50 ) of each oligonucleotide is also presented. GHR mRNA levels were significantly reduced in a dose-dependent manner in antisense oligonucleotide treated cells. 
     
       
         
           
               
               
               
               
               
               
               
               
             
               
                 TABLE 86 
               
               
                   
               
               
                   
                   
                 0.12  
                 0.37  
                 1.11  
                 3.33  
                 10.00  
                 IC 50    
               
               
                 ISIS No  
                 Chemistry  
                 μM  
                 μM  
                 μM  
                 μM  
                 μM  
                 (μM) 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 541262  
                 Deoxy, MOE  
                 40  
                 52  
                 75  
                 92  
                 98  
                 0.3  
               
               
                   
                 and cEt  
                   
                   
                   
                   
                   
                   
               
               
                 541742  
                 Deoxy, MOE  
                 40  
                 57  
                 51  
                 91  
                 96  
                 0.2  
               
               
                   
                 and cEt  
                   
                   
                   
                   
                   
                   
               
               
                 541767  
                 Deoxy, MOE  
                 36  
                 59  
                 60  
                 78  
                 91  
                 0.4  
               
               
                   
                 and cEt  
                   
                   
                   
                   
                   
                   
               
               
                 541875  
                 Deoxy, MOE  
                 54  
                 76  
                 88  
                 95  
                 95  
                 &lt;0.1  
               
               
                   
                 and cEt  
                   
                   
                   
                   
                   
                   
               
               
                 541881  
                 Deoxy, MOE  
                 53  
                 75  
                 85  
                 98  
                 98  
                 &lt;0.1  
               
               
                   
                 and cEt  
                   
                   
                   
                   
                   
                   
               
               
                 542101  
                 Deoxy, MOE  
                 38  
                 55  
                 78  
                 89  
                 97  
                 0.2  
               
               
                   
                 and cEt  
                   
                   
                   
                   
                   
                   
               
               
                 542112  
                 Deoxy, MOE  
                 28  
                 50  
                 74  
                 89  
                 96  
                 0.4  
               
               
                   
                 and cEt  
                   
                   
                   
                   
                   
                   
               
               
                 542118  
                 Deoxy, MOE  
                 20  
                 45  
                 69  
                 84  
                 91  
                 0.5  
               
               
                   
                 and cEt  
                   
                   
                   
                   
                   
                   
               
               
                 542125  
                 Deoxy, MOE  
                 33  
                 62  
                 77  
                 92  
                 97  
                 0.3  
               
               
                   
                 and cEt  
                   
                   
                   
                   
                   
                   
               
               
                 542127  
                 Deoxy, MOE  
                 30  
                 50  
                 65  
                 86  
                 92  
                 0.4  
               
               
                   
                 and cEt  
                   
                   
                   
                   
                   
                   
               
               
                 542128  
                 Deoxy, MOE  
                 25  
                 40  
                 52  
                 80  
                 93  
                 0.7  
               
               
                   
                 and cEt  
                   
                   
                   
                   
                   
                   
               
               
                 542153  
                 Deoxy, MOE  
                 10  
                 31  
                 51  
                 73  
                 85  
                 1.0  
               
               
                   
                 and cEt  
                   
                   
                   
                   
                   
                   
               
               
                 542185  
                 Deoxy, MOE  
                 12  
                 45  
                 65  
                 85  
                 93  
                 0.6  
               
               
                   
                 and cEt  
                   
                   
                   
                   
                   
                   
               
               
                 542186  
                 Deoxy, MOE  
                 36  
                 54  
                 74  
                 90  
                 96  
                 0.3  
               
               
                   
                 and cEt  
                   
                   
                   
                   
                   
                   
               
               
                 542051  
                 Deoxy, MOE  
                 9  
                 29  
                 32  
                 32  
                 42  
                 &gt;10  
               
               
                   
                 and cEt 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
               
               
               
               
               
               
               
             
               
                 TABLE 87 
               
               
                   
               
               
                   
                   
                 0.12  
                 0.37  
                 1.11  
                 3.33  
                 10.00  
                 IC 50    
               
               
                 ISIS No  
                 Chemistry  
                 μM  
                 μM  
                 μM  
                 μM  
                 μM  
                 (μM) 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 523435  
                 5-10-5  
                 35  
                 47  
                 61  
                 74  
                 85  
                 0.5  
               
               
                   
                 MOE  
                   
                   
                   
                   
                   
                   
               
               
                 523723  
                 5-10-5  
                 4  
                 16  
                 40  
                 66  
                 86  
                 1.8  
               
               
                   
                 MOE  
                   
                   
                   
                   
                   
                   
               
               
                 532254  
                 5-10-5  
                 14  
                 15  
                 24  
                 16  
                 9  
                 &gt;10  
               
               
                   
                 MOE  
                   
                   
                   
                   
                   
                   
               
               
                 532401  
                 5-10-5  
                 37  
                 54  
                 73  
                 88  
                 94  
                 0.3  
               
               
                   
                 MOE  
                   
                   
                   
                   
                   
                   
               
               
                 533932  
                 5-10-5  
                 23  
                 40  
                 69  
                 78  
                 86  
                 0.6  
               
               
                   
                 MOE  
                   
                   
                   
                   
                   
                   
               
               
                 539376  
                 3-10-4  
                 3  
                 0  
                 44  
                 65  
                 91  
                 2.0  
               
               
                   
                 MOE  
                   
                   
                   
                   
                   
                   
               
               
                 539399  
                 3-10-4  
                 0  
                 0  
                 9  
                 42  
                 67  
                 5.0  
               
               
                   
                 MOE  
                   
                   
                   
                   
                   
                   
               
               
                 539404  
                 3-10-4  
                 0  
                 0  
                 26  
                 52  
                 71  
                 3.5  
               
               
                   
                 MOE  
                   
                   
                   
                   
                   
                   
               
               
                 539416  
                 3-10-4  
                 8  
                 29  
                 62  
                 89  
                 93  
                 0.7  
               
               
                   
                 MOE  
                   
                   
                   
                   
                   
                   
               
               
                 539432  
                 3-10-4  
                 0  
                 24  
                 55  
                 85  
                 93  
                 0.9  
               
               
                   
                 MOE  
                   
                   
                   
                   
                   
                   
               
               
                 541262  
                 Deoxy,  
                 23  
                 52  
                 73  
                 92  
                 96  
                 0.4  
               
               
                   
                 MOE and  
                   
                   
                   
                   
                   
                   
               
               
                   
                 cEt  
                   
                   
                   
                   
                   
                   
               
               
                 541742  
                 Deoxy,  
                 15  
                 51  
                 73  
                 86  
                 97  
                 0.5  
               
               
                   
                 MOE and  
                   
                   
                   
                   
                   
                   
               
               
                   
                 cEt  
                   
                   
                   
                   
                   
                   
               
               
                 541767  
                 Deoxy,  
                 19  
                 20  
                 39  
                 68  
                 81  
                 1.8  
               
               
                   
                 MOE and  
                   
                   
                   
                   
                   
                   
               
               
                   
                 cEt  
                   
                   
                   
                   
                   
                   
               
               
                 545439  
                 Deoxy,  
                 0  
                 0  
                 30  
                 61  
                 90  
                 2.4  
               
               
                   
                 MOE and  
                   
                   
                   
                   
                   
                   
               
               
                   
                 cEt  
                   
                   
                   
                   
                   
                   
               
               
                 545447  
                 Deoxy,  
                 0  
                 17  
                 17  
                 19  
                 27  
                 &gt;10  
               
               
                   
                 MOE and  
                   
                   
                   
                   
                   
                   
               
               
                   
                 cEt 
               
               
                   
               
            
           
         
       
     
     Example 12: Dose-Dependent Antisense Inhibition of GHR in Hep3B Cells 
     Gapmers from studies described above exhibiting significant in vitro inhibition of GHR mRNA were selected and tested for their potency for GHR mRNA at various doses in Hep3B cells. Cells were plated at a density of 20,000 cells per well and transfected using electroporation with 0.12 μM, 0.37 μM, 1.11 μM, 3.33 μM, and 10.00 μM concentrations of antisense oligonucleotide. After a treatment period of approximately 16 hours, RNA was isolated from the cells and GHR mRNA levels were measured by quantitative real-time PCR. Human primer probe set RTS3437_MGB was used to measure mRNA levels. GHR mRNA levels were adjusted according to total RNA content, as measured by RIBOGREEN®. Results are presented as percent inhibition of GHR, relative to untreated control cells. 
     The half maximal inhibitory concentration (IC 50 ) of each oligonucleotide is also presented. GHR mRNA levels were significantly reduced in a dose-dependent manner in antisense oligonucleotide treated cells. 
     
       
         
           
               
               
               
               
               
               
               
             
               
                 TABLE 88 
               
               
                   
               
               
                   
                 0.12  
                 0.37  
                 1.11  
                 3.33  
                 10.00  
                 IC 50    
               
               
                 ISIS No  
                 μM  
                 μM  
                 μM  
                 μM  
                 μM  
                 (μM) 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                 541262  
                 25  
                 43  
                 76  
                 85  
                 94  
                 0.5  
               
               
                 541742  
                 32  
                 55  
                 76  
                 88  
                 97  
                 0.3  
               
               
                 541767  
                 29  
                 56  
                 83  
                 89  
                 97  
                 0.3  
               
               
                 541875  
                 38  
                 68  
                 84  
                 93  
                 94  
                 0.1  
               
               
                 541881  
                 32  
                 57  
                 81  
                 94  
                 97  
                 0.3  
               
               
                 542051  
                 34  
                 66  
                 83  
                 95  
                 98  
                 0.2  
               
               
                 542101  
                 25  
                 55  
                 85  
                 95  
                 98  
                 0.3  
               
               
                 542112  
                 18  
                 56  
                 83  
                 95  
                 98  
                 0.4  
               
               
                 542118  
                 42  
                 61  
                 88  
                 95  
                 97  
                 0.1  
               
               
                 542125  
                 30  
                 63  
                 87  
                 95  
                 98  
                 0.2  
               
               
                 542127  
                 50  
                 70  
                 91  
                 91  
                 98  
                 0.1  
               
               
                 542128  
                 38  
                 63  
                 88  
                 96  
                 98  
                 0.2  
               
               
                 542153  
                 37  
                 59  
                 85  
                 94  
                 97  
                 0.2  
               
               
                 542185  
                 44  
                 51  
                 76  
                 89  
                 96  
                 0.2  
               
               
                 542186  
                 46  
                 59  
                 84  
                 95  
                 97  
                 0.1 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
               
               
               
               
               
               
             
               
                 TABLE 89 
               
               
                   
               
               
                   
                 0.12  
                 0.37  
                 1.11  
                 3.33  
                 10.00  
                 IC 50    
               
               
                 ISIS No  
                 μM  
                 μM  
                 μM  
                 μM  
                 μM  
                 (μM) 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                 523435  
                 9  
                 26  
                 49  
                 78  
                 93  
                 1.0  
               
               
                 523723  
                 7  
                 16  
                 39  
                 72  
                 90  
                 1.4  
               
               
                 532254  
                 36  
                 46  
                 69  
                 86  
                 94  
                 0.4  
               
               
                 532401  
                 25  
                 54  
                 71  
                 86  
                 91  
                 0.4  
               
               
                 533932  
                 8  
                 47  
                 69  
                 80  
                 94  
                 0.7  
               
               
                 539376  
                 26  
                 31  
                 54  
                 73  
                 86  
                 0.8  
               
               
                 539399  
                 23  
                 43  
                 72  
                 89  
                 94  
                 0.5  
               
               
                 539404  
                 30  
                 60  
                 88  
                 95  
                 98  
                 0.2  
               
               
                 539416  
                 30  
                 59  
                 84  
                 93  
                 98  
                 0.3  
               
               
                 539432  
                 35  
                 62  
                 88  
                 95  
                 98  
                 0.2  
               
               
                 541262  
                 43  
                 60  
                 84  
                 89  
                 98  
                 0.2  
               
               
                 541742  
                 23  
                 53  
                 73  
                 84  
                 97  
                 0.4  
               
               
                 541767  
                 22  
                 49  
                 74  
                 85  
                 92  
                 0.4  
               
               
                 545439  
                 41  
                 69  
                 88  
                 95  
                 96  
                 0.1  
               
               
                 545447  
                 31  
                 47  
                 63  
                 74  
                 82  
                 0.5 
               
               
                   
               
            
           
         
       
     
     Example 13: Dose-Dependent Antisense Inhibition of GHR in Cynomolgus Primary Hepatocytes 
     Gapmers from studies described above exhibiting significant in vitro inhibition of GHR mRNA were selected and tested at various doses in cynomolgous monkey primary hepatocytes. Cells were plated at a density of 35,000 cells per well and transfected using electroporation with 0.04 μM, 0.12 μM, 0.37 μM, 1.11 μM, 3.33 μM, and 10.00 μM concentrations of antisense oligonucleotide. After a treatment period of approximately 16 hours, RNA was isolated from the cells and GHR mRNA levels were measured by quantitative real-time PCR. Primer probe set RTS3437_MGB was used to measure mRNA levels. GHR mRNA levels were adjusted according to total RNA content, as measured by RIBOGREEN®. Results are presented as percent inhibition of GHR, relative to untreated control cells. 
     The half maximal inhibitory concentration (IC 50 ) of each oligonucleotide is also presented. GHR mRNA levels were significantly reduced in a dose-dependent manner in antisense oligonucleotide treated cells. 
     
