Patent Publication Number: US-2023158059-A1

Title: Prekallikrein-modulating compositions and methods of use thereof

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
     This application claims the benefit of U.S. Provisional Application No. 63/251,571, filed Oct. 1, 2021; U.S. Provisional Application No. 63/252,554, filed Oct. 5, 2021; U.S. Provisional Application No. 63/270,504, filed Oct. 21, 2021; U.S. Provisional Application No. 63/283,175, filed Nov. 24, 2021; and U.S. Provisional Application No. 63/287,969, filed Dec. 9, 2021. The disclosure of each of the prior applications is considered part of and is incorporated by reference in its entirety in the disclosure of this application. 
     REFERENCE TO AN ELECTRONIC SEQUENCE LISTING 
     The contents of the electronic sequence listing (A127870009US05-SEQ-JIB.xml; Size: 638,286 bytes; and Date of Creation: Sep. 30, 2022) is herein incorporated by reference in its entirety. 
    
    
     BACKGROUND 
     Plasma prekallikrein (PKK) is a glycoprotein that participates in the surface-dependent activation of blood coagulation, fibrinolysis, kinin generation, and inflammation. PKK, which is encoded by the KLKB1 gene, is the precursor of plasma kallikrein (PK). PKK is present in plasma as a contact factor that forms non-covalent complexes with high molecular weight kininogen. PKK is converted to PK by Factor XIIa through the cleavage of an internal Arg-Ile peptide bond. PK is a member of the kinin-kallikrein pathway, which consists of several proteins that play a role in inflammation, blood pressure control, coagulation, and pain. PK liberates kinins from kininogens and also generates plasmin from plasminogen. For example, plasma kallikrein cleaves high molecular weight kininogen (HMWK) to generate bradykinin. The kinins, especially bradykinin, go on to induce downstream effects including vasodilation and edema (See, e.g., Schmaier. J. Thromb. Haemost 14: 28-39, 2016). 
     Certain mutations in PKK cause PKK deficiency, also known as Fletcher Factor deficiency, a rare coagulation deficiency characterized by a prolonged activated partial thromboplastin time (PTT). PKK deficiency has been linked to inflammatory and thrombotic disorders. 
     Mutations in PKK prevent the release of plasmin and kinins (e.g., bradykinin), and/or reduce fibrinolysis. This results in reduced vasodilation and increased blood clot formation, which in turn increase the likelihood of contracting inflammatory or thrombotic diseases. People with PKK deficiency are often asymptomatic, but still present a prolonged activated PTT, and are at risk of developing such diseases. 
     An inflammatory disorder occurs when the immune system mistakenly attacks the body&#39;s own cells or tissues. This causes abnormal inflammation that can result in chronic pain, redness, swelling, stiffness and damage to otherwise healthy body tissues. Inflammatory diseases include a vast array of disorders and conditions that are characterized by inflammation. Examples include rheumatoid arthritis, allergy, asthma, autoimmune diseases, coeliac disease, glomerulonephritis, hepatitis, inflammatory bowel disease, pre-perfusion injury and transplant rejection. It is estimated that over 1.36 million adults in the US suffer from rheumatoid arthritis and 3 million from inflammatory bowel disease. 
     Thrombosis is the formation of a blood clot inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel is injured, the body uses platelets and fibrin to form a blood clot to prevent blood loss. Even when a blood vessel is not injured, blood clots may form in the body under certain conditions. In healthy people, homeostatic balance exists between procoagulant (clotting) forces and anticoagulant and fibrinolytic forces. Numerous genetic, acquired, and environmental factors can tip the balance in favor of coagulation, leading to the pathologic formation of thrombi in veins (e.g., deep venous thrombosis), arteries (e.g., myocardial infarction, ischemic stroke), or cardiac chambers. Thrombi can obstruct blood flow at the site of formation or detach and embolize to block a distant blood vessel (e.g., pulmonary embolism, embolic stroke). In the US alone, about 900,000 people are affected by blood clots each year, and about 100,000 of those people will die from blood clot-related complications. 
     Hereditary angioedema (HAE) is a rare inflammatory disease characterized by recurrent episodes of swelling around the head and extremities (Zuraw, B. L. N. Engl. J. Med. 359: 1027-36, 2008). Angioedema attacks occur with unpredictable frequency and are typically focused on the skin, and gastric, oropharyngeal, and laryngeal mucosas. Asphyxiation due to laryngeal swelling can result in mortality. HAE is caused by deficiency or malfunction of the serine protease inhibitor C1-INH (Kaplan, A. P. et al. J. Allergy Clin. Immunol. 109: 195-209, 2002). C1-INH is the primary inhibitor of coagulation factors 12 and 11 (Factor 11) of the intrinsic coagulation pathway as well as plasma kallikrein (Gigli, I. et al. J. Immunol. 104:574-581, 1970). C1-INH mediated inhibition of plasma kallikrein and Factor 12 results in inactivation of the kallikrein pathway and decreased levels of bradykinin (BK). C1-INH deficiency or dysfunction results in overproduction of BK, which is the mechanism by which HAE attacks are believed to occur. Type III HAE has been linked with mutations in the Factor 12 gene, which encodes coagulation protein Factor 12 (Cichon, S. et al. Am. J. Hum. Genet. 79: 1098-1104, 2006). 
     There is currently no cure for certain inflammatory conditions, such as HAE, or thrombotic conditions associated with dysregulation of PKK or other members of the kallikrein pathway. Accordingly, there is a need to find effective treatments for PKK related diseases. 
     SUMMARY 
     The present disclosure provides compounds, compositions, and methods for modulating the expression or activity of PKK. In certain embodiments, the compounds, compositions, and methods can be used to reduce the expression of PKK mRNA in a cell or animal. In certain embodiments, the compounds, compositions, and methods can be used to reduce the amount of PKK protein in a cell or animal. 
     In certain embodiments, the animal has an inflammatory or thrombotic disease, disorder or condition or a symptom thereof. In certain embodiments, the disease is hereditary angioedema (HAE), edema, angioedema, swelling, angioedema of the lids, ocular edema, macular edema, cerebral edema, thrombosis, embolism, thromboembolism, deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke, or infarct. Certain compounds, compositions and methods provided herein are directed to reducing an inflammatory or thrombotic disease, disorder or condition or a symptom thereof or hereditary angioedema (HAE), edema, angioedema, swelling, angioedema of the lids, ocular edema, macular edema, cerebral edema, thrombosis, embolism, thromboembolism, deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke, or infarct in an animal. In certain embodiments, the compounds and compositions provided herein are potent and tolerable and inhibit PKK expression, which can be used to treat, prevent, ameliorate, or slow progression of an inflammatory or thrombotic disease, disorder or condition or a symptom thereof or hereditary angioedema (HAE), edema, angioedema, swelling, angioedema of the lids, ocular edema, macular edema, cerebral edema, thrombosis, embolism, thromboembolism, deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke, or infarct. 
     In certain embodiments, the compounds and compositions comprise one or more features that are effective for increasing potency. In certain embodiments, the compounds and compositions comprise one or more features that are effective for increasing tolerability. In certain embodiments, compounds and compositions comprise one or more features that are effective for targeting the compound or composition to a cell or tissue. In certain embodiments, the compounds and compositions are more potent or have greater therapeutic value than compounds publicly disclosed. 
    
    
     DETAILED DESCRIPTION 
     It is to be understood that both the foregoing summary and the following detailed description are exemplary and explanatory only and are not restrictive of the embodiments, as claimed. 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, treatises, and GenBank, NCBI and other sequence reference records are hereby expressly incorporated by reference for the portions of the document discussed herein, as well as in their entirety as of the date of filing this application. 
     It is understood that the sequence set forth in each SEQ ID NO contained herein is independent of any modification to a sugar moiety, an internucleoside linkage, or a nucleobase even if shown in context with a modified compound. As such, compounds defined by a SEQ ID NO may comprise, independently, one or more modifications to a sugar moiety, an internucleoside linkage, or a nucleobase. Oligomeric compounds referenced by Compound Number or Ref ID NO indicate a combination of nucleobase sequence, chemical modification, and motif. 
     Herein, the use of the singular includes the plural unless specifically stated otherwise. For example, the articles “a” and “an” are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element, e.g., a plurality of elements. 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 and is used interchangeably with, the phrase “including but not limited to”. 
     Definitions 
     Unless otherwise indicated, the following terms have the following meanings: 
     “Plasma prekallikrein” or “kallikrein B1,” used interchangeably with the term “PKK,” refers to any nucleic acid or protein of PKK. Exemplary nucleotide and amino acid sequences of PKK can be found, for example, at GenBank Accession No. NM_000892.5 (incorporated herein as SEQ ID NO: 1), NG_012095.2 truncated from 23529 . . . 54493 (incorporated herein as SEQ ID NO: 2), XM_017008181.1 (incorporated herein as SEQ ID NO: 3), NC_000004.12 truncated from 186215714 to 186258477 (incorporated herein as SEQ ID NO: 4), NM_001318394.2 (incorporated herein as SEQ ID NO: 5) and NM_001318396.2 (incorporated herein as SEQ ID NO: 6). Additional examples of PKK sequences are readily available through publicly available databases, e.g., GenBank, UniProt, and OMIM. Further information on PKK can be found, for example, at ncbi.nlm.nih.gov/gene/?term=PKK. PKK, as used herein, also refers to variations of the PKK gene including variants provided in the SNP database. Numerous sequence variations within the PKK gene have been identified and may be found at, for example, NCBI dbSNP and UniProt (see, e.g., ncbi.nlm.nih.gov/snp/?term=PKK). “PKK mRNA” means an mRNA encoding a PKK protein. PKK may be referred to in either upper or lower case. 
     “PKK specific inhibitor” refers to any agent capable of specifically inhibiting PKK RNA and/or PKK protein expression or activity at the molecular level. For example, PKK specific inhibitors include nucleic acids (including oligonucleotide compounds), peptides, antibodies, small molecules, and other agents capable of inhibiting the expression of PKK RNA and/or PKK protein. 
     “2′-O-methoxyethyl” or “2′-MOE” means a 2′-O(CH 2 ) 2 -OCH 3  modification. A 2′-O-methoxyethyl modified sugar is a modified sugar with 2′-O(CH 2 ) 2 -OCH 3  in the place of the 2′-OH group of a ribosyl ring. 
     “5′ start site” means the nucleotide of the target nucleic acid or region which is aligned to the 3′-most nucleoside of an antisense oligonucleotide. 
     “3′ stop site” means the nucleotide of the target nucleic acid or region which is aligned to the 5′-most nucleoside of an antisense oligonucleotide. 
     “About” means within ±10% of a value. For example, if it is stated, “a compound achieved about 70% inhibition of PKK”, it is implied that PKK levels are inhibited within a range of 60% and 80%. When about is present before a series of numbers or a range, it is understood that “about” can modify each of the numbers in the series or range. 
     “Administer” or “administering” refers to routes of introducing a compound or composition provided herein to an individual to perform its intended function. An example, routes of administration that can be used include, but are not limited to, parenteral administration, such as subcutaneous, intravenous, or intramuscular injection or infusion. 
     “Ameliorate” refers to an improvement or 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 or severity of one or more indicators of a condition or disease. The progression or 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 oligonucleotide” or “antisense strand” means an oligonucleotide which includes a region that is complementary to a target nucleic acid, e.g., a PKK RNA or a region thereof. 
     “Complementarity” in reference to an oligonucleotide means the nucleobase sequence of such oligonucleotide or one or more regions thereof that is complementary to the nucleobase sequence of another oligonucleotide or nucleic acid or one or more regions thereof when the two nucleobase sequences are aligned in opposing directions. Complementary nucleobases, as described herein, are limited to the following pairs: adenine (A) and thymine (T), adenine (A) and uracil (U), and cytosine (C) and guanine (G) unless otherwise specified. Complementary oligonucleotides and/or nucleic acids need not have nucleobase complementarity at each nucleoside and may include one or more nucleobase mismatches. By contrast, “fully complementary” or “100% complementary” in reference to oligonucleotides means that such oligonucleotides have nucleobase matches at each nucleoside without any nucleobase mismatches. 
     “Composition” or “pharmaceutical composition” means a mixture of substances suitable for administering to an individual. For example, a composition may comprise one or more compounds or salt thereof and a sterile aqueous solution. 
     “Co-administration” means administration of two or more compounds in any manner in which the pharmacological effects of both are manifest in the patient. Co-administration does not require both compounds to be administered in a single pharmaceutical composition, in the same dosage form, by the same route of administration, or at the same time. The effects of both compounds need not manifest themselves at the same time. The effects need only be overlapping for a period of time and need not be coextensive. Co-administration includes parallel or sequential administration of the one or more compounds. 
     “Conjugate group” means a group of atoms that is attached to an oligonucleotide. A conjugate group is optionally attached to an oligonucleotide through a conjugate linker. A conjugate group may, for example, alter the distribution, targeting, or half-life of a compound into which it is incorporated. Conjugate groups include targeting moieties. 
     “Conjugate linker” means a group of atoms comprising at least one bond that connects a linked moiety to an oligonucleotide. 
     “Identity” in reference to an oligonucleotide means the nucleobase sequence of such oligonucleotide or one or more regions thereof that matches the nucleobase sequence of another oligonucleotide or nucleic acid or one or more regions thereof. Identity of an oligonucleotide to another oligonucleotide or nucleic acid need not require each nucleobase to match and may include one or more different nucleobases. By contrast, “fully identical” or “100% identity” in reference to oligonucleotides means that such oligonucleotides have the same nucleobase at each relative position over its length as the other oligonucleotide or nucleic acid. 
     “Individual” means a human or non-human animal selected for treatment or therapy. 
     “Inhibiting the expression or activity” with reference to a target nucleic acid or protein means to reduce or block the expression or activity of such target relative to the expression or activity in an untreated or control sample and does not necessarily indicate a total elimination of expression or activity. 
     As used herein, the term “internucleoside linkage” is the covalent linkage between adjacent nucleosides in an oligonucleotide. As used herein, “modified internucleoside linkage” means any internucleoside linkage other than a phosphodiester internucleoside linkage. “Phosphorothioate internucleoside linkage” is a modified internucleoside linkage in which one of the non-bridging oxygen atoms of a phosphodiester internucleoside linkage is replaced with a sulfur atom. 
     Representative internucleoside linkages having a chiral center include but are not limited to alkylphosphonates and phosphorothioates. Modified oligonucleotides comprising internucleoside linkages having a chiral center can be prepared as populations of modified oligonucleotides comprising stereorandom internucleoside linkages, or as populations of modified oligonucleotides comprising phosphorothioate linkages in particular stereochemical configurations as further described below. Unless otherwise indicated, chiral internucleoside linkages of modified oligonucleotides described herein can be stereorandom or in a particular stereochemical configuration. 
     The compounds of the present disclosure may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium ( 3 H), iodine-125 ( 125 I), or carbon-14 ( 14 C). All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure. 
     The term “isotopic variant” refers to a therapeutic agent (e.g., a compound and/or modified oligonucleotide disclosed herein) that contains an unnatural proportion of an isotope at one or more of the atoms that constitute such a therapeutic agent. In certain embodiments, an “isotopic variant” of a therapeutic agent contains unnatural proportions of one or more isotopes, including, but not limited to, hydrogen (H), deuterium ( 2 H), tritium ( 3 H), carbon-11 ( 11 C), carbon-12 ( 12 C), carbon-13 ( 13 C), carbon-14 ( 14 C), nitrogen-13 ( 13 N), nitrogen-14 ( 14 N), nitrogen-15 ( 5 N), oxygen-14 ( 14 O), oxygen-15 ( 15 O), oxygen-16 ( 16 O), oxygen-17 ( 17 O), oxygen-18 ( 18 O), fluorine-17 ( 17 F), fluorine-18 ( 18 F), phosphorus-31 ( 31 P), phosphorus-32 ( 32 P), phosphorus-33 ( 33 P), sulfur-32 ( 32 S), sulfur-33 ( 33 S), sulfur-34 ( 34 S), sulfur-35 ( 35 S), sulfur-36 ( 36 S), chlorine-35 ( 35 Cl), chlorine-36 ( 36 Cl), chlorine-37 ( 37 Cl), bromine-79 ( 79 Br), bromine-81 ( 81 Br), iodine 123 ( 123 I), iodine-125 ( 125 I), iodine-127 ( 127 I), iodine-129 ( 129 I), and iodine-131 ( 131 I). In certain embodiments, an “isotopic variant” of a therapeutic agent contains unnatural proportions of one or more isotopes, including, but not limited to, hydrogen (H), deuterium ( 2 H), tritium ( 3 H), carbon-11 ( 11 C), carbon-12 ( 12 C), carbon-13 ( 13 C), carbon-14 ( 14 C), nitrogen-13 ( 13 N), nitrogen-14 ( 14 N), nitrogen-15 ( 15 N), oxygen-14 ( 14 O), oxygen-15 ( 15 O), oxygen-16 ( 16 O), oxygen-17 ( 17 O), oxygen-18 ( 18 O), fluorine-17 ( 17 F), fluorine-18 ( 18 F), phosphorus-31 ( 31 P), phosphorus-32 ( 32 P), phosphorus-33 ( 33 P), sulfur-32 ( 32 S), sulfur-33 ( 33 S), sulfur-34 ( 34 S), sulfur-35 ( 35 S), sulfur-36 ( 36 S), chlorine-35 ( 35 Cl), chlorine-36 ( 36 Cl), chlorine-37 ( 37 Cl), bromine-79 ( 79 Br), bromine-81 ( 81 Br), iodine 123 ( 123 I), iodine-125 ( 125 I), iodine-127 ( 127 I), iodine-129 ( 129 I), and iodine-131 ( 131 I). 
     It will be understood that, in a therapeutic agent (e.g., a compound and/or modified oligonucleotide disclosed herein), any hydrogen can be  2 H, for example, or any carbon can be  13 C, for example, or any nitrogen can be  15 N, for example, or any oxygen can be  18 O, for example, where feasible according to the judgment of one of skill. In certain embodiments, an “isotopic variant” of a therapeutic agent contains unnatural proportions of deuterium (D). 
     “Mismatch” or “non-complementary” means a nucleobase of a first oligonucleotide or nucleic acid that is not complementary to the corresponding nucleobase of a second oligonucleotide or nucleic acid when the first oligonucleotide/nucleic acid and second oligonucleotide/nucleic acid are aligned in an antiparallel orientation. For example, nucleobases including, but not limited to, a universal nucleobase, inosine, and hypoxanthine, are capable of hybridizing with at least one nucleobase but are still mismatched or non-complementary with respect to the nucleobase to which they are hybridized. As another example, a nucleobase of a first oligonucleotide/nucleic acid that is not capable of hybridizing to the corresponding nucleobase of a second oligonucleotide/nucleic acid when the first and second oligonucleotides are aligned in an antiparallel orientation is a mismatch or non-complementary nucleobase. 
     “Modified oligonucleotide” means an oligonucleotide, wherein at least one sugar, nucleobase, or internucleoside linkage is modified. 
     “Modulating” refers to changing or adjusting a feature in a cell, tissue, organ or organism. For example, modulating PKK RNA can mean to increase or decrease the level of PKK RNA and/or PKK protein in a cell, tissue, organ or organism. A “modulator” effects the change in the cell, tissue, organ or organism. For example, a PKK compound can be a modulator that decreases the amount of PKK RNA and/or PKK protein in a cell, tissue, organ or organism. 
     “Motif” means the pattern of unmodified and modified sugar moieties, nucleobases, and/or internucleoside linkages, in an oligonucleotide. 
     “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. As used herein a “naturally occurring nucleobase” is adenine (A), thymine (T), cytosine (C), uracil (U), and guanine (G). A “modified nucleobase” is a naturally occurring nucleobase that is chemically modified. A “universal base” or “universal nucleobase” is a nucleobase other than a naturally occurring nucleobase and modified nucleobase and is capable of pairing with any nucleobase. 
     “Nucleobase sequence” means the order of contiguous nucleobases in a nucleic acid or oligonucleotide independent of any sugar or internucleoside linkage. 
     “Nucleoside” means a compound comprising a nucleobase and a sugar moiety. The nucleobase and sugar moiety are each, independently, unmodified or modified. “Modified nucleoside” means a nucleoside comprising a modified nucleobase and/or a modified sugar moiety. Modified nucleosides include abasic nucleosides, which lack a nucleobase. 
     “Oligomeric Compound” means a compound comprising one or more oligonucleotides and optionally one or more additional features, such as a conjugate group or terminal group. Examples of oligomeric compounds include single-stranded and double-stranded compounds, such as, oligonucleotides, antisense oligonucleotides, interfering RNA compounds (RNAi compounds), microRNA targeting oligonucleotides, occupancy-based compounds (e.g., mRNA processing or translation blocking compounds and splicing compounds). RNAi compounds include double-stranded compounds (e.g., short-interfering RNA (siRNA) and double-stranded RNA (dsRNA)) and single-stranded compounds (e.g., single-stranded siRNA (ssRNA), single-stranded RNAi (ssRNAi), short hairpin RNA (shRNA) and microRNA mimics) which work at least in part through the RNA-induced silencing complex (RISC) pathway resulting in sequence specific degradation and/or sequestration of a target nucleic acid through a process known as RNA interference (RNAi). The term “RNAi compound” is meant to be equivalent to other terms used to describe nucleic acid compounds that are capable of mediating sequence-specific RNA interference, for example, interfering RNA (iRNA), iRNA agent, RNAi agent, short interfering oligonucleotide, short interfering nucleic acid, short interfering modified oligonucleotide, chemically modified siRNA, and others. Additionally, the term “RNAi” is meant to be equivalent to other terms used to describe sequence-specific RNA interference. 
     “Oligonucleotide” means a polymer of linked nucleosides, each of which can be modified or unmodified, independent from one another. 
     The term “oligomeric duplex” means a duplex formed by two oligomeric compounds having complementary nucleobase sequences. Each oligomeric compound of an oligomeric duplex may be referred to as a “duplexed oligomeric compound.” The oligonucleotides of each oligomeric compound of an oligomeric duplex may include non-complementary overhanging nucleosides. In some embodiments, the terms “duplexed oligomeric compound” and “modified oligonucleotide” are used interchangeably. In other embodiments, the terms “oligomeric duplex” and “compound” are used interchangeably. 
     “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. 
     “Pharmaceutically acceptable carrier or diluent” means any substance suitable for use in administering to an individual. In certain embodiments, a pharmaceutically acceptable carrier or diluent aids the administration of a compound to and absorption by an individual and can be included in the compositions of the present disclosure without causing a significant adverse toxicological effect on the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline solutions, and the like. For example, a pharmaceutically acceptable carrier can be a sterile aqueous solution, such as PBS or water-for-injection. One of skill in the art will recognize that other pharmaceutical excipients are useful in the present disclosure. 
     “Pharmaceutically acceptable salts” means or refers to physiologically and pharmaceutically acceptable salts of compounds, such as oligomeric compounds or oligonucleotides, i.e., salts that retain the desired biological activity of the parent compound and do not impart undesired toxicological effects thereto. 
     As used herein, a pharmaceutically acceptable salt is any salt of a compound provided herein which retains its biological properties and which is not toxic or otherwise undesirable for pharmaceutical use. The pharmaceutically acceptable salts of the therapeutic agents disclosed herein include salts that are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds or modified oligonucleotides described herein. 
     When compounds of the present disclosure contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. 
     When compounds of the present disclosure contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. 
     Thus, the compounds of the present disclosure may exist as salts, such as with pharmaceutically acceptable acids. Such salts may be derived from a variety of organic and inorganic counter-ions well known in the art. Such salts include, but are not limited to: (1) acid addition salts formed with organic or inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, sulfamic, acetic, trifluoroacetic, trichloroacetic, propionic, hexanoic, cyclopentylpropionic, glycolic, glutaric, pyruvic, lactic, malonic, succinic, sorbic, ascorbic, malic, maleic, fumaric, tartaric, citric, benzoic, 3-(4-hydroxybenzoyl)benzoic, picric, cinnamic, mandelic, phthalic, lauric, methanesulfonic, ethanesulfonic, 1,2-ethane-disulfonic, 2-hydroxyethanesulfonic, benzenesulfonic, 4-chlorobenzenesulfonic, 2-naphthalenesulfonic, 4-toluenesulfonic, camphoric, camphorsulfonic, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic, glucoheptonic, 3-phenylpropionic, trimethylacetic, tert-butylacetic, lauryl sulfuric, gluconic, benzoic, glutamic, hydroxynaphthoic, salicylic, stearic, cyclohexylsulfamic, quinic, muconic acid and the like acids; or (2) salts formed when an acidic proton present in the parent compound either (a) is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion or an aluminum ion, or alkali metal or alkaline earth metal hydroxides, such as sodium, potassium, calcium, magnesium, aluminum, lithium, zinc, and barium hydroxide, ammonia, or (b) coordinates with an organic base, such as aliphatic, alicyclic, or aromatic organic amines, such as ammonia, methylamine, dimethylamine, diethylamine, picoline, ethanolamine, diethanolamine, triethanolamine, ethylenediamine, lysine, arginine, ornithine, choline, N,N′-dibenzylethylene-diamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, N-methylglucamine piperazine, tris(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide, and the like (see, for example, Berge et al., “Pharmaceutical Salts,” Journal of Pharmaceutical Science, 1977, 66, 1-19). 
     Pharmaceutically acceptable salts further include, by way of example only and without limitation, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like, and when the compound contains a basic functionality, salts of non-toxic organic or inorganic acids, such as hydrohalides, e.g. hydrochloride and hydrobromide, sulfate, phosphate, sulfamate, nitrate, acetate, trifluoroacetate, trichloroacetate, propionate, hexanoate, cyclopentylpropionate, glycolate, glutarate, pyruvate, lactate, malonate, succinate, sorbate, ascorbate, malate, maleate, fumarate, tartarate, citrate, benzoate, 3-(4-hydroxybenzoyl)benzoate, picrate, cinnamate, mandelate, phthalate, laurate, methanesulfonate (mesylate), ethanesulfonate, 1,2-ethane-disulfonate, 2-hydroxyethanesulfonate, benzenesulfonate (besylate), 4-chlorobenzenesulfonate, 2-naphthalenesulfonate, 4-toluenesulfonate, camphorate, camphorsulfonate, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylate, glucoheptonate, 3-phenylpropionate, trimethylacetate, tert-butylacetate, lauryl sulfate, gluconate, benzoate, glutamate, hydroxynaphthoate, salicylate, stearate, cyclohexylsulfamate, quinate, muconate, and the like. In some embodiments, the pharmaceutically acceptable salt of the compounds and modified oligonucleotides disclosed herein is a sodium or a potassium salt. In some embodiments, the pharmaceutically acceptable salt of the compounds and modified oligonucleotides disclosed herein is a sodium salt. 
     The neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound may differ from the various salt forms in certain physical properties, such as solubility in polar solvents. In embodiments, compounds of the present disclosure contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts. The neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in a conventional manner. The parent form of the compounds differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but, unless specifically indicated, the salts disclosed herein are equivalent to the parent form of the compound for the purposes of the present disclosure. 
     “Pharmaceutical agent” means a compound that provides a therapeutic benefit when administered to an individual. 
     “Phosphorothioate linkage” means a modified phosphate linkage in which one of the non-bridging oxygen atoms is replaced with a sulfur atom. 
     “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 oligonucleotide. 
     “Prevent” refers to delaying or forestalling the onset, development or progression of a disease, disorder, or condition for a period of time. 
     “RNA interference compound” or “RNAi compound” means a compound that acts, at least in part, through an RNA-induced silencing complex (RISC) pathway or Ago2, but not through RNase H, to modulate a target nucleic acid and/or protein encoded by a target nucleic acid. RNAi compounds include, but are not limited to double-stranded siRNA, single-stranded siRNA, and microRNA, including microRNA mimics. 
     “Sense oligonucleotide” or “sense strand” means the strand of a double-stranded compound that includes a region that is substantially complementary to a region of the antisense strand of the compound. 
     “Specifically inhibit” with reference to a target nucleic acid or protein means to reduce or block expression or activity of the target nucleic acid or protein while minimizing or eliminating effects on non-target nucleic acids or proteins. 
     “Subunit” with reference to an oligonucleotide means a nucleotide, nucleoside, nucleobase or sugar or a modified nucleotide, nucleoside, nucleobase or sugar as provided herein. 
     “Target nucleic acid,” “target RNA,” and “nucleic acid target” all mean a nucleic acid capable of being targeted by compounds described herein. 
     “Target region” means a portion of a target nucleic acid to which one or more compounds is targeted. 
     “Targeting moiety” means a conjugate group that provides an enhanced affinity for a selected target, e.g., molecule, cell or cell type, compartment, e.g., a cellular or organ compartment, tissue, organ or region of the body, as, e.g., compared to a compound absent such a moiety. 
     “Terminal group” means a chemical group or group of atoms that is covalently linked to a terminus of an oligonucleotide. 
     “Therapeutically effective amount” or “effective amount” means an amount of a compound, pharmaceutical agent, or composition that provides a therapeutic benefit to an individual. A “therapeutically effective amount” or “effective amount” is an amount sufficient for a compound to accomplish a stated purpose relative to the absence of the compound (e.g., achieve the effect for which it is administered, treat, prevent or ameliorate a disease or reduce one or more symptoms of a disease or condition). An example of a “therapeutically effective amount” or “effective amount” is an amount sufficient to contribute to the treatment, prevention, amelioration, or reduction of a symptom or symptoms of a disease. A “reduction” of a symptom or symptoms (and grammatical equivalents of this phrase) means decreasing of the severity or frequency of the symptom(s), or elimination of the symptom(s). A “prophylactically effective amount” of a drug is an amount of a drug that, when administered to a subject, will have the intended prophylactic effect, e.g., preventing or delaying the onset (or reoccurrence) of an injury, disease, pathology or condition, or reducing the likelihood of the onset (or reoccurrence) of an injury, disease, pathology, or condition, or their symptoms. The term “therapeutically effective amount,” as used herein, refers to that amount of the therapeutic agent sufficient to provide a therapeutic benefit to an individual, such as treating, preventing or ameliorating the disease or disorder or symptom thereof, as described above. For example, for the given parameter, a therapeutically effective amount will show an increase or decrease of at least 5%, 10%, 15%, 20%, 25%, 40%, 50%, 60%, 75%, 80%, 90%, or at least 100%. Therapeutic efficacy can also be expressed as “-fold” increase or decrease. For example, a therapeutically effective amount can have at least a 1.2-fold, 1.5-fold, 2-fold, 5-fold, or more effect over a control. 
     The terms “treating” or “treatment” refer to any indicia of success in the therapy or amelioration of an injury, disease, pathology or condition, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, pathology or condition more tolerable to the patient; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating; improving a patient&#39;s physical or mental well-being. The treatment or amelioration of symptoms can be based on objective or subjective parameters, including the results of a physical examination. The term “treating” and conjugations thereof, may include prevention of an injury, pathology, condition, or disease. In embodiments, treating is preventing. In embodiments, treating does not include preventing. 
     “Treating” or “treatment” as used herein (and as well-understood in the art) also broadly includes any approach for obtaining beneficial or desired results in a subject&#39;s condition, including clinical results. Beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of the extent of a disease, stabilizing (i.e., not worsening) the state of disease, prevention of a disease&#39;s transmission or spread, delay or slowing of disease progression, amelioration or palliation of the disease state, diminishment of the reoccurrence of disease, and remission, whether partial or total and whether detectable or undetectable. In other words, “treatment” as used herein includes any cure, amelioration, or prevention of a disease. Treatment may prevent the disease from occurring; inhibit the disease&#39;s spread; relieve the disease&#39;s symptoms, fully or partially remove the disease&#39;s underlying cause, shorten a disease&#39;s duration, or do a combination of these things. 
     “Treating” and “treatment” as used herein include prophylactic treatment. Treatment methods include administering to a subject a therapeutically effective amount of a compound described herein. The administering step may consist of a single administration or may include a series of administrations. The length of the treatment period depends on a variety of factors, such as the severity of the condition, the age of the patient, the concentration of the compound, the activity of the compositions used in the treatment, or a combination thereof. It will also be appreciated that the effective dosage of an agent used for the treatment or prophylaxis may increase or decrease over the course of a particular treatment or prophylaxis regime. In some instances, chronic administration may be required. For example, the compositions are administered to the subject in an amount and for a duration sufficient to treat the patient. 
     “Treat” refers to administering a compound or pharmaceutical composition to an animal in order to effect an alteration or improvement of a disease, disorder, or condition in the animal. 
     Certain compounds of the present disclosure possess asymmetric carbon atoms (optical or chiral centers) or double bonds; the enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisometric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)- or, as (D)- or (L)- for amino acids, and individual isomers are encompassed within the scope of the present disclosure. The compounds of the present disclosure do not include those that are known in art to be too unstable to synthesize and/or isolate. The present disclosure is meant to include compounds in racemic and optically pure forms. Optically active (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents or resolved using conventional techniques. When the compounds described herein contain olefinic bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. 
     As used herein, the term “isomers” refers to compounds having the same number and kind of atoms, and hence the same molecular weight, but differing in respect to the structural arrangement or configuration of the atoms. 
     The term “tautomer,” as used herein, refers to one of two or more structural isomers which exist in equilibrium and which are readily converted from one isomeric form to another. 
     It will be apparent to one skilled in the art that certain compounds of this disclosure may exist in tautomeric forms, all such tautomeric forms of the compounds being within the scope of the disclosure. 
     Unless otherwise stated, structures depicted herein are also meant to include all stereochemical forms of the structure (i.e., the R and S configurations for each asymmetric center). Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the disclosure. 
     As used herein, “chirally enriched population” means a plurality of molecules of identical molecular formula, wherein the number or percentage of molecules within the population that contain a particular stereochemical configuration at a particular chiral center is greater than the number or percentage of molecules expected to contain the same particular stereochemical configuration at the same particular chiral center within the population if the particular chiral center were stereorandom. Chirally enriched populations of molecules having multiple chiral centers within each molecule may contain one or more stereorandom chiral centers. In certain embodiments, the molecules are modified oligonucleotides. In certain embodiments, the molecules are compounds comprising modified oligonucleotides. 
     Unless otherwise stated, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by  13 C- or  14 C-enriched carbon are within the scope of this disclosure. 
     As used herein, “stereorandom chiral center” in the context of a population of molecules of identical molecular formula means a chiral center having a random stereochemical configuration. For example, in a population of molecules comprising a stereorandom chiral center, the number of molecules having the (S) configuration of the stereorandom chiral center may be but is not necessarily the same as the number of molecules having the (R) configuration of the stereorandom chiral center. The stereochemical configuration of a chiral center is considered random when it is the results of a synthetic method that is not designed to control the stereochemical configuration. In certain embodiments, a stereorandom chiral center is a stereorandom phosphorothioate internucleoside linkage. 
     Certain Embodiments 
     In certain aspects, the disclosure relates to methods, compounds and compositions for inhibiting PKK. In certain embodiments, PKK is specifically inhibited. In certain embodiments, PKK is specifically degraded. In certain embodiments, PKK expression is inhibited. In certain embodiments, PKK translation is inhibited. In certain embodiments, PKK activity is inhibited. In certain embodiments, PKK expression, translation, or activity is reduced by at least 10% relative to the expression, translation, or activity in an untreated or control sample. For example, in certain embodiments, PKK expression, translation, or activity is reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, 10-50%, 25-50%, 25-75%, 50-75%, 50-99%, or 75-99% relative to the expression, translation, or activity in an untreated or control sample. In certain embodiments, PKK expression, translation, or activity is reduced as measured by any suitable assay, including but not limited to, an immunoassay, a hybridization-based assay, or a sequencing-based assay (e.g., RNA-Seq). 
     In certain aspects, the disclosure relates to compounds targeted to a PKK nucleic acid. In certain embodiments, the PKK nucleic acid has the sequence set forth in GENBANK Accession No. NM_000892.5 (incorporated herein as SEQ ID NO: 1), NG_012095.2 truncated from 23529 . . . 54493 (incorporated herein as SEQ ID NO: 2), XM_017008181.1 (incorporated herein as SEQ ID NO: 3), NC_000004.12 truncated from 186215714 to 186258477 (incorporated herein as SEQ ID NO: 4), NM_001318394.2 (incorporated herein as SEQ ID NO: 5) and NM_001318396.2 (incorporated herein as SEQ ID NO: 6). 
     In certain embodiments, the compound is an oligomeric compound. In certain embodiments, the compound is single-stranded. In certain embodiments, the compound is double-stranded. 
     Certain embodiments provide a compound comprising a modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases of any of the nucleobase sequence of SEQ ID NOs: 10-313, 626, 627, and 628. 
     Certain embodiments provide a compound comprising a modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 10-313, 626, 627, and 628. 
     Certain embodiments provide a compound comprising a modified oligonucleotide having a nucleobase sequence selected from any one of SEQ ID NOs: 10-313, 626, 627, and 628. 
     In certain embodiments, the modified oligonucleotide has a nucleobase sequence that is at least 80%, at least 85%, at least 90%, or at least 95% complementary to SEQ ID NO: 1, 3, 5 or 6. In certain embodiments, the modified oligonucleotide comprises at least one modification selected from a modified internucleoside linkage, a modified sugar, and a modified nucleobase. In certain embodiments, the compound is double-stranded. 
     Certain embodiments provide a compound comprising a first modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases of any of the nucleobase sequence of SEQ ID NOs: 10-631 and a second modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a region of complementarity to the first modified oligonucleotide. 
     In certain embodiments, the compound comprises a first modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases of any of the nucleobase sequence provided in Tables 2-4, 6, and 8, and a second modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a region of complementarity to the first modified oligonucleotide. 
     Certain embodiments provide a compound comprising a first modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 10-631 and a second modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a region of complementarity to the first modified oligonucleotide. 
     Certain embodiments provide a compound comprising a first modified oligonucleotide having a nucleobase sequence selected from any one of SEQ ID NOs: 10-631 and a second modified oligonucleotide 19 to 23 linked nucleosides in length having a region of complementarity to the first modified oligonucleotide. 
     In certain embodiments, a compound comprises a modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases of any of the nucleobase sequences of SEQ ID NO: 307, 312 or 626. In certain embodiments, a compound comprises a modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases of the nucleobase sequences of SEQ ID NO: 468, 611, 616, 619 or 629. In certain embodiments, a compound comprises a modified oligonucleotide having a nucleobase sequence selected from the nucleobase sequences of SEQ ID NO: 307, SEQ ID NO: 312 and SEQ ID NO: 626. In certain embodiments, a compound comprises a modified oligonucleotide having a nucleobase sequence selected from the nucleobase sequence of SEQ ID NO: 468, SEQ ID NO: 611, SEQ ID NO: 616, SEQ ID NO: 619 and SEQ ID NO: 629. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 312 and a second modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 619. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 626 and a second modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 629. 
     In certain embodiments, the modified oligonucleotide or first modified oligonucleotide of any preceding compound has at least 80%, at least 85%, at least 90%, or at least 95% complementarity or identity to SEQ ID NO: 1, 3, 5 or 6 over its length. In certain embodiments, the modified oligonucleotide or first modified oligonucleotide has at least 1, at least 2, at least 3 mismatches to a region of SEQ ID NO: 1, 3, 5 or 6. In certain embodiments, the region of complementarity between the first modified oligonucleotide or first strand and the second modified oligonucleotide or second strand is 14 to 30 linked nucleosides in length. 
     In certain embodiments, the region of complementarity between the first modified oligonucleotide or first strand and the second modified oligonucleotide or second strand is 14 to 23 linked nucleosides in length. In certain embodiments, the region of complementarity between the first modified oligonucleotide or first strand and the second modified oligonucleotide or second strand is 19 to 23 linked nucleosides in length. In certain embodiments, the region of complementarity between the first modified oligonucleotide or first strand and the second modified oligonucleotide or second strand is 21 to 23 linked nucleosides in length. In certain embodiments, the first modified oligonucleotide is fully complementary to the second modified oligonucleotide. 
     In certain embodiments, the modified oligonucleotide or first modified oligonucleotide of any preceding compound comprises at least one modification selected from a modified internucleoside linkage, a modified sugar, and a modified nucleobase. In certain embodiments, the second modified oligonucleotide of any preceding compound comprises at least one modification selected from the group consisting of a modified internucleoside linkage, a modified sugar, and a modified nucleobase. In certain embodiments, the modified internucleoside linkage is a phosphorothioate internucleoside linkage or a methylphosphonate internucleoside linkage. In certain embodiments, the phosphorothioate internucleoside linkage or methylphosphonate internucleoside linkage is at the 3′ terminus of the first or second modified oligonucleotide or at the 5′ terminus of the first modified oligonucleotide. In certain embodiments, the modified sugar comprises a modification selected from the group consisting of a halogen, an alkoxy group and a bicyclic sugar. In certain embodiments, the modified sugar comprises a 2′-F modification. In certain embodiments, the modified sugar comprises a 2′-OMe modification. In certain embodiments, each nucleoside of the first modified oligonucleotide comprises a modified sugar. In certain embodiments, each nucleoside of the second modified oligonucleotide comprises a modified sugar. In certain embodiments, the modified sugar comprises a modification selected from the group consisting of a halogen, an alkoxy group and a bicyclic sugar or a combination thereof. In certain embodiments, the modified sugar comprises a modification selected from the group consisting of 2′-MOE, 2′-F, and 2′-OMe or a combination thereof. In certain embodiments, the first modified oligonucleotide comprises no more than ten 2′-F sugar modifications. In certain embodiments, the second modified oligonucleotide comprises no more than five 2′-F sugar modifications. 
     In certain embodiments, the compound of any preceding embodiment comprises a conjugate group. In certain embodiments, the conjugate group is attached to the 5′ end of the modified oligonucleotide. In certain embodiments, the conjugate group is a targeting moiety. In certain embodiments, the targeting moiety comprises one or more GalNAc. In certain embodiments, the modified oligonucleotide is the second modified oligonucleotide or sense oligonucleotide. In certain embodiments, the one or more GalNAc is attached to the 2′ or 3′ position of the ribosyl ring. In certain embodiments, the one or more GalNAc is attached to the 5′ nucleoside of the modified oligonucleotide. In certain embodiments, the 5′ nucleoside of a modified oligonucleotide is selected from the following Formulae or a salt, solvate, or hydrate thereof, wherein R is the portion of the modified oligonucleotide other than the 5′ nucleoside: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     In certain embodiments, R′ is O. In certain embodiments, R′ is S. In certain embodiments, the 5′ nucleoside of the modified oligonucleotide is Formula I and R′ is O. In certain embodiments, the 5′ nucleoside of the modified oligonucleotide is Formula I and R′ is S. In certain embodiments, the 5′ nucleoside of the modified oligonucleotide is Formula II and R′ is O. In certain embodiments, the 5′ nucleoside of the modified oligonucleotide is Formula II and R′ is S. In certain embodiments, the 5′ nucleoside of the modified oligonucleotide is Formula III and R′ is O. In certain embodiments, the 5′ nucleoside of the modified oligonucleotide is Formula III and R′ is S. In certain embodiments, the 5′ nucleoside of the modified oligonucleotide is Formula IV and R′ is O. In certain embodiments, the 5′ nucleoside of the modified oligonucleotide is Formula IV and R′ is S. In certain embodiments, the 5′ nucleoside of the modified oligonucleotide is Formula V and R′ is O. In certain embodiments, the 5′ nucleoside of the modified oligonucleotide is Formula V and R′ is S. In certain embodiments, the 5′ nucleoside of the modified oligonucleotide is Formula VI and R′ is O. In certain embodiments, the 5′ nucleoside of the modified oligonucleotide is Formula VI and R′ is S. In certain embodiments, the 5′ nucleoside of the modified oligonucleotide is Formula VII and R′ is O. In certain embodiments, the 5′ nucleoside of the modified oligonucleotide is Formula VII and R′ is S. In certain embodiments, the 5′ nucleoside of the modified oligonucleotide is Formula VIII and R′ is O. In certain embodiments, the 5′ nucleoside of the modified oligonucleotide is Formula VIII and R′ is S. 
     Certain embodiments provide a compound comprising a first modified oligonucleotide selected from any one of Ref ID NOs: IA0812-821 and a second modified oligonucleotide 14 to 21 linked nucleosides in length fully complementary to the first modified oligonucleotide. 
     Certain embodiments provide a compound comprising a first modified oligonucleotide consisting of IA0813 and a second modified oligonucleotide consisting of IS1002. 
     Certain embodiments provide a compound comprising a first modified oligonucleotide consisting of IA0818 and a second modified oligonucleotide consisting of IS1007. 
     Certain embodiments provide a compound comprising a first modified oligonucleotide consisting of IA0818 and a second modified oligonucleotide consisting of IS1068. 
     Certain embodiments provide a compound comprising a first modified oligonucleotide selected from any one of Ref ID NOs: IA0864-866 and a second modified oligonucleotide 14 to 21 linked nucleosides in length fully complementary to the first modified oligonucleotide. 
     Certain embodiments provide a compound comprising a first modified oligonucleotide selected from Ref ID NOs: IA0818 and IA0864 and a second modified oligonucleotide selected from Ref ID NOs: IS1058 and IS1059. 
     Certain embodiments provide a compound comprising a first modified oligonucleotide consisting of IA0864 and a second modified oligonucleotide consisting of IS1059. Certain embodiments provide a compound comprising a first modified oligonucleotide consisting of IA0818 and a second modified oligonucleotide consisting of IS1058. 
     In certain embodiments, the compound comprises a first modified oligonucleotide consisting of IA0864 and a second modified oligonucleotide consisting of IS1059. In certain embodiments, the compound comprises a first modified oligonucleotide consisting of IA0818 and a second modified oligonucleotide consisting of IS1058. 
     In certain embodiments, the compound of any foregoing embodiment is in a pharmaceutically acceptable salt form. In certain embodiments, the pharmaceutically acceptable salt is a sodium salt. In certain embodiments, the pharmaceutically acceptable salt is a potassium salt. 
     In an aspect provided herein, is a modified oligonucleotide according to the following chemical structure: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt or stereoisomer thereof. In certain embodiments, Ref ID NO: IA0818 is a modified oligonucleotide, or a pharmaceutically acceptable salt or stereoisomer thereof, according to the preceding chemical structure. 
     In an aspect provided herein, is a modified oligonucleotide according to the following chemical structure: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt or stereoisomer thereof. In certain embodiments, Ref ID NO: IS1058 is a modified oligonucleotide, or a pharmaceutically acceptable salt or stereoisomer thereof, according to the preceding chemical structure. 
     In an aspect provided herein, is a modified oligonucleotide according to the following chemical structure: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt or stereoisomer thereof. In certain embodiments, Ref ID NO: IA0864 is a modified oligonucleotide, or a pharmaceutically acceptable salt or stereoisomer thereof, according to the preceding chemical structure. 
     In an aspect provided herein, is a modified oligonucleotide according to the following chemical structure: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt or stereoisomer thereof. In certain embodiments, Ref ID NO: IS1059 is a modified oligonucleotide, or a pharmaceutically acceptable salt or stereoisomer thereof, according to the preceding chemical structure. 
     In certain embodiments, the pharmaceutically acceptable salt of the modified oligonucleotides provided herein is a sodium salt or a potassium salt. 
     In an aspect provided herein, is a sodium salt of a modified oligonucleotide according to the following chemical structure: 
     
       
         
         
             
             
         
       
     
     or a stereoisomer thereof. In certain embodiments, Ref ID NO: IA0818 is a modified oligonucleotide or a stereoisomer thereof, according to the preceding chemical structure. 
     In an aspect provided herein, is a sodium salt of a modified oligonucleotide according to the following chemical structure: 
     
       
         
         
             
             
         
       
     
     or a stereoisomer thereof. In certain embodiments, Ref ID NO: IS1058 is a modified oligonucleotide or a stereoisomer thereof, according to the preceding chemical structure. 
     In an aspect provided herein, is a sodium salt of a modified oligonucleotide according to the following chemical structure: 
     
       
         
         
             
             
         
       
     
     or a stereoisomer thereof. In certain embodiments, Ref ID NO: IA0864 is a modified oligonucleotide or a stereoisomer thereof, according to the preceding chemical structure. 
     In an aspect provided herein, is a sodium salt of a modified oligonucleotide according to the following chemical structure: 
     
       
         
         
             
             
         
       
     
     or a stereoisomer thereof. In certain embodiments, Ref ID NO: IS1059 is a modified oligonucleotide or a stereoisomer thereof, according to the preceding chemical structure. 
     In an aspect provided herein, is a compound according to the following chemical structure: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt or stereoisomer thereof. In certain embodiments, Compound Number RD2423 is a compound, or a pharmaceutically acceptable salt or stereoisomer thereof, according to the preceding chemical structure. 
     In an aspect provided herein, is a compound according to the following chemical structure: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt or stereoisomer thereof. In certain embodiments, Compound Number RD2424 is a compound, or a pharmaceutically acceptable salt or stereoisomer thereof, according to the preceding chemical structure. 
     In certain embodiments, the pharmaceutically acceptable salt of the compounds provided herein is a sodium salt or a potassium salt. 
     In an aspect provided herein, is a sodium salt of a compound according to the following chemical structure: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     or a stereoisomer thereof. In certain embodiments, Compound Number RD2423 is a compound, or a stereoisomer thereof, according to the preceding chemical structure. 
     In an aspect provided herein, is a sodium salt of a compound according to the following chemical structure: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     or a stereoisomer thereof. In certain embodiments, Compound Number RD2424 is a compound, or a stereoisomer thereof, according to the preceding chemical structure. 
     In certain embodiments, provided herein is a population of modified oligonucleotides, wherein all of the phosphorothioate internucleoside linkages of the modified oligonucleotide are stereorandom. In certain embodiments, provided herein is a population of compounds, wherein all of the phosphorothioate internucleoside linkages of the modified oligonucleotide are stereorandom. 
     Certain embodiments provide a composition comprising the compound of any one of the foregoing embodiments and a pharmaceutically acceptable carrier. 
     Certain embodiments provide a composition comprising a compound of any preceding embodiment, for use in therapy. 
     Certain embodiments provide a method of treating, preventing, or ameliorating a disease, disorder or condition associated with PKK and/or a dysregulated kallikrein pathway in an individual comprising administering to the individual a compound targeted to PKK, thereby treating, preventing, or ameliorating the disease, disorder or condition. In certain embodiments, the compound or composition of any foregoing embodiment is administered to an individual. In certain embodiments, the disease, disorder, or condition is an inflammatory or thrombotic disease, disorder or condition or a symptom thereof. In certain embodiments, the disease, disorder, or condition is hereditary angioedema (HAE), edema, angioedema, swelling, angioedema of the lids, ocular edema, macular edema, cerebral edema, thrombosis, embolism, thromboembolism, deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke, or infarct. In certain embodiments, administering the compound inhibits or reduces or improves an inflammatory or thrombotic disease, disorder or condition or a symptom thereof. In certain embodiments, administering the compound inhibits or reduces or improves hereditary angioedema (HAE), edema, angioedema, swelling, angioedema of the lids, ocular edema, macular edema, cerebral edema, thrombosis, embolism, thromboembolism, deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke, or infarct, or a symptom thereof. 
     In certain embodiments, a compound or composition comprising a compound of any preceding embodiment is administered to an individual in a therapeutically effective amount. In certain embodiments, a composition comprising a compound of any preceding embodiment is administered to an individual at a dosage level sufficient to deliver about 1 to 100 mg/kg of body weight of the individual. In certain embodiments, a compound or composition comprising a compound of any preceding embodiment is administered to an individual at a fixed dose of about 25 mg to about 1,000 mg. In certain embodiments, the compound or composition is administered to the individual one or more times in a day up to the dosage level or fixed dose. 
     In certain embodiments, a composition comprising a compound of any preceding embodiment is administered to an individual daily, weekly, monthly, quarterly or yearly. In certain embodiments, a compound or composition comprising a compound of any preceding embodiment is administered to an individual about once per quarter (i.e., once every three months) to about once per year. In certain embodiments, a compound or composition comprising a compound of any preceding embodiment is administered to an individual about once per quarter, about once every six months or about once per year. 
     Certain embodiments provide a method of inhibiting expression of PKK in a cell comprising contacting the cell with a compound targeted to PKK, thereby inhibiting expression of PKK in the cell. In certain embodiments, the cell is in the liver of an individual. In certain embodiments, the individual has, or is at risk of having, an inflammatory or thrombotic disease, disorder or condition or a symptom thereof. In certain embodiments, the individual has, or is at risk of having, hereditary angioedema (HAE), edema, angioedema, swelling, angioedema of the lids, ocular edema, macular edema, cerebral edema, thrombosis, embolism, thromboembolism, deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke, or infarct. 
     Certain embodiments provide a method of reducing or inhibiting an inflammatory or thrombotic disease, disorder or condition or a symptom thereof in an individual, comprising administering a compound targeted to PKK to the individual, thereby reducing or inhibiting an inflammatory or thrombotic disease, disorder or condition or a symptom thereof in the individual. In certain embodiments, the individual has, or is at risk of having, hereditary angioedema (HAE), edema, angioedema, swelling, angioedema of the lids, ocular edema, macular edema, cerebral edema, thrombosis, embolism, thromboembolism, deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke, or infarct. In certain embodiments, the compound is a compound targeted to PKK. In certain embodiments, the compound is any of the foregoing compounds. In certain embodiments, the compound or composition is administered parenterally. 
     Certain embodiments provide use of a compound targeted to PKK for treating, preventing, or ameliorating a disease, disorder or condition associated with PKK. In certain embodiments, the disease, disorder or condition is an inflammatory disease, a thrombotic disease, hereditary angioedema (HAE), edema, angioedema, swelling, angioedema of the lids, ocular edema, macular edema, cerebral edema, thrombosis, embolism, thromboembolism, deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke, or infarct. In certain embodiments, the compound is a compound targeted to PKK. In certain embodiments, the compound is any of the foregoing compounds. 
     Certain embodiments provide use of a compound targeted to PKK in the manufacture of a medicament for treating, preventing, or ameliorating a disease, disorder or condition associated with PKK. In certain embodiments, the disease, disorder or condition is an inflammatory disease, a thrombotic disease, hereditary angioedema (HAE), edema, angioedema, swelling, angioedema of the lids, ocular edema, macular edema, cerebral edema, thrombosis, embolism, thromboembolism, deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke, or infarct. In certain embodiments, the compound is a compound targeted to PKK. In certain embodiments, the compound is any of the foregoing compounds. 
     Certain Indications 
     In certain aspects, the disclosure relates to methods of inhibiting PKK expression, which can be useful for treating, preventing, or ameliorating a disease, disorder or condition associated with PKK in an individual, by administration of a compound that targets PKK. In certain embodiments, the compound can be a PKK specific inhibitor. In certain embodiments, the compound can be an antisense oligonucleotide, an oligomeric compound, or an oligonucleotide targeted to PKK. 
     In certain aspects, the disclosure relates to treating, preventing, or ameliorating a disease, disorder or condition associated with PKK. In certain embodiments, diseases, disorders or conditions associated with PKK treatable, preventable, and/or ameliorable with the methods provided herein include an inflammatory disease, a thrombotic disease, hereditary angioedema (HAE), edema, angioedema, swelling, angioedema of the lids, ocular edema, macular edema, cerebral edema, thrombosis, embolism, thromboembolism, deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke, or infarct. Certain compounds provided herein are directed to compounds and compositions that reduce an inflammatory disease, a thrombotic disease, hereditary angioedema (HAE), edema, angioedema, swelling, angioedema of the lids, ocular edema, macular edema, cerebral edema, thrombosis, embolism, thromboembolism, deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke, or infarct in an animal. 
     In certain embodiments, a method of treating, preventing, or ameliorating a disease, disorder or condition associated with PKK in an individual comprises administering to the individual a compound comprising a PKK specific inhibitor, thereby treating, preventing, or ameliorating the disease, disorder or condition. In certain embodiments, the individual is identified as having, or at risk of having, a disease, disorder or condition associated with PKK. In certain embodiments, the disease, disorder or condition is a an inflammatory disease or a thrombotic disease. In certain embodiments, the compound comprises an antisense oligonucleotide targeted to PKK. In certain embodiments, the compound comprises an oligonucleotide targeted to PKK. In certain embodiments, a compound comprises a modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides) in length having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs: 10-313, 626, 627, and 628. In certain embodiments, a compound comprises a modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 10-313, 626, 627, and 628. In certain embodiments, a compound comprises a modified oligonucleotide having a nucleobase sequence selected from the nucleobase sequence of any one of SEQ ID NOs: 10-313, 626, 627, and 628. In certain embodiments, a compound comprises a modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising any one of SEQ ID NOs: 307, 312 and 626. In certain embodiments, a compound comprises a modified oligonucleotide having a nucleobase sequence consisting of any one of SEQ ID NOs: 307, 312 and 626. 
     In any of the foregoing embodiments, the compound can be single-stranded or double-stranded. In certain embodiments, a single-stranded compound can be 14 to 30, 14 to 23, 14 to 20, 16 to 20, or 14 to 16, linked nucleosides in length. In certain embodiments, a single-stranded compound can be 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30, linked nucleosides in length. In certain embodiments, a double-stranded compound can comprise two oligonucleotides of the same or different lengths, as described elsewhere herein. In certain embodiments, a compound comprises a modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases of the nucleobase sequence of SEQ ID NO: 307, 312 or 626. In certain embodiments, a compound comprises a modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases of the nucleobase sequence of SEQ ID NO: 468, 611, 616, 619 or 629. In certain embodiments, a compound comprises a modified oligonucleotide having a nucleobase sequence selected from the nucleobase sequence of SEQ ID NO: 307, SEQ ID NO: 312 and SEQ ID NO: 626. In certain embodiments, a compound comprises a modified oligonucleotide having a nucleobase sequence selected from the nucleobase sequence of SEQ ID NO: 468, SEQ ID NO: 611, SEQ ID NO: 616, SEQ ID NO: 619 and SEQ ID NO: 629. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 312 and a second modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 619. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 626 and a second modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 629. 
     In any of the foregoing embodiments, the compound can be an antisense oligonucleotide or oligomeric compound. In certain embodiments, a compound comprises a first modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases of any of the nucleobase sequence of SEQ ID NOs: 10-631 and a second modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a region of complementarity to the first modified oligonucleotide. In certain embodiments, a compound comprises a first modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 10-313, 626, 627, and 628, and a second modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a region of complementarity to the first modified oligonucleotide. In certain embodiments, a compound comprises a first modified oligonucleotide having a nucleobase sequence selected from any one of SEQ ID NOs: 10-631 and a second modified oligonucleotide 19 to 23 linked nucleosides in length having a region of complementarity to the first modified oligonucleotide. In certain embodiments, the compound is administered to the individual parenterally. In certain embodiments, administering the compound improves, preserves, or prevents an inflammatory disease, a thrombotic disease, hereditary angioedema (HAE), edema, angioedema, swelling, angioedema of the lids, ocular edema, macular edema, cerebral edema, thrombosis, embolism, thromboembolism, deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke, or infarct in an animal. 
     In certain embodiments, a method of treating, preventing, or ameliorating an inflammatory disease, a thrombotic disease, hereditary angioedema (HAE), edema, angioedema, swelling, angioedema of the lids, ocular edema, macular edema, cerebral edema, thrombosis, embolism, thromboembolism, deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke, or infarct in an animal comprises administering to the individual a compound comprising a PKK specific inhibitor, thereby treating, preventing, or ameliorating an inflammatory disease, a thrombotic disease, hereditary angioedema (HAE), edema, angioedema, swelling, angioedema of the lids, ocular edema, macular edema, cerebral edema, thrombosis, embolism, thromboembolism, deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke, or infarct. In certain embodiments, the compound comprises an antisense oligonucleotide targeted to PKK. In certain embodiments, the compound comprises an oligonucleotide targeted to PKK. In certain embodiments, a compound comprises a modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs: 10-313, 626, 627, and 628. In certain embodiments, a compound comprises a modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 10-313, 626, 627, and 628. In certain embodiments, a compound comprises a modified oligonucleotide having a nucleobase sequence selected from the nucleobase sequence of any one of SEQ ID NOs: 10-313, 626, 627, and 628. In certain embodiments, a compound comprises a modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising any one of SEQ ID NOs: 307, 312 and 626. In certain embodiments, a compound comprises a modified oligonucleotide having a nucleobase sequence selected from any one of SEQ ID NOs: 307, 312 and 626. In certain embodiments, a compound comprises a modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases of the nucleobase sequence of SEQ ID NO: 307, 312 or 626. In certain embodiments, a compound comprises a modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases of the nucleobase sequence of SEQ ID NO: 468, 611, 616, 619 or 629. In certain embodiments, a compound comprises a modified oligonucleotide having a nucleobase sequence selected from the nucleobase sequence of SEQ ID NO: 307, SEQ ID NO: 312 and SEQ ID NO: 626. In certain embodiments, a compound comprises a modified oligonucleotide having a nucleobase sequence selected from the nucleobase sequence of SEQ ID NO: 468, SEQ ID NO: 611, SEQ ID NO: 616, SEQ ID NO: 619 and SEQ ID NO: 629. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 312 and a second modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 619. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 626 and a second modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 629. In any of the foregoing embodiments, the compound can be single-stranded or double-stranded. In any of the foregoing embodiments, the compound can be an antisense oligonucleotide or oligomeric compound. In certain embodiments, a compound comprises a first modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases of any of the nucleobase sequence of SEQ ID NOs: 10-631 and a second modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a region of complementarity to the first modified oligonucleotide. In certain embodiments, a compound comprises a first modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 10-631 and a second modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a region of complementarity to the first modified oligonucleotide. In certain embodiments, a compound comprises a first modified oligonucleotide having a nucleobase sequence selected from any one of SEQ ID NOs: 10-631 and a second modified oligonucleotide 19 to 23 linked nucleosides in length having a region of complementarity to the first modified oligonucleotide. In certain embodiments, administering the compound improves, preserves, or prevents an inflammatory disease, a thrombotic disease, hereditary angioedema (HAE), edema, angioedema, swelling, angioedema of the lids, ocular edema, macular edema, cerebral edema, thrombosis, embolism, thromboembolism, deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke, or infarct in an animal. In certain embodiments, the individual is identified as having, or at risk of having, a disease associated with PKK. 
     In certain embodiments, a method of inhibiting expression of PKK in an individual having, or at risk of having, a disease, disorder or condition associated with PKK comprises administering to the individual a compound comprising a PKK specific inhibitor, thereby inhibiting expression of PKK in the individual. In certain embodiments, administering the compound inhibits expression of PKK in the liver. In certain embodiments, the disease, disorder or condition is an inflammatory disease or a thrombotic disease. In certain embodiments, the individual has, or is at risk of having, an inflammatory disease, a thrombotic disease, hereditary angioedema (HAE), edema, angioedema, swelling, angioedema of the lids, ocular edema, macular edema, cerebral edema, thrombosis, embolism, thromboembolism, deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke, or infarct. In certain embodiments, the compound comprises an antisense oligonucleotide targeted to PKK. In certain embodiments, the compound comprises an oligonucleotide targeted to PKK. In certain embodiments, a compound comprises a modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs: 10-313, 626, 627, and 628. In certain embodiments, a compound comprises a modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 10-313, 626, 627, and 628. In certain embodiments, a compound comprises a modified oligonucleotide having a nucleobase sequence selected from the nucleobase sequence of any one of SEQ ID NOs: 10-313, 626, 627, and 628. In certain embodiments, a compound comprises a modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence selected from any one of SEQ ID NOs: 307, 312 and 626. In certain embodiments, a compound comprises a modified oligonucleotide having a nucleobase sequence selected from any one of SEQ ID NOs: 307, 312 and 626. In certain embodiments, a compound comprises a modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases of the nucleobase sequence of SEQ ID NO: 307, 312 or 626. In certain embodiments, a compound comprises a modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases of the nucleobase sequence of SEQ ID NO: 468, 611, 616, 619 or 629. In certain embodiments, a compound comprises a modified oligonucleotide having a nucleobase sequence selected from the nucleobase sequences of SEQ ID NO: 307, SEQ ID NO: 312 and SEQ ID NO: 626. In certain embodiments, a compound comprises a modified oligonucleotide having a nucleobase sequence selected from the nucleobase sequences of SEQ ID NO: 468, SEQ ID NO: 611, SEQ ID NO: 616, SEQ ID NO: 619 and SEQ ID NO: 629. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 312 and a second modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 619. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 626 and a second modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 629. In any of the foregoing embodiments, the compound can be single-stranded or double-stranded. In any of the foregoing embodiments, the compound can be an antisense oligonucleotide or oligomeric compound. In certain embodiments, a compound comprises a first modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases of any of the nucleobase sequence of SEQ ID NOs: 10-631 and a second modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a region of complementarity to the first modified oligonucleotide. In certain embodiments, a compound comprises a first modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 10-631 and a second modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a region of complementarity to the first modified oligonucleotide. In certain embodiments, a compound comprises a first modified oligonucleotide having a nucleobase sequence selected from any one of SEQ ID NOs: 10-631 and a second modified oligonucleotide 19 to 23 linked nucleosides in length having a region of complementarity to the first modified oligonucleotide. In certain embodiments, the compound is administered to the individual parenterally. In certain embodiments, administering the compound improves, preserves, or prevents an inflammatory disease, a thrombotic disease, hereditary angioedema (HAE), edema, angioedema, swelling, angioedema of the lids, ocular edema, macular edema, cerebral edema, thrombosis, embolism, thromboembolism, deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke, or infarct. 
     In certain embodiments, a method of inhibiting expression of PKK in a cell comprises contacting the cell with a compound comprising a PKK specific inhibitor, thereby inhibiting expression of PKK in the cell. In certain embodiments, the cell is a hepatocyte. In certain embodiments, the cell is in the liver. In certain embodiments, the cell is in the liver of an individual who has, or is at risk of having, an inflammatory disease, a thrombotic disease, hereditary angioedema (HAE), edema, angioedema, swelling, angioedema of the lids, ocular edema, macular edema, cerebral edema, thrombosis, embolism, thromboembolism, deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke, or infarct. In certain embodiments, the compound comprises an antisense oligonucleotide targeted to PKK. In certain embodiments, the compound comprises an oligonucleotide targeted to PKK. In certain embodiments, a compound comprises a modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs: 10-313, 626, 627, and 628. In certain embodiments, a compound comprises a modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 10-313, 626, 627, and 628. In certain embodiments, a compound comprises a modified oligonucleotide having a nucleobase sequence selected from the nucleobase sequence of any one of SEQ ID NOs: 10-313, 626, 627, and 628. In certain embodiments, a compound comprises a modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising any one of SEQ ID NOs: 307, 312 and 626. In certain embodiments, a compound comprises a modified oligonucleotide having a nucleobase sequence selected from any one of SEQ ID NOs: 307, 312 and 626. In certain embodiments, a compound comprises a modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases of the nucleobase sequence of SEQ ID NO: 307, 312 or 626. In certain embodiments, a compound comprises a modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases of the nucleobase sequence of SEQ ID NO: 468, 611, 616, 619 or 629. In certain embodiments, a compound comprises a modified oligonucleotide having a nucleobase sequence selected from the nucleobase sequences of SEQ ID NO: 307, SEQ ID NO: 312 and SEQ ID NO: 626. In certain embodiments, a compound comprises a modified oligonucleotide having a nucleobase sequence selected from the nucleobase sequences of SEQ ID NO: 468, SEQ ID NO: 611, SEQ ID NO: 616, SEQ ID NO: 619 and SEQ ID NO: 629. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 312 and a second modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 619. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 626 and a second modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 629. 
     In any of the foregoing embodiments, the compound can be single-stranded or double-stranded. In any of the foregoing embodiments, the compound can be an antisense oligonucleotide or oligomeric compound. In certain embodiments, a compound comprises a first modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases of any of the nucleobase sequence of SEQ ID NOs: 10-631 and a second modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a region of complementarity to the first modified oligonucleotide. In certain embodiments, a compound comprises a first modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 10-631 and a second modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a region of complementarity to the first modified oligonucleotide. In certain embodiments, a compound comprises a first modified oligonucleotide having a nucleobase sequence selected from any one of SEQ ID NOs: 10-631 and a second modified oligonucleotide 19 to 23 linked nucleosides in length having a region of complementarity to the first modified oligonucleotide. 
     In certain embodiments, a method of reducing or inhibiting an inflammatory disease, a thrombotic disease, hereditary angioedema (HAE), edema, angioedema, swelling, angioedema of the lids, ocular edema, macular edema, cerebral edema, thrombosis, embolism, thromboembolism, deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke, or infarct in an individual having, or at risk of having, a disease associated with PKK comprises administering to the individual a compound comprising a PKK specific inhibitor, thereby reducing or inhibiting an inflammatory disease, a thrombotic disease, hereditary angioedema (HAE), edema, angioedema, swelling, angioedema of the lids, ocular edema, macular edema, cerebral edema, thrombosis, embolism, thromboembolism, deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke, or infarct in the individual. In certain embodiments, the individual has, or is at risk of having, an inflammatory disease, a thrombotic disease, hereditary angioedema (HAE), edema, angioedema, swelling, angioedema of the lids, ocular edema, macular edema, cerebral edema, thrombosis, embolism, thromboembolism, deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke, or infarct. In certain embodiments, the compound comprises an antisense oligonucleotide targeted to PKK. In certain embodiments, the compound comprises an oligonucleotide targeted to PKK. In certain embodiments, a compound comprises a modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs: 10-313, 626, 627, and 628. In certain embodiments, a compound comprises a modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 10-313, 626, 627, and 628. In certain embodiments, a compound comprises a modified oligonucleotide selected from the nucleobase sequence of any one of SEQ ID NOs: 10-313, 626, 627, and 628. In certain embodiments, a compound comprises a modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising any one of SEQ ID NOs: 307, 312 and 626. In certain embodiments, a compound comprises a modified oligonucleotide having a nucleobase sequence selected from any one of SEQ ID NOs: 307, 312 and 626. In certain embodiments, a compound comprises a modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases of the nucleobase sequence of SEQ ID NO: 307, 312 or 626. In certain embodiments, a compound comprises a modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases of the nucleobase sequence of SEQ ID NO: 468, 611, 616, 619 or 629. In certain embodiments, a compound comprises a modified oligonucleotide having a nucleobase sequence selected from the nucleobase sequences of SEQ ID NO: 307, SEQ ID NO: 312 and SEQ ID NO: 626. In certain embodiments, a compound comprises a modified oligonucleotide having a nucleobase sequence selected from the nucleobase sequences of SEQ ID NO: 468, SEQ ID NO: 611, SEQ ID NO: 616, SEQ ID NO: 619 and SEQ ID NO: 629. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 312 and a second modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 619. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 626 and a second modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 629. In any of the foregoing embodiments, the compound can be single-stranded or double-stranded. In any of the foregoing embodiments, the compound can be an antisense oligonucleotide or oligomeric compound. In certain embodiments, a compound comprises a first modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases of any of the nucleobase sequence of SEQ ID NOs: 10-631 and a second modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a region of complementarity to the first modified oligonucleotide. In certain embodiments, a compound comprises a first modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 10-631 and a second modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a region of complementarity to the first modified oligonucleotide. In certain embodiments, a compound comprises a first modified oligonucleotide having a nucleobase sequence selected from any one of SEQ ID NOs: 10-631 and a second modified oligonucleotide 19 to 23 linked nucleosides in length having a region of complementarity to the first modified oligonucleotide. In certain embodiments, the compound is administered to the individual parenterally. In certain embodiments, the individual is identified as having, or at risk of having, a disease, disorder or condition associated with PKK. 
     Certain embodiments are drawn to a compound comprising a PKK specific inhibitor for use in treating a disease, disorder or condition associated with PKK. In certain embodiments, the disease, disorder or condition is an inflammatory disease, a thrombotic disease, hereditary angioedema (HAE), edema, angioedema, swelling, angioedema of the lids, ocular edema, macular edema, cerebral edema, thrombosis, embolism, thromboembolism, deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke, or infarct. In certain embodiments, the compound comprises an antisense oligonucleotide targeted to PKK. In certain embodiments, the compound comprises an oligonucleotide targeted to PKK. In certain embodiments, a compound comprises a modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs: 10-313, 626, 627, and 628. In certain embodiments, a compound comprises a modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 10-313, 626, 627, and 628. In certain embodiments, a compound comprises a modified oligonucleotide selected from the nucleobase sequence of any one of SEQ ID NOs: 10-313, 626, 627, and 628. In certain embodiments, a compound comprises a modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising any one of SEQ ID NOs: 307, 312 and 626. In certain embodiments, a compound comprises a modified oligonucleotide having a nucleobase sequence selected from any one of SEQ ID NOs: 307, 312 and 626. In certain embodiments, a compound comprises a modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases of the nucleobase sequence of SEQ ID NO: 307, 312 or 626. In certain embodiments, a compound comprises a modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases of the nucleobase sequence of SEQ ID NO: 468, 611, 616, 619 or 629. In certain embodiments, a compound comprises a modified oligonucleotide having a nucleobase sequence selected from the nucleobase sequences of SEQ ID NO: 307, SEQ ID NO: 312 and SEQ ID NO: 626. In certain embodiments, a compound comprises a modified oligonucleotide having a nucleobase sequence selected from the nucleobase sequences of SEQ ID NO: 468, SEQ ID NO: 611, SEQ ID NO: 616, SEQ ID NO: 619 and SEQ ID NO: 629. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 312 and a second modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 619. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 626 and a second modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 629. In any of the foregoing embodiments, the compound can be single-stranded or double-stranded. In any of the foregoing embodiments, the compound can be an antisense oligonucleotide or oligomeric compound. In certain embodiments, a compound comprises a first modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases of any of the nucleobase sequence of SEQ ID NOs: 10-631 and a second modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a region of complementarity to the first modified oligonucleotide. In certain embodiments, a compound comprises a first modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 10-631 and a second modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a region of complementarity to the first modified oligonucleotide. In certain embodiments, a compound comprises a first modified oligonucleotide having a nucleobase sequence selected from any one of SEQ ID NOs: 10-631 and a second modified oligonucleotide 19 to 23 linked nucleosides in length having a region of complementarity to the first modified oligonucleotide. In certain embodiments, the compound is administered to the individual parenterally. 
     Certain embodiments are drawn to a compound comprising a PKK specific inhibitor for use in reducing or inhibiting an inflammatory disease, a thrombotic disease, hereditary angioedema (HAE), edema, angioedema, swelling, angioedema of the lids, ocular edema, macular edema, cerebral edema, thrombosis, embolism, thromboembolism, deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke, or infarct. In certain embodiments, the compound comprises an antisense oligonucleotide targeted to PKK. In certain embodiments, the compound comprises an oligonucleotide targeted to PKK. In certain embodiments, a compound comprises a modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs: 10-313, 626, 627, and 628. In certain embodiments, a compound comprises a modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 10-313, 626, 627, and 628. In certain embodiments, a compound comprises a modified oligonucleotide selected from the nucleobase sequence of any one of SEQ ID NOs: 10-313, 626, 627, and 628. In certain embodiments, a compound comprises a modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising any one of SEQ ID NOs: 307, 312 and 626. In certain embodiments, a compound comprises a modified oligonucleotide having a nucleobase sequence selected from any one of SEQ ID NOs: 307, 312 and 626. In certain embodiments, a compound comprises a modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases of the nucleobase sequence of SEQ ID NO: 307, 312 or 626. In certain embodiments, a compound comprises a modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases of the nucleobase sequence of SEQ ID NO: 468, 611, 616, 619 or 629. In certain embodiments, a compound comprises a modified oligonucleotide having a nucleobase sequence selected from the nucleobase sequences of SEQ ID NO: 307, SEQ ID NO: 312 and SEQ ID NO: 626. In certain embodiments, a compound comprises a modified oligonucleotide having a nucleobase sequence selected from the nucleobase sequences of SEQ ID NO: 468, SEQ ID NO: 611, SEQ ID NO: 616, SEQ ID NO: 619 and SEQ ID NO: 629. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 312 and a second modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 619. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 626 and a second modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 629. In any of the foregoing embodiments, the compound can be single-stranded or double-stranded. In any of the foregoing embodiments, the compound can be an antisense oligonucleotide or oligomeric compound. In certain embodiments, a compound comprises a first modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases of any of the nucleobase sequence of SEQ ID NOs: 10-631 and a second modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a region of complementarity to the first modified oligonucleotide. In certain embodiments, a compound comprises a first modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 10-631 and a second modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a region of complementarity to the first modified oligonucleotide. In certain embodiments, a compound comprises a first modified oligonucleotide having a nucleobase sequence selected from any one of SEQ ID NOs: 10-631 and a second modified oligonucleotide 19 to 23 linked nucleosides in length having a region of complementarity to the first modified oligonucleotide. 