       
         
           
               
               
               
               
               
               
               
               
             
               
                 TABLE 90 
               
               
                   
               
               
                   
                 0.04  
                 0.12  
                 0.37  
                 1.11  
                 3.33  
                 10.00  
                 IC 50    
               
               
                 ISIS No  
                 μM  
                 μM  
                 μM  
                 μM  
                 μM  
                 μM  
                 (μM) 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 541767  
                 8  
                 17  
                 29  
                 48  
                 59  
                 58  
                 0.4  
               
               
                 541875  
                 20  
                 39  
                 48  
                 51  
                 55  
                 58  
                 0.2  
               
               
                 541881  
                 23  
                 36  
                 49  
                 60  
                 56  
                 58  
                 0.1  
               
               
                 542112  
                 23  
                 21  
                 35  
                 42  
                 54  
                 68  
                 0.5  
               
               
                 542118  
                 19  
                 14  
                 26  
                 38  
                 54  
                 59  
                 0.8  
               
               
                 542153  
                 17  
                 20  
                 27  
                 39  
                 46  
                 52  
                 2.2  
               
               
                 542185  
                 20  
                 23  
                 27  
                 46  
                 39  
                 56  
                 2.0  
               
               
                 532254  
                 1  
                 20  
                 23  
                 11  
                 1  
                 23  
                 &gt;10  
               
               
                 532401  
                 0  
                 15  
                 24  
                 39  
                 47  
                 55  
                 1.6  
               
               
                 523723  
                 0  
                 0  
                 7  
                 24  
                 49  
                 54  
                 2.0 
               
               
                   
               
            
           
         
       
     
     Example 14: Comparative Analysis of Dose-Dependent Antisense Inhibition of GHR in Hep3B Cells 
     ISIS 532401 was compared with specific antisense oligonucleotides disclosed in US 2006/0178325 by testing at various doses in Hep3B cells. The oligonucleotides were selected based on the potency demonstrated in studies described in the application. Cells were plated at a density of 20,000 cells per well and transfected using electroporation with 0.11 μM, 0.33 μM, 1.00 μM, 1.11 μM, 3.00 μM, and 9.00 μM concentrations of antisense oligonucleotide. After a treatment period of approximately 16 hours, RNA was isolated from the cells and GHR mRNA levels were measured by quantitative real-time PCR. Human primer probe set RTS3437_MGB was used to measure mRNA levels. GHR mRNA levels were adjusted according to total RNA content, as measured by RIBOGREEN©. Results are presented as percent inhibition of GHR, relative to untreated control cells. 
     The half maximal inhibitory concentration (IC 50 ) of each oligonucleotide is also presented. The results indicate that ISIS 532401 was markedly more potent than the most potent oligonucleotides of US 2006/0178325. 
     
       
         
           
               
               
               
               
               
               
               
             
               
                 TABLE 91 
               
               
                   
               
               
                   
                 0.11  
                 0.33  
                 1.00  
                 3.00  
                 9.00  
                 IC 50    
               
               
                 ISIS No  
                 μM  
                 μM  
                 μM  
                 μM  
                 μM  
                 (μM) 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                 227452  
                 11  
                 12  
                 46  
                 73  
                 92  
                 1.4  
               
               
                 227488  
                 26  
                 25  
                 39  
                 76  
                 88  
                 1.2  
               
               
                 272309  
                 16  
                 14  
                 39  
                 66  
                 91  
                 1.6  
               
               
                 272322  
                 13  
                 20  
                 44  
                 70  
                 86  
                 1.4  
               
               
                 272328  
                 22  
                 20  
                 24  
                 43  
                 56  
                 5.7  
               
               
                 272338  
                 22  
                 24  
                 52  
                 71  
                 85  
                 1.1  
               
               
                 532401  
                 34  
                 53  
                 72  
                 87  
                 94  
                 0.3 
               
               
                   
               
            
           
         
       
     
     Example 15: Tolerability of 5-10-5 MOE Gapmers Targeting Human GHR in CD1 Mice 
     CD1 ® mice (Charles River, Mass.) are a multipurpose mice model, frequently utilized for safety and efficacy testing. The mice were treated with ISIS antisense oligonucleotides selected from studies described above and evaluated for changes in the levels of various plasma chemistry markers. 
     Treatment 
     Groups of eight- to ten-week old male CD1 mice were injected subcutaneously twice a week for 6 weeks with 50 mg/kg of ISIS oligonucleotides (100 mg/kg/week dose). One group of male CD1 mice was injected subcutaneously twice a week for 6 weeks with PBS. Mice were euthanized 48 hours after the last dose, and organs and plasma were harvested for further analysis. 
     Plasma Chemistry Markers 
     To evaluate the effect of ISIS oligonucleotides on liver and kidney function, plasma levels of transaminases, bilirubin, creatinine, and BUN were measured using an automated clinical chemistry analyzer (Hitachi Olympus AU400e, Melville, N.Y.). The results are presented in Table 92. ISIS oligonucleotides that caused changes in the levels of any of the liver or kidney function markers outside the expected range for antisense oligonucleotides were excluded in further studies. 
     
       
         
           
               
             
               
                 TABLE 92 
               
             
            
               
                   
               
               
                 Plasma chemistry markers in CD1 mice plasma at week 6  
               
            
           
           
               
               
               
               
               
               
            
               
                   
                 ALT  
                 AST  
                 Bilirubin  
                 Creatinine  
                 BUN  
               
               
                   
                 (IU/L)  
                 (IU/L)  
                 (mg/dL)  
                 (mg/dL)  
                 (mg/dL) 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 PBS  
                 31  
                 50  
                 0.28  
                 0.15  
                 28  
               
               
                 ISIS 523271  
                 366  
                 285  
                 0.18  
                 0.11  
                 29  
               
               
                 ISIS 523324  
                 222  
                 139  
                 0.19  
                 0.10  
                 31  
               
               
                 ISIS 523604  
                 2106  
                 1157  
                 0.41  
                 0.06  
                 48  
               
               
                 ISIS 532254  
                 66  
                 84  
                 0.11  
                 0.10  
                 27  
               
               
                 ISIS 533121  
                 176  
                 155  
                 0.19  
                 0.09  
                 27  
               
               
                 ISIS 533161  
                 1094  
                 904  
                 0.23  
                 0.07  
                 29  
               
               
                 ISIS 533178  
                 78  
                 83  
                 0.18  
                 0.08  
                 28  
               
               
                 ISIS 533234  
                 164  
                 147  
                 0.21  
                 0.09  
                 26 
               
               
                   
               
            
           
         
       
     
     Hematology Assays 
     Blood obtained from all mice groups were sent to Antech Diagnostics for hematocrit (HCT) measurements and analysis, as well as measurements of the various blood cells, such as WBC, RBC, and platelets, and total hemoglobin content. The results are presented in Table 93. ISIS oligonucleotides that caused changes in the levels of any of the hematology markers outside the expected range for antisense oligonucleotides were excluded in further studies. 
     
       
         
           
               
             
               
                 TABLE 93 
               
             
            
               
                   
               
               
                 Hematology markers in CD1 mice plasma at week 6  
               
            
           
           
               
               
               
               
               
               
            
               
                   
                 HCT  
                 Hemoglobin  
                 RBC  
                 WBC  
                 Platelets  
               
               
                   
                 (%)  
                 (g/dL)  
                 (10 6 /μL)  
                 (10 3 /μL)  
                 (10 3 /μL) 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 PBS  
                 45  
                 13  
                 8.2  
                 4.1  
                 689  
               
               
                 ISIS 523271  
                 42  
                 12  
                 7.9  
                 4.5  
                 1181  
               
               
                 ISIS 523324  
                 39  
                 11  
                 7.5  
                 7.9  
                 980  
               
               
                 ISIS 523604  
                 33  
                 10  
                 6.9  
                 14.1  
                 507  
               
               
                 ISIS 532254  
                 35  
                 10  
                 6.9  
                 7.2  
                 861  
               
               
                 ISIS 533121  
                 39  
                 12  
                 7.9  
                 8.4  
                 853  
               
               
                 ISIS 533161  
                 49  
                 14  
                 9.3  
                 9.0  
                 607  
               
               
                 ISIS 533178  
                 44  
                 13  
                 8.5  
                 6.9  
                 765  
               
               
                 ISIS 533234  
                 42  
                 12  
                 7.8  
                 9.2  
                 1045 
               
               
                   
               
            
           
         
       
     
     Example 16: Tolerability of 5-10-5 MOE Gapmers Targeting Human GHR in CD1 Mice 
     CD1 @ mice were treated with ISIS antisense oligonucleotides selected from studies described above and evaluated for changes in the levels of various plasma chemistry markers. 
     Treatment 
     Groups of eight- to ten-week old male CD1 mice were injected subcutaneously twice a week for 6 weeks with 50 mg/kg of ISIS oligonucleotide (100 mg/kg/week dose). One group of male CD1 mice was injected subcutaneously twice a week for 6 weeks with PBS. Mice were euthanized 48 hours after the last dose, and organs and plasma were harvested for further analysis. 
     Plasma Chemistry Markers 
     To evaluate the effect of ISIS oligonucleotides on liver and kidney function, plasma levels of transaminases, bilirubin, creatinine, and BUN were measured using an automated clinical chemistry analyzer (Hitachi Olympus AU400e, Melville, N.Y.). The results are presented in Table 94. ISIS oligonucleotides that caused changes in the levels of any of the liver or kidney function markers outside the expected range for antisense oligonucleotides were excluded in further studies. 
     
       
         
           
               
             
               
                 TABLE 94 
               
             
            
               
                   
               
               
                 Plasma chemistry markers in CD1 mice plasma at week 6  
               
            
           
           
               
               
               
               
               
               
            
               
                   
                 ALT  
                 AST  
                 Bilirubin  
                 Creatinine  
                 BUN  
               
               
                   
                 (IU/L)  
                 (IU/L)  
                 (mg/dL)  
                 (mg/dL)  
                 (mg/dL) 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 PBS  
                 30  
                 59  
                 0.26  
                 0.14  
                 20  
               
               
                 ISIS 523715  
                 636  
                 505  
                 0.24  
                 0.14  
                 22  
               
               
                 ISIS 523723  
                 57  
                 80  
                 0.20  
                 0.16  
                 23  
               
               
                 ISIS 523726  
                 165  
                 167  
                 0.18  
                 0.15  
                 23  
               
               
                 ISIS 523736  
                 140  
                 177  
                 0.20  
                 0.15  
                 23  
               
               
                 ISIS 523747  
                 96  
                 108  
                 0.17  
                 0.14  
                 23  
               
               
                 ISIS 523789  
                 45  
                 74  
                 0.20  
                 0.15  
                 22  
               
               
                 ISIS 532395  
                 64  
                 ill  
                 0.23  
                 0.12  
                 21  
               
               
                 ISIS 532401  
                 47  
                 88  
                 0.21  
                 0.17  
                 22  
               
               
                 ISIS 532411  
                 225  
                 426  
                 0.17  
                 0.16  
                 22  
               
               
                 ISIS 532420  
                 60  
                 99  
                 0.21  
                 0.12  
                 25  
               
               
                 ISIS 532468  
                 319  
                 273  
                 0.15  
                 0.14  
                 21  
               
               
                 ISIS 533932  
                 62  
                 81  
                 0.18  
                 0.14  
                 21 
               
               
                   
               
            
           
         
       
     
     Hematology Assays 
     Blood obtained from all mice groups were sent to Antech Diagnostics for hematocrit (HCT) measurements and analysis, as well as measurements of the various blood cells, such as WB), RBC, and platelets, and total hemoglobin content. The results are presented in Table 95. ISIS oligonucleotides that caused changes in the levels of any of the hematology markers outside the expected range for antisense oligonucleotides were excluded in further studies. 
     
       
         
           
               
             
               
                 TABLE 95 
               
             
            
               
                   
               
               
                 Hematology markers in CD1 mice plasma at week 6  
               
            
           
           
               
               
               
               
               
               
            
               
                   
                 HCT  
                 Hemoglobin  
                 RBC  
                 WBC  
                 Platelets  
               
               
                   
                 (%)  
                 (g/dL)  
                 (10 6 /μL)  
                 (10 3 /μL)  
                 (10 3 /μL) 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 PBS  
                 43  
                 13  
                 8.1  
                 3.3  
                 1047  
               
               
                 ISIS 523715  
                 40  
                 12  
                 8.1  
                 4.2  
                 1153  
               
               
                 ISIS 523723  
                 35  
                 11  
                 6.8  
                 2.9  
                 1154  
               
               
                 ISIS 523726  
                 32  
                 10  
                 6.8  
                 5.8  
                 1056  
               
               
                 ISIS 523736  
                 35  
                 11  
                 7.1  
                 3.6  
                 1019  
               
               
                 ISIS 523747  
                 37  
                 11  
                 7.7  
                 2.8  
                 1146  
               
               
                 ISIS 523789  
                 37  
                 11  
                 7.3  
                 2.5  
                 1033  
               
               
                 ISIS 532395  
                 37  
                 11  
                 7.4  
                 4.5  
                 890  
               
               
                 ISIS 532401  
                 36  
                 11  
                 7.1  
                 3.7  
                 1175  
               
               
                 ISIS 532411  
                 27  
                 8  
                 5.3  
                 3.2  
                 641  
               
               
                 ISIS 532420  
                 35  
                 11  
                 7.0  
                 3.3  
                 1101  
               
               
                 ISIS 532468  
                 36  
                 11  
                 7.4  
                 4.0  
                 1043  
               
               
                 ISIS 533932  
                 36  
                 11  
                 7.2  
                 3.8  
                 981 
               
               
                   
               
            
           
         
       
     
     Example 17: Tolerability of 3-10-4 MOE Gapmers Targeting Human GHR in CD1 Mice 
     CD1® mice were treated with ISIS antisense oligonucleotides selected from studies described above and evaluated for changes in the levels of various plasma chemistry markers. 
     Treatment 
     Groups of eight- to ten-week old male CD1 mice were injected subcutaneously twice a week for 6 weeks with 50 mg/kg of ISIS oligonucleotide (100 mg/kg/week dose). One group of male CD1 mice was injected subcutaneously twice a week for 6 weeks with PBS. Mice were euthanized 48 hours after the last dose, and organs and plasma were harvested for further analysis. 
     Plasma Chemistry Markers 
     To evaluate the effect of ISIS oligonucleotides on liver and kidney function, plasma levels of transaminases, bilirubin, creatinine, and BUN were measured using an automated clinical chemistry analyzer (Hitachi Olympus AU400e, Melville, N.Y.). The results are presented in Table 96. ISIS oligonucleotides that caused changes in the levels of any of the liver or kidney function markers outside the expected range for antisense oligonucleotides were excluded in further studies. 
     
       
         
           
               
             
               
                 TABLE 96 
               
             
            
               
                   
               
               
                 Plasma chemistry markers in CD1 mice plasma at week 6  
               
            
           
           
               
               
               
               
               
               
            
               
                   
                 ALT  
                 AST  
                 Bilirubin  
                 Creatinine  
                 BUN  
               
               
                   
                 (IU/L)  
                 (IU/L)  
                 (mg/dL)  
                 (mg/dL)  
                 (mg/dL) 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 PBS  
                 48  
                 63  
                 0.20  
                 0.13  
                 28  
               
               
                 ISIS 539302  
                 204  
                 192  
                 0.15  
                 0.15  
                 24  
               
               
                 ISIS 539321  
                 726  
                 455  
                 0.17  
                 0.12  
                 27  
               
               
                 ISIS 539360  
                 3287  
                 2495  
                 0.58  
                 0.13  
                 22  
               
               
                 ISIS 539361  
                 310  
                 226  
                 0.17  
                 0.11  
                 21  
               
               
                 ISIS 539376  
                 77  
                 75  
                 0.14  
                 0.12  
                 27  
               
               
                 ISIS 539379  
                 134  
                 136  
                 0.16  
                 0.13  
                 24  
               
               
                 ISIS 539380  
                 180  
                 188  
                 0.14  
                 0.12  
                 23  
               
               
                 ISIS 539383  
                 80  
                 81  
                 0.15  
                 0.12  
                 25  
               
               
                 ISIS 539399  
                 119  
                 127  
                 0.13  
                 0.12  
                 24  
               
               
                 ISIS 539401  
                 1435  
                 1172  
                 0.24  
                 0.11  
                 24  
               
               
                 ISIS 539403  
                 1543  
                 883  
                 0.18  
                 0.12  
                 26  
               
               
                 ISIS 539404  
                 75  
                 109  
                 0.16  
                 0.13  
                 23  
               
               
                 ISIS 539416  
                 100  
                 107  
                 0.19  
                 0.15  
                 26  
               
               
                 ISIS 539432  
                 55  
                 64  
                 0.20  
                 0.14  
                 22  
               
               
                 ISIS 539433  
                 86  
                 91  
                 0.12  
                 0.13  
                 22 
               
               
                   
               
            
           
         
       
     
     Hematology Assays 
     Blood obtained from all mice groups were sent to Antech Diagnostics for hematocrit (HCT) measurements and analysis, as well as measurements of the various blood cells, such as WBC, RBC, and platelets, and total hemoglobin content. The results are presented in Table 97. ISIS oligonucleotides that caused changes in the levels of any of the hematology markers outside the expected range for antisense oligonucleotides were excluded in further studies. 
     
       
         
           
               
             
               
                 TABLE 97 
               
             
            
               
                   
               
               
                 Hematology markers in CD1 mice plasma at week 6  
               
            
           
           
               
               
               
               
               
               
            
               
                   
                 HCT  
                 Hemoglobin  
                 RBC  
                 WBC  
                 Platelets  
               
               
                   
                 (%)  
                 (g/dL)  
                 (10 6 /μL)  
                 (10 3 /μL)  
                 (10 3 /μL) 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 PBS  
                 46  
                 13  
                 8.5  
                 6  
                 954  
               
               
                 ISIS 539302  
                 40  
                 11  
                 8.1  
                 13  
                 830  
               
               
                 ISIS 539321  
                 39  
                 11  
                 7.8  
                 16  
                 723  
               
               
                 ISIS 539360  
                 49  
                 14  
                 9.0  
                 14  
                 671  
               
               
                 ISIS 539361  
                 45  
                 13  
                 8.5  
                 9  
                 893  
               
               
                 ISIS 539376  
                 42  
                 12  
                 7.7  
                 6  
                 988  
               
               
                 ISIS 539379  
                 42  
                 12  
                 8.1  
                 7  
                 795  
               
               
                 ISIS 539380  
                 38  
                 10  
                 7.7  
                 8  
                 950  
               
               
                 ISIS 539383  
                 45  
                 12  
                 8.4  
                 8  
                 795  
               
               
                 ISIS 539399  
                 41  
                 12  
                 8.0  
                 10  
                 895  
               
               
                 ISIS 539401  
                 41  
                 11  
                 8.2  
                 9  
                 897  
               
               
                 ISIS 539403  
                 33  
                 9  
                 6.2  
                 13  
                 1104  
               
               
                 ISIS 539404  
                 42  
                 12  
                 8.4  
                 7  
                 641  
               
               
                 ISIS 539416  
                 41  
                 11  
                 7.5  
                 5  
                 686  
               
               
                 ISIS 539432  
                 44  
                 12  
                 8.0  
                 6  
                 920  
               
               
                 ISIS 539433  
                 40  
                 11  
                 7.4  
                 6  
                 987 
               
               
                   
               
            
           
         
       
     
     Example 18: Tolerability of Deoxy, MOE and cEt Gapmers Targeting Human GHR in CD1 Mice 
     CD1@ mice were treated with ISIS antisense oligonucleotides selected from studies described above and evaluated for changes in the levels of various plasma chemistry markers. 
     Treatment 
     Groups of eight- to ten-week old male CD1 mice were injected subcutaneously twice a week for 6 weeks with 25 mg/kg of ISIS oligonucleotide (50 mg/kg/week dose). One group of male CD1 mice was injected subcutaneously twice a week for 6 weeks with PBS. Mice were euthanized 48 hours after the last dose, and organs and plasma were harvested for further analysis. 
     Plasma Chemistry Markers 
     To evaluate the effect of ISIS oligonucleotides on liver and kidney function, plasma levels of transaminases, bilirubin, creatinine, and BUN were measured using an automated clinical chemistry analyzer (Hitachi Olympus AU400e, Melville, N.Y.). The results are presented in Table 98. ISIS oligonucleotides that caused changes in the levels of any of the liver or kidney function markers outside the expected range for antisense oligonucleotides were excluded in further studies. 
     
       
         
           
               
             
               
                 TABLE 98 
               
             
            
               
                   
               
               
                 Plasma chemistry markers in CD1 mice plasma at week 6  
               
            
           
           
               
               
               
               
               
               
            
               
                   
                 ALT  
                 AST  
                 Bilirubin  
                 Creatinine  
                 BUN  
               
               
                   
                 (IU/L)  
                 (IU/L)  
                 (mg/dL)  
                 (mg/dL)  
                 (mg/dL) 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 PBS  
                 36  
                 71  
                 0.22  
                 0.18  
                 22  
               
               
                 ISIS 541262  
                 115  
                 133  
                 0.21  
                 0.18  
                 21  
               
               
                 ISIS 541724  
                 543  
                 531  
                 0.34  
                 0.17  
                 21  
               
               
                 ISIS 541742  
                 44  
                 71  
                 0.18  
                 0.16  
                 21  
               
               
                 ISIS 541748  
                 269  
                 582  
                 0.16  
                 0.15  
                 22  
               
               
                 ISIS 541749  
                 626  
                 491  
                 0.20  
                 0.20  
                 22  
               
               
                 ISIS 541750  
                 1531  
                 670  
                 0.20  
                 0.18  
                 23  
               
               
                 ISIS 541766  
                 2107  
                 1139  
                 0.21  
                 0.21  
                 23  
               
               
                 ISIS 541767  
                 42  
                 62  
                 0.21  
                 0.17  
                 20  
               
               
                 ISIS 541822  
                 493  
                 202  
                 0.13  
                 0.16  
                 22  
               
               
                 ISIS 541826  
                 889  
                 398  
                 0.21  
                 0.14  
                 17  
               
               
                 ISIS 541838  
                 266  
                 172  
                 0.16  
                 0.15  
                 20  
               
               
                 ISIS 541870  
                 445  
                 272  
                 0.23  
                 0.16  
                 23  
               
               
                 ISIS 541875  
                 103  
                 114  
                 0.20  
                 0.15  
                 20  
               
               
                 ISIS 541907  
                 940  
                 725  
                 0.16  
                 0.19  
                 35  
               
               
                 ISIS 541991  
                 1690  
                 1733  
                 0.31  
                 0.20  
                 23 
               
               
                   
               
            
           
         
       
     
     Hematology Assays 
     Blood obtained from all mice groups were sent to Antech Diagnostics for hematocrit (HCT) measurements and analysis, as well as measurements of the various blood cells, such as WBC, RBC, and platelets, and total hemoglobin content. The results are presented in Table 99. ISIS oligonucleotides that caused changes in the levels of any of the hematology markers outside the expected range for antisense oligonucleotides were excluded in further studies. 
     
       
         
           
               
             
               
                 TABLE 99 
               
             
            
               
                   
               
               
                 Hematology markers in CD1 mice plasma at week 6  
               
            
           
           
               
               
               
               
               
               
            
               
                   
                 HCT  
                 Hemoglobin  
                 RBC  
                 WBC  
                 Platelets  
               
               
                   
                 (%)  
                 (g/dL)  
                 (10 6 /μL)  
                 (10 3 /μL)  
                 (10 3 /μL) 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 PBS  
                 37  
                 11  
                 7  
                 3  
                 1083  
               
               
                 ISIS 541262  
                 38  
                 11  
                 7  
                 6  
                 1010  
               
               
                 ISIS 541724  
                 52  
                 16  
                 10  
                 9  
                 940  
               
               
                 ISIS 541742  
                 47  
                 14  
                 9  
                 6  
                 1134  
               
               
                 ISIS 541748  
                 41  
                 12  
                 8  
                 7  
                 941  
               
               
                 ISIS 541749  
                 41  
                 12  
                 8  
                 5  
                 1142  
               
               
                 ISIS 541750  
                 42  
                 12  
                 8  
                 4  
                 1409  
               
               
                 ISIS 541766  
                 39  
                 11  
                 7  
                 7  
                 989  
               
               
                 ISIS 541767  
                 46  
                 14  
                 9  
                 2  
                 994  
               
               
                 ISIS 541822  
                 42  
                 12  
                 8  
                 3  
                 1190  
               
               
                 ISIS 541826  
                 41  
                 12  
                 8  
                 10  
                 1069  
               
               
                 ISIS 541838  
                 44  
                 13  
                 8  
                 6  
                 1005  
               
               
                 ISIS 541870  
                 38  
                 11  
                 7  
                 8  
                 1020  
               
               
                 ISIS 541875  
                 44  
                 13  
                 8  
                 6  
                 1104  
               
               
                 ISIS 541907  
                 40  
                 11  
                 8  
                 9  
                 1271  
               
               
                 ISIS 541991  
                 34  
                 10  
                 6  
                 6  
                 1274 
               
               
                   
               
            
           
         
       
     
     Example 19: Tolerability of Deoxy, MOE and cEt Gapmers Targeting Human GHR in CD1 Mice 
     CD1® mice were treated with ISIS antisense oligonucleotides selected from studies described above and evaluated for changes in the levels of various plasma chemistry markers. The 3-10-4 MOE gapmer ISIS 539376 was also included in the study. 
     Treatment 
     Groups of eight- to ten-week old male CD1 mice were injected subcutaneously twice a week for 6 weeks with 25 mg/kg of ISIS oligonucleotide (50 mg/kg/week dose). One group of male CD1 mice was injected subcutaneously twice a week for 6 weeks with PBS. Mice were euthanized 48 hours after the last dose, and organs and plasma were harvested for further analysis. 
     Plasma Chemistry Markers 
     To evaluate the effect of ISIS oligonucleotides on liver and kidney function, plasma levels of transaminases, bilirubin, creatinine, and BUN were measured using an automated clinical chemistry analyzer (Hitachi Olympus AU400e, Melville, N.Y.). The results are presented in Table 100. ISIS oligonucleotides that caused changes in the levels of any of the liver or kidney function markers outside the expected range for antisense oligonucleotides were excluded in further studies. 
     