     Certain embodiments are drawn to the use of a compound comprising a PKK specific inhibitor for the manufacture or preparation of a medicament for treating a disease, disorder or condition associated with PKK. Certain embodiments are drawn to the use of a compound comprising a PKK specific inhibitor for the preparation of a medicament for treating a disease, disorder or condition associated with PKK. In certain embodiments, the disease is an inflammatory or thrombotic disease. In certain embodiments, the disease is hereditary angioedema (HAE), edema, angioedema, swelling, angioedema of the lids, ocular edema, macular edema, cerebral edema, thrombosis, embolism, thromboembolism, deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke, or infarct. In certain embodiments, the compound comprises an antisense oligonucleotide targeted to PKK. In certain embodiments, the compound comprises an oligonucleotide targeted to PKK. In certain embodiments, a compound comprises a modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs: 10-313, 626, 627, and 628. In certain embodiments, a compound comprises a modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 10-313, 626, 627, and 628. In certain embodiments, a compound comprises a modified oligonucleotide having a nucleobase sequence selected from the nucleobase sequence of any one of SEQ ID NOs: 10-313, 626, 627, and 628. In certain embodiments, a compound comprises a modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising any one of SEQ ID NOs: 307, 312 and 626. In certain embodiments, a compound comprises a modified oligonucleotide having a nucleobase sequence selected from any one of SEQ ID NOs: 307, 312 and 626. In certain embodiments, a compound comprises a modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases of the nucleobase sequence of SEQ ID NO: 307, 312 or 626. In certain embodiments, a compound comprises a modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases of the nucleobase sequence of SEQ ID NO: 468, 611, 616, 619 or 629. In certain embodiments, a compound comprises a modified oligonucleotide having a nucleobase sequence selected from the nucleobase sequences of SEQ ID NO: 307, SEQ ID NO: 312 and SEQ ID NO: 626. In certain embodiments, a compound comprises a modified oligonucleotide having a nucleobase sequence selected from the nucleobase sequences of SEQ ID NO: 468, SEQ ID NO: 611, SEQ ID NO: 616, SEQ ID NO: 619 and SEQ ID NO: 629. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 312 and a second modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 619. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 626 and a second modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 629. In any of the foregoing embodiments, the compound can be single-stranded or double-stranded. In any of the foregoing embodiments, the compound can be an antisense oligonucleotide or oligomeric compound. In certain embodiments, a compound comprises a first modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases of any of the nucleobase sequence of SEQ ID NOs: 10-631 and a second modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a region of complementarity to the first modified oligonucleotide. In certain embodiments, a compound comprises a first modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 10-631 and a second modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a region of complementarity to the first modified oligonucleotide. In certain embodiments, a compound comprises a first modified oligonucleotide having a nucleobase sequence selected from any one of SEQ ID NOs: 10-631 and a second modified oligonucleotide 19 to 23 linked nucleosides in length having a region of complementarity to the first modified oligonucleotide. 
     Certain embodiments are drawn to the use of a compound comprising a PKK specific inhibitor for the manufacture or preparation of a medicament for reducing or inhibiting an inflammatory disease, a thrombotic disease in an individual having, or at risk of having, an inflammatory disease or a thrombotic disease associated with PKK. In certain embodiments, the inflammatory disease or thrombotic disease is hereditary angioedema (HAE), edema, angioedema, swelling, angioedema of the lids, ocular edema, macular edema, cerebral edema, thrombosis, embolism, thromboembolism, deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke, or infarct. Certain embodiments are drawn to use of a compound comprising a PKK specific inhibitor for the preparation of a medicament for treating a disease associated with PKK. In certain embodiments, the disease is an inflammatory disease, thrombotic disease, hereditary angioedema (HAE), edema, angioedema, swelling, angioedema of the lids, ocular edema, macular edema, cerebral edema, thrombosis, embolism, thromboembolism, deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke, or infarct. In certain embodiments, the compound comprises an antisense oligonucleotide targeted to PKK. In certain embodiments, the compound comprises an oligonucleotide targeted to PKK. In certain embodiments, a compound comprises a modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs: 10-313, 626, 627, and 628. In certain embodiments, a compound comprises a modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 10-313, 626, 627, and 628. In certain embodiments, a compound comprises a modified oligonucleotide selected from the nucleobase sequence of any one of SEQ ID NOs: 10-313, 626, 627, and 628. In certain embodiments, a compound comprises a modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising any one of SEQ ID NOs: 307, 312 and 626. In certain embodiments, a compound comprises a modified oligonucleotide having a nucleobase sequence selected from any one of SEQ ID NOs: 307, 312 and 626. In certain embodiments, a compound comprises a modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases of the nucleobase sequence of SEQ ID NO: 307, 312 or 626. In certain embodiments, a compound comprises a modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases of the nucleobase sequence of SEQ ID NO: 468, 611, 616, 619 or 629. In certain embodiments, a compound comprises a modified oligonucleotide having a nucleobase sequence selected from the nucleobase sequences of SEQ ID NO: 307, SEQ ID NO: 312 and SEQ ID NO: 626. In certain embodiments, a compound comprises a modified oligonucleotide having a nucleobase sequence selected from the nucleobase sequences of SEQ ID NO: 468, SEQ ID NO: 611, SEQ ID NO: 616, SEQ ID NO: 619 and SEQ ID NO: 629. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 312 and a second modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 619. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 626 and a second modified oligonucleotide having a nucleobase sequence of SEQ ID NO: 629. In any of the foregoing embodiments, the compound can be single-stranded or double-stranded. In any of the foregoing embodiments, the compound can be an antisense oligonucleotide or oligomeric compound. In certain embodiments, a compound comprises a first modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases of any of the nucleobase sequence of SEQ ID NOs: 10-631 and a second modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a region of complementarity to the first modified oligonucleotide. In certain embodiments, a compound comprises a first modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 10-631 and a second modified oligonucleotide (e.g., of 14 to 30, for example, 14 to 23, linked nucleosides in length) having a region of complementarity to the first modified oligonucleotide. In certain embodiments, a compound comprises a first modified oligonucleotide having a nucleobase sequence selected from any one of SEQ ID NOs: 10-631 and a second modified oligonucleotide 19 to 23 linked nucleosides in length having a region of complementarity to the first modified oligonucleotide. 
     In any of the foregoing methods or uses, the compound can be an oligomeric compound. In any of the foregoing methods or uses, the compound can be single-stranded or double-stranded. In any of the foregoing methods or uses, the compound can be targeted to PKK. In certain embodiments, the compound comprises or consists of a modified oligonucleotide. In certain embodiments, the compound comprises one or more modified oligonucleotides. In certain embodiments, the compound comprises a first modified oligonucleotide and a second modified oligonucleotide. In certain embodiments, a modified oligonucleotide is 8 to 80 linked nucleosides in length, 10 to 30 linked nucleosides in length, 14 to 30 linked nucleosides in length, 14 to 23 linked nucleosides in length, or 19 to 23 linked nucleosides in length. In certain embodiments, a modified oligonucleotide is at least 80%, at least 85%, at least 90%, at least 95% or 100% complementary to any of the nucleobase sequences recited in SEQ ID NOs: 1, 3, 5 or 6 over its length. In certain embodiments, a modified oligonucleotide comprises at least one modified internucleoside linkage, at least one modified sugar and/or at least one modified nucleobase. In certain embodiments, the modified internucleoside linkage is a phosphorothioate internucleoside linkage. In certain embodiments, the modified sugar is a bicyclic sugar, 2′-MOE, 2′-F, or 2′-OMe. In certain embodiments, the modified nucleobase is a 5-methylcytosine. In any of the foregoing embodiments, each modified oligonucleotide is independently 12 to 30, 14 to 30, 14 to 25, 14 to 24, 14 to 23, 16 to 23, 17 to 23, 18 to 23, 19 to 23, 19 to 22, or 19 to 20 linked nucleosides in length. In certain embodiments, a modified oligonucleotide has at least 1, at least 2, at least 3 mismatches to a region of SEQ ID NOs: 1, 3, 5 or 6. 
     In any of the forgoing methods or uses, the compound comprises a first and second modified oligonucleotide, wherein there is a region of complementarity between a first modified oligonucleotide and a second modified oligonucleotide. In certain embodiments, the region of complementarity between the first oligonucleotide and the second oligonucleotide is 14 to 23, 19 to 23, or 21 to 23 linked nucleosides in length. In certain embodiments, the first modified oligonucleotide is fully complementary to the second modified oligonucleotide. In certain embodiments, the first modified oligonucleotide comprises at least one modification selected from a modified internucleoside linkage, a modified sugar, and a modified nucleobase. In certain embodiments, the second modified oligonucleotide comprises at least one modification selected from the group consisting of a modified internucleoside linkage, a modified sugar, and a modified nucleobase. In certain embodiments, the modified internucleoside linkage is a phosphorothioate internucleoside linkage or a methylphosphonate internucleoside linkage. In certain embodiments, the modified internucleoside linkage is at the 3′ terminus of the first or second modified oligonucleotide or at the 5′ terminus of the first or second modified oligonucleotide. In certain embodiments, the first or second modified oligonucleotide comprises one or more modified sugars. In certain embodiments, each nucleoside of the first or second modified oligonucleotide comprises a modified sugar. In certain embodiments, the modified sugar comprises a modification selected from the group consisting of a halogen, an alkoxy group and a bicyclic sugar. In certain embodiments, the modified sugar comprises a modification selected from group consisting of 2′-MOE, 2′-F, and 2′-OMe or a combination thereof. In certain embodiments, the first or second modified oligonucleotide comprises no more than ten 2′-F sugar modifications. In certain embodiments, the first or second modified oligonucleotide comprises no more than five 2′-F sugar modifications. 
     In any of the forgoing methods or uses, a compound comprises a conjugate group. In certain embodiments, the conjugate group is attached to the 5′ end of a modified oligonucleotide. In certain embodiments, the conjugate group is a targeting moiety. In certain embodiments, the targeting moiety comprises one or more GalNAc. In certain embodiments, the one or more GalNAc is attached to the 2′ or 3′ position of the ribosyl ring. In certain embodiments, the one or more GalNAc is attached to the 5′ nucleoside of the modified oligonucleotide. In certain embodiments, the 5′ nucleoside of a modified oligonucleotide is selected from Formulae I-VIII, or a salt, solvate, or hydrate thereof, wherein R is the modified oligonucleotide other than the 5′ nucleoside. In certain embodiments, the 5′ nucleoside of the modified oligonucleotide is Formula I and R′ is O. In certain embodiments, the 5′ nucleoside of the modified oligonucleotide is Formula I and R′ is S. In certain embodiments, the 5′ nucleoside of the modified oligonucleotide is Formula II and R′ is O. In certain embodiments, the 5′ nucleoside of the modified oligonucleotide is Formula II and R′ is S. In certain embodiments, the 5′ nucleoside of the modified oligonucleotide is Formula III and R′ is O. In certain embodiments, the 5′ nucleoside of the modified oligonucleotide is Formula III and R′ is S. In certain embodiments, the 5′ nucleoside of the modified oligonucleotide is Formula IV and R′ is O. In certain embodiments, the 5′ nucleoside of the modified oligonucleotide is Formula IV and R′ is S. In certain embodiments, the 5′ nucleoside of the modified oligonucleotide is Formula V and R′ is O. In certain embodiments, the 5′ nucleoside of the modified oligonucleotide is Formula V and R′ is S. In certain embodiments, the 5′ nucleoside of the modified oligonucleotide is Formula VI and R′ is O. In certain embodiments, the 5′ nucleoside of the modified oligonucleotide is Formula VI and R′ is S. In certain embodiments, the 5′ nucleoside of the modified oligonucleotide is Formula VII and R′ is O. In certain embodiments, the 5′ nucleoside of the modified oligonucleotide is Formula VII and R′ is S. In certain embodiments, the 5′ nucleoside of the modified oligonucleotide is Formula VIII and R′ is O. In certain embodiments, the 5′ nucleoside of the modified oligonucleotide is Formula VIII and R′ is S. 
     In any of the foregoing methods or uses, the compound comprises a first modified oligonucleotide selected from any one of Ref ID NOs: IA0812-821 and a second modified oligonucleotide 14 to 21 linked nucleosides in length fully complementary to the first modified oligonucleotide. In certain embodiments, the compound comprises a first modified oligonucleotide consisting of IA0813 and a second modified oligonucleotide consisting of IS1002. In certain embodiments, the compound comprises a first modified oligonucleotide consisting of IA0818 and a second modified oligonucleotide consisting of IS1007. In certain embodiments, the compound comprises a first modified oligonucleotide consisting of IA0818 and a second modified oligonucleotide consisting of IS1068. 
     In any of the foregoing methods or uses, the compound comprises a first modified oligonucleotide selected from any one of Ref ID NOs: IA0864-866 and a second modified oligonucleotide 14 to 21 linked nucleosides in length fully complementary to the first modified oligonucleotide. In certain embodiments, the compound comprises a first modified oligonucleotide consisting of IA0864 and a second modified oligonucleotide consisting of IS1059. Certain embodiments provide a compound comprising a first modified oligonucleotide selected from Ref ID NOs: IA0818 and IA0864 and a second modified oligonucleotide selected from Ref ID NOs: IS1058 and IS1059. Certain embodiments provide a compound comprising a first modified oligonucleotide consisting of IA0864 and a second modified oligonucleotide consisting of IS1059. Certain embodiments provide a compound comprising a first modified oligonucleotide consisting of IA0818 and a second modified oligonucleotide consisting of IS1058. 
     In certain embodiments, the compound comprises a first modified oligonucleotide selected from Ref ID NOs: IA0818 and IA0864 and a second modified oligonucleotide selected from Ref ID NOs: IS1058 and IS1059. In certain embodiments, the compound comprises a first modified oligonucleotide consisting of IA0864 and a second modified oligonucleotide consisting of IS1059. In certain embodiments, the compound comprises a first modified oligonucleotide consisting of IA0818 and a second modified oligonucleotide consisting of IS1058. 
     In certain embodiments, the compound is in a pharmaceutically acceptable salt form. In certain embodiments, the pharmaceutically acceptable salt is a sodium salt. In certain embodiments, the pharmaceutically acceptable salt is a potassium salt. In certain embodiments, a composition comprises the compound of any one of the foregoing embodiments and a pharmaceutically acceptable carrier. 
     In any of the foregoing methods or uses, a compound or composition comprising a compound of any preceding embodiment is administered to an individual in a therapeutically effective amount. In certain embodiments, a compound or composition comprising a compound of any preceding embodiment is administered to an individual at a dosage level sufficient to deliver about 1 to 100 mg/kg of body weight of the individual. In certain embodiments, a compound or composition comprising a compound of any preceding embodiment is administered to an individual at a fixed dose of about 25 mg to about 1,000 mg. In certain embodiments, the composition is administered to the individual one or more times in a day up to the dosage level or fixed dose. 
     In any of the foregoing methods or uses, a compound or composition comprising a compound of any preceding embodiment is administered to an individual daily, weekly, monthly, quarterly or yearly. In certain embodiments, a compound or composition comprising a compound of any preceding embodiment is administered to an individual about once per quarter (i.e., once every three months) to about once per year. In certain embodiments, a compound or composition comprising a compound of any preceding embodiment is administered to an individual about once per quarter, about once every six months or about once per year. 
     Certain Compounds 
     In certain aspects, the disclosure relates to a compound that comprises or consists of an oligomeric compound. In certain embodiments, the oligomeric compound comprises a nucleobase sequence complementary to that of a target nucleic acid. 
     In certain aspects, the disclosure relates to a compound that comprises or consists of a modified oligonucleotide. In certain embodiments, the modified oligonucleotide has a nucleobase sequence complementary to that of a target nucleic acid. 
     In certain aspects, the disclosure relates to a compound that comprises or consists of an antisense oligonucleotide. In certain embodiments, the antisense oligonucleotide has a nucleobase sequence complementary to that of a target nucleic acid. 
     In certain aspects, the disclosure relates to a compound that is a single-stranded compound. In certain embodiments, the single-stranded compound comprises or consists of an oligomeric compound. In certain embodiments, such an oligomeric compound comprises or consists of an oligonucleotide and optionally a conjugate group. In certain embodiments, the oligonucleotide is a modified oligonucleotide. In certain embodiments, the oligonucleotide is an antisense oligonucleotide. In certain embodiments, the oligonucleotide or modified oligonucleotide of a single-stranded compound comprises a self-complementary nucleobase sequence. 
     In certain aspects, the disclosure relates to a compound that is a double-stranded compound. In certain embodiments, the double-stranded compound comprises or consists of an oligomeric compound. In certain embodiments, the double-stranded compound comprises a first oligonucleotide and a second oligonucleotide. In certain embodiments, the first oligonucleotide has a region complementarity to a target nucleic acid and the second oligonucleotide has a region complementarity to the first modified oligonucleotide. In certain embodiments, the double-stranded compound comprises a modified oligonucleotide. In certain embodiments, the modified oligonucleotide has a region complementarity to a target nucleic acid. In certain embodiments, the double-stranded compound comprises a first modified oligonucleotide and a second modified oligonucleotide. In certain embodiments, the first modified oligonucleotide has a region complementarity to a target nucleic acid and the second modified oligonucleotide has a region complementarity to the first modified oligonucleotide. In certain embodiments, an oligonucleotide or modified oligonucleotide of a double-stranded compound is an RNA oligonucleotide. In such embodiments, the thymine nucleobase in the modified oligonucleotide is replaced by a uracil nucleobase. 
     In certain embodiments, a compound described herein comprises a conjugate group. In certain embodiments, the first oligonucleotide or first modified oligonucleotide of a double-stranded compound comprises a conjugate group. In certain embodiments, the second oligonucleotide or second modified oligonucleotide of a double-stranded compound comprises a conjugate group. In certain embodiments, a first oligonucleotide or first modified oligonucleotide and a second oligonucleotide or second modified oligonucleotide of a double-stranded compound each comprises a conjugate group. 
     In certain embodiments, a compound is 14-30 linked nucleosides in length. In certain embodiments, the first oligonucleotide or first modified oligonucleotide of a double-stranded compound is 14-30 linked nucleosides in length. In certain embodiments, the second oligonucleotide or second modified oligonucleotide is 14-30 linked nucleosides in length. In certain embodiments, the oligonucleotides or modified oligonucleotides of a double-stranded compound are blunt ended at one or both ends of the compound. In certain embodiments, the oligonucleotides or modified oligonucleotides of a double-stranded compound include non-complementary overhanging nucleosides at one or both ends of the compound. 
     In certain embodiments, a compound has a nucleobase sequence comprising at least 14 contiguous nucleobases of any of SEQ ID NOs: 10-313, 626, 627, and 628. In certain embodiments, one of the oligonucleotides or modified oligonucleotides of a double-stranded compound has a nucleobase sequence comprising at least 14 contiguous nucleobases of any of SEQ ID NOs: 10-313, 626, 627, and 628. 
     Examples of single-stranded and double-stranded compounds include, but are not limited to, oligonucleotides, antisense oligonucleotides, siRNAs, microRNA targeting oligonucleotides, occupancy-based compounds (e.g., mRNA processing or translation blocking compounds and splicing compounds), and single-stranded RNAi compounds (e.g. small hairpin RNAs (shRNAs), single stranded siRNAs (ssRNAs) and microRNA mimics). 
     In certain embodiments, a compound described herein has a nucleobase sequence that, when written in the 5′ to 3′ direction, comprises the reverse complement of the target region of a target nucleic acid to which it is targeted. 
     In certain embodiments, a compound described herein comprises an oligonucleotide 12 to 30 linked subunits in length. In certain embodiments, a compound described herein comprises an oligonucleotide 12 to 23 linked subunits in length. In certain embodiments, compound described herein comprises an oligonucleotide 14 to 30 linked subunits in length. In certain embodiments, compound described herein comprises an oligonucleotide 14 to 23 linked subunits in length. In certain embodiments, a compound described herein comprises an oligonucleotide 15 to 30 linked subunits in length. In certain embodiments, a compound described herein comprises an oligonucleotide 15 to 23 linked subunits in length. In certain embodiments, a compound described herein comprises an oligonucleotide 16 to 30 linked subunits in length. In certain embodiments, a compound described herein comprises an oligonucleotide 16 to 23 linked subunits in length. In certain embodiments, a compound described herein comprises an oligonucleotide 17 to 30 linked subunits in length. In certain embodiments, a compound described herein comprises an oligonucleotide 17 to 23 linked subunits in length. In certain embodiments, a compound described herein comprises an oligonucleotide 18 to 30 linked subunits in length. In certain embodiments, a compound described herein comprises an oligonucleotide 18 to 23 linked subunits in length. In certain embodiments, a compound described herein comprises an oligonucleotide 19 to 30 linked subunits in length. In certain embodiments, a compound described herein comprises an oligonucleotide 19 to 23 linked subunits in length. In other words, such oligonucleotides are 12 to 30 linked subunits, 12 to 23 linked subunits, 14 to 30 linked subunits, 14 to 23 linked subunits, 15 to 30 linked subunits, 15 to 23 linked subunits, 16 to 30 linked subunits, 16 to 23 linked subunits, 17 to 30 linked subunits, 17 to 23 linked subunits, 18 to 30 linked subunits, 18 to 23 linked subunits, 19 to 30 linked subunits or 19 to 23 linked subunits, respectively. In certain embodiments, a compound described herein comprises an oligonucleotide 14 linked subunits in length. In certain embodiments, a compound described herein comprises an oligonucleotide 16 linked subunits in length. In certain embodiments, a compound described herein comprises an oligonucleotide 17 linked subunits in length. In certain embodiments, compound described herein comprises an oligonucleotide 18 linked subunits in length. In certain embodiments, a compound described herein comprises an oligonucleotide 19 linked subunits in length. In certain embodiments, a compound described herein comprises an oligonucleotide 20 linked subunits in length. In certain embodiments, a compound described herein comprises an oligonucleotide 21 linked subunits in length. In certain embodiments, a compound described herein comprises an oligonucleotide 22 linked subunits in length. In certain embodiments, a compound described herein comprises an oligonucleotide 23 linked subunits in length. In other embodiments, a compound described herein comprises an oligonucleotide 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 23, 18 to 24, 18 to 25, 18 to 50, 19 to 23, 19 to 30, 19 to 50, 20 to 23 or 20 to 30 linked subunits. In certain such embodiments, the compound described herein comprises an oligonucleotide 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 linked subunits in length, or a range defined by any two of the above values. 
     In certain embodiments, the compound may further comprise an additional moiety, such as a conjugate group or delivery moiety. In certain embodiments, such compounds are oligomeric compounds, and the additional moiety is attached to an oligonucleotide. In certain embodiments, a conjugate group is attached to a nucleoside of an oligonucleotide. 
     In certain embodiments, compounds may be shortened or truncated. For example, one or more subunits may be deleted from the 5′ end (5′ truncation), or alternatively from the 3′ end (3′ truncation) of an oligonucleotide. 
     In certain embodiments, compounds may be lengthened. For example, one or more subunits may be attached to the 3′ end or 5′ end of an oligonucleotide. In certain embodiments, at least one subunit (e.g., 1, 2, 3, 4, 5, 6, 7, 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, or more subunits) is attached to the 5′ end of an oligonucleotide. In certain embodiments, at least one subunit (e.g., 1, 2, 3, 4, 5, 6, 7, 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, or more subunits) is attached to the 3′ end of an oligonucleotide. In certain embodiments, at least one or more subunits may be attached to the 3′ end or 5′ end of an oligonucleotide of a double-stranded compound creating a 3′ and/or 5′ end overhang. In certain embodiments, at least one subunit (e.g., 1, 2, 3, 4, 5, 6, 7, 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, or more subunits) is attached to the 5′ end of both oligonucleotides of a double-stranded compound. In certain embodiments, at least one subunit (e.g., 1, 2, 3, 4, 5, 6, 7, 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, or more subunit) is attached to the 3′ end of both oligonucleotides of a double-stranded compound. In certain embodiments, subunits are attached to both oligonucleotides of a double-stranded compound at the same end (e.g., that subunits are attached to the 3′ end of one of the oligonucleotides and subunits are attached to the 5′ end of the other oligonucleotide). In certain embodiments, when subunits are attached to both oligonucleotides of a double-stranded compound at the same end, the number of subunits attached to each oligonucleotide may be the same or may be different. In certain embodiments, when subunits are attached to both oligonucleotides of a double-stranded compound at the same end, the number of subunits attached to each oligonucleotide is the same. In certain embodiments, when subunits are attached to both oligonucleotides of a double-stranded compound at the same end, the number of subunits attached to each oligonucleotide is different. This scenario, where subunits are attached to both oligonucleotides of a double-stranded compound at the same end, may occur at one or both ends of a double-stranded compound. In certain embodiments, the subunits attached to the 3′ and/or 5′ end are modified. 
     In certain embodiments, compounds described herein are oligonucleotides. In certain embodiments, compounds described herein are modified oligonucleotides. In certain embodiments, compounds described herein are antisense oligonucleotides. In certain embodiments, compounds described herein are oligomeric compounds. In certain embodiments, compounds described herein are RNAi compounds. In certain embodiments, compounds described herein are siRNA compounds. 
     In certain embodiments, a compound described herein can comprise any of the oligonucleotide sequences targeted to PKK described herein. In certain embodiments, the compound can be double-stranded. 
     In certain embodiments, the compound comprises an oligonucleotide comprising at least an 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22 or 23 contiguous nucleobase portion of any one of SEQ ID NOs: 10-313, 626, 627, and 628. In certain embodiments, the compound comprises an oligonucleotide comprising at least an 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22 or 23 contiguous nucleobase portion of SEQ ID NO: 307, 312 or 626. In certain embodiments, the compound comprises a second oligonucleotide. In certain embodiments, the compound comprises an oligonucleotide comprising at least an 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22 or 23 contiguous nucleobase portion of SEQ ID NO: 468, 611, 616, 619 or 629. In certain embodiments, the compound comprises a first oligonucleotide comprising at least an 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22 or 23 contiguous nucleobase portion of SEQ ID NO: 312 and a second oligonucleotide comprising at least an 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22 or 23 contiguous nucleobase portion of SEQ ID NO: 619. In certain embodiments, the compound comprises a first oligonucleotide comprising at least an 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22 or 23 contiguous nucleobase portion of SEQ ID NO: 626 and a second oligonucleotide comprising at least an 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22 or 23 contiguous nucleobase portion of SEQ ID NO: 629. 
     In certain embodiments, the compound comprises ribonucleotides in which the oligonucleotide has uracil (U) in place of thymine (T) for any of the sequences provided here. 
     In certain embodiments, the compound comprises deoxyribonucleotides in which the oligonucleotide has thymine (T) in place of uracil (U) for any of the sequences provided here. 
     Certain Mechanisms 
     In certain embodiments, compounds described herein comprise or consist of modified oligonucleotides. In certain embodiments, compounds described herein comprise or consist of antisense oligonucleotides. In certain embodiments, compounds comprise or consist of oligomeric compounds. In certain embodiments, compounds described herein are capable of hybridizing to a target nucleic acid. In certain embodiments, compounds described herein selectively affect one or more target nucleic acid. Such compounds comprise a nucleobase sequence that hybridizes to one or more target nucleic acid, resulting in one or more desired activity and does not hybridize to one or more non-target nucleic acid or does not hybridize to one or more non-target nucleic acid in such a way that results in a significant undesired activity. 
     In certain embodiments, hybridization of a compound described herein to a target nucleic acid results in recruitment of one or more proteins that cause the cleavage of the target nucleic acid. For example, certain compounds described herein or a portion of the compound is loaded into an RNA-induced silencing complex (RISC), ultimately resulting in cleavage of the target nucleic acid. For example, certain compounds described herein result in cleavage of the target nucleic acid by Argonaute. Compounds that are loaded into RISC are RNAi compounds. RNAi compounds may be double-stranded (siRNA) or single-stranded (ssRNA). 
     In certain embodiments, hybridization of compounds described herein to a target nucleic acid does not result in recruitment of a protein that cleaves that target nucleic acid. In certain such embodiments, hybridization of the compound to the target nucleic acid results in the alteration of splicing of the target nucleic acid. In certain embodiments, hybridization of the compound to a target nucleic acid results in inhibition of a binding interaction between the target nucleic acid and a protein or other nucleic acid. In certain such embodiments, hybridization of the compound to the target nucleic acid results in the alteration of RNA processing. In certain such embodiments, hybridization of the compound to a target nucleic acid results in alteration of translation of the target nucleic acid. 
     Activities resulting from the hybridization of a compound to a target nucleic acid may be observed directly or indirectly. In certain embodiments, observation or detection of an activity involves observation or detection of a change in an amount of a target nucleic acid or protein encoded by such target nucleic acid, a change in the ratio of splice variants of a nucleic acid or protein, and/or a phenotypic change in a cell or animal. 
     Certain Modifications 
     In certain aspects, the disclosure relates to compounds that comprise or consist of oligonucleotides. Oligonucleotides consist of linked nucleosides. In certain embodiments, oligonucleotides may be unmodified RNA or DNA or may be modified. In certain embodiments, the oligonucleotides are modified oligonucleotides. In certain embodiments, the modified oligonucleotides comprise at least one modified sugar, modified nucleobase or modified internucleoside linkage relative to an unmodified RNA or DNA. In certain embodiments, an oligonucleotide has a modified nucleoside. A modified nucleoside may comprise a modified sugar, a modified nucleobase or both a modified sugar and a modified nucleobase. Modified oligonucleotides may also include end modifications, e.g., 5′-end modifications and 3′-end modifications. 
     Sugar Modifications and Motifs 
     In certain embodiments, a modified sugar is a substituted furanosyl sugar or non-bicyclic modified sugar. In certain embodiments, a modified sugar is a bicyclic or tricyclic modified sugar. In certain embodiments, a modified sugar is a sugar surrogate. A sugar surrogate may comprise one or more substitutions described herein. 
     In certain embodiments, a modified sugar is a substituted furanosyl or non-bicyclic modified sugar. In certain embodiments, the furanosyl sugar is a ribosyl sugar. In certain embodiments, the furanosyl sugar comprises one or more substituent groups, including, but not limited to, substituent groups at the 2′, 3′, 4′, and 5′ positions. 