       
         
           
               
             
               
                 TABLE 100 
               
             
            
               
                   
               
               
                 Plasma chemistry markers in CD1 mice plasma at week 6  
               
            
           
           
               
               
               
               
               
               
            
               
                   
                 ALT  
                 AST  
                 Bilirubin  
                 Creatinine  
                 BUN  
               
               
                   
                 (IU/L)  
                 (IU/L)  
                 (mg/dL)  
                 (mg/dL)  
                 (mg/dL) 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 PBS  
                 43  
                 66  
                 0.21  
                 0.11  
                 20  
               
               
                 ISIS 541881  
                 63  
                 109  
                 0.28  
                 0.13  
                 23  
               
               
                 ISIS 541936  
                 3260  
                 2108  
                 0.40  
                 0.13  
                 24  
               
               
                 ISIS 542051  
                 97  
                 119  
                 0.23  
                 0.12  
                 23  
               
               
                 ISIS 542052  
                 454  
                 236  
                 0.23  
                 0.12  
                 25  
               
               
                 ISIS 542069  
                 293  
                 211  
                 0.23  
                 0.13  
                 27  
               
               
                 ISIS 542085  
                 91  
                 87  
                 0.18  
                 0.10  
                 21  
               
               
                 ISIS 542086  
                 137  
                 133  
                 0.24  
                 0.10  
                 23  
               
               
                 ISIS 542094  
                 86  
                 143  
                 0.23  
                 0.13  
                 21  
               
               
                 ISIS 542101  
                 46  
                 74  
                 0.19  
                 0.10  
                 21  
               
               
                 ISIS 542102  
                 4920  
                 2432  
                 2.30  
                 0.15  
                 29  
               
               
                 ISIS 542105  
                 1255  
                 575  
                 0.35  
                 0.13  
                 21  
               
               
                 ISIS 542106  
                 3082  
                 2295  
                 3.42  
                 0.17  
                 23  
               
               
                 ISIS 542107  
                 4049  
                 3092  
                 0.50  
                 0.14  
                 20  
               
               
                 ISIS 542108  
                 1835  
                 859  
                 0.32  
                 0.11  
                 21  
               
               
                 ISIS 539376  
                 40  
                 79  
                 0.27  
                 0.08  
                 22 
               
               
                   
               
            
           
         
       
     
     Hematology Assays 
     Blood obtained from all mice groups were sent to Antech Diagnostics for hematocrit (HCT) measurements and analysis, as well as measurements of the various blood cells, such as WBC, RBC, and total hemoglobin content. The results are presented in Table 101. ISIS oligonucleotides that caused changes in the levels of any of the hematology markers outside the expected range for antisense oligonucleotides were excluded in further studies. 
     
       
         
           
               
             
               
                 TABLE 101 
               
             
            
               
                   
               
               
                 Hematology markers in CD1 mice plasma at week 6  
               
            
           
           
               
               
               
               
               
               
            
               
                   
                   
                 HCT  
                 Hemoglobin  
                 RBC  
                 WBC  
               
               
                   
                   
                 (%)  
                 (g/dL)  
                 (10 6 /μL)  
                 (10 3 /μL) 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
               
            
               
                   
                 PBS  
                 46  
                 13  
                 8  
                 6  
               
               
                   
                 ISIS 541881  
                 53  
                 15  
                 10  
                 7  
               
               
                   
                 ISIS 541936  
                 41  
                 11  
                 8  
                 18  
               
               
                   
                 ISIS 542051  
                 49  
                 14  
                 9  
                 8  
               
               
                   
                 ISIS 542052  
                 46  
                 13  
                 9  
                 9  
               
               
                   
                 ISIS 542069  
                 43  
                 13  
                 8  
                 7  
               
               
                   
                 ISIS 542085  
                 38  
                 11  
                 7  
                 5  
               
               
                   
                 ISIS 542086  
                 49  
                 14  
                 9  
                 9  
               
               
                   
                 ISIS 542094  
                 36  
                 10  
                 6  
                 5  
               
               
                   
                 ISIS 542101  
                 44  
                 13  
                 9  
                 5  
               
               
                   
                 ISIS 542102  
                 27  
                 7  
                 5  
                 25  
               
               
                   
                 ISIS 542105  
                 42  
                 12  
                 8  
                 7  
               
               
                   
                 ISIS 542106  
                 37  
                 10  
                 7  
                 14  
               
               
                   
                 ISIS 542107  
                 41  
                 12  
                 7  
                 17  
               
               
                   
                 ISIS 542108  
                 51  
                 14  
                 8  
                 10  
               
               
                   
                 ISIS 539376  
                 49  
                 14  
                 10  
                 5 
               
               
                   
                   
               
            
           
         
       
     
     Example 20: Tolerability of Deoxy, MOE and cEt Gapmers Targeting Human GHR in CD1 Mice 
     CD1® mice were treated with ISIS antisense oligonucleotides selected from studies described above and evaluated for changes in the levels of various plasma chemistry markers. 
     Treatment 
     Groups of eight- to ten-week old male CD1 mice were injected subcutaneously twice a week for 6 weeks with 25 mg/kg of ISIS oligonucleotide (50 mg/kg/week dose). One group of male CD1 mice was injected subcutaneously twice a week for 6 weeks with PBS. Mice were euthanized 48 hours after the last dose, and organs and plasma were harvested for further analysis. 
     Plasma Chemistry Markers 
     To evaluate the effect of ISIS oligonucleotides on liver and kidney function, plasma levels of transaminases, bilirubin, creatinine, and BUN were measured using an automated clinical chemistry analyzer (Hitachi Olympus AU400e, Melville, N.Y.). The results are presented in Table 102. ISIS oligonucleotides that caused changes in the levels of any of the liver or kidney function markers outside the expected range for antisense oligonucleotides were excluded in further studies. 
     
       
         
           
               
             
               
                 TABLE 102 
               
             
            
               
                   
               
               
                 Plasma chemistry markers in CD1 mice plasma at week 6 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                 ALT 
                 AST 
                 Bilirubin 
                 Creatinine 
                 BUN 
               
               
                   
                 (IU/L) 
                 (IU/L) 
                 (mg/dL) 
                 (mg/dL) 
                 (mg/dL) 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 PBS 
                 51 
                 63 
                 0.3 
                 0.14 
                 27 
               
               
                 ISIS 542109 
                 3695 
                 2391 
                 0.8 
                 0.19 
                 24 
               
               
                 ISIS 542112 
                 119 
                 104 
                 0.3 
                 0.16 
                 28 
               
               
                 ISIS 542118 
                 66 
                 86 
                 0.3 
                 0.15 
                 26 
               
               
                 ISIS 542122 
                 1112 
                 350 
                 0.3 
                 0.16 
                 27 
               
               
                 ISIS 542125 
                 79 
                 92 
                 0.2 
                 0.13 
                 26 
               
               
                 ISIS 542126 
                 381 
                 398 
                 0.5 
                 0.14 
                 23 
               
               
                 ISIS 542127 
                 54 
                 85 
                 0.3 
                 0.16 
                 26 
               
               
                 ISIS 542128 
                 55 
                 89 
                 0.2 
                 0.12 
                 24 
               
               
                 ISIS 542145 
                 834 
                 671 
                 0.3 
                 0.11 
                 24 
               
               
                 ISIS 542146 
                 163 
                 107 
                 0.2 
                 0.14 
                 30 
               
               
                 ISIS 542149 
                 974 
                 752 
                 0.3 
                 0.12 
                 26 
               
               
                 ISIS 542150 
                 2840 
                 2126 
                 2.4 
                 0.17 
                 23 
               
               
                 ISIS 542153 
                 53 
                 75 
                 0.2 
                 0.14 
                 28 
               
               
                 ISIS 542157 
                 137 
                 122 
                 0.3 
                 0.13 
                 25 
               
               
                 ISIS 542185 
                 57 
                 72 
                 0.2 
                 0.11 
                 23 
               
               
                 ISIS 542186 
                 62 
                 84 
                 0.2 
                 0.12 
                 24 
               
               
                 ISIS 545431 
                 2622 
                 1375 
                 3.0 
                 0.15 
                 28 
               
               
                 ISIS 545438 
                 1710 
                 1000 
                 0.3 
                 0.14 
                 26 
               
               
                 ISIS 545439 
                 70 
                 117 
                 0.2 
                 0.12 
                 28 
               
               
                 ISIS 545447 
                 141 
                 108 
                 0.3 
                 0.13 
                 26 
               
               
                   
               
            
           
         
       
     
     Hematology Assays 
     Blood obtained from all mice groups were sent to Antech Diagnostics for hematocrit (HCT) measurements and analysis, as well as measurements of the various blood cells, such as WBC, RBC, and total hemoglobin content. The results are presented in Table 103. ISIS oligonucleotides that caused changes in the levels of any of the hematology markers outside the expected range for antisense oligonucleotides were excluded in further studies. 
     
       
         
           
               
             
               
                 TABLE 103 
               
             
            
               
                   
               
               
                 Hematology markers in CD1 mice plasma at week 6 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                 HCT 
                 Hemoglobin 
                 RBC 
                 WBC 
                 Platelets 
               
               
                   
                 (%) 
                 (g/dL) 
                 (10 6 /μL) 
                 (10 3 /μL) 
                 (10 3 /μL) 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 PBS 
                 40 
                 12 
                 7 
                 6 
                 1210 
               
               
                 ISIS 542109 
                 47 
                 13 
                 9 
                 16 
                 1244 
               
               
                 ISIS 542112 
                 50 
                 13 
                 8 
                 7 
                 1065 
               
               
                 ISIS 542118 
                 42 
                 12 
                 8 
                 8 
                 1120 
               
               
                 ISIS 542122 
                 37 
                 11 
                 7 
                 7 
                 1064 
               
               
                 ISIS 542125 
                 42 
                 13 
                 8 
                 7 
                 1063 
               
               
                 ISIS 542126 
                 34 
                 10 
                 7 
                 9 
                 1477 
               
               
                 ISIS 542127 
                 41 
                 12 
                 7 
                 7 
                 1144 
               
               
                 ISIS 542128 
                 40 
                 12 
                 7 
                 6 
                 1196 
               
               
                 ISIS 542145 
                 42 
                 12 
                 8 
                 8 
                 1305 
               
               
                 ISIS 542146 
                 45 
                 13 
                 8 
                 7 
                 1310 
               
               
                 ISIS 542149 
                 33 
                 10 
                 6 
                 12 
                 903 
               
               
                 ISIS 542150 
                 27 
                 7 
                 5 
                 18 
                 1202 
               
               
                 ISIS 542153 
                 46 
                 13 
                 8 
                 5 
                 1130 
               
               
                 ISIS 542157 
                 44 
                 12 
                 9 
                 6 
                 791 
               
               
                 ISIS 542185 
                 45 
                 13 
                 8 
                 3 
                 1031 
               
               
                 ISIS 542186 
                 44 
                 12 
                 8 
                 6 
                 985 
               
               
                 ISIS 545431 
                 28 
                 7 
                 6 
                 13 
                 2609 
               
               
                 ISIS 545438 
                 40 
                 11 
                 8 
                 8 
                 1302 
               
               
                 ISIS 545439 
                 48 
                 13 
                 9 
                 4 
                 857 
               
               
                 ISIS 545447 
                 45 
                 13 
                 9 
                 9 
                 964 
               
               
                   
               
            
           
         
       
     
     Example 21: Tolerability of MOE Gapmers Targeting Human GHR in Sprague-Dawley Rats 
     Sprague-Dawley rats are a multipurpose model used for safety and efficacy evaluations. The rats were treated with ISIS antisense oligonucleotides from the studies described in the Examples above and evaluated for changes in the levels of various plasma chemistry markers. 
     Treatment 
     Male Sprague-Dawley rats were maintained on a 12-hour light/dark cycle and fed ad libitum with Purina normal rat chow, diet 5001. Groups of 4 Sprague-Dawley rats each were injected subcutaneously twice a week for 6 weeks with 50 mg/kg of ISIS oligonucleotide (100 mg/kg weekly dose). Forty eight hours after the last dose, rats were euthanized and organs and plasma were harvested for further analysis. 
     Liver Function 
     To evaluate the effect of ISIS oligonucleotides on hepatic function, plasma levels of transaminases were measured using an automated clinical chemistry analyzer (Hitachi Olympus AU400e, Melville, N.Y.). Plasma levels of ALT (alanine transaminase) and AST (aspartate transaminase) were measured and the results are presented in Table 104 expressed in IU/L. Plasma levels of bilirubin were also measured using the same clinical chemistry analyzer and the results are also presented in Table 104 expressed in mg/dL. ISIS oligonucleotides that caused changes in the levels of any markers of liver function outside the expected range for antisense oligonucleotides were excluded in further studies. 
     
       
         
           
               
             
               
                 TABLE 104 
               
             
            
               
                   
               
               
                 Liver function markers in Sprague-Dawley rats 
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                 ALT 
                 AST 
                 Bilirubin 
               
               
                   
                   
                 (IU/L) 
                 (IU/L) 
                 (mg/dL) 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
            
               
                   
                 PBS 
                 69 
                 90 
                 0.15 
               
               
                   
                 ISIS 523723 
                 79 
                 123 
                 0.12 
               
               
                   
                 ISIS 523789 
                 71 
                 105 
                 0.15 
               
               
                   
                 ISIS 532254 
                 67 
                 97 
                 0.14 
               
               
                   
                 ISIS 532401 
                 61 
                 77 
                 0.12 
               
               
                   
                 ISIS 532420 
                 102 
                 127 
                 0.17 
               
               
                   
                 ISIS 533178 
                 157 
                 219 
                 0.34 
               
               
                   
                 ISIS 533234 
                 71 
                 90 
                 0.11 
               
               
                   
                 ISIS 533932 
                 58 
                 81 
                 0.12 
               
               
                   
                 ISIS 539376 
                 75 
                 101 
                 0.14 
               
               
                   
                 ISIS 539380 
                 86 
                 128 
                 0.16 
               
               
                   
                 ISIS 539383 
                 64 
                 94 
                 0.14 
               
               
                   
                 ISIS 539399 
                 52 
                 95 
                 0.14 
               
               
                   
                 ISIS 539404 
                 88 
                 118 
                 0.13 
               
               
                   
                 ISIS 539416 
                 63 
                 104 
                 0.14 
               
               
                   
                 ISIS 539432 
                 63 
                 90 
                 0.13 
               
               
                   
                 ISIS 539433 
                 69 
                 92 
                 0.13 
               
               
                   
                   
               
            
           
         
       
     
     Kidney Function 
     To evaluate the effect of ISIS oligonucleotides on kidney function, plasma levels of blood urea nitrogen (BUN) and creatinine were measured using an automated clinical chemistry analyzer (Hitachi Olympus AU400e, Melville, N.Y.). Results are presented in Table 105, expressed in mg/dL. ISIS oligonucleotides that caused changes in the levels of any of the kidney function markers outside the expected range for antisense oligonucleotides were excluded in further studies. 
     
       
         
           
               
             
               
                 TABLE 105 
               
             
            
               
                   
               
               
                 Kidney function markers (mg/dL) 
               
               
                 in Sprague-Dawley rats 
               
            
           
           
               
               
               
               
            
               
                   
                   
                 BUN 
                 Creatinine 
               
               
                   
                   
               
               
                   
                 PBS 
                 24 
                 0.32 
               
               
                   
                 ISIS 523723 
                 20 
                 0.39 
               
               
                   
                 ISIS 523789 
                 19 
                 0.37 
               
               
                   
                 ISIS 532254 
                 21 
                 0.43 
               
               
                   
                 ISIS 532401 
                 17 
                 0.36 
               
               
                   
                 ISIS 532420 
                 20 
                 0.31 
               
               
                   
                 ISIS 533178 
                 20 
                 0.43 
               
               
                   
                 ISIS 533234 
                 22 
                 0.41 
               
               
                   
                 ISIS 533932 
                 19 
                 0.43 
               
               
                   
                 ISIS 539376 
                 19 
                 0.36 
               
               
                   
                 ISIS 539380 
                 18 
                 0.35 
               
               
                   
                 ISIS 539383 
                 19 
                 0.35 
               
               
                   
                 ISIS 539399 
                 18 
                 0.39 
               
               
                   
                 ISIS 539404 
                 23 
                 0.39 
               
               
                   
                 ISIS 539416 
                 17 
                 0.39 
               
               
                   
                 ISIS 539432 
                 20 
                 0.39 
               
               
                   
                 ISIS 539433 
                 20 
                 0.34 
               
               
                   
                   
               
            
           
         
       
     
     Hematology Assays 
     Blood obtained from all rat groups were sent to Antech Diagnostics for hematocrit (HCT) measurements and analysis, as well as measurements of the various blood cells, such as WBC, RBC, and total hemoglobin content. The results are presented in Table 106. ISIS oligonucleotides that caused changes in the levels of any of the hematology markers outside the expected range for antisense oligonucleotides were excluded in further studies. 
     
       
         
           
               
             
               
                 TABLE 106 
               
             
            
               
                   
               
               
                 Hematology markers in Sprague-Dawley rats 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                 HCT 
                 Hemoglobin 
                 RBC 
                 WBC 
                 Platelets 
               
               
                   
                 (%) 
                 (g/dL) 
                 (10 6 /μL) 
                 (10 3 /μL) 
                 (10 3 /μL) 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 PBS 
                 46 
                 15 
                 8 
                 11 
                 1078 
               
               
                 ISIS 523723 
                 38 
                 12 
                 7 
                 19 
                 626 
               
               
                 ISIS 523789 
                 38 
                 12 
                 8 
                 12 
                 702 
               
               
                 ISIS 532254 
                 36 
                 12 
                 7 
                 11 
                 547 
               
               
                 ISIS 532401 
                 42 
                 14 
                 8 
                 12 
                 858 
               
               
                 ISIS 532420 
                 37 
                 12 
                 7 
                 17 
                 542 
               
               
                 ISIS 533178 
                 37 
                 12 
                 7 
                 15 
                 1117 
               
               
                 ISIS 533234 
                 38 
                 12 
                 7 
                 8 
                 657 
               
               
                 ISIS 533932 
                 40 
                 13 
                 7 
                 9 
                 999 
               
               
                 ISIS 539376 
                 43 
                 14 
                 9 
                 8 
                 910 
               
               
                 ISIS 539380 
                 33 
                 11 
                 5 
                 6 
                 330 
               
               
                 ISIS 539383 
                 39 
                 13 
                 7 
                 10 
                 832 
               
               
                 ISIS 539399 
                 37 
                 11 
                 7 
                 4 
                 603 
               
               
                 ISIS 539404 
                 37 
                 12 
                 7 
                 6 
                 639 
               
               
                 ISIS 539416 
                 33 
                 11 
                 6 
                 9 
                 601 
               
               
                 ISIS 539432 
                 44 
                 14 
                 9 
                 10 
                 810 
               
               
                 ISIS 539433 
                 38 
                 12 
                 7 
                 9 
                 742 
               
               
                   
               
            
           
         
       
     
     Organ Weights 
     Liver, heart, spleen and kidney weights were measured at the end of the study, and are presented in Table 107. ISIS oligonucleotides that caused any changes in organ weights outside the expected range for antisense oligonucleotides were excluded from further studies. 
     
       
         
           
               
             
               
                 TABLE 107 
               
             
            
               
                   
               
               
                 Organ weights (g) 
               
            
           
           
               
               
               
               
               
            
               
                   
                 Heart 
                 Liver 
                 Spleen 
                 Kidney 
               
               
                   
               
               
                 PBS 
                 0.35 
                 3.6 
                 0.2 
                 0.8 
               
               
                 ISIS 523723 
                 0.31 
                 4.9 
                 0.7 
                 0.8 
               
               
                 ISIS 523789 
                 0.34 
                 4.8 
                 0.6 
                 0.8 
               
               
                 ISIS 532254 
                 0.32 
                 5.0 
                 0.6 
                 1.0 
               
               
                 ISIS 532401 
                 0.32 
                 3.8 
                 0.4 
                 0.8 
               
               
                 ISIS 532420 
                 0.29 
                 4.6 
                 0.7 
                 1.0 
               
               
                 ISIS 533178 
                 0.34 
                 5.2 
                 0.7 
                 0.9 
               
               
                 ISIS 533234 
                 0.30 
                 4.4 
                 0.6 
                 1.0 
               
               
                 ISIS 533932 
                 0.31 
                 3.9 
                 0.5 
                 0.9 
               
               
                 ISIS 539376 
                 0.29 
                 4.4 
                 0.4 
                 0.8 
               
               
                 ISIS 539380 
                 0.31 
                 6.3 
                 1.6 
                 1.2 
               
               
                 ISIS 539383 
                 0.31 
                 4.5 
                 0.6 
                 1.0 
               
               
                 ISIS 539399 
                 0.31 
                 4.5 
                 0.8 
                 1.0 
               
               
                 ISIS 539404 
                 0.34 
                 4.9 
                 0.6 
                 1.0 
               
               
                 ISIS 539416 
                 0.32 
                 4.7 
                 0.7 
                 0.9 
               
               
                 ISIS 539432 
                 0.30 
                 3.8 
                 0.4 
                 0.8 
               
               
                 ISIS 539433 
                 0.28 
                 4.1 
                 0.7 
                 1.0 
               
               
                   
               
            
           
         
       
     
     Example 22: Tolerability of Deoxy, MOE, and cEt Gapmers Targeting Human GHR in Sprague-Dawley Rats 
     Sprague-Dawley rats were treated with ISIS antisense oligonucleotides from the studies described in the Examples above and evaluated for changes in the levels of various plasma chemistry markers. 
     Treatment 
     Male Sprague-Dawley rats were maintained on a 12-hour light/dark cycle and fed ad libitum with Purina normal rat chow, diet 5001. Groups of 4 Sprague-Dawley rats each were injected subcutaneously once a week for 6 weeks with 50 mg/kg of ISIS oligonucleotide (50 mg/kg weekly dose). Two groups of rats were injected subcutaneously once a week for 6 weeks with PBS. Forty eight hours after the last dose, rats were euthanized and organs and plasma were harvested for further analysis. 
     Liver Function 
     To evaluate the effect of ISIS oligonucleotides on hepatic function, plasma levels of transaminases were measured using an automated clinical chemistry analyzer (Hitachi Olympus AU400e, Melville, N.Y.). Plasma levels of ALT and AST were measured and the results are presented in Table 108 expressed in IU/L. Plasma levels of bilirubin were also measured using the same clinical chemistry analyzer and the results are also presented in Table 108 expressed in mg/dL. ISIS oligonucleotides that caused changes in the levels of any markers of liver function outside the expected range for antisense oligonucleotides were excluded in further studies. 
     
       
         
           
               
             
               
                 TABLE 108 
               
             
            
               
                   
               
               
                 Liver function markers in Sprague-Dawley rats 
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                 ALT 
                 AST 
                 Bilirubin 
               
               
                   
                   
                 (IU/L) 
                 (IU/L) 
                 (mg/dL) 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
            
               
                   
                 PBS group 1 
                 34 
                 56 
                 0.08 
               
               
                   
                 PBS group 2 
                 37 
                 54 
                 0.09 
               
               
                   
                 ISIS 541881 
                 53 
                 77 
                 0.12 
               
               
                   
                 ISIS 542051 
                 61 
                 96 
                 0.09 
               
               
                   
                 ISIS 542101 
                 64 
                 214 
                 0.10 
               
               
                   
                 ISIS 542112 
                 46 
                 72 
                 0.10 
               
               
                   
                 ISIS 542118 
                 42 
                 60 
                 0.08 
               
               
                   
                 ISIS 542125 
                 39 
                 67 
                 0.10 
               
               
                   
                 ISIS 542127 
                 56 
                 75 
                 0.12 
               
               
                   
                 ISIS 542128 
                 45 
                 71 
                 0.12 
               
               
                   
                 ISIS 542153 
                 44 
                 69 
                 0.11 
               
               
                   
                 ISIS 542185 
                 44 
                 93 
                 0.09 
               
               
                   
                 ISIS 542186 
                 51 
                 107 
                 0.12 
               
               
                   
                 ISIS 545439 
                 41 
                 73 
                 0.10 
               
               
                   
                 ISIS 545447 
                 103 
                 114 
                 0.10 
               
               
                   
                 ISIS 541262 
                 106 
                 133 
                 0.12 
               
               
                   
                 ISIS 541742 
                 56 
                 102 
                 0.11 
               
               
                   
                 ISIS 541767 
                 53 
                 69 
                 0.09 
               
               
                   
                 ISIS 541875 
                 70 
                 133 
                 0.08 
               
               
                   
                   
               
            
           
         
       
     
     Kidney Function 
     To evaluate the effect of ISIS oligonucleotides on kidney function, plasma levels of blood urea nitrogen (BUN) and creatinine were measured using an automated clinical chemistry analyzer (Hitachi Olympus AU400e, Melville, N.Y.). Results are presented in Table 109, expressed in mg/dL. ISIS oligonucleotides that caused changes in the levels of any of the kidney function markers outside the expected range for antisense oligonucleotides were excluded in further studies. 
     