     In certain embodiments, substituents at the 2′ position include, but are not limited to, F and OCH 3  (“OMe”, “O-methyl” or “methoxy”). In certain embodiments, substituent groups at the 2′ position suitable for non-bicyclic modified sugars include, but are not limited to, halo, allyl, amino, azido, SH, CN, OCN, CF 3 , OCF 3 , F, Cl, Br, SCH 3 , SOCH 3 , SO 2 CH 3 , ONO 2 , NO 2 , N 3 , and NH 2 . In certain embodiments, substituent groups at the 2′ position include, but are not limited to, O—(C 1 -C 10 ) alkoxy, alkoxyalkyl, O-alkyl, S-alkyl, N-alkyl, O-alkenyl, S-alkenyl, N-alkenyl, O-alkynyl, S-alkynyl, N-alkynyl, O-alkyl-O-alkyl, alkynyl, wherein the alkyl, alkenyl and alkynyl can be substituted or unsubstituted C 1  to C 10  alkyl or C 2  to C 10  alkenyl and alkynyl. In certain embodiments, substituent groups at the 2′ position include, but are not limited to, alkaryl, aralkyl, O-alkaryl, and O-aralkyl. In certain embodiments, these 2′ substituent groups can be further substituted with one or more substituent groups independently selected from hydroxyl, alkoxy, carboxy, benzyl, phenyl, nitro (NO 2 ), thiol, thioalkoxy, thioalkyl, halogen, alkyl, aryl, alkenyl, and alkynyl. In certain embodiments, substituent groups at the 2′ position include, but are not limited to, O[(CH 2 ) n O] m CH 3 , O(CH 2 ) n OCH 3 , O(CH 2 ) n CH 3 , O(CH 2 ) n ONH 2 , O(CH 2 ) n NH 2 , O(CH 2 ) n SCH 3 , and O(CH 2 ) n ON[(CH 2 ) n CH 3 )] 2 , where n and m are independently from 1 to about 10. In certain embodiments, substituent groups at the 2′ position include, but are not limited to, OCH 2 CH 2 OCH 3  (“MOE”), O(CH 2 ) 2 ON(CH 3 ) 2  (“DMAOE”), O(CH 2 ) 2 O(CH 2 ) 2 N(CH 3 ) 2  (“DMAEOE”), and OCH 2 C(═O)—N(H)CH 3  (“NMA”). 
     In certain embodiments, substituent groups at the 4′ position suitable for non-bicyclic modified sugars include, but are not limited to, alkoxy (e.g., methoxy), alkyl, and those described in Manoharan et al., WO 2015/106128. In certain embodiments, substituent groups at the 5′ position suitable for non-bicyclic modified sugars include, but are not limited to, methyl (“Me”) (R or S), vinyl, and methoxy. In certain embodiments, substituents described herein for the 2′, 4′ and 5′ position can be added to other specific positions on the sugar. In certain embodiments, such substituents may be added to the 3′ position of the sugar on the 3′ terminal nucleoside or the 5′ position of the 5′ terminal nucleoside. In certain embodiments, a non-bicyclic modified sugar may comprise more than one non-bridging sugar substituent. In certain such embodiments, non-bicyclic modified sugars substituents include, but are not limited to, 5′-Me-2′-F, 5′-Me-2′-OMe (including both R and S isomers). In certain embodiments, modified sugar substituents include those described in Migawa et al., WO 2008/101157 and Rajeev et al., US2013/0203836. 
     In certain embodiments, a modified sugar is a bicyclic sugar. A bicyclic sugar is a modified sugar comprising two rings, wherein the second ring is formed via a bridge connecting two of the atoms in the first ring thereby forming a bicyclic structure. In certain embodiments, a bicyclic sugar comprises a bridging substituent that bridges two atoms of the furanosyl ring to form a second ring. In certain embodiments, a bicyclic sugar does not comprise a furanosyl moiety. A “bicyclic nucleoside” (“BNA”) is a nucleoside having a bicyclic sugar. In certain embodiments, the bicyclic sugar comprises a bridge between the 4′ and 2′ furanose ring atoms. In certain embodiments, the bicyclic sugar comprises a bridge between the 5′ and 3′ furanose ring atoms. In certain such embodiments, the furanose ring is a ribose ring. In certain embodiments, 4′ to 2′ bridging substituents include, but are not limited to, 4′-CH 2 -2′, 4′-(CH 2 ) 2 -2′, 4′-(CH 2 ) 3 -2′, 4′-CH 2 —O-2′ (“LNA”), 4′-CH 2 —S-2′, 4′-(CH 2 ) 2 -O-2′ (“ENA”), 4′-CH(CH 3 )—O-2′ (“constrained ethyl” or “cEt” when in the S configuration), 4′-CH 2 —O—CH 2 -2′, 4′-CH 2 —N(R)-2′, 4′-CH(CH 2 OCH 3 )—O-2′ (“constrained MOE” or “cMOE”) and analogs thereof (e.g., U.S. Pat. No. 7,399,845), 4′-C(CH 3 )(CH 3 )—O-2′ and analogs thereof (e.g., U.S. Pat. No. 8,278,283), 4′-CH 2 —N(OCH 3 )-2′ and analogs thereof (e.g., U.S. Pat. No. 8,278,425), 4′-CH 2 —O—N(CH 3 )-2′ (e.g., U.S. Patent Publication No. 2004/0171570), 4′-CH 2 —N(R)—O-2′, wherein R is H, C 1 -C 12  alkyl, or a protecting group (e.g., U.S. Pat. No. 7,427,672), 4′-CH 2 —C(H)(CH 3 )-2′ (e.g., Chattopadhyaya el al., J. Org. Chem., 2009, 74, 118-134), and 4′-CH 2 —C(═CH 2 )-2′ and analogs thereof (e.g., U.S. Pat. No. 8,278,426). The entire contents of each of the foregoing are hereby incorporated herein by reference. Additional representative U.S. patents and U.S. patenttent Publications that teach the preparation of bicyclic nucleic acid nucleotides include, but are not limited to, the following: U.S. Pat. Nos. 6,268,490; 6,525,191; 6,670,461; 6,770,748; 6,794,499; 6,998,484; 7,053,207; 7,034,133; 7,084,125; 7,399,845; 7,427,672; 7,569,686; 7,741,457; 8,022,193; 8,030,467; 8,278,425; 8,278,426; 8,278,283; US 2008/0039618; and US 2009/0012281, US 2013/0190383; and WO 2013/036868, the entire contents of each of which are hereby incorporated herein by reference. Any 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 e.g., WO 99/14226). Specified bicyclic nucleosides herein are in the β-D configuration, unless otherwise specified. 
     In certain embodiments, a modified sugar is a sugar surrogate. In certain embodiments, a sugar surrogate has the oxygen atom replaced, e.g., with a sulfur, carbon or nitrogen atom. In certain such embodiments, the sugar surrogate may also comprise bridging and/or non-bridging substituents as described herein. In certain embodiments, sugar surrogates comprise rings having other than 5 atoms. In certain such embodiments, the sugar surrogate comprises a cyclobutyl moiety in place of the pentofuranosyl sugar. In certain embodiments, the sugar surrogate comprises a six membered ring in place of the pentofuranosyl sugar. In certain embodiments, the sugar surrogate comprises a tetrahydropyran (“THP”) in place of the pentofuranosyl sugar. In certain embodiments, the sugar surrogate comprises a morpholino in place of the pentofuranosyl sugar. Representative US patents that teach the preparation of such modified sugar structures include, but are not limited to, U.S. Pat. Nos. 4,981,957; 5,118,800; 5,166,315; 5,185,444; 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; 5,658,873; 5,670,633; 5,700,920; 7,875,733; 7,939,677, 8,088,904; 8,440,803; and 9,005,906, the entire contents of each of the foregoing are hereby incorporated herein by reference. 
     In some embodiments, sugar surrogates comprise acyclic moieties. In certain embodiments, the sugar surrogate is an unlocked nucleic acid (“UNA”). A UNA is unlocked acyclic nucleic acid, wherein any of the bonds of the sugar has been removed, forming an unlocked “sugar” residue. In one example, UNA also encompasses a monomer where the bonds between C1′-C4′ have been removed (i.e. the covalent carbon-oxygen-carbon bond between the C1′ and C4′ carbons). In another example, the C2′-C3′ bond (i.e. the covalent carbon-carbon bond between the C2′ and C3′ carbons) of the sugar has been removed. 
     Representative U.S. publications that teach the preparation of UNA include, but are not limited to, U.S. Pat. No. 8,314,227; and U.S. Patent Publication Nos. 2013/0096289; 2013/0011922; and 2011/0313020, the entire contents of each of which are hereby incorporated herein by reference. In certain embodiments, sugar surrogates comprise peptide nucleic acid (“PNA”), acyclic butyl nucleic acid (see, e.g., Kumar et al., Org. Biomol. Chem., 2013, 11, 5853-5865), and nucleosides and oligonucleotides described in Manoharan et al., US2013/130378, the entire contents of which is hereby incorporated herein by reference. Many other bicyclic and tricyclic sugar and sugar surrogate ring systems are known in the art that can be used in modified nucleosides. 
     In certain aspects, the disclosure relates to compounds comprising at least one oligonucleotide wherein the nucleosides of such oligonucleotide comprise one or more types of modified sugars and/or unmodified sugars arranged along the oligonucleotide or region thereof in a defined pattern or “sugar motif”. In certain instances, such sugar motifs include, but are not limited to, any of the patterns of sugar modifications described herein. 
     In certain embodiments, an oligonucleotide comprises a gapmer sugar motif. A gapmer oligonucleotide comprises or consists of a region having two external “wing” regions and a central or internal “gap” region. The gap and wing regions form a contiguous sequence of nucleosides, wherein the majority of nucleoside sugars of each of the wings differ from the majority of nucleoside sugars of the gap. In certain embodiments, the wing regions comprise a majority of modified sugars and the gap comprises a majority of unmodified sugars. In certain embodiments, the nucleosides of the gap are deoxynucleosides. Compounds with a gapmer sugar motif are described in, for example U.S. Pat. No. 8,790,919, the entire contents of which is hereby incorporated herein by reference. 
     In certain embodiments, one or both oligonucleotides of a double-stranded compound comprise a triplet sugar motif. An oligonucleotide with a triplet sugar motif comprises three identical sugar modifications on three consecutive nucleosides. In certain embodiments, the triplet is at or near the cleavage site of the oligonucleotide. In certain embodiments, an oligonucleotide of a double-stranded compound may contain more than one triplet sugar motif. In certain embodiments, the identical sugar modification of the triplet sugar motif is a 2′-F modification. Compounds with a triplet sugar motif are disclosed, for example, in U.S. Pat. No. 10,668,170, the entire contents of which is incorporated herein by reference. 
     In certain embodiments, one or both oligonucleotides of a double-stranded compound comprise a quadruplet sugar motif. An oligonucleotide with a quadruplet sugar motif comprises four identical sugar modifications on four consecutive nucleosides. In certain embodiments, the quadruplet is at or near the cleavage site. In certain embodiments, an oligonucleotide of a double-stranded compound may contain more than one quadruplet sugar motif. In certain embodiments, the identical sugar modification of the quadruplet sugar motif is a 2′-F modification. For a double-stranded compound having a duplex region of 19-23 nucleotides in length, the cleavage site of the antisense oligonucleotide is typically around the 10, 11, and 12 positions from the 5′-end. In certain embodiments, the quadruplet sugar motif is at the 8, 9, 10, 11 positions; the 9, 10, 11, 12 positions; the 10, 11, 12, 13 positions; the 11, 12, 13, 14 positions; or the 12, 13, 14, 15 positions of the sense oligonucleotide, counting from the first nucleoside of the 5′-end of the sense oligonucleotide, or, the count starting from the first paired nucleotide within the duplex region from the 5′-end of the sense oligonucleotide. In certain embodiments, the quadruplet sugar motif is at the 8, 9, 10, 11 positions; the 9, 10, 11, 12 positions; the 10, 11, 12, 13 positions; the 11, 12, 13, 14 positions; or the 12, 13, 14, 15 positions of the antisense oligonucleotide, counting from the first nucleoside of the 5′-end of the antisense oligonucleotide, or, the count starting from the first paired nucleotide within the duplex region from the 5′-end of the antisense oligonucleotide. The cleavage site may change according to the length of the duplex region of the double-stranded compound and may change the position of the quadruplet accordingly. 
     In certain embodiments, an oligonucleotide comprises an alternating sugar motif. In certain embodiments, one or both oligonucleotides of a double-stranded compound comprise an alternating sugar motif. An oligonucleotide with an alternating sugar motif comprises at least two different sugar modifications wherein one or more consecutive nucleosides comprising a first sugar modification alternates with one or more consecutive nucleosides comprising a second sugar modification and one or more consecutive nucleosides comprising a third sugar modification, etc. For example, if A, B and C each represent one type of modification to the nucleoside, the alternating motif can be “ABABABABABAB . . . ,” “AABBAABBAABB . . . ,” “AABAABAABAAB . . . ,” “AAABAAABAAAB . . . ,” “AAABBBAAABBB . . . ,” or “ABCABCABCABC . . . ” etc. In certain embodiments, the alternating sugar motif is repeated for at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23 contiguous nucleobases along an oligonucleotide. In certain embodiments, the alternating sugar motif is comprised of two different sugar modifications. In certain embodiments, the alternating sugar motif comprises 2′-OMe and 2′-F sugar modifications. 
     In certain embodiments, each nucleoside of an oligonucleotide is independently modified with one or more sugar modifications provided herein. In certain embodiments, each oligonucleotide of a double-stranded compound independently has one or more sugar motifs provided herein. In certain embodiments, an oligonucleotide containing a sugar motif, is fully modified in that each nucleoside other than the nucleosides comprising the sugar motif comprises a sugar modification. 
     Nucleobase Modifications and Motifs 
     In certain embodiments, compounds described herein comprise modified oligonucleotides. In certain embodiments, modified oligonucleotides comprise one or more nucleosides comprising a modified nucleobase. In certain embodiments, modified oligonucleotides comprise one or more nucleosides that do not comprise a nucleobase, referred to as an abasic nucleoside. 
     In certain embodiments, modified nucleobases are selected from: 5-substituted pyrimidines, 6-azapyrimidines, alkyl or alkynyl substituted pyrimidines, alkyl substituted purines, and N-2, N-6 and O-6 substituted purines. In certain embodiments, modified nucleobases are selected from: 2-aminopropyladenine, 5-hydroxymethyl cytosine, 5-methylcytosine, xanthine, hypoxanthine, 2-aminoadenine, 6-N-methylguanine, 6-N-methyladenine, 2-propyladenine, 2-thiouracil, 2-thiothymine and 2-thiocytosine, 5-propynyl (C≡C—CH 3 ) uracil, 5-propynylcytosine, 6-azouracil, 6-azocytosine, 6-azothymine, 5-ribosyluracil (pseudouracil), 4-thiouracil, 8-halo, 8-amino, 8-thiol, 8-thioalkyl, 8-hydroxyl, 8-aza and other 8-substituted purines, 5-halo, particularly, 5-bromo, 5-trifluoromethyl, 5-halouracil, and 5-halocytosine, 7-methylguanine, 7-methyladenine, 2-F-adenine, 2-aminoadenine, 7-deazaguanine, 7-deazaadenine, 3-deazaguanine, 3-deazaadenine, 6-N-benzoyladenine, 2-N-isobutyrylguanine, 4-N-benzoylcytosine, 4-N-benzoyluracil, 5-methyl 4-N-benzoylcytosine, 5-methyl 4-N-benzoyluracil, universal bases, hydrophobic bases, promiscuous bases, size expanded bases, and fluorinated bases. Further modified nucleobases include tricyclic pyrimidines, such as 1,3-diazaphenoxazine-2-one, 1,3-diazaphenothiazine-2-one, and 9-(2-aminoethoxy)-1,3-diazaphenoxazine-2-one (G-clamp). Modified nucleobases may also include those in which the purine or pyrimidine base is replaced with other heterocycles, for example, 7-deaza-adenine, 7-deazaguanosine, 2-aminopyridine and 2-pyridone. 
     Further nucleobases include those disclosed in U.S. Pat. No. 3,687,808; Modified Nucleosides in Biochemistry, Biotechnology and Medicine, Herdewijn, P. ed. Wiley-VCH, 2008; The Concise Encyclopedia Of Polymer Science And Engineering, pages 858-859; Kroschwitz, J. L., Ed., John Wiley &amp; Sons, 1990, 858-859; Englisch et al., Angewandte Chemie, International Edition, 1991, 30, 613; Sanghvi, Y. S., Chapter 15, dsRNA Research and Applications, pages 289-302; Antisense Research and Applications, Crooke, S. T. and Lebleu, B., Eds., CRC Press, 1993, 273-288; Antisense Drug Technology, Crooke S. T., Ed., CRC Press, 2008, 163-166 and 442-443 (Chapters 6 and 15), each of which are hereby incorporated herein by reference. 
     Publications that teach the preparation of certain of the above noted modified nucleobases, as well as other modified nucleobases include without limitation, US Applications 2003/0158403 and 2003/0175906; U.S. Pat. Nos. 4,845,205; 5,130,302; 5,134,066; 5,175,273; 5,367,066; 5,432,272; 5,434,257; 5,457,187; 5,459,255; 5,484,908; 5,502,177; 5,525,711; 5,552,540; 5,587,469; 5,594,121; 5,596,091; 5,614,617; 5,645,985; 5,681,941; 5,811,534; 5,750,692; 5,948,903; 5,587,470; 5,457,191; 5,763,588; 5,830,653; 5,808,027; 6,005,096. 6,015,886; 6,147,200; 6,166,197; 6,166,199; 6,222,025; 6,235,887; 6,380,368; 6,528,640; 6,639,062; 6,617,438; 7,045,610; 7,427,672; and 7,495,088, the entire contents of each of which are hereby incorporated herein by reference. 
     In certain embodiments, compounds described herein comprise oligonucleotides. In certain embodiments, oligonucleotides comprise modified and/or unmodified nucleobases arranged along the oligonucleotide or region thereof in a defined pattern or motif. In certain embodiments, each nucleobase is modified. In certain embodiments, none of the nucleobases are modified. In certain embodiments, each purine or each pyrimidine is modified. In certain embodiments, each adenine is modified. In certain embodiments, each guanine is modified. In certain embodiments, each thymine is modified. In certain embodiments, each uracil is modified. In certain embodiments, each cytosine is modified. In certain embodiments, some or all of the cytosine nucleobases in a modified oligonucleotide are 5-methylcytosines. 
     In certain embodiments, modified oligonucleotides comprise a block of modified nucleobases. In certain such embodiments, the block is at the 3′-end of the oligonucleotide. In certain embodiments, the block is within 3 nucleosides of the 3′-end of the oligonucleotide. In certain embodiments, the block is at the 5′-end of the oligonucleotide. In certain embodiments, the block is within 3 nucleosides of the 5′-end of the oligonucleotide. 
     Internucleoside Linkage Modifications and Motifs 
     A 3′ to 5′ phosphodiester linkage is the naturally occurring internucleoside linkage of RNA and DNA. In certain embodiments, compounds described herein have one or more modified, i.e., non-naturally occurring, internucleoside linkages. Certain non-naturally occurring internucleoside linkages may impart desirable properties such as, for example, enhanced cellular uptake, enhanced affinity for target nucleic acids, and increased stability in the presence of nucleases. Representative phosphorus-containing modified internucleoside linkages include, but are not limited to, phosphotriesters, alkylphosphonates (e.g. methylphosphonates), phosphoramidates, and phosphorothioates (“P═S”), and phosphorodithioates (“HS-P═S”). Representative non-phosphorus containing internucleoside linking groups include, but are not limited to, methylenemethylimino (—CH 2 —N(CH 3 )—O—CH 2 ), thiodiester, thionocarbamate (—O—C(═O)(NH)—S—); siloxane (—O—SiH 2 —O—); and N,N′-dimethylhydrazine (—CH 2 —N((CH 3 )—N((CH 3 )—). Methods of preparation of phosphorous-containing and non-phosphorous-containing internucleoside linkages are well known to those skilled in the art. Neutral internucleoside linkages include, without limitation, phosphotriesters, methylphosphonates, MMI (3′-CH 2 —N(CH 3 )—O-5′), amide-3 (3′-CH 2 —C(═O)—N(H)-5′), amide-4 (3′-CH 2 —N(H)—C(═O)-5′), formacetal (3′-O—CH 2 —O-5′), methoxypropyl, and thioformacetal (3′-S—CH 2 —O-5′). Further neutral internucleoside linkages include nonionic linkages comprising siloxane (dialkylsiloxane), carboxylate ester, carboxamide, sulfide, sulfonate ester and amides (See, for example: Carbohydrate Modifications in Antisense Research; Y. S. Sanghvi and P. D. Cook, Eds., ACS Symposium Series 580; Chapters 3 and 4, 40-65). Further neutral internucleoside linkages include nonionic linkages comprising mixed N, O, S and CH 2  component parts. 
     In certain embodiments, compounds provided herein comprise at least one modified internucleoside linkage. A modified internucleoside linkage may be placed at any position of an oligonucleotide. For double-stranded compounds, a modified internucleoside linkage may be placed within the sense oligonucleotide, antisense oligonucleotide, or both oligonucleotides of the double-stranded compound. 
     In certain embodiments, the internucleoside linkage modification may occur on every nucleoside of an oligonucleotide. In certain embodiments, internucleoside linkage modifications may occur in an alternating pattern along an oligonucleotide. In certain embodiments, essentially each internucleoside linking group is a phosphate internucleoside linkage (P═O). In certain embodiments, each internucleoside linking group of a modified oligonucleotide is a phosphorothioate (P═S). In certain embodiments, each internucleoside linking group of a modified oligonucleotide is independently selected from a phosphorothioate and phosphate internucleoside linkage. In certain embodiments, the pattern of the internucleoside linkage modification on each oligonucleotide of a double-stranded compound is the same. In certain embodiments, the pattern of the internucleoside linkage modification on each oligonucleotide of a double-stranded compound is different. In certain embodiments, a double-stranded compound comprises 6-8 modified internucleoside linkages. In certain embodiments, the 6-8 modified internucleoside linkages are phosphorothioate internucleoside linkages or alkylphosphonate internucleoside linkages. In certain embodiments, the sense oligonucleotide comprises at least two modified internucleoside linkages at either or both the 5′-end and the 3′-end. In certain such embodiments, the modified internucleoside linkages are phosphorothioate internucleoside linkages or alkylphosphonate internucleoside linkages. In certain embodiments, the antisense oligonucleotide comprises at least two modified internucleoside linkages at either or both the 5′-end and the 3′-end. In certain such embodiments, the modified internucleoside linkages are phosphorothioate internucleoside linkages or alkylphosphonate internucleoside linkages. 
     In certain embodiments, a double-stranded compound comprises an overhang region. In certain embodiments, a double-stranded compound comprises a phosphorothioate or alkylphosphonate internucleoside linkage modification in the overhang region. In certain embodiments, a double-stranded compound comprises a phosphorothioate or alkylphosphonate internucleotide linkage linking the overhang nucleotide with a paired nucleotide that is next to the overhang nucleotide. For instance, there may be at least two phosphorothioate internucleoside linkages between the terminal three nucleosides, in which two of the three nucleosides are overhang nucleosides, and the third is a paired nucleoside next to the overhang nucleoside. These terminal three nucleosides may be at the 3′-end of the antisense oligonucleotide, the 3′-end of the sense oligonucleotide, the 5′-end of the antisense oligonucleotide, or the 5′end of the antisense oligonucleotide. 
     In certain embodiments, modified oligonucleotides comprise one or more internucleoside linkages having chiral centers. Representative chiral internucleoside linkages include, but are not limited to, alkylphosphonates and phosphorothioates. Modified oligonucleotides comprising internucleoside linkages having chiral centers can be prepared as populations of modified oligonucleotides comprising stereorandom internucleoside linkages, or as populations of modified oligonucleotides comprising phosphorothioate linkages in particular stereochemical configurations. In certain embodiments, populations of modified oligonucleotides comprise phosphorothioate internucleoside linkages wherein all of the phosphorothioate internucleoside linkages are stereorandom. Such modified oligonucleotides can be generated using synthetic methods that result in random selection of the stereochemical configuration of each phosphorothioate linkage. As is well understood by those of skill in the art, each individual phosphorothioate of each individual oligonucleotide molecule has a defined stereoconfiguration. In certain embodiments, populations of modified oligonucleotides are enriched for modified oligonucleotides comprising one or more particular phosphorothioate internucleoside linkages in a particular, independently selected stereochemical configuration. In certain embodiments, the particular configuration of the particular phosphorothioate linkage is present in at least 65% of the molecules in the population. In certain embodiments, the particular configuration of the particular phosphorothioate linkage is present in at least 70% of the molecules in the population. In certain embodiments, the particular configuration of the particular phosphorothioate linkage is present in at least 80% of the molecules in the population. In certain embodiments, the particular configuration of the particular phosphorothioate linkage is present in at least 90% of the molecules in the population. In certain embodiments, the particular configuration of the particular phosphorothioate linkage is present in at least 99% of the molecules in the population. Such enriched populations of modified oligonucleotides can be generated using synthetic methods known in the art, e.g., methods described in Oka et al., JACS 125, 8307 (2003), Wan et al. Nuc. Acid. Res. 42, 13456 (2014), and WO 2017/015555. In certain embodiments, a population of modified oligonucleotides is enriched for modified oligonucleotides having at least one indicated phosphorothioate in the (Sp) configuration. In certain embodiments, a population of modified oligonucleotides is enriched for modified oligonucleotides having at least one phosphorothioate in the (Rp) configuration. 
     Conjugate Groups 
     In certain embodiments, the compounds described herein comprise or consist of one or more oligonucleotides and, optionally, one or more conjugate groups. Conjugate groups may be attached to either or both ends of an oligonucleotide and/or at any internal position. In certain embodiments, a conjugate group is attached at the 3′ end of an oligonucleotide. In certain embodiments, a conjugate group is attached at the 5′ end of an oligonucleotide. In certain embodiments, oligonucleotides are covalently attached to one or more conjugate groups. 
     In certain embodiments, conjugate groups are terminal groups attached to either or both ends of an oligonucleotide. In certain such embodiments, terminal groups are attached at the 3′ end of an oligonucleotide. In certain such embodiments, terminal groups are attached at the 5′ end of an oligonucleotide. In certain embodiments, terminal groups include, but are not limited to, capping groups, phosphate moieties, protecting groups, modified or unmodified nucleosides, and two or more nucleosides that are independently modified or unmodified, such as an overhang. 
     In certain embodiments, conjugate groups modify one or more properties of the attached oligonucleotide, including, but not limited to, pharmacodynamics, pharmacokinetics, stability, activity, half-life, binding, absorption, tissue distribution, cellular distribution, cellular uptake, charge and clearance. In certain embodiments, conjugate groups enhance the affinity of a compound for a selected target, e.g., molecule, cell or cell type, compartment, e.g., a cellular or organ compartment, tissue, organ or region of the body, as, e.g., compared to a compound absent such a conjugate group. In certain embodiments, conjugate groups impart a new property on the attached oligonucleotide, e.g., fluorophores or reporter groups that enable detection of the oligonucleotide. 
     In certain embodiments, conjugate groups include, but are not limited to, intercalators, reporter molecules, polyamines, polyamides, peptides, carbohydrates, vitamin moieties, polyethylene glycols, thioethers, polyethers, cholesterols, thiocholesterols, cholic acid moieties, folate, lipids, phospholipids, biotin, phenazine, phenanthridine, anthraquinone, adamantane, acridine, fluoresceins, rhodamines, coumarins, fluorophores, and dyes. 
     In certain embodiments, conjugate groups include an active drug substance, for example, aspirin, warfarin, phenylbutazone, ibuprofen, suprofen, fen-bufen, ketoprofen, (S)-(+)-pranoprofen, carprofen, dansylsarcosine, 2,3,5-triiodobenzoic acid, fingolimod, flufenamic acid, folinic acid, a benzothiadiazide, chlorothiazide, a diazepine, indo-methicin, a barbiturate, a cephalosporin, a sulfa drug, an antidiabetic, an antibacterial, or an antibiotic. 
     In certain embodiments, conjugate groups are targeting moieties. In certain embodiments, a targeting moiety includes, but is not limited to, a lectin, glycoprotein, lipid, protein, peptide, peptide mimetic, receptor ligand, antibody, thyrotropin, melanotropin, surfactant protein A, carbohydrate, carbohydrate derivative, modified carbohydrate, carbohydrate cluster, polysaccharide, modified polysaccharide, or polysaccharide derivative, mucin carbohydrate, multivalent lactose, multivalent galactose, N-acetyl-galactosamine (GalNAc), N-acetylglucosamine multivalent mannose, multivalent fucose, glycosylated polyaminoacids, multivalent galactose, transferrin, bisphosphonate, polyglutamate, polyaspartate, a lipid, cholesterol, a steroid, bile acid, folate, vitamin B12, vitamin A, biotin, or an RGD peptide or RGD peptide mimetic. 
     In certain embodiments, conjugate groups may include, but are not limited to, the conjugate groups described in the following references such as cholesterol (e.g., Letsinger et al., Proc. Natl. Acid. Sci. USA, 1989, 86: 6553-6556), cholic acid (e.g., Manoharan et al., Biorg. Med. Chem. Let., 1994, 4:1053-1060), thioether, e.g., hexyl-S-tritylthiol (e.g., Manoharan et al., Ann. NY. Acad. Sci., 1992, 660:306-309; Manoharan et al., Biorg. Med. Chem. Let., 1993, 3:2765-2770), thiocholesterol (e.g., Oberhauser et al., Nucl. Acids Res., 1992, 20:533-538), aliphatic chains, e.g., do-decan-diol or undecyl residues (e.g., 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), phospholipids, e.g., di-hexadecyl-rac-glycerol or triethyl-ammonium 1,2-di-O-hexadecyl-rac-glycero-3-H-phosphonate (e.g, Manoharan et al., Tetrahedron Lett., 1995, 36:3651-3654; Shea et al., Nucl. Acids Res., 1990, 18:3777-3783), polyamines or a polyethylene glycol chains (e.g., Manoharan et al., Nucleosides &amp; Nucleotides, 1995, 14:969-973), adamantane acetic acid (e.g., Manoharan et al., Tetrahedron Lett., 1995, 36:3651-3654), palmityl (e.g., Mishra et al., Biochim. Biophys. Acta, 1995, 1264:229-237), octadecylamine or hexylamino-carbonyloxychole sterol moiety (e.g., Crooke et al. J. Pharmacol. Exp. Ther., 1996, 277:923-937), tocopherol (e.g., Nishina et al., Molecular Therapy Nucleic Acids, 2015, 4, e220 and Nishina et al., Molecular Therapy, 2008, 16:734-740), GalNAc and other carbohydrates (e.g., Maier et al., Bioconjugate Chemistry, 2003, 14, 18-29; Rensen et al., J. Med. Chem. 2004, 47, 5798-5808; WO2009/073809 and U.S. Pat. Nos. 8,106,022; 8,450,467 and 8,828,957; and WO2014/179445; WO2014/179620 and U.S. Pat. Nos. 9,127,276; 9,181,549 and 10,844,379) each of which is incorporated herein by reference in its entirety. 
     Conjugate groups may be attached to oligonucleotides through conjugate linkers. In certain embodiments, a conjugate linker comprises a chain structure, such as a hydrocarbyl chain, or an oligomer of repeating units or combination of such repeating units. In certain embodiments, a conjugate linker comprises one or more groups selected from alkyl, amino, oxo, amide, disulfide, polyethylene glycol, ether, thioether, and hydroxylamino. In certain embodiments, a conjugate linker comprises at least one phosphorus group. In certain embodiments, a conjugate linker comprises at least one phosphate group. In certain embodiments, a conjugate linker includes at least one neutral linking group. In certain embodiments, conjugate linkers include, but are not limited to, pyrrolidine, 8-amino-3,6-dioxaoctanoic acid (ADO), succinimidyl 4-(N-maleimidomethyl) cyclohexane-1-carboxylate (SMCC) and 6-aminohexanoic acid (AHEX or AHA). Other conjugate linkers include, but are not limited to, substituted or unsubstituted C 1 -C 10  alkyl, substituted or unsubstituted C 2 -C 10  alkenyl, or substituted or unsubstituted C 2 -C 10  alkynyl, wherein a nonlimiting list of preferred substituent groups includes hydroxyl, amino, alkoxy, carboxy, benzyl, phenyl, nitro, thiol, thioalkoxy, halogen, alkyl, aryl, alkenyl, and alkynyl. In certain embodiments, conjugate linkers comprise 1-10 linker-nucleosides. In certain embodiments, such linker-nucleosides may be modified or unmodified nucleosides. It is typically desirable for linker-nucleosides to be cleaved from the compound after it reaches a target tissue. Accordingly, linker-nucleosides herein can be linked to one another and to the remainder of the compound through cleavable bonds. Herein, linker-nucleosides are not considered to be part of the oligonucleotide. Accordingly, in embodiments in which a compound comprises an oligonucleotide consisting of a specified number or range of linked nucleosides and/or a specified percent complementarity to a reference nucleic acid and the compound also comprises a conjugate group comprising a conjugate linker comprising linker-nucleosides, those linker-nucleosides are not counted toward the length of the oligonucleotide and are not used in determining the percent complementarity of the oligonucleotide for the reference nucleic acid. 
     In certain embodiments, conjugate groups and conjugate linkers as well as other modifications include, without limitation, those described in the following references: U.S. Pat. Nos. 5,994,517; 6,300,319; 6,660,720; 6,906,182; 7,262,177; 7,491,805; 8,106,022; 7,723,509; 9,127,276; US 2006/0148740; US 2011/0123520; WO2013/033230; WO2012/037254, Biessen et al., J. Med. Chem. 1995, 38, 1846-1852; Lee et al., Bioorganic &amp; Medicinal Chemistry 2011, 19, 2494-2500; Rensen et al., J. Biol. Chem. 2001, 276, 37577-37584; Rensen et al., J. Med. Chem. 2004, 47, 5798-5808; Sliedregt et al., J. Med. Chem. 1999, 42, 609-618; Valentijn et al., Tetrahedron, 1997, 53, 759-770; Lee, Carhohydr Res, 1978, 67, 509-514; Connolly et al., J Biol Chem, 1982, 257, 939-945;  Pavia  et al., Int J Pep Protein Res, 1983, 22, 539-548; Lee et al., Biochem, 1984, 23, 4255-4261; Lee et al., Glycoconjugate J, 1987, 4, 317-328; Toyokuni et al., Tetrahedron Lett, 1990, 31, 2673-2676; Biessen et al., J Med Chem, 1995, 38, 1538-1546; Valentijn et al., Tetrahedron, 1997, 53, 759-770; Kim et al., Tetrahedron Lett, 1997, 38, 3487-3490; Lee et al., Bioconjug Chem, 1997, 8, 762-765; Kato et al., Glycohiol, 2001, 11, 821-829; Rensen et al., J Biol Chem, 2001, 276, 37577-37584; Lee et al., Methods Enzymol, 2003, 362, 38-43; Westerlind et al., Glycoconj J, 2004, 21, 227-241; Lee et al., Bioorg Med Chem Lett, 2006, 16(19), 5132-5135; Maierhofer et al., Bioorg Med Chem, 2007, 15, 7661-7676; Khorev et al., Bioorg Med Chem, 2008, 16, 5216-5231; Lee et al., Bioorg Med Chem, 2011, 19, 2494-2500; Kornilova et al., Analyt Biochem, 2012, 425, 43-46; Pujol et al., Angew Chemie Int Ed Engl, 2012, 51, 7445-7448; Biessen et al., J Med Chem, 1995, 38, 1846-1852; Sliedregt et al., J Med Chem, 1999, 42, 609-618; Rensen et al., J Med Chem, 2004, 47, 5798-5808; Rensen et al., Arterioscler Thromh Vase Biol, 2006, 26, 169-175; van Rossenberg et al., Gene Ther, 2004, 11, 457-464; Sato et al., JAm Chem Soc, 2004, 126, 14013-14022; Lee et al., J Org Chem, 2012, 77, 7564-7571; Biessen et al., FASEB J, 2000, 14, 1784-1792; Rajur et al., Bioconjug Chem, 1997, 8, 935-940; Duff et al., Methods Enzymol, 2000, 313, 297-321; Maier et al., Bioconjug Chem, 2003, 14, 18-29; Jayaprakash et al., Org Lett, 2010, 12, 5410-5413; Manoharan, Antisense Nucleic Acid Drug Dev, 2002, 12, 103-128; Merwin et al., Bioconjug Chem, 1994, 5, 612-620; Tomiya et al., Bioorg Med Chem, 2013, 21, 5275-5281; International applications WO1998/013381; WO2011/038356; WO1997/046098; WO2008/098788; WO2004/101619; WO2012/037254; WO2011/120053; WO2011/100131; WO2011/163121; WO2012/177947; WO2013/033230; WO2013/075035; WO2012/083185; WO2012/083046; WO2009/082607; WO2009/134487; WO2010/144740; WO2010/148013; WO1997/020563; WO2010/088537; WO2002/043771; WO2010/129709; WO2012/068187; WO2009/126933; WO2004/024757; WO2010/054406; WO2012/089352; WO2012/089602; WO2013/166121; WO2013/165816; U.S. Pat. Nos. 4,751,219; 7,582,744; 8,552,163; 8,137,695; 6,908,903; 6,383,812; 7,262,177; 6,525,031; 5,994,517; 6,660,720; 6,300,319; 7,723,509; 8,106,022; 7,491,805; 7,491,805; 8,541,548; 8,344,125; 8,313,772; 8,349,308; 8,450,467; 8,501,930; 8,158,601; 7,262,177; 6,906,182; 6,620,916; 8,435,491; 8,404,862; 7,851,615; Published U.S. Patent Application Publications US2011/0097264; US2011/0097265; US2013/0004427; US2003/0119724; US2011/0207799; US2012/0035115; US2012/0230938; US2005/0164235; US2006/0183886; US2012/0136042; US2012/0095075; US2013/0109817; US2006/0148740; US2008/0206869; US2012/0165393; US2012/0101148; US2013/0121954; US2011/0123520; US2003/0077829; US2008/0108801; and US2009/0203132; each of which is incorporated herein by reference in its entirety. 
     Certain Targeting Moieties 
     In certain embodiments, a compound provided herein comprises a conjugate group. In certain embodiments, an oligonucleotide provided herein comprises a conjugate group. In certain embodiments, the conjugate group is a targeting moiety. In certain embodiments, the targeting moiety comprises one or more GalNAc. In certain embodiments, the one or more GalNAc are attached to one or more positions on a furanose ring. In certain embodiments, the one or more GalNAc are attached to the 2′ or 3′ position on a furanose ring. In certain embodiments, the furanose ring is a subunit of the oligonucleotide. In certain embodiments, the furanose ring is the 5′ nucleoside sugar of an oligonucleotide. In certain embodiments, the furanose ring is the 5′ nucleoside sugar of a sense oligonucleotide. In certain embodiments, a compound or oligonucleotide comprises one or more subunits with the following formula or a salt, solvate, or hydrate thereof: 
     