       
         
           
               
             
               
                 TABLE 109 
               
             
            
               
                   
               
               
                 Kidney function markers (mg/dL) in 
               
               
                 Sprague-Dawley rats 
               
            
           
           
               
               
               
               
            
               
                   
                   
                 BUN 
                 Creatinine 
               
               
                   
                   
               
               
                   
                 PBS group 1 
                 16 
                 0.2 
               
               
                   
                 PBS group 2 
                 15 
                 0.2 
               
               
                   
                 ISIS 541881 
                 22 
                 0.3 
               
               
                   
                 ISIS 542051 
                 18 
                 0.2 
               
               
                   
                 ISIS 542101 
                 22 
                 0.3 
               
               
                   
                 ISIS 542112 
                 18 
                 0.2 
               
               
                   
                 ISIS 542118 
                 18 
                 0.3 
               
               
                   
                 ISIS 542125 
                 18 
                 0.3 
               
               
                   
                 ISIS 542127 
                 19 
                 0.3 
               
               
                   
                 ISIS 542128 
                 18 
                 0.3 
               
               
                   
                 ISIS 542153 
                 17 
                 0.3 
               
               
                   
                 ISIS 542185 
                 19 
                 0.3 
               
               
                   
                 ISIS 542186 
                 19 
                 0.3 
               
               
                   
                 ISIS 545439 
                 16 
                 0.2 
               
               
                   
                 ISIS 545447 
                 16 
                 0.2 
               
               
                   
                 ISIS 541262 
                 21 
                 0.4 
               
               
                   
                 ISIS 541742 
                 19 
                 0.2 
               
               
                   
                 ISIS 541767 
                 15 
                 0.2 
               
               
                   
                 ISIS 541875 
                 16 
                 0.2 
               
               
                   
                   
               
            
           
         
       
     
     Hematology Assays 
     Blood obtained from all rat groups were sent to Antech Diagnostics for hematocrit (HCT) measurements and analysis, as well as measurements of the various blood cells, such as WBC, RBC, and total hemoglobin content. The results are presented in Table 110. ISIS oligonucleotides that caused changes in the levels of any of the hematology markers outside the expected range for antisense oligonucleotides were excluded in further studies. 
     
       
         
           
               
             
               
                 TABLE 110 
               
             
            
               
                   
               
               
                 Hematology markers in Sprague-Dawley rats 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                 HCT 
                 Hemoglobin 
                 RBC 
                 WBC 
                 Platelets 
               
               
                   
                 (%) 
                 (g/dL) 
                 (10 6 /μL) 
                 (10 3 /μL) 
                 (10 3 /μL) 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 PBS group 1 
                 43 
                 14 
                 7 
                 7 
                 775 
               
               
                 PBS group 2 
                 49 
                 15 
                 8 
                 8 
                 1065 
               
               
                 ISIS 541881 
                 41 
                 13 
                 8 
                 6 
                 553 
               
               
                 ISIS 542051 
                 39 
                 13 
                 7 
                 9 
                 564 
               
               
                 ISIS 542101 
                 37 
                 12 
                 7 
                 15 
                 603 
               
               
                 ISIS 542112 
                 45 
                 14 
                 8 
                 10 
                 587 
               
               
                 ISIS 542118 
                 47 
                 15 
                 8 
                 7 
                 817 
               
               
                 ISIS 542125 
                 41 
                 13 
                 7 
                 7 
                 909 
               
               
                 ISIS 542127 
                 44 
                 14 
                 8 
                 10 
                 872 
               
               
                 ISIS 542128 
                 44 
                 14 
                 8 
                 7 
                 679 
               
               
                 ISIS 542153 
                 48 
                 15 
                 8 
                 7 
                 519 
               
               
                 ISIS 542185 
                 44 
                 14 
                 8 
                 9 
                 453 
               
               
                 ISIS 542186 
                 44 
                 14 
                 8 
                 12 
                 433 
               
               
                 ISIS 545439 
                 40 
                 12 
                 7 
                 11 
                 733 
               
               
                 ISIS 545447 
                 43 
                 13 
                 8 
                 9 
                 843 
               
               
                 ISIS 541262 
                 46 
                 14 
                 8 
                 17 
                 881 
               
               
                 ISIS 541742 
                 47 
                 15 
                 8 
                 10 
                 813 
               
               
                 ISIS 541767 
                 53 
                 16 
                 9 
                 9 
                 860 
               
               
                 ISIS 541875 
                 42 
                 13 
                 7 
                 9 
                 840 
               
               
                   
               
            
           
         
       
     
     Organ Weights 
     Liver, heart, spleen and kidney weights were measured at the end of the study, and are presented in Table 111. ISIS oligonucleotides that caused any changes in organ weights outside the expected range for antisense oligonucleotides were excluded from further studies. 
     
       
         
           
               
             
               
                 TABLE 111 
               
             
            
               
                   
               
               
                 Organ weights (g) 
               
            
           
           
               
               
               
               
               
            
               
                   
                 Heart 
                 Liver 
                 Spleen 
                 Kidney 
               
               
                   
               
               
                 PBS group 1 
                 0.4 
                 3.7 
                 0.2 
                 0.9 
               
               
                 PBS group 2 
                 0.3 
                 3.2 
                 0.2 
                 0.7 
               
               
                 ISIS 541881 
                 0.4 
                 3.4 
                 0.4 
                 0.9 
               
               
                 ISIS 542051 
                 0.4 
                 3.8 
                 0.4 
                 1.0 
               
               
                 ISIS 542101 
                 0.3 
                 4.2 
                 0.6 
                 1.1 
               
               
                 ISIS 542112 
                 0.3 
                 3.7 
                 0.4 
                 0.8 
               
               
                 ISIS 542118 
                 0.4 
                 3.6 
                 0.2 
                 0.8 
               
               
                 ISIS 542125 
                 0.4 
                 3.7 
                 0.3 
                 1.1 
               
               
                 ISIS 542127 
                 0.3 
                 4.2 
                 0.3 
                 0.8 
               
               
                 ISIS 542128 
                 0.3 
                 3.5 
                 0.3 
                 0.8 
               
               
                 ISIS 542153 
                 0.3 
                 3.5 
                 0.3 
                 0.8 
               
               
                 ISIS 542185 
                 0.4 
                 3.8 
                 0.4 
                 0.9 
               
               
                 ISIS 542186 
                 0.3 
                 3.8 
                 0.6 
                 0.9 
               
               
                 ISIS 545439 
                 0.4 
                 4.1 
                 0.3 
                 0.9 
               
               
                 ISIS 545447 
                 0.4 
                 3.4 
                 0.3 
                 1.1 
               
               
                 ISIS 541262 
                 0.3 
                 3.4 
                 0.3 
                 2.0 
               
               
                 ISIS 541742 
                 0.3 
                 3.8 
                 0.3 
                 0.8 
               
               
                 ISIS 541767 
                 0.3 
                 3.4 
                 0.2 
                 0.8 
               
               
                 ISIS 541875 
                 0.3 
                 5.2 
                 0.4 
                 1.0 
               
               
                   
               
            
           
         
       
     
     Example 23: Effect of ISIS Antisense Oligonucleotides Targeting Human GHR in Cynomolgus Monkeys 
     Cynomolgus monkeys were treated with ISIS antisense oligonucleotides selected from studies described in the Examples above. Antisense oligonucleotide efficacy and tolerability, as well as their pharmacokinetic profile in the liver and kidney, were evaluated. 
     At the time this study was undertaken, the cynomolgus monkey genomic sequence was not available in the National Center for Biotechnology Information (NCBI) database; therefore, cross-reactivity with the cynomolgus monkey gene sequence could not be confirmed. Instead, the sequences of the ISIS antisense oligonucleotides used in the cynomolgus monkeys was compared to a rhesus monkey sequence for homology. It is expected that ISIS oligonucleotides with homology to the rhesus monkey sequence are fully cross-reactive with the cynomolgus monkey sequence as well. The human antisense oligonucleotides tested are cross-reactive with the rhesus genomic sequence (GENBANK Accession No. NW_001120958.1 truncated from nucleotides 4410000 to 4720000, designated herein as SEQ ID NO: 2296). The greater the complementarity between the human oligonucleotide and the rhesus monkey sequence, the more likely the human oligonucleotide can cross-react with the rhesus monkey sequence. The start and stop sites of each oligonucleotide to SEQ ID NO: 2296 is presented in Table 112. “Start site” indicates the 5′-most nucleotide to which the gapmer is targeted in the rhesus monkey gene sequence. 
     
       
         
           
               
             
               
                 TABLE 112 
               
             
            
               
                   
               
               
                 Antisense oligonucleotides complementary to the rhesus 
               
               
                 GHR genomic sequence (SEQ ID NO: 2296) 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                   
                 Target 
                 Target 
                   
                   
               
               
                   
                   
                 Start 
                 Stop 
                   
                 SEQ ID 
               
               
                   
                 ISIS No 
                 Site 
                 Site 
                 Chemistry 
                 NO 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
               
            
               
                   
                 523723 
                 149071 
                 149090 
                 5-10-5 MOE 
                 918 
               
               
                   
                 532254 
                 64701 
                 64720 
                 5-10-5 MOE 
                 479 
               
               
                   
                 532401 
                 147560 
                 147579 
                 5-10-5 MOE 
                 703 
               
               
                   
                 541767 
                 152700 
                 152715 
                 Deoxy, MOE 
                 1800 
               
               
                   
                   
                   
                   
                 and cEt 
                   
               
               
                   
                 541875 
                 210099 
                 210114 
                 Deoxy, MOE 
                 1904 
               
               
                   
                   
                   
                   
                 and cEt 
                   
               
               
                   
                 542112 
                 146650 
                 146665 
                 Deoxy, MOE 
                 2122 
               
               
                   
                   
                   
                   
                 and cEt 
                   
               
               
                   
                 542118 
                 149074 
                 149089 
                 Deoxy, MOE 
                 2127 
               
               
                   
                   
                   
                   
                 and cEt 
                   
               
               
                   
                 542185 
                 245782 
                 245797 
                 Deoxy, MOE 
                 2194 
               
               
                   
                   
                   
                   
                 and cEt 
               
               
                   
                   
               
            
           
         
       
     
     Study 1 
     Prior to the study, the monkeys were kept in quarantine during which the animals were observed daily for general health. The monkeys were 2-4 years old and weighed between 2 and 4 kg. Nine groups of 5 randomly assigned male cynomolgus monkeys each were injected subcutaneously with ISIS oligonucleotide or PBS using a stainless steel dosing needle and syringe of appropriate size into the intracapsular region and outer thigh of the monkeys. The monkeys were dosed three times (days 1, 4, and 7) for the first week, and then subsequently once a week for 12 weeks with 40 mg/kg of ISIS oligonucleotide. A control group of 5 cynomolgus monkeys was injected with PBS in a similar manner and served as the control group. 
     During the study period, the monkeys were observed twice daily for signs of illness or distress. Any animal experiencing more than momentary or slight pain or distress due to the treatment, injury or illness was treated by the veterinary staff with approved analgesics or agents to relieve the pain after consultation with the Study Director. Any animal in poor health or in a possible moribund condition was identified for further monitoring and possible euthanasia. Scheduled euthanasia of the animals was conducted on day 86 by exsanguination after ketamine/xylazine-induced anesthesia and administration of sodium pentobarbital. The protocols described in the Example were approved by the Institutional Animal Care and Use Committee (IACUC). 
     Target Reduction 
     RNA Analysis 
     On day 86, RNA was extracted from liver, white adipose tissue (WAT) and kidney for real-time PCR analysis of measurement of mRNA expression of GHR. Results are presented as percent inhibition of mRNA, relative to PBS control, normalized with RIBOGREEN®. ‘n.d.’ indicates that the data for that particular oligonucleotide was not measured. As shown in Table 113, treatment with ISIS antisense oligonucleotides resulted in significant reduction of GHR mRNA in comparison to the PBS control. Specifically, treatment with ISIS 532401 resulted in significant reduction of mRNA expression in all tissues. 
     The expression of the growth hormone-responsive gene, ALS was also measured in liver, kidney and adipose tissue. Treatment with ISIS 532401 resulted in ALS RNA expression reduction in liver by 44±9%, correlating with GHR levels. There was no reduction observed in adipose tissue. The expression of IGF1 in the liver was also measured. Treatment with ISIS 532401 resulted in IGF1 RNA expression reduction in liver by 71±10%, correlating with GHR levels. 
     