       
         
         
             
             
         
       
     
     wherein:
         R 1  is H, adenine, guanine, thymine, cytosine, uracil, carbocyclyl, heterocyclyl, aryl, heteroaryl, or a nucleobase isostere;   R 2  is the oligonucleotide sequence;   L 1  is alkyl, or alkyl-C(═O)—NH-alkyl;   L 2  is alkyl, or alkyl-C(═O)—NH-alkyl;   L 3  is a bond, a phosphodiester bond, a phosphorothioate bond, a triazole, a tetrazole, an amide, a reverse-amide, a carbamate, a carbonate, urea, O, S, S(═O), S(═O) 2 , NH, substituted N group, alkyl, alkenyl, dienyl, alkynyl, heteroalkyl, phosphate;   R 3  is H, —C═(O)—NH—(CH 2 CH 2 O) j -GalNAc, or —C(═O)—NH-alkyl-NH—C(═O)-alkyl-O-GalNAc;   R 4  is H, —C═(O)—NH—(CH 2 CH 2 O) k -GalNAc, or —C(═O)—NH-alkyl-NH—C(═O)-alkyl-O-GalNAc;   R 5  is —C═(O)—NH—(CH 2 CH 2 O) m -GalNAc, or —C(═O)—NH-alkyl-NH—C(═O)-alkyl-O-GalNAc;   R 6  is —C═(O)—NH—(CH 2 CH 2 O) n -GalNAc, or —C(═O)—NH-alkyl-NH—C(═O)-alkyl-O-GalNAc;   W and Q are each independently O, NH, CH 2 , or CH 2 O;   S 1  and S 2  are each independently C(R 7 ) or N, wherein each instance of R 7  is independently H, alkyl, heteroalkyl, or halogen;   j is an integer 1-10, inclusive;   k is an integer 1-10, inclusive;   m is an integer 1-10, inclusive; and   n is an integer 1-10, inclusive.       

     In certain embodiments, R 3 , R 4 , R 5 , and R 6  are the same. In certain embodiments, R 3 , R 5 , and R 6  are the same. In certain embodiments, R 3  or R 4  is H. 
     In certain embodiments, L 1  and L 2  are the same. 
     In certain embodiments, L 1  and L 2  are each independently alkyl; R 3  is H, —C═(O)—NH—(CH 2 CH 2 O) j -GalNAc, or —C(═O)—NH-alkyl-NH—C(═O)-alkyl-O-GalNAc; R 4  is H, —C═(O)—NH—(CH 2 CH 2 O) k -GalNAc, or —C(═O)—NH-alkyl-NH—C(═O)-alkyl-O-GalNAc; R 5  is —C═(O)—NH—(CH 2 CH 2 O) m -GalNAc, or —C(═O)—NH-alkyl-NH—C(═O)-alkyl-O-GalNAc; and R 6  is —C═(O)—NH—(CH 2 CH 2 O) n -GalNAc, or —C(═O)—NH-alkyl-NH—C(═O)-alkyl-O-GalNAc. 
     In certain embodiments, L 1  and L 2  are each independently alkyl-C(═O)—NH-alkyl; R 3  is H, —C═(O)—NH—(CH 2 CH 2 O) j -GalNAc, or —C(═O)—NH-alkyl-NH—C(═O)-alkyl-O-GalNAc; R 4  is H, —C═(O)—NH—(CH 2 CH 2 O) k -GalNAc, or —C(═O)—NH-alkyl-NH—C(═O)-alkyl-O-GalNAc; R 5  is —C═(O)—NH—(CH 2 CH 2 O) m -GalNAc, or —C(═O)—NH-alkyl-NH—C(═O)-alkyl-O-GalNAc; and R 6  is —C═(O)—NH—(CH 2 CH 2 O) n -GalNAc, or —C(═O)—NH-alkyl-NH—C(═O)-alkyl-O-GalNAc. 
     In certain embodiments, R 4  is H. 
     In certain embodiments, L 1  and L 2  are each independently alkyl; R 3  is —C═(O)—NH—(CH 2 CH 2 O) j -GalNAc, or —C(═O)—NH-alkyl-NH—C(═O)-alkyl-O-GalNAc; R 4  is H; R 5  is —C═(O)—NH—(CH 2 CH 2 O) m -GalNAc, or —C(═O)—NH-alkyl-NH—C(═O)-alkyl-O-GalNAc; and R 6  is —C═(O)—NH—(CH 2 CH 2 O) n -GalNAc, or —C(═O)—NH-alkyl-NH—C(═O)-alkyl-O-GalNAc. 
     In certain embodiments, L 1  and L 2  are each independently alkyl-C(═O)—NH-alkyl; R 3  is —C═(O)—NH—(CH 2 CH 2 O) j -GalNAc, or —C(═O)—NH-alkyl-NH—C(═O)-alkyl-O-GalNAc; R 4  is H; R 5  is —C═(O)—NH—(CH 2 CH 2 O) m -GalNAc, or —C(═O)—NH-alkyl-NH—C(═O)-alkyl-O-GalNAc; and R 6  is —C═(O)—NH—(CH 2 CH 2 O) n -GalNAc, or —C(═O)—NH-alkyl-NH—C(═O)-alkyl-O-GalNAc. 
     In certain embodiments, R 3  is —C═(O)—NH—(CH 2 CH 2 O) j -GalNAc; R 4  is H; R 5  is —C═(O)—NH—(CH 2 CH 2 O) m -GalNAc; and R 6  is —C═(O)—NH—(CH 2 CH 2 O) n -GalNAc. 
     In certain embodiments, R 3  is —C(═O)—NH-alkyl-NH—C(═O)-alkyl-O-GalNAc; R 4  is H; R 5  is —C(═O)—NH-alkyl-NH—C(═O)-alkyl-O-GalNAc; and R 6  is —C(═O)—NH-alkyl-NH—C(═O)-alkyl-O-GalNAc. 
     In certain embodiments, a compound or oligonucleotide comprises one or more subunits with the following formula or a salt, solvate, or hydrate thereof: 
     
       
         
         
             
             
         
       
     
     wherein:
         R 9  is H, adenine, guanine, thymine, cytosine, or uracil, or adenine, guanine, thymine, cytosine, or uracil, each comprising a Protecting Group (PG), a modified nucleobase, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, or a nucleobase isostere;   L is a bond, a phosphodiester bond, a phosphorothioate bond, a triazole, a tetrazole, an amide, a reverse-amide, a carbamate, a carbonate, urea, alkyl, or heteroalkyl;   R 2  is the oligonucleotide sequence;   Y 1  is O, CH 2 , CH 2 O, or optionally substituted NH;   Y 2  is O, CH 2 , CH 2 O, or optionally substituted NH;   Y 3  is CO, SO 2 , P(O)O, CH 2 —O—C(O), CH 2 —NH—C(O), CH 2 —NH—SO 2 , or CH 2 ;   Y 4  is CO, SO 2 , P(O)O, CH 2 —O—C(O), CH 2 —NH—C(O), CH 2 —NH—SO 2 , or CH 2 ;   n 2  is 0, 1, 2, 3, 4, 5, or 6; and   each n 1 , n 3 , n 4  and n 5  is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.       