       
         
           
               
             
               
                 TABLE 113 
               
             
            
               
                   
               
               
                 Percent inhibition of GHR mRNA in the cynomolgus 
               
               
                 monkey liver relative to the PBS control 
               
            
           
           
               
               
               
               
               
            
               
                   
                 ISIS No 
                 Liver 
                 Kidney 
                 WAT 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
            
               
                   
                 532401 
                 60 
                 47 
                 59 
               
               
                   
                 532254 
                 63 
                 65 
                 n.d. 
               
               
                   
                 523723 
                 38 
                 0 
                 n.d. 
               
               
                   
                 542112 
                 61 
                 60 
                 36 
               
               
                   
                 542118 
                 0 
                 22 
                 27 
               
               
                   
                 542185 
                 66 
                 53 
                 n.d. 
               
               
                   
                 541767 
                 0 
                 14 
                 n.d. 
               
               
                   
                 541875 
                 34 
                 77 
                 n.d. 
               
               
                   
                   
               
            
           
         
       
     
     Protein Analysis 
     Approximately 1 mL of blood was collected from all available animals at day 85 and placed in tubes containing the potassium salt of EDTA. The tubes were centrifuged (3000 rpm for 10 min at room temperature) to obtain plasma. Plasma levels of IGF-1 and GH were measured in the plasma. The results are presented in Table 114. The results indicate that treatment with ISIS oligonucleotides resulted in reduced IGF-1 protein levels. 
     Plasma levels of IGF1 after treatment with ISIS 532401 are also presented in Table 115 and demonstrate the effect of antisense inhibition of GHR in reducing IGF1 levels at day 7 and day 85. 
     
       
         
           
               
             
               
                 TABLE 114 
               
             
            
               
                   
               
               
                 Plasma protein levels in the cynomolgus monkey 
               
            
           
           
               
               
               
               
            
               
                   
                   
                 IGF-1 
                 GH 
               
               
                   
                   
                 (% baseline) 
                 (ng/mL) 
               
               
                   
                   
               
            
           
           
               
               
               
               
            
               
                   
                 PBS 
                 121 
                 19 
               
               
                   
                 532401 
                 57 
                 39 
               
               
                   
                 532254 
                 51 
                 26 
               
               
                   
                 523723 
                 77 
                 16 
               
               
                   
                 542112 
                 46 
                 48 
               
               
                   
                 542118 
                 97 
                 6 
               
               
                   
                 542185 
                 59 
                 32 
               
               
                   
                 541767 
                 101 
                 22 
               
               
                   
                 541875 
                 45 
                 47 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 115 
               
             
            
               
                   
               
               
                 Plasma IGF1 levels in the cynomolgus monkey 
               
            
           
           
               
               
               
            
               
                   
                 Day 7 
                 Day 85 
               
               
                   
               
               
                 PBS 
                 458 
                 643 
               
               
                 ISIS 532401 
                 326 
                 263 
               
               
                   
               
            
           
         
       
     
     Tolerability Studies 
     Body and Organ Weight Measurements 
     To evaluate the effect of ISIS oligonucleotides on the overall health of the animals, body and organ weights were measured. Body weights were measured on day 84 and are presented in Table 115. Organ weights were measured on day 86 and the data is also presented in Table 115. The results indicate that effect of treatment with antisense oligonucleotides on body and organ weights was within the expected range for antisense oligonucleotides. Specifically, treatment with ISIS 532401 was well tolerated in terms of the body and organ weights of the monkeys. 
     
       
         
           
               
             
               
                 TABLE 115 
               
             
            
               
                   
               
               
                 Final body and organ weights in cynomolgus monkey 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                   
                 Body 
                 Spleen 
                 Kidney 
                 Liver 
               
               
                   
                   
                 Wt (kg) 
                 (g) 
                 (g) 
                 (g) 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
               
            
               
                   
                 PBS 
                 2.7 
                 2.8 
                 12.3 
                 56.7 
               
               
                   
                 532401 
                 2.6 
                 4.0 
                 11.5 
                 58.5 
               
               
                   
                 532254 
                 2.6 
                 4.8 
                 15.4 
                 69.5 
               
               
                   
                 523723 
                 2.8 
                 3.1 
                 14.8 
                 69.4 
               
               
                   
                 542112 
                 2.6 
                 3.5 
                 13.6 
                 60.0 
               
               
                   
                 542118 
                 2.7 
                 2.7 
                 11.9 
                 58.6 
               
               
                   
                 542185 
                 2.6 
                 5.5 
                 17.2 
                 68.5 
               
               
                   
                 541767 
                 2.8 
                 5.1 
                 11.7 
                 65.1 
               
               
                   
                 541875 
                 2.8 
                 5.5 
                 13.2 
                 55.0 
               
               
                   
                   
               
            
           
         
       
     
     Liver Function 
     To evaluate the effect of ISIS oligonucleotides on hepatic function, blood samples were collected from all the study groups. The blood samples were collected via femoral venipuncture, 48 hrs post-dosing. The monkeys were fasted overnight prior to blood collection. Blood was collected in tubes containing K 2 -EDTA anticoagulant, which were centrifuged to obtain plasma. Levels of various liver function markers were measured using a Toshiba 200FR NEO chemistry analyzer (Toshiba Co., Japan). Plasma levels of ALT and AST and bilirubin were measured. The Tables below present the results for ALT and AST levels at various time points. The results indicate that antisense oligonucleotides had no effect on liver function outside the expected range for antisense oligonucleotides. Specifically, treatment with ISIS 532401 was well tolerated in terms of the liver function in monkeys. 
     
       
         
           
               
             
               
                 TABLE 116 
               
             
            
               
                   
               
               
                 ALT levels (IU/L) in cynomolgus monkey 
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                 Day 16 
                 Day 44 
                 Day 86 
               
               
                   
                   
               
               
                   
                 PBS 
                 46 
                 37 
                 40 
               
               
                   
                 ISIS 532401 
                 63 
                 59 
                 88 
               
               
                   
                 ISIS 532254 
                 62 
                 46 
                 56 
               
               
                   
                 ISIS 523723 
                 50 
                 77 
                 86 
               
               
                   
                 ISIS 542112 
                 53 
                 54 
                 60 
               
               
                   
                 ISIS 542118 
                 38 
                 41 
                 52 
               
               
                   
                 ISIS 542185 
                 58 
                 59 
                 91 
               
               
                   
                 ISIS 541767 
                 56 
                 45 
                 46 
               
               
                   
                 ISIS 541875 
                 70 
                 54 
                 71 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 117 
               
             
            
               
                   
               
               
                 AST levels (IU/L) in cynomolgus monkey 
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                 Day 16 
                 Day 44 
                 Day 86 
               
               
                   
                   
               
               
                   
                 PBS 
                 58 
                 40 
                 45 
               
               
                   
                 ISIS 532401 
                 47 
                 48 
                 61 
               
               
                   
                 ISIS 532254 
                 71 
                 81 
                 98 
               
               
                   
                 ISIS 523723 
                 56 
                 61 
                 73 
               
               
                   
                 ISIS 542112 
                 58 
                 65 
                 89 
               
               
                   
                 ISIS 542118 
                 41 
                 40 
                 46 
               
               
                   
                 ISIS 542185 
                 61 
                 63 
                 98 
               
               
                   
                 ISIS 541767 
                 52 
                 39 
                 63 
               
               
                   
                 ISIS 541875 
                 70 
                 50 
                 70 
               
               
                   
                   
               
            
           
         
       
     
     Kidney Function 
     To evaluate the effect of ISIS oligonucleotides on kidney function, blood samples were collected from all the study groups. The blood samples were collected via femoral venipuncture, 48 hrs post-dosing. The monkeys were fasted overnight prior to blood collection. Blood was collected in tubes containing K 2 -EDTA anticoagulant, which were centrifuged to obtain plasma. Levels of BUN and creatinine were measured using a Toshiba 200FR NEO chemistry analyzer (Toshiba Co., Japan). The Tables below present the results for BUN and creatinine levels at various time points. 
     The plasma chemistry data indicate that most of the ISIS oligonucleotides did not have any effect on the kidney function outside the expected range for antisense oligonucleotides. Specifically, treatment with ISIS 532401 was well tolerated in terms of the kidney function of the monkeys. 
     
       
         
           
               
             
               
                 TABLE 118 
               
             
            
               
                   
               
               
                 BUN levels (mg/dL) in cynomolgus monkey 
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                 Day 16 
                 Day 44 
                 Day 86 
               
               
                   
                   
               
               
                   
                 PBS 
                 29 
                 26 
                 26 
               
               
                   
                 ISIS 532401 
                 27 
                 27 
                 27 
               
               
                   
                 ISIS 532254 
                 21 
                 22 
                 25 
               
               
                   
                 ISIS 523723 
                 25 
                 24 
                 22 
               
               
                   
                 ISIS 542112 
                 26 
                 24 
                 24 
               
               
                   
                 ISIS 542118 
                 29 
                 27 
                 29 
               
               
                   
                 ISIS 542185 
                 22 
                 21 
                 22 
               
               
                   
                 ISIS 541767 
                 29 
                 24 
                 24 
               
               
                   
                 ISIS 541875 
                 29 
                 24 
                 21 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 119 
               
             
            
               
                   
               
               
                 Creatinine levels (mg/dL) in cynomolgus monkey 
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                 Day 16 
                 Day 44 
                 Day 86 
               
               
                   
                   
               
               
                   
                 PBS 
                 0.9 
                 0.8 
                 0.9 
               
               
                   
                 ISIS 532401 
                 1.1 
                 1.0 
                 1.1 
               
               
                   
                 ISIS 532254 
                 1.0 
                 1.0 
                 1.0 
               
               
                   
                 ISIS 523723 
                 1.0 
                 1.0 
                 1.0 
               
               
                   
                 ISIS 542112 
                 1.0 
                 0.9 
                 1.0 
               
               
                   
                 ISIS 542118 
                 0.9 
                 0.9 
                 0.9 
               
               
                   
                 ISIS 542185 
                 1.0 
                 0.9 
                 0.9 
               
               
                   
                 ISIS 541767 
                 1.1 
                 0.9 
                 0.9 
               
               
                   
                 ISIS 541875 
                 1.2 
                 1.1 
                 1.1 
               
               
                   
                   
               
            
           
         
       
     
     Hematology 
     To evaluate any effect of ISIS oligonucleotides in cynomolgus monkeys on hematologic parameters, blood samples of approximately 1.3 mL of blood was collected from each of the available study animals in tubes containing K 2 -EDTA. Samples were analyzed for red blood cell (RBC) count, white blood cells (WBC) count, individual white blood cell counts, such as that of monocytes, neutrophils, lymphocytes, as well as for platelet count, hemoglobin content and hematocrit, using an ADVIA120 hematology analyzer (Bayer, USA). The Table below presents the results for platelet count at various time points. ‘n/a’ indicates that the data for that time point is not available. 
     The data indicate the oligonucleotides did not cause any changes in hematologic parameters outside the expected range for antisense oligonucleotides at this dose. Specifically, treatment with ISIS 532401 was well tolerated in terms of the hematologic parameters of the monkeys. 
     
       
         
           
               
             
               
                 TABLE 120 
               
             
            
               
                   
               
               
                 Platelet count (×10 3 /uL) in cynomolgus monkey 
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                 Day 30 
                 Day 58 
                 Day 86 
               
               
                   
                   
               
               
                   
                 PBS 
                 538 
                 464 
                 403 
               
               
                   
                 ISIS 532401 
                 493 
                 465 
                 395 
               
               
                   
                 ISIS 532254 
                 334 
                 328 
                 306 
               
               
                   
                 ISIS 523723 
                 352 
                 304 
                 268 
               
               
                   
                 ISIS 542112 
                 454 
                 430 
                 368 
               
               
                   
                 ISIS 542118 
                 418 
                 379 
                 377 
               
               
                   
                 ISIS 542185 
                 370 
                 303 
                 296 
               
               
                   
                 ISIS 541767 
                 435 
                 326 
                 325 
               
               
                   
                 ISIS 541875 
                 437 
                 359 
                 n/a 
               
               
                   
                   
               
            
           
         
       
     
     C-Reactive Protein and Complement C3 Level Analysis 
     To evaluate any inflammatory effect of ISIS oligonucleotides in cynomolgus monkeys, blood samples were taken for analysis. The monkeys were fasted overnight prior to blood collection. Approximately 1.5 mL of blood was collected from each animal and put into tubes without anticoagulant for serum separation. The tubes were kept at room temperature for a minimum of 90 min and then centrifuged at 3,000 rpm for 10 min at room temperature to obtain serum. C-reactive protein (CRP), which is synthesized in the liver and which serves as a marker of inflammation, was measured using a Toshiba 200FR NEO chemistry analyzer (Toshiba Co., Japan). The Tables below present the results for CRP and C3 levels at various time points. The results indicate that treatment with ISIS 532401 did not cause inflammation in monkeys. 
     