     In certain embodiments, a compound or oligonucleotide comprises one or more subunits with the following formula or a salt, solvate, or hydrate thereof: 
     
       
         
         
             
             
         
       
     
     wherein:
         each n is independently 1, 2, 3, 4, or 5;   each m is independently 0, 1, 2, 3, 4, 5, or 6;   each o is independently 0, 1, 2, 3, 4, 5, or 6;   each of L 1 , L 2 , and L 3  is independently absent, C(═O), or C(═O)NH;   each Y 1  is independently O, CH(R a ), S, S(═O), S(═O) 2 , NH, substituted N group, NHC(═O), C(═O)NH, P(═O) 2 —O—, P(═O)(═S)—O, P(═S) 2 —O, —O—P(═O) 2 -O—, —O—P(═O)(═S)—O—, —O—P(═S) 2 —O—, —O—P(═O) 2 —, —O—P(═O)(═S)—, —O—P(═S) 2 —;   each Y 2  is independently O, CH(R b ), S, S(═O), S(═O) 2 , NH, substituted N group, NHC(═O), C(═O)NH, P(═O) 2 —O—, P(═O)(═S)-0, P(═S) 2 —O, —O—P(═O) 2 —O—, —O—P(═O)(═S)—O—, —O—P(═S) 2 —O—, —O—P(═O) 2 —, —O—P(═O)(═S)—, —O—P(═S) 2 —;   each of Het 1 , Het 2 , and Het 3  is independently optionally substituted heteroaryl or optionally substituted heterocyclyl;   R 1  is the oligonucleotide sequence linked by a bond, a phosphodiester bond, a phosphorothioate bond, a triazole, a tetrazole, an amide, a reverse-amide, a carbamate, a carbonate, urea, alkyl, or heteroalkyl;       

     
       
         
         
             
             
         
       
         
         
           
             each R 5 , R 6 , and R 7  is independently OH R 9  is optionally substituted heterocyclyl; each R a  is independently H, alkyl, halo, OR c , or SR c ; 
             each R b  is independently H, alkyl, halo, OR c , or SR c ; and 
             each R′ is independently H or alkyl. 
           
         
       
    
     In certain embodiments, the subunit is selected from Formulae I through VIII or a salt, solvate, or hydrate thereof, wherein R is the modified oligonucleotide other than the 5′ nucleoside. In certain embodiments, the 5′ nucleoside of the modified oligonucleotide is Formula I and R′ is O. In certain embodiments, the 5′ nucleoside of the modified oligonucleotide is Formula I and R′ is S. In certain embodiments, the 5′ nucleoside of the modified oligonucleotide is Formula II and R′ is O. In certain embodiments, the 5′ nucleoside of the modified oligonucleotide is Formula II and R′ is S. In certain embodiments, the 5′ nucleoside of the modified oligonucleotide is Formula III and R′ is O. In certain embodiments, the 5′ nucleoside of the modified oligonucleotide is Formula III and R′ is S. In certain embodiments, the 5′ nucleoside of the modified oligonucleotide is Formula IV and R′ is O. In certain embodiments, the 5′ nucleoside of the modified oligonucleotide is Formula IV and R′ is S. In certain embodiments, the 5′ nucleoside of the modified oligonucleotide is Formula V and R′ is O. In certain embodiments, the 5′ nucleoside of the modified oligonucleotide is Formula V and R′ is S. In certain embodiments, the 5′ nucleoside of the modified oligonucleotide is Formula VI and R′ is O. In certain embodiments, the 5′ nucleoside of the modified oligonucleotide is Formula VI and R′ is S. In certain embodiments, the 5′ nucleoside of the modified oligonucleotide is Formula VII and R′ is O. In certain embodiments, the 5′ nucleoside of the modified oligonucleotide is Formula VII and R′ is S. In certain embodiments, the 5′ nucleoside of the modified oligonucleotide is Formula VIII and R′ is O. In certain embodiments, the 5′ nucleoside of the modified oligonucleotide is Formula VIII and R′ is S. 
     Target Nucleic Acids and Target Regions 
     In certain embodiments, compounds described herein comprise or consist of an oligonucleotide comprising a region that is complementary to a target nucleic acid. In certain embodiments, the target nucleic acid is an endogenous RNA molecule. In certain embodiments, the target nucleic acid encodes a protein. In certain embodiments, the target nucleic acid is non-coding. In certain such embodiments, the target nucleic acid is selected from an mRNA and a pre-mRNA, including intronic, exonic and untranslated regions. In certain embodiments, the target RNA is an mRNA. In certain embodiments, the target nucleic acid is a pre-mRNA. In certain such embodiments, the target region is entirely within an exon. In certain such embodiments, the target region is entirely within an intron. In certain embodiments, the target region spans an intron/exon junction. In certain embodiments, the target region is at least 50% within an intron. 
     In certain embodiments, compounds disclosed herein hybridize with a PKK nucleic acid. The most common mechanism of hybridization involves hydrogen bonding between complementary nucleobases of the nucleic acid molecules. Hybridization can occur under varying conditions. Hybridization 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 hybridizes specifically to a target nucleic acid are well known in the art. In certain embodiments, the compounds provided herein specifically hybridize with a PKK nucleic acid. 
     Nucleotide sequences that encode PKK include, without limitation, the following: GENBANK Accession Nos. NM_000892.5 (incorporated herein as SEQ ID NO: 1), NG_012095.2 truncated from 23529 . . . 54493 (incorporated herein as SEQ ID NO: 2), XM_017008181.1 (incorporated herein as SEQ ID NO: 3), NC_000004.12 truncated from 186215714 to 186258477 (incorporated herein as SEQ ID NO: 4), NM_001318394.2 (incorporated herein as SEQ ID NO: 5) and NM_001318396.2 (incorporated herein as SEQ ID NO: 6). 
     Complementarity 
     Oligonucleotides provided herein may have a defined percent complementarity to a particular nucleic acid, target region, oligonucleotide, or portion thereof. Non-complementary nucleobases may be tolerated provided that the oligonucleotide remains able to specifically hybridize to the nucleic acid, oligonucleotide, or portion thereof. In certain embodiments, the oligonucleotides provided herein, or a specified portion thereof are at least, or are up to 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% complementary to a target nucleic acid, a target region, an oligonucleotide or specified portion thereof. In certain embodiments, the oligonucleotides provided herein, or a specified portion thereof, are 70% to 75%, 75% to 80%, 80% to 85%, 85% to 90%, 90% to 95%, 95% to 100%, or any number in between these ranges, complementary to a target nucleic acid, a target region, an oligonucleotide or specified portion thereof. Percent complementarity of an oligonucleotide with a target nucleic acid, a target region, an oligonucleotide or specified portion thereof can be determined using routine methods. For example, an oligonucleotide in which 18 of 20 nucleobases of the oligonucleotide are complementary to a target region, and would therefore specifically hybridize, would represent 90 percent complementarity. In this example, the remaining non-complementary nucleobases may be clustered or interspersed with complementary nucleobases and need not be contiguous to each other or to complementary nucleobases. As such, an oligonucleotide which is 18 nucleobases in length having four non-complementary 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. Percent complementarity of an oligonucleotide with a region of a target nucleic acid, a target region, an oligonucleotide or specified portion thereof can be determined routinely using BLAST programs (basic local alignment search tools) known in the art. In certain embodiments, oligonucleotides described herein, or specified portions thereof, are fully complementary (i.e. 100% complementary) to a target nucleic acid, a target region, an oligonucleotide or specified portion thereof. For example, an oligonucleotide may be fully complementary to a target nucleic acid, a target region, an oligonucleotide, or specified portion thereof. As used herein, “fully complementary” means each nucleobase of an oligonucleotide is complementary to the corresponding nucleobase of a target nucleic acid, a target region, an oligonucleotide, or a specified portion thereof. For example, a 20 nucleobase oligonucleotide 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 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 oligonucleotide can be “fully complementary” to a 20 nucleobase region of a target sequence that is 400 nucleobases long. The 20 nucleobase portion of the 30 nucleobase compound 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 compound. At the same time, the entire 30 nucleobase compound may or may not be fully complementary to the target sequence, depending on whether the remaining 10 nucleobases of the compound are also complementary to the target sequence. 
     In certain embodiments, oligonucleotides described herein comprise one or more mismatched nucleobases relative to a target nucleic acid, a target region, an oligonucleotide or a specified portion thereof. In certain embodiments, oligonucleotides described herein that are, or are up to 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23 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, or specified portion thereof. In certain embodiments, oligonucleotides described herein that are, or are up to 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, a target region, an oligonucleotide, or specified portion thereof. In certain embodiments, the mismatch is at position 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 from the 5′-end of the oligonucleotide. In certain embodiments, the mismatch is at position 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, 13 or 14 from the 3′-end of the oligonucleotide. In certain embodiments, the mismatch forms a wobble base pair with a corresponding nucleobase on the target nucleic acid. For example, in certain embodiments, the mismatch forms a wobble base pair selected from hypoxanthine (nucleobase of inosine) and uracil (I:U base pair); guanine and uracil (G:U base pair); hypoxanthine and adenine (I:A base pair); and hypoxanthine and cytosine (I:C base pair). Accordingly, in certain embodiments, a mismatched nucleobase on an oligonucleotide comprises hypoxanthine, guanine, or uracil. 
     In certain embodiments, oligonucleotides described herein may be complementary to a portion of a nucleic acid. As used herein, “portion” refers to a defined number of contiguous nucleobases within a region of a nucleic acid. A “portion” can also refer to a defined number of contiguous nucleobases of an oligonucleotide. In certain embodiments, the oligonucleotides are complementary to at least an 8 nucleobase portion of a nucleic acid. In certain embodiments, the oligonucleotides are complementary to at least a 9 nucleobase portion of a nucleic acid. In certain embodiments, the oligonucleotides are complementary to at least a 10 nucleobase portion of a nucleic acid. In certain embodiments, the oligonucleotides are complementary to at least an 11 nucleobase portion of a nucleic acid. In certain embodiments, the oligonucleotides are complementary to at least a 12 nucleobase portion of a nucleic acid. In certain embodiments, the oligonucleotides are complementary to at least a 13 nucleobase portion of a nucleic acid. In certain embodiments, the oligonucleotides are complementary to at least a 14 nucleobase portion of a nucleic acid. In certain embodiments, the oligonucleotides are complementary to at least a 15 nucleobase portion of a nucleic acid. In certain embodiments, the oligonucleotides are complementary to at least a 16 nucleobase portion of a nucleic acid. Also contemplated are oligonucleotides that are complementary to at least a 9, 10, 17, 18, 19, 20, 21, 22, 23 or more nucleobase portion of a nucleic acid, or a range defined by any two of these values. In certain embodiments, the oligonucleotide is an antisense oligonucleotide. 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. In certain embodiments, the oligonucleotide is a sense oligonucleotide. In certain embodiments, a portion of the sense oligonucleotide is compared to an equal length portion of an antisense oligonucleotide. 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 of a sense oligonucleotide is compared to an equal length portion of an antisense oligonucleotide. 
     Identity 
     The oligonucleotides provided herein may also have a defined percent identity to a particular nucleic acid, target region, oligonucleotide, or specified portion thereof. As used herein, an oligonucleotide is identical to a sequence disclosed herein if it has the same nucleobase pairing ability. For example, a DNA which contains thymidine in place of uracil in a disclosed RNA sequence would be considered identical to the RNA sequence since both uracil and thymidine pair with adenine. Shortened and lengthened versions of the compounds described herein as well as compounds having non-identical bases relative to the compounds provided herein also are contemplated. The non-identical bases may be adjacent to each other or dispersed throughout the compound. Percent identity of an oligonucleotide 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, oligonucleotides described herein, or portions thereof, are, or are at least, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to one or more of the nucleic acids, oligonucleotides, or a portion thereof, disclosed herein. In certain embodiments, oligonucleotides described herein are about 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical, or any percentage between such values, to a particular nucleic acid or oligonucleotide, or portion thereof. 
     In certain embodiments, an oligonucleotide may have one or more mismatched nucleobases. In certain such embodiments, the mismatch is at position 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 from the 5′-end of the oligonucleotide. In certain such embodiments, the mismatch is at position 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, 13 or 14 from the 3′-end of the oligonucleotide. In certain embodiments, a portion of the 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. In certain embodiments, the oligonucleotide is a sense oligonucleotides. In certain embodiments, a portion of the sense 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. 
     Pharmaceutical Compositions and Formulations 
     Compounds described herein may be admixed with pharmaceutically acceptable active or inert substances for the preparation of pharmaceutical compositions or formulations. Compositions and methods for the formulation of pharmaceutical compositions are dependent upon a number of criteria, including, but not limited to, route of administration, extent of disease, or dose to be administered. Certain embodiments provide pharmaceutical compositions comprising one or more compounds or a salt thereof. In certain embodiments, the compounds are antisense oligonucleotides. In certain embodiments, the compounds are oligomeric compounds. In certain embodiments, the compounds comprise or consist of one or more modified oligonucleotides. In certain such embodiments, the pharmaceutical composition comprises one or more compound and a suitable pharmaceutically acceptable diluent or carrier. In certain embodiments, a pharmaceutical composition comprises one or more compound and a sterile saline solution. In certain embodiments, such pharmaceutical composition consists of one compound and a sterile saline solution. In certain embodiments, the sterile saline is pharmaceutical grade saline. In certain embodiments, a pharmaceutical composition comprises one or more compound and sterile water. In certain embodiments, a pharmaceutical composition consists of one compound and sterile water. In certain embodiments, the sterile water is pharmaceutical grade water. In certain embodiments, a pharmaceutical composition comprises one or more compounds and phosphate-buffered saline (PBS). In certain embodiments, a pharmaceutical composition consists of one compound and sterile PBS. In certain embodiments, the sterile PBS is pharmaceutical grade PBS. 
     A compound described herein targeted to PKK can be utilized in pharmaceutical compositions by combining the compound with a suitable pharmaceutically acceptable diluent or carrier. In certain embodiments, a pharmaceutically acceptable diluent is water, such as sterile water suitable for injection. Accordingly, in one embodiment, employed in the methods described herein is a pharmaceutical composition comprising a compound targeted to PKK and a pharmaceutically acceptable diluent. In certain embodiments, the pharmaceutically acceptable diluent is water. In certain embodiments, the compound comprises or consists of one or more modified oligonucleotide provided herein. 
     Pharmaceutical compositions comprising compounds provided herein encompass any pharmaceutically acceptable salts, esters, or salts of such esters, or any other oligonucleotide which, upon administration to an animal, including a human, is capable of providing (directly or indirectly) the biologically active metabolite or residue thereof. In certain embodiments, the compounds are antisense oligonucleotides. In certain embodiments, the compounds are oligomeric compounds. In certain embodiments, the compound comprises or consists of one or more modified oligonucleotide. Accordingly, for example, the disclosure is also drawn to pharmaceutically acceptable salts of compounds, prodrugs, pharmaceutically acceptable salts of such prodrugs, and other bioequivalents. Suitable pharmaceutically acceptable salts include, but are not limited to, sodium and potassium salts. A prodrug can include the incorporation of additional nucleosides at one or both ends of a compound which are cleaved by endogenous nucleases within the body, to form the active compound. In certain embodiments, the compounds or compositions further comprise a pharmaceutically acceptable carrier or diluent. 
     Examples 
     The following examples describe the process to identify lead compounds targeted to PKK. Certain compounds are distinguished as having high potency and tolerability. 
     The following examples serve only to illustrate the compounds described herein and are not intended to limit the same. The following examples and related sequence listing accompanying this filing may identify sequence as either “RNA” or “DNA”; however, as disclosed herein, those sequences may be modified with any combination of chemical modifications. One of skill in the art will readily appreciate that the designation of a sequence as “RNA” or “DNA” is, in certain instances, arbitrary. For example, an oligonucleotide comprising a nucleoside comprising a 2′-OH sugar moiety and a thymine base could be described as a DNA having a modified sugar (2′-OH for the natural 2′-H of DNA) or as an RNA having a modified base (methylated uracil for natural uracil of RNA). Accordingly, nucleic acid sequences provided herein, including, but not limited to, those in the sequence listing, are intended to encompass nucleic acids containing any combination of natural or modified RNA and/or DNA, including, but not limited to, such nucleic acids having modified nucleobases. 
     Each of the references recited in the present application is incorporated herein by reference in its entirety. 
     Unless otherwise indicated in a separate compound chemistry table below, compounds are unmodified. Abbreviations for chemical modifications are provided in Table 1 below. IA and IS in a Ref ID NO:, identifies an antisense strand and sense strand of a compound, respectively. 
     
       
         
           
               
             
               
                 TABLE 1 
               
             
            
               
                   
               
               
                 Chemical Nomenclature 
               
            
           
           
               
               
            
               
                 Abbreviation 
                 Structure 
               
               
                   
               
               
                 ‘m’ 
                 2′-O-methyl sugar modification (e.g., mA, mG, mC, mU) 
               
               
                 ‘f’ 
                 2′-F sugar modification (e.g., fA, fG, fC, fU) 
               
               
                 ‘*’ 
                 Phosphorothioate intemucleoside linkage 
               
               
                 ‘.’ 
                 Phosphate internucleoside linkage 
               
               
                 ‘dQ’ 
                 Inverted abasic deoxyribose 
               
               
                 ‘H1’ 
                 Formula I 
               
               
                 ‘H2’ 
                 Formula II 
               
               
                 ‘H4” 
                 Formula III 
               
               
                 ‘H6” 
                 Formula IV 
               
               
                 ‘H7’ 
                 Formula V 
               
               
                 ‘H9’ 
                 Formula VI 
               
               
                 ‘Hd’ 
                 Formula VII 
               
               
                 Hl 
                 Formula VIII 
               
               
                   
               
            
           
         
       
     
     Example 1—Inhibition of PKK in HEK-293T Cells 
     HEK-293T cells were seeded in antibiotic-free media at 20,000 cells/well in white-walled 96-well plates. The following day, the cells were co-transfected with 50 ng of PKK-siCHECK-2 and 10 nM PKK compound using Lipofectamine 2000 (each transfection was performed in triplicate). The cells were then incubated at 37° C./5% CO 2  for 48 hours. 
     Dual-Luciferase Reporter 1000 Assay (Promega Cat #E1980) was used to evaluate expression offirefly and  renilla  luciferase according to kit instructions. Firefly and  renilla  luciferase expression were measured using a luminimeter.  Renilla  luciferase was the readout for PKK gene expression while firefly served as the internal control. All  renillla  readings from each well were normalized to its corresponding firefly reading to obtain a  renilla :firefly ratio. The ratios obtained for each well of transfected compound were then further normalized to the ratios obtained for cells that were not transfected with compound. These untransfected cells served as the 100% control. PKK inhibition was determined by comparing PKK expression to the untransfected cells and reported as % PKK inhibition (Tables 2-4). 
     
       
         
           
               
             
               
                 TABLE 2 
               
             
            
               
                   
               
               
                 Inhibition of PKK mRNA by double-stranded compounds targeting SEQ ID NO: 1 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                 Seq 
                 SEQ 
                   
                   
                   
                   
                   
               
               
                   
                 ID 
                 ID 
                   
                   
                   
                   
                 PKK 
               
               
                   
                 NO: 1 
                 NO: 1 
                   
                 SEQ 
                   
                 SEQ 
                 % 
               
               
                 Compound 
                 Start 
                 Stop 
                 Antisense Sequence 
                 ID 
                 Sense Sequence 
                 ID 
                 inhi- 
               
               
                 Number 
                 Site 
                 Site 
                 (5′-3′) 
                 NO: 
                 (5′-3′) 
                 NO: 
                 bition 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 RD1839 
                 171 
                 191 
                 UUACAUCCCCACCUCUGAAGA 
                 10 
                 UCUUCAGAGGUGGGGAUGUAA 
                 314 
                 70 
               
               
                   
               
               
                 RD1840 
                 172 
                 192 
                 UCUACAUCCCCACCUCUGAAG 
                 11 
                 CUUCAGAGGUGGGGAUGUAGA 
                 315 
                 56 
               
               
                   
               
               
                 RD1841 
                 173 
                 193 
                 AGCUACAUCCCCACCUCUGAA 
                 12 
                 UUCAGAGGUGGGGAUGUAGCU 
                 316 
                 34 
               
               
                   
               
               
                 RD1842 
                 174 
                 194 
                 AAGCUACAUCCCCACCUCUGA 
                 13 
                 UCAGAGGUGGGGAUGUAGCUU 
                 317 
                 53 
               
               
                   
               
               
                 RD1843 
                 175 
                 195 
                 UAAGCUACAUCCCCACCUCUG 
                 14 
                 CAGAGGUGGGGAUGUAGCUUA 
                 318 
                 64 
               
               
                   
               
               
                 RD1844 
                 176 
                 196 
                 UGAAGCUACAUCCCCACCUCU 
                 15 
                 AGAGGUGGGGAUGUAGCUUCA 
                 319 
                 71 
               
               
                   
               
               
                 RD1845 
                 177 
                 197 
                 UGGAAGCUACAUCCCCACCUC 
                 16 
                 GAGGUGGGGAUGUAGCUUCCA 
                 320 
                 70 
               
               
                   
               
               
                 RD1846 
                 178 
                 198 
                 AUGGAAGCUACAUCCCCACCU 
                 17 
                 AGGUGGGGAUGUAGCUUCCAU 
                 321 
                 81 
               
               
                   
               
               
                 RD1847 
                 179 
                 199 
                 UAUGGAAGCUACAUCCCCACC 
                 18 
                 GGUGGGGAUGUAGCUUCCAUA 
                 322 
                 74 
               
               
                   
               
               
                 RD1848 
                 180 
                 200 
                 ACAUGGAAGCUACAUCCCCAC 
                 19 
                 GUGGGGAUGUAGCUUCCAUGU 
                 323 
                 64 
               
               
                   
               
               
                 RD1849 
                 181 
                 201 
                 UACAUGGAAGCUACAUCCCCA 
                 20 
                 UGGGGAUGUAGCUUCCAUGUA 
                 324 
                 74 
               
               
                   
               
               
                 RD1850 
                 182 
                 202 
                 UUACAUGGAAGCUACAUCCCC 
                 21 
                 GGGGAUGUAGCUUCCAUGUAA 
                 325 
                 70 
               
               
                   
               
               
                 RD1851 
                 232 
                 252 
                 UACCUUGGGUGGAAUGUGCAC 
                 22 
                 GUGCACAUUCCACCCAAGGUA 
                 326 
                 77 
               
               
                   
               
               
                 RD1852 
                 233 
                 253 
                 ACACCUUGGGUGGAAUGUGCA 
                 23 
                 UGCACAUUCCACCCAAGGUGU 
                 327 
                 62 
               
               
                   
               
               
                 RD1853 
                 234 
                 254 
                 AACACCUUGGGUGGAAUGUGC 
                 24 
                 GCACAUUCCACCCAAGGUGUU 
                 328 
                 72 
               
               
                   
               
               
                 RD1854 
                 237 
                 257 
                 UCAAACACCUUGGGUGGAAUG 
                 25 
                 CAUUCCACCCAAGGUGUUUGA 
                 329 
                 61 
               
               
                   
               
               
                 RD1855 
                 238 
                 258 
                 AGCAAACACCUUGGGUGGAAU 
                 26 
                 AUUCCACCCAAGGUGUUUGCU 
                 330 
                 51 
               
               
                   
               
               
                 RD1856 
                 241 
                 261 
                 AAUAGCAAACACCUUGGGUGG 
                 27 
                 CCACCCAAGGUGUUUGCUAUU 
                 331 
                 82 
               
               
                   
               
               
                 RD1857 
                 242 
                 262 
                 UAAUAGCAAACACCUUGGGUG 
                 28 
                 CACCCAAGGUGUUUGCUAUUA 
                 332 
                 62 
               
               
                   
               
               
                 RD1858 
                 243 
                 263 
                 UGAAUAGCAAACACCUUGGGU 
                 29 
                 ACCCAAGGUGUUUGCUAUUCA 
                 333 
                 91 
               
               
                   
               
               
                 RD1859 
                 245 
                 265 
                 ACUGAAUAGCAAACACCUUGG 
                 30 
                 CCAAGGUGUUUGCUAUUCAGU 
                 334 
                 91 
               
               
                   
               
               
                 RD1860 
                 246 
                 266 
                 AACUGAAUAGCAAACACCUUG 
                 31 
                 CAAGGUGUUUGCUAUUCAGUU 
                 335 
                 94 
               
               
                   
               
               
                 RD1861 
                 247 
                 267 
                 AAACUGAAUAGCAAACACCUU 
                 32 
                 AAGGUGUUUGCUAUUCAGUUU 
                 336 
                 90 
               
               
                   
               
               
                 RD1862 
                 248 
                 268 
                 AAAACUGAAUAGCAAACACCU 
                 33 
                 AGGUGUUUGCUAUUCAGUUUU 
                 337 
                 91 
               
               
                   
               
               
                 RD1863 
                 249 
                 269 
                 UAAAACUGAAUAGCAAACACC 
                 34 
                 GGUGUUUGCUAUUCAGUUUUA 
                 338 
                 92 
               
               
                   
               
               
                 RD1864 
                 250 
                 270 
                 AGAAAACUGAAUAGCAAACAC 
                 35 
                 GUGUUUGCUAUUCAGUUUUCU 
                 339 
                 90 
               
               
                   
               
               
                 RD1865 
                 254 
                 274 
                 UGGAAGAAAACUGAAUAGCAA 
                 36 
                 UUGCUAUUCAGUUUUCUUCCA 
                 340 
                 91 
               
               
                   
               
               
                 RD1866 
                 262 
                 282 
                 UAACUUGCUGGAAGAAAACUG 
                 37 
                 CAGUUUUCUUCCAGCAAGUUA 
                 341 
                 89 
               
               
                   
               
               
                 RD1867 
                 284 
                 304 
                 UCUUUUCUCCAUGUCAUUGAU 
                 38 
                 AUCAAUGACAUGGAGAAAAGA 
                 342 
                 93 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 3 
               
             
            
               
                   
               
               
                 Inhibition of PKK mRNA by double-stranded compounds targeting SEQ ID NO: 1 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                 Seq 
                 SEQ 
                   
                   
                   
                   
                   
               
               
                   
                 ID 
                 ID 
                   
                   
                   
                   
                 PKK 
               
               
                   
                 NO: 1 
                 NO: 1 
                   
                 SEQ 
                   
                 SEQ 
                 % 
               
               
                 Compound 
                 Start 
                 Stop 
                 Antisense Sequence 
                 ID 
                 Sense Sequence 
                 ID 
                 inhi- 
               
               
                 Number 
                 Site 
                 Site 
                 (5′-3′) 
                 NO: 
                 (5′-3′) 
                 NO: 
                 bition 
               
               
                   
               
               
                 RD1868 
                 287 
                 307 
                 AAACCUUUUCUCCAUGUCAUU 
                 39 
                 AAUGACAUGGAGAAAAGGUUU 
                 343 
                 65 
               
               
                   
               
               
                 RD1869 
                 288 
                 308 
                 UAAACCUUUUCUCCAUGUCAU 
                 40 
                 AUGACAUGGAGAAAAGGUUUA 
                 344 
                 44 
               
               
                   
               
               
                 RD1870 
                 484 
                 504 
                 UACCUUUUUUGGCAUUCUUCA 
                 41 
                 UGAAGAAUGCCAAAAAAGGUA 
                 345 
                 66 
               
               
                   
               
               
                 RD1871 
                 489 
                 509 
                 UGGUGCACCUUUUUUGGCAUU 
                 42 
                 AAUGCCAAAAAAGGUGCACCA 
                 346 
                 45 
               
               
                   
               
               
                 RD1872 
                 662 
                 682 
                 ACCAAUUUCUGAAAGGGCACA 
                 43 
                 UGUGCCCUUUCAGAAAUUGGU 
                 347 
                 66 
               
               
                   
               
               
                 RD1873 
                 663 
                 683 
                 AACCAAUUUCUGAAAGGGCAC 
                 44 
                 GUGCCCUUUCAGAAAUUGGUU 
                 348 
                 50 
               
               
                   
               
               
                 RD1874 
                 691 
                 711 
                 UCAAGAUGCUGGAAGAUGUUC 
                 45 
                 GAACAUCUUCCAGCAUCUUGA 
                 349 
                 49 
               
               
                   
               
               
                 RD1875 
                 867 
                 887 
                 AGGAACUUGGUGUGCCACUUU 
                 46 
                 AAAGUGGCACACCAAGUUCCU 
                 350 
                 17 
               
               
                   
               
               
                 RD1876 
                 868 
                 888 
                 UAGGAACUUGGUGUGCCACUU 
                 47 
                 AAGUGGCACACCAAGUUCCUA 
                 351 
                 52 
               
               
                   
               
               
                 RD1877 
                 869 
                 889 
                 AGAGGAACUUGGUGUGCCACU 
                 48 
                 AGUGGCACACCAAGUUCCUCU 
                 352 
                 70 
               
               
                   
               
               
                 RD1878 
                 870 
                 890 
                 UAGAGGAACUUGGUGUGCCAC 
                 49 
                 GUGGCACACCAAGUUCCUCUA 
                 353 
                 68 
               
               
                   
               
               
                 RD1879 
                 871 
                 891 
                 UUAGAGGAACUUGGUGUGCCA 
                 50 
                 UGGCACACCAAGUUCCUCUAA 
                 354 
                 38 
               
               
                   
               
               
                 RD1880 
                 876 
                 896 
                 UAGGAGUAGAGGAACUUGGUG 
                 51 
                 CACCAAGUUCCUCUACUCCUA 
                 355 
                 75 
               
               
                   
               
               
                 RD1881 
                 877 
                 897 
                 UGAGGAGUAGAGGAACUUGGU 
                 52 
                 ACCAAGUUCCUCUACUCCUCA 
                 356 
                 69 
               
               
                   
               
               
                 RD1882 
                 878 
                 898 
                 UUGAGGAGUAGAGGAACUUGG 
                 53 
                 CCAAGUUCCUCUACUCCUCAA 
                 357 
                 85 
               
               
                   
               
               
                 RD1883 
                 879 
                 899 
                 UUUGAGGAGUAGAGGAACUUG 
                 54 
                 CAAGUUCCUCUACUCCUCAAA 
                 358 
                 82 
               
               
                   
               
               
                 RD1884 
                 880 
                 900 
                 UCUUGAGGAGUAGAGGAACUU 
                 55 
                 AAGUUCCUCUACUCCUCAAGA 
                 359 
                 69 
               
               
                   
               
               
                 RD1885 
                 881 
                 901 
                 UUCUUGAGGAGUAGAGGAACU 
                 56 
                 AGUUCCUCUACUCCUCAAGAA 
                 360 
                 68 
               
               
                   
               
               
                 RD1886 
                 882 
                 902 
                 UUUCUUGAGGAGUAGAGGAAC 
                 57 
                 GUUCCUCUACUCCUCAAGAAA 
                 361 
                 63 
               
               
                   
               
               
                 RD1887 
                 883 
                 903 
                 UUUUCUUGAGGAGUAGAGGAA 
                 58 
                 UUCCUCUACUCCUCAAGAAAA 
                 362 
                 71 
               
               
                   
               
               
                 RD1888 
                 886 
                 906 
                 UUGUUUUCUUGAGGAGUAGAG 
                 59 
                 CUCUACUCCUCAAGAAAACAA 
                 363 
                 64 
               
               
                   
               
               