       
         
           
               
             
               
                 TABLE 121 
               
             
            
               
                   
               
               
                 CRP (mg/L) in cynomolgus monkey 
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                 Day 16 
                 Day 44 
                 Day 86 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
            
               
                   
                 PBS 
                 3.8 
                 2.0 
                 2.0 
               
               
                   
                 ISIS 532401 
                 2.3 
                 1.7 
                 1.9 
               
               
                   
                 ISIS 532254 
                 2.1 
                 3.2 
                 5.9 
               
               
                   
                 ISIS 523723 
                 6.1 
                 4.5 
                 4.4 
               
               
                   
                 ISIS 542112 
                 2.5 
                 2.7 
                 2.7 
               
               
                   
                 ISIS 542118 
                 2.2 
                 2.8 
                 2.1 
               
               
                   
                 ISIS 542185 
                 2.3 
                 11.9 
                 9.3 
               
               
                   
                 ISIS 541767 
                 1.9 
                 1.5 
                 6.7 
               
               
                   
                 ISIS 541875 
                 4.9 
                 3.5 
                 8.4 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 122 
               
             
            
               
                   
               
               
                 C3 (mg/dL) on day 85 (24 hours after  
               
               
                 dosing) in cynomolgus monkey 
               
            
           
           
               
               
               
            
               
                   
                   
                 C3 
               
               
                   
                   
               
            
           
           
               
               
               
            
               
                   
                 PBS 
                 114 
               
               
                   
                 ISIS 532401 
                 96 
               
               
                   
                 ISIS 532254 
                 100 
               
               
                   
                 ISIS 523723 
                 87 
               
               
                   
                 ISIS 542112 
                 100 
               
               
                   
                 ISIS 542118 
                 110 
               
               
                   
                 ISIS 542185 
                 98 
               
               
                   
                 ISIS 541767 
                 99 
               
               
                   
                 ISIS 541875 
                 81 
               
               
                   
                   
               
            
           
         
       
     
     Measurement of Oligonucleotide Concentration 
     The concentration of the full-length oligonucleotide in the liver and the kidney of the monkeys was measured. The method used is a modification of previously published methods (Leeds et al., 1996; Geary et al., 1999) which consist of a phenol-chloroform (liquid-liquid) extraction followed by a solid phase extraction. An internal standard (ISIS 355868, a 27-mer 2′-O-methoxyethyl modified phosphorothioate oligonucleotide, GCGTTTGCTCTTCTTCTTGCGTTTTTT, designated herein as SEQ ID NO: 2300) was added prior to extraction. Tissue sample concentrations were calculated using calibration curves, with a lower limit of quantitation (LLOQ) of approximately 1.14 μg/g. Half-lives were then calculated using WinNonlin software (PHARSIGHT). 
     The results are presented in Table 123, expressed as μg/g of tissue, as well as the ratio of concentration in kidney versus liver. 
     
       
         
           
               
             
               
                 TABLE 123 
               
             
            
               
                   
               
               
                 Oligonucleotide concentration in the liver  
               
               
                 and kidney of cynomolgus monkeys 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                   
                   
                   
                   
                 K/L 
               
               
                   
                   
                 Chemistry 
                 Liver 
                 Kidney 
                 ratio 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
               
            
               
                   
                 ISIS 532401 
                 5-10-5 MOE 
                 725 
                 2154 
                 3.0 
               
               
                   
                 ISIS 532254 
                 5-10-5 MOE 
                 911 
                 4467 
                 4.9 
               
               
                   
                 ISIS 523723 
                 5-10-5 MOE 
                 657 
                 3093 
                 4.7 
               
               
                   
                 ISIS 542112 
                 3-10-3 cEt/MOE 
                 491 
                 2863 
                 5.8 
               
               
                   
                 ISIS 542118 
                 3-10-3 cEt/MOE 
                 429 
                 1222 
                 2.8 
               
               
                   
                 ISIS 542185 
                 3-10-3 cEt/MOE 
                 432 
                 3126 
                 7.2 
               
               
                   
                 ISIS 541767 
                 3-10-3 cEt/MOE 
                 280 
                 994 
                 3.5 
               
               
                   
                 ISIS 541875 
                 3-10-3 cEt/MOE 
                 766 
                 3892 
                 5.1 
               
               
                   
                   
               
            
           
         
       
     
     Study 2 
     One group of 5 randomly assigned male cynomolgus monkeys was injected subcutaneously with ISIS 532401 or PBS using a stainless steel dosing needle and syringe of appropriate size into the intracapsular region and outer thigh of the monkeys. The monkeys were dosed a loading dose per week (days 1, 3, 5, and 7) for the first week, and then subsequently once a week (days 14, 21, 28, 35, 42, 49, 56, 63, 70, 77, 84, and 91) with 40 mg/kg of ISIS 532401. A control group of 5 cynomolgus monkeys was injected with PBS in a similar manner and served as the control group. 
     Target Reduction 
     RNA Analysis 
     On day 93, RNA was extracted from liver, white adipose tissue (WAT) and muscle for real-time PCR analysis of measurement of mRNA expression of GHR. Treatment with ISIS 532401 resulted in significant reduction of GHR mRNA in liver and white adipose tissue. 
     The expression of the growth hormone-responsive gene, ALS was also measured in the liver. Treatment with ISIS 532401 resulted in ALS RNA expression reduction in liver by 38%, correlating with GHR levels. ‘n.d.’ indicates that the levels were not checked in that particular tissue. The expression of IGF1 in the liver, muscle and fat tissues was also measured. Treatment with ISIS 532401 resulted in IGF1 RNA expression reduction in liver and in the WAT, correlating with GHR levels. 
     
       
         
           
               
             
               
                 TABLE 124 
               
             
            
               
                   
               
               
                 Effect of treatment with ISIS 532401 on mRNA levels  
               
               
                 (% inhibition compared to the PBS control) in the 
               
               
                 cynomolgus monkey 
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                 Liver 
                 WAT 
                 Muscle 
               
               
                   
                   
               
               
                   
                 GHR 
                 64 
                 75 
                 21 
               
               
                   
                 ALS 
                 38 
                 n.d. 
                 n.d. 
               
               
                   
                 IGF1 
                 73 
                 56 
                 35 
               
               
                   
                   
               
            
           
         
       
     
     Protein Analysis 
     Plasma levels of IGF-1 and GH were measured in the plasma. The results are presented in the Table below. The results indicate that treatment with ISIS 532401 resulted in reduced IGF-1 protein levels. There was no increase in plasma growth hormone levels. 
     
       
         
           
               
             
               
                 TABLE 125 
               
             
            
               
                   
               
               
                 Plasma IGF1 levels (ng/mL) in the cynomolgus monkey 
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                 Day 7 
                 Day 49 
                 Day 91 
               
               
                   
                   
               
               
                   
                 PBS 
                 625 
                 776 
                 850 
               
               
                   
                 ISIS 532401 
                 378 
                 455 
                 363 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 126 
               
             
            
               
                   
               
               
                 Plasma growth hormone levels (ng/mL) in the cynomolgus monkey 
               
            
           
           
               
               
               
               
            
               
                   
                 Day 7 
                 Day 49 
                 Day 91 
               
               
                   
               
               
                 PBS 
                 25 
                 27 
                 33 
               
               
                 ISIS 532401 
                 16 
                 13 
                 17 
               
               
                   
               
            
           
         
       
     
     Example 24: Measurement of Viscosity of ISIS Antisense Oligonucleotides Targeting Human GHR 
     The viscosity of select antisense oligonucleotides from the study described in the Examples above was measured with the aim of screening out antisense oligonucleotides which have a viscosity more than 40 cP. Oligonucleotides having a viscosity greater than 40 cP would be too viscous to be administered to any subject. 
     ISIS oligonucleotides (32-35 mg) were weighed into a glass vial, 120 μL of water was added and the antisense oligonucleotide was dissolved into solution by heating the vial at 50° C. Part of (75 μL) the pre-heated sample was pipetted to a micro-viscometer (Cambridge). The temperature of the micro-viscometer was set to 25° C. and the viscosity of the sample was measured. Another part (20 μL) of the pre-heated sample was pipetted into 10 mL of water for UV reading at 260 nM at 85° C. (Cary UV instrument). The results are presented in Table 127 and indicate that all the antisense oligonucleotides solutions are optimal in their viscosity under the criterion stated above. 
     
       
         
           
               
             
               
                 TABLE 127 
               
             
            
               
                   
               
               
                 Viscosity of ISIS antisense oligonucleotides targeting human GHR 
               
            
           
           
               
               
               
               
            
               
                   
                 ISIS 
                   
                 Viscosity 
               
               
                   
                 No. 
                 Chemistry 
                 (cP) 
               
               
                   
                   
               
            
           
           
               
               
               
               
            
               
                   
                 523723 
                 5-10-5 MOE 
                 8 
               
               
                   
                 532254 
                 5-10-5 MOE 
                 22 
               
               
                   
                 532401 
                 5-10-5 MOE 
                 12 
               
               
                   
                 541767 
                 Deoxy, MOE 
                 13 
               
               
                   
                   
                 and cEt 
                   
               
               
                   
                 541875 
                 Deoxy, MOE 
                 33 
               
               
                   
                   
                 and cEt 
                   
               
               
                   
                 542112 
                 Deoxy, MOE 
                 10 
               
               
                   
                   
                 and cEt 
                   
               
               
                   
                 542118 
                 Deoxy, MOE 
                 14 
               
               
                   
                   
                 and cEt 
                   
               
               
                   
                 542185 
                 Deoxy, MOE 
                 17 
               
               
                   
                   
                 and cEt 
               
               
                   
                   
               
            
           
         
       
     
     Example 25: Effect of Antisense Inhibition of GHR in Mice 
     In order to confirm the effect of antisense inhibition of GHR in the primate model, an ISIS oligonucleotide targeting murine GHR was employed to replicate the result in a mouse model. 
     ISIS 563223 (GAGACTTTTCCTTGTACACA, designated herein as SEQ ID NO: 2301) is a 5-10-5 MOE gapmer murine antisense oligonucleotide targeting murine GHR (GENBANK Accession No; NM_010284.2, designated herein as SEQ ID NO: 2302) at target start site 3230. A group of male and female CD1 mice were injected with a loading dose (on days 1, 3, 5, and 7) on the first week and subsequently with a once weekly dose (on days 14, 21, 28, 35, 42, 49, 56, 63, 70, 77, 84, and 91) with 40 mg/kg of ISIS 563223. One group of CD1 mice was injected in a similar manner with PBS. Mice were euthanized 48 hours after the last dose, and organs and plasma were harvested for further analysis. 
     mRNA Expression 
     Liver mRNA expression of GHR, GHBP, IGF1, and ALS were measured. The results are presented in Table 128. Antisense inhibition of GHR resulted in inhibition of GHBP, IGF1 and ALS gene expression levels. 
     
       
         
           
               
             
               
                 TABLE 128 
               
             
            
               
                   
               
               
                 mRNA expression (% Inhibition) in CD 1 mice liver 
               
            
           
           
               
               
               
            
               
                   
                 % (in male mice) 
                 % (in female mice) 
               
               
                   
               
               
                 GHR 
                 98 
                 96 
               
               
                 GHBP 
                 74 
                 66 
               
               
                 IGF1 
                 60 
                 48 
               
               
                 ALS 
                 84 
                 74 
               
               
                   
               
            
           
         
       
     
     Protein Expression 
     Plasma levels of IGF1 and growth hormone were measured. The results are presented in Table 129. Antisense inhibition of GHR resulted in decrease in IGF1 levels, and had no effect on growth hormone levels. 
     
       
         
           
               
             
               
                 TABLE 129 
               
             
            
               
                   
               
               
                 IGF1 protein levels (ng/mL) in CD 1 mice liver 
               
            
           
           
               
               
               
            
               
                   
                 in male mice 
                 in female mice 
               
               
                   
               
               
                 PBS 
                 949 
                 1002 
               
               
                 ISIS 563223 
                 439 
                 740 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 130 
               
             
            
               
                   
               
               
                 Growth hormone protein levels (ng/mL) in CD1 mice liver 
               
            
           
           
               
               
               
            
               
                   
                 in male mice 
                 in female mice 
               
               
                   
               
               
                 PBS 
                 3.3 ± 2.2 
                 2.2 ± 1.3 
               
               
                 ISIS 563223 
                 5.6 ± 6.7 
                 2.9 ± 1.7