                 RD1889 
                 887 
                 907 
                 UGUGUUUUCUUGAGGAGUAGA 
                 60 
                 UCUACUCCUCAAGAAAACACA 
                 364 
                 75 
               
               
                   
               
               
                 RD1890 
                 888 
                 908 
                 UGGUGUUUUCUUGAGGAGUAG 
                 61 
                 CUACUCCUCAAGAAAACACCA 
                 365 
                 88 
               
               
                   
               
               
                 RD1891 
                 920 
                 940 
                 UCUUUUGCAGGUUAAAAGGCU 
                 62 
                 AGCCUUUUAACCUGCAAAAGA 
                 366 
                 88 
               
               
                   
               
               
                 RD1892 
                 936 
                 956 
                 AGGGUUCAGGUAAAGUUCUUU 
                 63 
                 AAAGAACUUUACCUGAACCCU 
                 367 
                 58 
               
               
                   
               
               
                 RD1893 
                 937 
                 957 
                 UAGGGUUCAGGUAAAGUUCUU 
                 64 
                 AAGAACUUUACCUGAACCCUA 
                 368 
                 83 
               
               
                   
               
               
                 RD1894 
                 938 
                 958 
                 UCAGGGUUCAGGUAAAGUUCU 
                 65 
                 AGAACUUUACCUGAACCCUGA 
                 369 
                 78 
               
               
                   
               
               
                 RD1895 
                 939 
                 959 
                 UGCAGGGUUCAGGUAAAGUUC 
                 66 
                 GAACUUUACCUGAACCCUGCA 
                 370 
                 76 
               
               
                   
               
               
                 RD1924 
                 1060 
                 1080 
                 UAAGUGAAAAACUGACAGCGA 
                 95 
                 UCGCUGUCAGUUUUUCACUUA 
                 399 
                 77 
               
               
                   
               
               
                 RD1925 
                 1061 
                 1081 
                 AUAAGUGAAAAACUGACAGCG 
                 96 
                 CGCUGUCAGUUUUUCACUUAU 
                 400 
                 73 
               
               
                   
               
               
                 RD1926 
                 1062 
                 1082 
                 AAUAAGUGAAAAACUGACAGC 
                 97 
                 GCUGUCAGUUUUUCACUUAUU 
                 401 
                 81 
               
               
                   
               
               
                 RD1927 
                 1065 
                 1085 
                 AAGAAUAAGUGAAAAACUGAC 
                 98 
                 GUCAGUUUUUCACUUAUUCUU 
                 402 
                 58 
               
               
                   
               
               
                 RD1928 
                 1066 
                 1086 
                 AAAGAAUAAGUGAAAAACUGA 
                 99 
                 UCAGUUUUUCACUUAUUCUUU 
                 403 
                 43 
               
               
                   
               
               
                 RD1929 
                 1070 
                 1090 
                 UAGUAAAGAAUAAGUGAAAAA 
                 100 
                 UUUUUCACUUAUUCUUUACUA 
                 404 
                 0 
               
               
                   
               
               
                 RD1930 
                 1071 
                 1091 
                 UGAGUAAAGAAUAAGUGAAAA 
                 101 
                 UUUUCACUUAUUCUUUACUCA 
                 405 
                 4 
               
               
                   
               
               
                 RD1931 
                 1072 
                 1092 
                 UGGAGUAAAGAAUAAGUGAAA 
                 102 
                 UUUCACUUAUUCUUUACUCCA 
                 406 
                 8 
               
               
                   
               
               
                 RD1932 
                 1073 
                 1093 
                 UGGGAGUAAAGAAUAAGUGAA 
                 103 
                 UUCACUUAUUCUUUACUCCCA 
                 407 
                 65 
               
               
                   
               
               
                 RD1933 
                 1074 
                 1094 
                 UUGGGAGUAAAGAAUAAGUGA 
                 104 
                 UCACUUAUUCUUUACUCCCAA 
                 408 
                 75 
               
               
                   
               
               
                 RD1934 
                 1075 
                 1095 
                 UCUGGGAGUAAAGAAUAAGUG 
                 105 
                 CACUUAUUCUUUACUCCCAGA 
                 409 
                 85 
               
               
                   
               
               
                 RD1935 
                 1076 
                 1096 
                 UUCUGGGAGUAAAGAAUAAGU 
                 106 
                 ACUUAUUCUUUACUCCCAGAA 
                 410 
                 69 
               
               
                   
               
               
                 RD1936 
                 1077 
                 1097 
                 UUUCUGGGAGUAAAGAAUAAG 
                 107 
                 CUUAUUCUUUACUCCCAGAAA 
                 411 
                 75 
               
               
                   
               
               
                 RD1937 
                 1078 
                 1098 
                 UCUUCUGGGAGUAAAGAAUAA 
                 108 
                 UUAUUCUUUACUCCCAGAAGA 
                 412 
                 55 
               
               
                   
               
               
                 RD1938 
                 1080 
                 1100 
                 AGUCUUCUGGGAGUAAAGAAU 
                 109 
                 AUUCUUUACUCCCAGAAGACU 
                 413 
                 53 
               
               
                   
               
               
                 RD1939 
                 1081 
                 1101 
                 UAGUCUUCUGGGAGUAAAGAA 
                 110 
                 UUCUUUACUCCCAGAAGACUA 
                 414 
                 58 
               
               
                   
               
               
                 RD1940 
                 1085 
                 1105 
                 UUUACAGUCUUCUGGGAGUAA 
                 111 
                 UUACUCCCAGAAGACUGUAAA 
                 415 
                 75 
               
               
                   
               
               
                 RD1941 
                 1086 
                 1106 
                 UCUUACAGUCUUCUGGGAGUA 
                 112 
                 UACUCCCAGAAGACUGUAAGA 
                 416 
                 80 
               
               
                   
               
               
                 RD1942 
                 1087 
                 1107 
                 UCCUUACAGUCUUCUGGGAGU 
                 113 
                 ACUCCCAGAAGACUGUAAGGA 
                 417 
                 53 
               
               
                   
               
               
                 RD1943 
                 1109 
                 1129 
                 UAAGAAACACUUACACUUCUC 
                 114 
                 GAGAAGUGUAAGUGUUUCUUA 
                 418 
                 85 
               
               
                   
               
               
                 RD1944 
                 1110 
                 1130 
                 UUAAGAAACACUUACACUUCU 
                 115 
                 AGAAGUGUAAGUGUUUCUUAA 
                 419 
                 87 
               
               
                   
               
               
                 RD1945 
                 1111 
                 1131 
                 UUUAAGAAACACUUACACUUC 
                 116 
                 GAAGUGUAAGUGUUUCUUAAA 
                 420 
                 77 
               
               
                   
               
               
                 RD1946 
                 1117 
                 1137 
                 UAUAAUCUUAAGAAACACUUA 
                 117 
                 UAAGUGUUUCUUAAGAUUAUA 
                 421 
                 84 
               
               
                   
               
               
                 RD1947 
                 1141 
                 1161 
                 AUCCUAGUUGGAGAACCAUCC 
                 118 
                 GGAUGGUUCUCCAACUAGGAU 
                 422 
                 77 
               
               
                   
               
               
                 RD1948 
                 1142 
                 1162 
                 AAUCCUAGUUGGAGAACCAUC 
                 119 
                 GAUGGUUCUCCAACUAGGAUU 
                 423 
                 82 
               
               
                   
               
               
                 RD1949 
                 1167 
                 1187 
                 UAGAGCUCCCUUGUGUCCCAU 
                 120 
                 AUGGGACACAAGGGAGCUCUA 
                 424 
                 86 
               
               
                   
               
               
                 RD1950 
                 1168 
                 1188 
                 UCAGAGCUCCCUUGUGUCCCA 
                 121 
                 UGGGACACAAGGGAGCUCUGA 
                 425 
                 73 
               
               
                   
               
               
                 RD1951 
                 1170 
                 1190 
                 AACCAGAGCUCCCUUGUGUCC 
                 122 
                 GGACACAAGGGAGCUCUGGUU 
                 426 
                 74 
               
               
                   
               
               
                 RD1952 
                 1171 
                 1191 
                 UAACCAGAGCUCCCUUGUGUC 
                 123 
                 GACACAAGGGAGCUCUGGUUA 
                 427 
                 32 
               
               
                   
               
               
                 RD1953 
                 1172 
                 1192 
                 UUAACCAGAGCUCCCUUGUGU 
                 124 
                 ACACAAGGGAGCUCUGGUUAA 
                 428 
                 64 
               
               
                   
               
               
                 RD1954 
                 1174 
                 1194 
                 UAGUAACCAGAGCUCCCUUGU 
                 125 
                 ACAAGGGAGCUCUGGUUACUA 
                 429 
                 78 
               
               
                   
               
               
                 RD1955 
                 1175 
                 1195 
                 AGAGUAACCAGAGCUCCCUUG 
                 126 
                 CAAGGGAGCUCUGGUUACUCU 
                 430 
                 81 
               
               
                   
               
               
                 RD1956 
                 1179 
                 1199 
                 UCAAAGAGUAACCAGAGCUCC 
                 127 
                 GGAGCUCUGGUUACUCUUUGA 
                 431 
                 61 
               
               
                   
               
               
                 RD1957 
                 1196 
                 1216 
                 UCCAGUGUUACACAAUCUCAA 
                 128 
                 UUGAGAUUGUGUAACACUGGA 
                 432 
                 85 
               
               
                   
               
               
                 RD1958 
                 1197 
                 1217 
                 UCCCAGUGUUACACAAUCUCA 
                 129 
                 UGAGAUUGUGUAACACUGGGA 
                 433 
                 71 
               
               
                   
               
               
                 RD1959 
                 1200 
                 1220 
                 UGUCCCCAGUGUUACACAAUC 
                 130 
                 GAUUGUGUAACACUGGGGACA 
                 434 
                 70 
               
               
                   
               
               
                 RD1960 
                 1261 
                 1281 
                 UCCCAAGAAGAGUUUGUUCCU 
                 131 
                 AGGAACAAACUCUUCUUGGGA 
                 435 
                 37 
               
               
                   
               
               
                 RD1961 
                 1262 
                 1282 
                 UCCCCAAGAAGAGUUUGUUCC 
                 132 
                 GGAACAAACUCUUCUUGGGGA 
                 436 
                 40 
               
               
                   
               
               
                 RD1962 
                 1263 
                 1283 
                 UUCCCCAAGAAGAGUUUGUUC 
                 133 
                 GAACAAACUCUUCUUGGGGAA 
                 437 
                 25 
               
               
                   
               
               
                 RD1963 
                 1264 
                 1284 
                 UCUCCCCAAGAAGAGUUUGUU 
                 134 
                 AACAAACUCUUCUUGGGGAGA 
                 438 
                 2 
               
               
                   
               
               
                 RD1964 
                 1265 
                 1285 
                 UUCUCCCCAAGAAGAGUUUGU 
                 135 
                 ACAAACUCUUCUUGGGGAGAA 
                 439 
                 0 
               
               
                   
               
               
                 RD1965 
                 1266 
                 1286 
                 ACUCUCCCCAAGAAGAGUUUG 
                 136 
                 CAAACUCUUCUUGGGGAGAGU 
                 440 
                 0 
               
               
                   
               
               
                 RD1966 
                 1268 
                 1288 
                 UCACUCUCCCCAAGAAGAGUU 
                 137 
                 AACUCUUCUUGGGGAGAGUGA 
                 441 
                 12 
               
               
                   
               
               
                 RD1967 
                 1269 
                 1289 
                 UCCACUCUCCCCAAGAAGAGU 
                 138 
                 ACUCUUCUUGGGGAGAGUGGA 
                 442 
                 8 
               
               
                   
               
               
                 RD1968 
                 1272 
                 1292 
                 AGGGCCACUCUCCCCAAGAAG 
                 139 
                 CUUCUUGGGGAGAGUGGCCCU 
                 443 
                 0 
               
               
                   
               
               
                 RD1969 
                 1273 
                 1293 
                 UAGGGCCACUCUCCCCAAGAA 
                 140 
                 UUCUUGGGGAGAGUGGCCCUA 
                 444 
                 11 
               
               
                   
               
               
                 RD1970 
                 1274 
                 1294 
                 UCAGGGCCACUCUCCCCAAGA 
                 141 
                 UCUUGGGGAGAGUGGCCCUGA 
                 445 
                 42 
               
               
                   
               
               
                 RD1971 
                 1343 
                 1363 
                 UUGGUGUCCUAUGAGUGACCC 
                 142 
                 GGGUCACUCAUAGGACACCAA 
                 446 
                 60 
               
               
                   
               
               
                 RD1972 
                 1344 
                 1364 
                 ACUGGUGUCCUAUGAGUGACC 
                 143 
                 GGUCACUCAUAGGACACCAGU 
                 447 
                 37 
               
               
                   
               
               
                 RD1973 
                 1347 
                 1367 
                 UCCACUGGUGUCCUAUGAGUG 
                 144 
                 CACUCAUAGGACACCAGUGGA 
                 448 
                 43 
               
               
                   
               
               
                 RD1974 
                 1348 
                 1368 
                 ACCCACUGGUGUCCUAUGAGU 
                 145 
                 ACUCAUAGGACACCAGUGGGU 
                 449 
                 8 
               
               
                   
               
               
                 RD1975 
                 1349 
                 1369 
                 UACCCACUGGUGUCCUAUGAG 
                 146 
                 CUCAUAGGACACCAGUGGGUA 
                 450 
                 59 
               
               
                   
               
               
                 RD1976 
                 1381 
                 1401 
                 UGAAGCCCAUCAAAGCAGUGG 
                 147 
                 CCACUGCUUUGAUGGGCUUCA 
                 451 
                 77 
               
               
                   
               
               
                 RD1977 
                 1425 
                 1445 
                 ACAGAUUUAAAAUGCCACUAU 
                 148 
                 AUAGUGGCAUUUUAAAUCUGU 
                 452 
                 78 
               
               
                   
               
               
                 RD1978 
                 1426 
                 1446 
                 UACAGAUUUAAAAUGCCACUA 
                 149 
                 UAGUGGCAUUUUAAAUCUGUA 
                 453 
                 91 
               
               
                   
               
               
                 RD1979 
                 1427 
                 1447 
                 UGACAGAUUUAAAAUGCCACU 
                 150 
                 AGUGGCAUUUUAAAUCUGUCA 
                 454 
                 90 
               
               
                   
               
               
                 RD1980 
                 1428 
                 1448 
                 UUGACAGAUUUAAAAUGCCAC 
                 151 
                 GUGGCAUUUUAAAUCUGUCAA 
                 455 
                 83 
               
               
                   
               
               
                 RD1981 
                 1429 
                 1449 
                 UCUGACAGAUUUAAAAUGCCA 
                 152 
                 UGGCAUUUUAAAUCUGUCAGA 
                 456 
                 90 
               
               
                   
               
               
                 RD1982 
                 1430 
                 1450 
                 UUCUGACAGAUUUAAAAUGCC 
                 153 
                 GGCAUUUUAAAUCUGUCAGAA 
                 457 
                 68 
               
               
                   
               
               
                 RD1983 
                 1431 
                 1451 
                 UGUCUGACAGAUUUAAAAUGC 
                 154 
                 GCAUUUUAAAUCUGUCAGACA 
                 458 
                 72 
               
               
                   
               
               
                 RD1984 
                 1436 
                 1456 
                 UGUAAUGUCUGACAGAUUUAA 
                 155 
                 UUAAAUCUGUCAGACAUUACA 
                 459 
                 92 
               
               
                   
               
               
                 RD1985 
                 1441 
                 1461 
                 UCUUUUGUAAUGUCUGACAGA 
                 156 
                 UCUGUCAGACAUUACAAAAGA 
                 460 
                 92 
               
               
                   
               
               
                 RD1986 
                 1513 
                 1533 
                 AUAUCAUGAUUCCCUUCUGAG 
                 157 
                 CUCAGAAGGGAAUCAUGAUAU 
                 461 
                 63 
               
               
                   
               
               
                 RD1987 
                 1516 
                 1536 
                 UCGAUAUCAUGAUUCCCUUCU 
                 158 
                 AGAAGGGAAUCAUGAUAUCGA 
                 462 
                 71 
               
               
                   
               
               
                 RD1988 
                 1517 
                 1537 
                 UGCGAUAUCAUGAUUCCCUUC 
                 159 
                 GAAGGGAAUCAUGAUAUCGCA 
                 463 
                 80 
               
               
                   
               
               
                 RD1989 
                 1518 
                 1538 
                 AGGCGAUAUCAUGAUUCCCUU 
                 160 
                 AAGGGAAUCAUGAUAUCGCCU 
                 464 
                 77 
               
               
                   
               
               
                 RD1990 
                 1545 
                 1565 
                 AAUUCAAAGGAGCCUGGAGUU 
                 161 
                 AACUCCAGGCUCCUUUGAAUU 
                 465 
                 61 
               
               
                   
               
               
                 RD1991 
                 1546 
                 1566 
                 UAAUUCAAAGGAGCCUGGAGU 
                 162 
                 ACUCCAGGCUCCUUUGAAUUA 
                 466 
                 55 
               
               
                   
               
               
                 RD1992 
                 1547 
                 1567 
                 UUAAUUCAAAGGAGCCUGGAG 
                 163 
                 CUCCAGGCUCCUUUGAAUUAA 
                 467 
                 65 
               
               
                   
               
               
                 RD1993 
                 1548 
                 1568 
                 UGUAAUUCAAAGGAGCCUGGA 
                 164 
                 UCCAGGCUCCUUUGAAUUACA 
                 468 
                 51 
               
               
                   
               
               
                 RD1994 
                 1549 
                 1569 
                 UUGUAAUUCAAAGGAGCCUGG 
                 165 
                 CCAGGCUCCUUUGAAUUACAA 
                 469 
                 82 
               
               
                   
               
               
                 RD1995 
                 1550 
                 1570 
                 AGUGUAAUUCAAAGGAGCCUG 
                 166 
                 CAGGCUCCUUUGAAUUACACU 
                 470 
                 74 
               
               
                   
               
               
                 RD1996 
                 1551 
                 1571 
                 UAGUGUAAUUCAAAGGAGCCU 
                 167 
                 AGGCUCCUUUGAAUUACACUA 
                 471 
                 80 
               
               
                   
               
               
                 RD1997 
                 1552 
                 1572 
                 UCAGUGUAAUUCAAAGGAGCC 
                 168 
                 GGCUCCUUUGAAUUACACUGA 
                 472 
                 71 
               
               
                   
               
               
                 RD1998 
                 1557 
                 1577 
                 UGAAUUCAGUGUAAUUCAAAG 
                 169 
                 CUUUGAAUUACACUGAAUUCA 
                 473 
                 0 
               
               
                   
               
               
                 RD1999 
                 1567 
                 1587 
                 AUUGGUUUUUGGAAUUCAGUG 
                 170 
                 CACUGAAUUCCAAAAACCAAU 
                 474 
                 88 
               
               
                   
               
               
                 RD2000 
                 1568 
                 1588 
                 UAUUGGUUUUUGGAAUUCAGU 
                 171 
                 ACUGAAUUCCAAAAACCAAUA 
                 475 
                 91 
               
               
                   
               
               
                 RD2001 
                 1570 
                 1590 
                 UAUAUUGGUUUUUGGAAUUCA 
                 172 
                 UGAAUUCCAAAAACCAAUAUA 
                 476 
                 77 
               
               
                   
               
               
                 RD2002 
                 1571 
                 1591 
                 UCAUAUUGGUUUUUGGAAUUC 
                 173 
                 GAAUUCCAAAAACCAAUAUGA 
                 477 
                 83 
               
               
                   
               
               
                 RD2003 
                 1575 
                 1595 
                 UUAGGCAUAUUGGUUUUUGGA 
                 174 
                 UCCAAAAACCAAUAUGCCUAA 
                 478 
                 70 
               
               
                   
               
               
                 RD2004 
                 1576 
                 1596 
                 UGUAGGCAUAUUGGUUUUUGG 
                 175 
                 CCAAAAACCAAUAUGCCUACA 
                 479 
                 63 
               
               
                   
               
               
                 RD2005 
                 1577 
                 1597 
                 AGGUAGGCAUAUUGGUUUUUG 
                 176 
                 CAAAAACCAAUAUGCCUACCU 
                 480 
                 52 
               
               
                   
               
               
                 RD2006 
                 1578 
                 1598 
                 AAGGUAGGCAUAUUGGUUUUU 
                 177 
                 AAAAACCAAUAUGCCUACCUU 
                 481 
                 71 
               
               
                   
               
               
                 RD2007 
                 1579 
                 1599 
                 UAAGGUAGGCAUAUUGGUUUU 
                 178 
                 AAAACCAAUAUGCCUACCUUA 
                 482 
                 77 
               
               
                   
               
               
                 RD2008 
                 1580 
                 1600 
                 UGAAGGUAGGCAUAUUGGUUU 
                 179 
                 AAACCAAUAUGCCUACCUUCA 
                 483 
                 0 
               
               
                   
               
               
                 RD2009 
                 1581 
                 1601 
                 UGGAAGGUAGGCAUAUUGGUU 
                 180 
                 AACCAAUAUGCCUACCUUCCA 
                 484 
                 66 
               
               
                   
               
               
                 RD2010 
                 1588 
                 1608 
                 UCACCUUUGGAAGGUAGGCAU 
                 181 
                 AUGCCUACCUUCCAAAGGUGA 
                 485 
                 65 
               
               
                   
               
               
                 RD2011 
                 1591 
                 1611 
                 UUGUCACCUUUGGAAGGUAGG 
                 182 
                 CCUACCUUCCAAAGGUGACAA 
                 486 
                 37 
               
               
                   
               
               
                 RD2012 
                 1592 
                 1612 
                 UGUGUCACCUUUGGAAGGUAG 
                 183 
                 CUACCUUCCAAAGGUGACACA 
                 487 
                 57 
               
               
                   
               
               
                 RD2013 
                 1593 
                 1613 
                 UUGUGUCACCUUUGGAAGGUA 
                 184 
                 UACCUUCCAAAGGUGACACAA 
                 488 
                 22 
               
               
                   
               
               
                 RD2014 
                 1849 
                 1869 
                 UUGAUGCCCACCAAACGCCAC 
                 185 
                 GUGGCGUUUGGUGGGCAUCAA 
                 489 
                 18 
               
               
                   
               
               
                 RD2015 
                 1880 
                 1900 
                 UUCCCUGCGGGCACAGCCUUC 
                 186 
                 GAAGGCUGUGCCCGCAGGGAA 
                 490 
                 36 
               
               
                   
               
               
                 RD2016 
                 1889 
                 1909 
                 ACCAGGUUGCUCCCUGCGGGC 
                 187 
                 GCCCGCAGGGAGCAACCUGGU 
                 491 
                 −6 
               
               
                   
               
               
                 RD2017 
                 1890 
                 1910 
                 UACCAGGUUGCUCCCUGCGGG 
                 188 
                 CCCGCAGGGAGCAACCUGGUA 
                 492 
                 45 
               
               
                   
               
               
                 RD2018 
                 1891 
                 1911 
                 ACACCAGGUUGCUCCCUGCGG 
                 189 
                 CCGCAGGGAGCAACCUGGUGU 
                 493 
                 51 
               
               
                   
               
               
                 RD2019 
                 1892 
                 1912 
                 UACACCAGGUUGCUCCCUGCG 
                 190 
                 CGCAGGGAGCAACCUGGUGUA 
                 494 
                 51 
               
               
                   
               
               
                 RD2020 
                 1893 
                 1913 
                 AGACACCAGGUUGCUCCCUGC 
                 191 
                 GCAGGGAGCAACCUGGUGUCU 
                 495 
                 2 
               
               
                   
               
               
                 RD2021 
                 1894 
                 1914 
                 UAGACACCAGGUUGCUCCCUG 
                 192 
                 CAGGGAGCAACCUGGUGUCUA 
                 496 
                 67 
               
               
                   
               
               
                 RD2022 
                 1895 
                 1915 
                 UUAGACACCAGGUUGCUCCCU 
                 193 
                 AGGGAGCAACCUGGUGUCUAA 
                 497 
                 85 
               
               
                   
               
               
                 RD2023 
                 1896 
                 1916 
                 UGUAGACACCAGGUUGCUCCC 
                 194 
                 GGGAGCAACCUGGUGUCUACA 
                 498 
                 75 
               
               
                   
               
               
                 RD2024 
                 1897 
                 1917 
                 UUGUAGACACCAGGUUGCUCC 
                 195 
                 GGAGCAACCUGGUGUCUACAA 
                 499 
                 55 
               
               
                   
               
               
                 RD2025 
                 1907 
                 1927 
                 AGCGACUUUGGUGUAGACACC 
                 196 
                 GGUGUCUACACCAAAGUCGCU 
                 500 
                 66 
               
               
                   
               
               
                 RD2026 
                 1922 
                 1942 
                 UCAGUCCAUGUACUCAGCGAC 
                 197 
                 GUCGCUGAGUACAUGGACUGA 
                 501 
                 69 
               
               
                   
               
               
                 RD2027 
                 1923 
                 1943 
                 UCCAGUCCAUGUACUCAGCGA 
                 198 
                 UCGCUGAGUACAUGGACUGGA 
                 502 
                 71 
               
               
                   
               
               
                 RD2028 
                 1924 
                 1944 
                 AUCCAGUCCAUGUACUCAGCG 
                 199 
                 CGCUGAGUACAUGGACUGGAU 
                 503 
                 75 
               
               
                   
               
               
                 RD2029 
                 1941 
                 1961 
                 UCUGUGUUUUCUCUAAAAUCC 
                 200 
                 GGAUUUUAGAGAAAACACAGA 
                 504 
                 73 
               
               
                   
               
               
                 RD2030 
                 1942 
                 1962 
                 UUCUGUGUUUUCUCUAAAAUC 
                 201 
                 GAUUUUAGAGAAAACACAGAA 
                 505 
                 67 
               
               
                   
               
               
                 RD2031 
                 1943 
                 1963 
                 UCUCUGUGUUUUCUCUAAAAU 
                 202 
                 AUUUUAGAGAAAACACAGAGA 
                 506 
                 68 
               
               
                   
               
               
                 RD2032 
                 1944 
                 1964 
                 UGCUCUGUGUUUUCUCUAAAA 
                 203 
                 UUUUAGAGAAAACACAGAGCA 
                 507 
                 71 
               
               
                   
               
               
                 RD2033 
                 1945 
                 1965 
                 UUGCUCUGUGUUUUCUCUAAA 
                 204 
                 UUUAGAGAAAACACAGAGCAA 
                 508 
                 82 
               
               
                   
               
               
                 RD2034 
                 1950 
                 1970 
                 UAUCACUGCUCUGUGUUUUCU 
                 205 
                 AGAAAACACAGAGCAGUGAUA 
                 509 
                 72 
               
               
                   
               
               
                 RD2035 
                 1953 
                 1973 
                 UUCCAUCACUGCUCUGUGUUU 
                 206 
                 AAACACAGAGCAGUGAUGGAA 
                 510 
                 81 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 4 
               
             
            
               
                   
               
               
                 Inhibition of PKK mRNA by double-stranded compounds targeting SEQ ID NO: 1 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                 Seq 
                 SEQ 
                   
                   
                   
                   
                   
               
               
                   
                 ID 
                 ID 
                   
                   
                   
                   
                 PKK 
               
               
                   
                 NO: 1 
                 NO: 1 
                   
                 SEQ 
                   
                 SEQ 
                 % 
               
               
                 Compound 
                 Start 
                 Stop 
                 Antisense Sequence 
                 ID 
                 Sense Sequence 
                 ID 
                 inhi- 
               
               
                 Number 
                 Site 
                 Site 
                 (5′-3′) 
                 NO: 
                 (5′-3′) 
                 NO: 
                 bition 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 RD1896 
                 940 
                 960 
                 UGGCAGGGUUCAGGUAAAGUU 
                 67 
                 AACUUUACCUGAACCCUGCCA 
                 371 
                 44 
               
               
                   
               
               
                 RD1897 
                 941 
                 961 
                 AUGGCAGGGUUCAGGUAAAGU 
                 68 
                 ACUUUACCUGAACCCUGCCAU 
                 372 
                 41 
               
               
                   
               
               
                 RD1898 
                 943 
                 963 
                 UAAUGGCAGGGUUCAGGUAAA 
                 69 
                 UUUACCUGAACCCUGCCAUUA 
                 373 
                 75 
               
               
                   
               
               
                 RD1899 
                 944 
                 964 
                 AGAAUGGCAGGGUUCAGGUAA 
                 70 
                 UUACCUGAACCCUGCCAUUCU 
                 374 
                 67 
               
               
                   
               
               
                 RD1900 
                 945 
                 965 
                 UAGAAUGGCAGGGUUCAGGUA 
                 71 
                 UACCUGAACCCUGCCAUUCUA 
                 375 
                 73 
               
               
                   
               
               
                 RD1901 
                 946 
                 966 
                 UUAGAAUGGCAGGGUUCAGGU 
                 72 
                 ACCUGAACCCUGCCAUUCUAA 
                 376 
                 72 
               
               
                   
               
               
                 RD1902 
                 947 
                 967 
                 UUUAGAAUGGCAGGGUUCAGG 
                 73 
                 CCUGAACCCUGCCAUUCUAAA 
                 377 
                 79 
               
               
                   
               
               
                 RD1903 
                 948 
                 968 
                 UUUUAGAAUGGCAGGGUUCAG 
                 74 
                 CUGAACCCUGCCAUUCUAAAA 
                 378 
                 80 
               
               
                   
               
               
                 RD1904 
                 949 
                 969 
                 AUUUUAGAAUGGCAGGGUUCA 
                 75 
                 UGAACCCUGCCAUUCUAAAAU 
                 379 
                 79 
               
               
                   
               
               
                 RD1905 
                 950 
                 970 
                 AAUUUUAGAAUGGCAGGGUUC 
                 76 
                 GAACCCUGCCAUUCUAAAAUU 
                 380 
                 67 
               
               
                   
               
               
                 RD1906 
                 951 
                 971 
                 AAAUUUUAGAAUGGCAGGGUU 
                 77 
                 AACCCUGCCAUUCUAAAAUUU 
                 381 
                 57 
               
               
                   
               
               
                 RD1907 
                 952 
                 972 
                 UAAAUUUUAGAAUGGCAGGGU 
                 78 
                 ACCCUGCCAUUCUAAAAUUUA 
                 382 
                 74 
               
               
                   
               
               
                 RD1908 
                 953 
                 973 
                 UUAAAUUUUAGAAUGGCAGGG 
                 79 
                 CCCUGCCAUUCUAAAAUUUAA 
                 383 
                 84 
               
               
                   
               
               
                 RD1909 
                 954 
                 974 
                 UGUAAAUUUUAGAAUGGCAGG 
                 80 
                 CCUGCCAUUCUAAAAUUUACA 
                 384 
                 83 
               
               
                   
               
               
                 RD1910 
                 957 
                 977 
                 UCGGGUAAAUUUUAGAAUGGC 
                 81 
                 GCCAUUCUAAAAUUUACCCGA 
                 385 
                 81 
               
               
                   
               
               
                 RD1911 
                 958 
                 978 
                 UCCGGGUAAAUUUUAGAAUGG 
                 82 
                 CCAUUCUAAAAUUUACCCGGA 
                 386 
                 78 
               
               
                   
               
               
                 RD1912 
                 989 
                 1009 
                 UACAUUCAAUUCUUCUCCUCC 
                 83 
                 GGAGGAGAAGAAUUGAAUGUA 
                 387 
                 73 
               
               
                   
               
               
                 RD1913 
                 990 
                 1010 
                 UCACAUUCAAUUCUUCUCCUC 
                 84 
                 GAGGAGAAGAAUUGAAUGUGA 
                 388 
                 91 
               
               
                   
               
               
                 RD1914 
                 992 
                 1012 
                 AGUCACAUUCAAUUCUUCUCC 
                 85 
                 GGAGAAGAAUUGAAUGUGACU 
                 389 
                 77 
               
               
                   
               
               
                 RD1915 
                 1017 
                 1037 
                 UGCAAACAUUCACUCCUUUAA 
                 86 
                 UUAAAGGAGUGAAUGUUUGCA 
                 390 
                 85 
               
               
                   
               
               
                 RD1916 
                 1050 
                 1070 
                 ACUGACAGCGAAUCAUCUUUG 
                 87 
                 CAAAGAUGAUUCGCUGUCAGU 
                 391 
                 93 
               
               
                   
               
               
                 RD1917 
                 1051 
                 1071 
                 AACUGACAGCGAAUCAUCUUU 
                 88 
                 AAAGAUGAUUCGCUGUCAGUU 
                 392 
                 92 
               
               
                   
               
               
                 RD1918 
                 1052 
                 1072 
                 AAACUGACAGCGAAUCAUCUU 
                 89 
                 AAGAUGAUUCGCUGUCAGUUU 
                 393 
                 91 
               
               
                   
               
               
                 RD1919 
                 1053 
                 1073 
                 AAAACUGACAGCGAAUCAUCU 
                 90 
                 AGAUGAUUCGCUGUCAGUUUU 
                 394 
                 81 
               
               
                   
               
               
                 RD1920 
                 1054 
                 1074 
                 AAAAACUGACAGCGAAUCAUC 
                 91 
                 GAUGAUUCGCUGUCAGUUUUU 
                 395 
                 93 
               
               
                   
               
               
                 RD1921 
                 1057 
                 1077 
                 UUGAAAAACUGACAGCGAAUC 
                 92 
                 GAUUCGCUGUCAGUUUUUCAA 
                 396 
                 91 
               
               
                   
               
               
                 RD1922 
                 1058 
                 1078 
                 AGUGAAAAACUGACAGCGAAU 
                 93 
                 AUUCGCUGUCAGUUUUUCACU 
                 397 
                 85 
               
               
                   
               
               
                 RD1923 
                 1059 
                 1079 
                 AAGUGAAAAACUGACAGCGAA 
                 94 
                 UUCGCUGUCAGUUUUUCACUU 
                 398 
                 93 
               
               
                   
               
               
                 RD2036 
                 1954 
                 1974 
                 UUUCCAUCACUGCUCUGUGUU 
                 207 
                 AACACAGAGCAGUGAUGGAAA 
                 511 
                 69 
               
               
                   
               
               
                 RD2037 
                 2037 
                 2057 
                 UGCUCAGAAUUUGACUUGAAC 
                 208 
                 GUUCAAGUCAAAUUCUGAGCA 
                 512 
                 0 
               
               
                   
               
               
                 RD2038 
                 2038 
                 2058 
                 AGGCUCAGAAUUUGACUUGAA 
                 209 
                 UUCAAGUCAAAUUCUGAGCCU 
                 513 
                 0 
               
               
                   
               
               
                 RD2039 
                 2039 
                 2059 
                 UAGGCUCAGAAUUUGACUUGA 
                 210 
                 UCAAGUCAAAUUCUGAGCCUA 
                 514 
                 0 
               
               
                   
               
               
                 RD2040 
                 2040 
                 2060 
                 UCAGGCUCAGAAUUUGACUUG 
                 211 
                 CAAGUCAAAUUCUGAGCCUGA 
                 515 
                 0 
               
               
                   
               
               
                 RD2041 
                 2041 
                 2061 
                 UCCAGGCUCAGAAUUUGACUU 
                 212 
                 AAGUCAAAUUCUGAGCCUGGA 
                 516 
                 0 
               
               
                   
               
               
                 RD2042 
                 2043 
                 2063 
                 UCCCCAGGCUCAGAAUUUGAC 
                 213 
                 GUCAAAUUCUGAGCCUGGGGA 
                 517 
                 0 
               
               
                   
               
               
                 RD2043 
                 2067 
                 2087 
                 UCUCCAUGCUUUGCAGAUGAG 
                 214 
                 CUCAUCUGCAAAGCAUGGAGA 
                 518 
                 0 
               
               
                   
               
               
                 RD2044 
                 2070 
                 2090 
                 UACUCUCCAUGCUUUGCAGAU 
                 215 
                 AUCUGCAAAGCAUGGAGAGUA 
                 519 
                 0 
               
               
                   
               
               
                 RD2045 
                 2071 
                 2091 
                 UCACUCUCCAUGCUUUGCAGA 
                 216 
                 UCUGCAAAGCAUGGAGAGUGA 
                 520 
                 11 
               
               
                   
               
               
                 RD2046 
                 2072 
                 2092 
                 UCCACUCUCCAUGCUUUGCAG 
                 217 
                 CUGCAAAGCAUGGAGAGUGGA 
                 521 
                 16 
               
               
                   
               
               
                 RD2047 
                 2073 
                 2093 
                 UGCCACUCUCCAUGCUUUGCA 
                 218 
                 UGCAAAGCAUGGAGAGUGGCA 
                 522 
                 28 
               
               
                   
               
               
                 RD2048 
                 2074 
                 2094 
                 AUGCCACUCUCCAUGCUUUGC 
                 219 
                 GCAAAGCAUGGAGAGUGGCAU 
                 523 
                 28 
               
               
                   
               
               
                 RD2049 
                 2075 
                 2095 
                 UAUGCCACUCUCCAUGCUUUG 
                 220 
                 CAAAGCAUGGAGAGUGGCAUA 
                 524 
                 35 
               
               
                   
               
               
                 RD2050 
                 2076 
                 2096 
                 AGAUGCCACUCUCCAUGCUUU 
                 221 
                 AAAGCAUGGAGAGUGGCAUCU 
                 525 
                 0 
               
               
                   
               
               
                 RD2051 
                 2131 
                 2151 
                 UAUUGUCCUCAGCAGCUCUGA 
                 222 
                 UCAGAGCUGCUGAGGACAAUA 
                 526 
                 0 
               
               
                   
               
               
                 RD2064 
                 172 
                 192 
                 UCUACAUCCCCACUUCUGAAG 
                 223 
                 CUUCAGAAGUGGGGAUGUAGA 
                 527 
                 48 
               
               
                   
               
               
                 RD2065 
                 173 
                 193 
                 AGCUACAUCCCCAUCUCUGAA 
                 224 
                 UUCAGAGAUGGGGAUGUAGCU 
                 528 
                 45 
               
               
                   
               
               
                 RD2066 
                 175 
                 195 
                 UAAGCUACAUCCCUACCUCUG 
                 225 
                 CAGAGGUAGGGAUGUAGCUUA 
                 529 
                 47 
               
               
                   
               
               
                 RD2067 
                 176 
                 196 
                 UGAAGCUACAUCCUCACCUCU 
                 226 
                 AGAGGUGAGGAUGUAGCUUCA 
                 530 
                 65 
               
               
                   
               
               
                 RD2068 
                 177 
                 197 
                 UGGAAGCUACAUCUCCACCUC 
                 227 
                 GAGGUGGAGAUGUAGCUUCCA 
                 531 
                 66 
               
               
                   
               
               
                 RD2069 
                 178 
                 198 
                 AUGGAAGCUACAUUCCCACCU 
                 228 
                 AGGUGGGAAUGUAGCUUCCAU 
                 532 
                 83 
               
               
                   
               
               
                 RD2070 
                 181 
                 201 
                 UACAUGGAAGCUAUAUCCCCA 
                 229 
                 UGGGGAUAUAGCUUCCAUGUA 
                 533 
                 79 
               
               
                   
               
               
                 RD2071 
                 242 
                 262 
                 UAAUAGCAAACACUUUGGGUG 
                 230 
                 CACCCAAAGUGUUUGCUAUUA 
                 534 
                 10 
               
               
                   
               
               
                 RD2072 
                 243 
                 263 
                 UGAAUAGCAAACAUCUUGGGU 
                 231 
                 ACCCAAGAUGUUUGCUAUUCA 
                 535 
                 90 
               
               
                   
               
               
                 RD2073 
                 245 
                 265 
                 ACUGAAUAGCAAAUACCUUGG 
                 232 
                 CCAAGGUAUUUGCUAUUCAGU 
                 536 
                 82 
               
               
                   
               
               
                 RD2074 
                 249 
                 269 
                 UAAAACUGAAUAGUAAACACC 
                 233 
                 GGUGUUUACUAUUCAGUUUUA 
                 537 
                 74 
               
               
                   
               
               
                 RD2075 
                 288 
                 308 
                 UAAACCUUUUCUCUAUGUCAU 
                 234 
                 AUGACAUAGAGAAAAGGUUUA 
                 538 
                 48 
               
               
                   
               
               
                 RD2076 
                 312 
                 332 
                 UAACACUAUCUUUUAAGAAGC 
                 235 
                 GCUUCUUAAAAGAUAGUGUUA 
                 539 
                 0 
               
               
                   
               
               
                 RD2077 
                 316 
                 336 
                 UCUGUAACACUAUUUUUCAAG 
                 236 
                 CUUGAAAAAUAGUGUUACAGA 
                 540 
                 0 
               
               
                   
               
               
                 RD2078 
                 438 
                 458 
                 AAUUGACUCCUCUUAUAUCAA 
                 237 
                 UUGAUAUAAGAGGAGUCAAUU 
                 541 
                 85 
               
               
                   
               
               
                 RD2079 
                 440 
                 460 
                 AAAAUUGACUCCUUUCAUAUC 
                 238 
                 GAUAUGAAAGGAGUCAAUUUU 
                 542 
                 76 
               
               
                   
               
               
                 RD2080 
                 442 
                 462 
                 UUAAAAUUGACUCUUCUCAUA 
                 239 
                 UAUGAGAAGAGUCAAUUUUAA 
                 543 
                 63 
               
               
                   
               
               
                 RD2081 
                 443 
                 463 
                 AUUAAAAUUGACUUCUCUCAU 
                 240 
                 AUGAGAGAAGUCAAUUUUAAU 
                 544 
                 29 
               
               
                   
               
               
                 RD2082 
                 445 
                 465 
                 ACAUUAAAAUUGAUUCCUCUC 
                 241 
                 GAGAGGAAUCAAUUUUAAUGU 
                 545 
                 28 
               
               
                   
               
               
                 RD2083 
                 473 
                 493 
                 UCAUUCUUCAACAUUGCUAAC 
                 242 
                 GUUAGCAAUGUUGAAGAAUGA 
                 546 
                 82 
               
               
                   
               
               
                 RD2084 
                 475 
                 495 
                 UGGCAUUCUUCAAUACUGCUA 
                 243 
                 UAGCAGUAUUGAAGAAUGCCA 
                 547 
                 71 
               
               
                   
               
               
                 RD2085 
                 478 
                 498 
                 UUUUGGCAUUCUUUAACACUG 
                 244 
                 CAGUGUUAAAGAAUGCCAAAA 
                 548 
                 86 
               
               
                   
               
               
                 RD2086 
                 631 
                 651 
                 UAGAAUCCAGAUUUCACGUUA 
                 245 
                 UAACGUGAAAUCUGGAUUCUA 
                 549 
                 52 
               
               
                   
               
               
                 RD2087 
                 637 
                 657 
                 UUCAGUGAGAAUCUAGAUUCC 
                 246 
                 GGAAUCUAGAUUCUCACUGAA 
                 550 
                 65 
               
               
                   
               
               
                 RD2088 
                 926 
                 946 
                 UAAAGUUCUUUUGUAGGUUAA 
                 247 
                 UUAACCUACAAAAGAACUUUA 
                 551 
                 0 
               
               
                   
               
               
                 RD2089 
                 932 
                 952 
                 UUCAGGUAAAGUUUUUUUGCA 
                 248 
                 UGCAAAAAAACUUUACCUGAA 
                 552 
                 8 
               
               
                   
               
               
                 RD2090 
                 943 
                 963 
                 UAAUGGCAGGGUUUAGGUAAA 
                 249 
                 UUUACCUAAACCCUGCCAUUA 
                 553 
                 82 
               
               
                   
               
               
                 RD2091 
                 950 
                 970 
                 AAUUUUAGAAUGGUAGGGUUC 
                 250 
                 GAACCCUACCAUUCUAAAAUU 
                 554 
                 81 
               
               
                   
               
               
                 RD2092 
                 969 
                 989 
                 UAAAGUCAACUCCUGGGUAAA 
                 251 
                 UUUACCCAGGAGUUGACUUUA 
                 555 
                 50 
               
               
                   
               
               
                 RD2093 
                 970 
                 990 
                 UCAAAGUCAACUCUCGGGUAA 
                 252 
                 UUACCCGAGAGUUGACUUUGA 
                 556 
                 65 
               
               
                   
               
               
                 RD2094 
                 971 
                 991 
                 UCCAAAGUCAACUUCCGGGUA 
                 253 
                 UACCCGGAAGUUGACUUUGGA 
                 557 
                 84 
               
               
                   
               
               
                 RD2095 
                 985 
                 1005 
                 UUCAAUUCUUCUCUUCCAAAG 
                 254 
                 CUUUGGAAGAGAAGAAUUGAA 
                 558 
                 91 
               
               
                   
               
               
                 RD2096 
                 986 
                 1006 
                 AUUCAAUUCUUCUUCUCCAAA 
                 255 
                 UUUGGAGAAGAAGAAUUGAAU 
                 559 
                 80 
               
               
                   
               
               
                 RD2097 
                 1020 
                 1040 
                 UUUGGCAAACAUUUACUCCUU 
                 256 
                 AAGGAGUAAAUGUUUGCCAAA 
                 560 
                 92 
               
               
                   
               
               
                 RD2098 
                 1050 
                 1070 
                 ACUGACAGCGAAUUAUCUUUG 
                 257 
                 CAAAGAUAAUUCGCUGUCAGU 
                 561 
                 92 
               
               
                   
               
               
                 RD2099 
                 1058 
                 1078 
                 AGUGAAAAACUGAUAGCGAAU 
                 258 
                 AUUCGCUAUCAGUUUUUCACU 
                 562 
                 74 
               
               
                   
               
               
                 RD2100 
                 1062 
                 1082 
                 AAUAAGUGAAAAAUUGACAGC 
                 259 
                 GCUGUCAAUUUUUCACUUAUU 
                 563 
                 78 
               
               
                   
               
               
                 RD2101 
                 1087 
                 1107 
                 UCCUUACAGUCUUUUGGGAGU 
                 260 
                 ACUCCCAAAAGACUGUAAGGA 
                 564 
                 36 
               
               
                   
               
               
                 RD2103 
                 1171 
                 1191 
                 UAACCAGAGCUCCUUUGUGUC 
                 261 
                 GACACAAAGGAGCUCUGGUUA 
                 565 
                 67 
               
               
                   
               
               
                 RD2104 
                 1172 
                 1192 
                 UUAACCAGAGCUCUCUUGUGU 
                 262 
                 ACACAAGAGAGCUCUGGUUAA 
                 566 
                 89 
               
               
                   
               
               
                 RD2105 
                 1175 
                 1195 
                 AGAGUAACCAGAGUUCCCUUG 
                 263 
                 CAAGGGAACUCUGGUUACUCU 
                 567 
                 93 
               
               
                   
               
               
                 RD2106 
                 1181 
                 1201 
                 UCUCAAAGAGUAAUCAGAGCU 
                 264 
                 AGCUCUGAUUACUCUUUGAGA 
                 568 
                 77 
               
               
                   
               
               
                 RD2107 
                 1197 
                 1217 
                 UCCCAGUGUUACAUAAUCUCA 
                 265 
                 UGAGAUUAUGUAACACUGGGA 
                 569 
                 44 
               
               
                   
               
               
                 RD2108 
                 1249 
                 1269 
                 UUUGUUCCUCCAAUAAUGCGU 
                 266 
                 ACGCAUUAUUGGAGGAACAAA 
                 570 
                 70 
               
               
                   
               
               
                 RD2109 
                 1252 
                 1272 
                 UAGUUUGUUCCUCUAACAAUG 
                 267 
                 CAUUGUUAGAGGAACAAACUA 
                 571 
                 49 
               
               
                   
               
               
                 RD2110 
                 1253 
                 1273 
                 AGAGUUUGUUCCUUCAACAAU 
                 268 
                 AUUGUUGAAGGAACAAACUCU 
                 572 
                 69 
               
               
                   
               
               
                 RD2111 
                 1255 
                 1275 
                 UAAGAGUUUGUUCUUCCAACA 
                 269 
                 UGUUGGAAGAACAAACUCUUA 
                 573 
                 48 
               
               
                   
               
               
                 RD2112 
                 1256 
                 1276 
                 AGAAGAGUUUGUUUCUCCAAC 
                 270 
                 GUUGGAGAAACAAACUCUUCU 
                 574 
                 78 
               
               
                   
               
               
                 RD2113 
                 1272 
                 1292 
                 AGGGCCACUCUCCUCAAGAAG 
                 271 
                 CUUCUUGAGGAGAGUGGCCCU 
                 575 
                 33 
               
               
                   
               
               
                 RD2114 
                 1273 
                 1293 
                 UAGGGCCACUCUCUCCAAGAA 
                 272 
                 UUCUUGGAGAGAGUGGCCCUA 
                 576 
                 59 
               
               
                   
               
               
                 RD2115 
                 1274 
                 1294 
                 UCAGGGCCACUCUUCCCAAGA 
                 273 
                 UCUUGGGAAGAGUGGCCCUGA 
                 577 
                 61 
               
               
                   
               
               
                 RD2116 
                 1331 
                 1351 
                 UAGUGACCCUCCAUACAGGUG 
                 274 
                 CACCUGUAUGGAGGGUCACUA 
                 578 
                 58 
               
               
                   
               
               
                 RD2117 
                 1334 
                 1354 
                 UAUGAGUGACCCUUCACACAG 
                 275 
                 CUGUGUGAAGGGUCACUCAUA 
                 579 
                 90 
               
               
                   
               
               
                 RD2118 
                 1336 
                 1356 
                 UCUAUGAGUGACCUUCCACAC 
                 276 
                 GUGUGGAAGGUCACUCAUAGA 
                 580 
                 76 
               
               
                   
               
               
                 RD2119 
                 1337 
                 1357 
                 UCCUAUGAGUGACUCUCCACA 
                 277 
                 UGUGGAGAGUCACUCAUAGGA 
                 581 
                 76 
               
               
                   
               
               
                 RD2120 
                 1338 
                 1358 
                 UUCCUAUGAGUGAUCCUCCAC 
                 278 
                 GUGGAGGAUCACUCAUAGGAA 
                 582 
                 81 
               
               
                   
               
               
                 RD2121 
                 1348 
                 1368 
                 ACCCACUGGUGUCUUAUGAGU 
                 279 
                 ACUCAUAAGACACCAGUGGGU 
                 583 
                 42 
               
               
                   
               
               
                 RD2122 
                 1349 
                 1369 
                 UACCCACUGGUGUUCUAUGAG 
                 280 
                 CUCAUAGAACACCAGUGGGUA 
                 584 
                 54 
               
               
                   
               
               
                 RD2123 
                 1441 
                 1461 
                 UCUUUUGUAAUGUUUGACAGA 
                 281 
                 UCUGUCAAACAUUACAAAAGA 
                 585 
                 90 
               
               
                   
               
               
                 RD2124 
                 1513 
                 1533 
                 AUAUCAUGAUUCCUUUCUGAG 
                 282 
                 CUCAGAAAGGAAUCAUGAUAU 
                 586 
                 59 
               
               
                   
               
               
                 RD2125 
                 1545 
                 1565 
                 AAUUCAAAGGAGCUUGGAGUU 
                 283 
                 AACUCCAAGCUCCUUUGAAUU 
                 587 
                 78 
               
               
                   
               
               
                 RD2126 
                 1546 
                 1566 
                 UAAUUCAAAGGAGUCUGGAGU 
                 284 
                 ACUCCAGACUCCUUUGAAUUA 
                 588 
                 78 
               
               
                   
               
               
                 RD2127 
                 1844 
                 1864 
                 UCCCACCAAACGCUACAUUCC 
                 285 
                 GGAAUGUAGCGUUUGGUGGGA 
                 589 
                 40 
               
               
                   
               
               
                 RD2128 
                 1845 
                 1865 
                 UGCCCACCAAACGUCACAUUC 
                 286 
                 GAAUGUGACGUUUGGUGGGCA 
                 590 
                 64 
               
               
                   
               
               
                 RD2129 
                 1847 
                 1867 
                 UAUGCCCACCAAAUGCCACAU 
                 287 
                 AUGUGGCAUUUGGUGGGCAUA 
                 591 
                 76 
               
               
                   
               
               
                 RD2130 
                 1880 
                 1900 
                 UUCCCUGCGGGCAUAGCCUUC 
                 288 
                 GAAGGCUAUGCCCGCAGGGAA 
                 592 
                 71 
               
               
                   
               
               
                 RD2131 
                 1889 
                 1909 
                 ACCAGGUUGCUCCUUGCGGGC 
                 289 
                 GCCCGCAAGGAGCAACCUGGU 
                 593 
                 36 
               
               
                   
               
               
                 RD2132 
                 1890 
                 1910 
                 UACCAGGUUGCUCUCUGCGGG 
                 290 
                 CCCGCAGAGAGCAACCUGGUA 
                 594 
                 63 
               
               
                   
               
               
                 RD2133 
                 1891 
                 1911 
                 ACACCAGGUUGCUUCCUGCGG 
                 291 
                 CCGCAGGAAGCAACCUGGUGU 
                 595 
                 52 
               
               
                   
               
               
                 RD2134 
                 1893 
                 1913 
                 AGACACCAGGUUGUUCCCUGC 
                 292 
                 GCAGGGAACAACCUGGUGUCU 
                 596 
                 6 
               
               
                   
               
               
                 RD2135 
                 1915 
                 1935 
                 AUGUACUCAGCGAUUUUGGUG 
                 293 
                 CACCAAAAUCGCUGAGUACAU 
                 597 
                 82 
               
               
                   
               
               
                 RD2136 
                 1918 
                 1938 
                 UCCAUGUACUCAGUGACUUUG 
                 294 
                 CAAAGUCACUGAGUACAUGGA 
                 598 
                 83 
               
               
                   
               
               
                 RD2137 
                 1921 
                 1941 
                 UAGUCCAUGUACUUAGCGACU 
                 295 
                 AGUCGCUAAGUACAUGGACUA 
                 599 
                 71 
               
               
                   
               
               
                 RD2138 
                 1923 
                 1943 
                 UCCAGUCCAUGUAUUCAGCGA 
                 296 
                 UCGCUGAAUACAUGGACUGGA 
                 600 
                 68 
               
               
                   
               
               
                 RD2139 
                 1929 
                 1949 
                 UUAAAAUCCAGUCUAUGUACU 
                 297 
                 AGUACAUAGACUGGAUUUUAA 
                 601 
                 57 
               
               
                   
               
               
                 RD2140 
                 1930 
                 1950 
                 UCUAAAAUCCAGUUCAUGUAC 
                 298 
                 GUACAUGAACUGGAUUUUAGA 
                 602 
                 68 
               
               
                   
               
               
                 RD2141 
                 1942 
                 1962 
                 UUCUGUGUUUUCUUUAAAAUC 
                 299 
                 GAUUUUAAAGAAAACACAGAA 
                 603 
                 26 
               
               
                   
               
               
                 RD2142 
                 1944 
                 1964 
                 UGCUCUGUGUUUUUUCUAAAA 
                 300 
                 UUUUAGAAAAAACACAGAGCA 
                 604 
                 68 
               
               
                   
               
               
                 RD2143 
                 1953 
                 1973 
                 UUCCAUCACUGCUUUGUGUUU 
                 301 
                 AAACACAAAGCAGUGAUGGAA 
                 605 
                 85 
               
               
                   
               
               
                 RD2144 
                 2067 
                 2087 
                 UCUCCAUGCUUUGUAGAUGAG 
                 302 
                 CUCAUCUACAAAGCAUGGAGA 
                 606 
                 39 
               
               
                   
               
               
                 RD2145 
                 2072 
                 2092 
                 UCCACUCUCCAUGUUUUGCAG 
                 303 
                 CUGCAAAACAUGGAGAGUGGA 
                 607 
                 28 
               
               
                   
               
               
                 RD2146 
                 2076 
                 2096 
                 AGAUGCCACUCUCUAUGCUUU 
                 304 
                 AAAGCAUAGAGAGUGGCAUCU 
                 608 
                 0 
               
               
                   
               
            
           
         
       
     
     Example 2—Dose-Dependent Inhibition of Human PKK in HEK-293T Cells 
     Compounds from the studies described above exhibiting significant in vitro inhibition of PKK mRNA were selected and tested at various doses in HEK-293T Cells as described above. Compounds were tested at concentrations of 0.01, 0.1, 1 and 10 nM and IC50 values were calculated (Table 5). 
     
       
         
           
               
               
               
             
               
                   
                 TABLE 5 
               
               
                   
                   
               
               
                   
                 Compound Number 
                 IC50 (nM) 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
            
               
                   
                 RD1872 
                 0.33 
               
               
                   
                 RD1874 
                 0.41 
               
               
                   
                 RD1913 
                 0.033 
               
               
                   
                 RD1923 
                 0.044 
               
               
                   
                 RD1948 
                 0.16 
               
               
                   
                 RD1956 
                 0.11 
               
               
                   
                 RD1978 
                 0.14 
               
               
                   
                 RD1993 
                 0.038 
               
               
                   
                 RD1996 
                 0.086 
               
               
                   
                 RD2022 
                 0.16 
               
               
                   
                 RD2028 
                 0.10 
               
               
                   
                   
               
            
           
         
       
     
     Example 3: Effect of Compounds Targeting Human PKK in Cynomolgus Monkeys 
     Compounds of interest, identified from in vitro gene expression screening, were evaluated in cynomolgus monkeys (Table 7). Prior to the study the monkeys were kept in quarantine during which the animals were observed daily for general health. Ten groups of 1 cynomolgus monkey each were injected with a single 6 mg/kg subcutaneous dose of oligonucleotide on Day 1 of the study. During the study period, the monkeys were observed daily for signs of illness or distress. Animals were bled on day −6 and on days 1 (prior to dosing), 4, 8, 15, 22, 29, 36, 43, 50, 57 and 64 for serum collection and analysis. The protocols described were approved by the Institutional Animal Care and Use Committee (IACUC). Circulating PKK levels were quantified using an ELISA specific for human angiotensinogen (and cross-reactive with cynomolgus), according to manufacturer&#39;s protocol (IBL America #27412). PKK inhibition data were expressed as percent of baseline value (Day 1 prior to dosing) (Table 8). 
     
       
         
           
               
             
               
                 TABLE 6 
               
             
            
               
                   
               
               
                 Compound Sequence 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                 Seq 
                 SEQ 
                   
                   
                   
                   
               
               
                   
                 ID 
                 ID 
                   
                   
                   
                   
               
               
                   
                 NO: 1 
                 NO: 1 
                   
                 SEQ 
                   
                 SEQ 
               
               
                 Compound 
                 Start 
                 Stop 
                 Antisense Sequence 
                 ID 
                 Sense Sequence 
                 ID 
               
               
                 Number 
                 Site 
                 Site 
                 (5′-3′) 
                 NO: 
                 (5′-3′) 
                 NO: 
               
               
                   
               
               
                 RD2305 
                 660 
                 682 
                 ACCAAUUUCUGAAAGGGCACAGG 
                 306 
                 UCCUGUGCCCUUUCAGAAAUUGGU 
                 610 
               
               
                   
               
               
                 RD2306 
                 988 
                 1010 
                 UCACAUUCAAUUCUUCUCCUCCA 
                 307 
                 CGGAGGAGAAGAAUUGAAUGUGA 
                 611 
               
               
                   
               
               
                 RD2307 
                 1057 
                 1079 
                 AAGUGAAAAACUGACAGCGAACC 
                 308 
                 UGGUUCGCUGUCAGUUUUUCACUU 
                 612 
               
               
                   
               
               
                 RD2308 
                 1140 
                 1162 
                 AAUCCUAGUUGGAGAACCAUCCG 
                 309 
                 CGGAUGGUUCUCCAACUAGGAUU 
                 613 
               
               
                   
               
               
                 RD2309 
                 1177 
                 1199 
                 UCAAAGAGUAACCAGAGCUCCCU 
                 310 
                 UGGAGCUCUGGUUACUCUUUGA 
                 614 
               
               
                   
               
               
                 RD2310 
                 1424 
                 1446 
                 UACAGAUUUAAAAUGCCACUGCG 
                 311 
                 UCGCAGUGGCAUUUUAAAUCUGUA 
                 615 
               
               
                   
               
               
                 RD2311 
                 1546 
                 1568 
                 UGUAAUUCAAAGGAGCCUGGAGU 
                 312 
                 UCUCCAGGCUCCUUUGAAUUACA 
                 616 
               
               
                   
               
               
                 RD2312 
                 1895 
                 1915 
                 UUAGACACCAGGUUGCUCCCU 
                 193 
                 UAGGGAGCAACCUGGUGUCUAA 
                 617 
               
               
                   
               
               
                 RD2313 
                 1924 
                 1944 
                 AUCCAGUCCAUGUACUCAGCG 
                 199 
                 UCGCUGAGUACAUGGACUGGAU 
                 618 
               
               
                   
               
               
                 RD2192 
                 1549 
                 1571 
                 UAGUGUAAUUCAAAGGAGCCUGG 
                 305 
                 CCAGGCUCCUUUGAAUUACACUA 
                 609 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 7 
               
             
            
               
                   
               
               
                 Compound Chemistry 
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                   
                 Ref 
                 SEQ 
               
               
                   
                 Com- 
                   
                 ID 
                 ID 
               
               
                   
                 pound 
                 Modified Strands (5′-3′) 
                 NO: 
                 NO: 
               
               
                   
               
               
                   
                 RD2305 
                 mA*fC*mC.fA.mA.fU.mU. 
                 IA0812 
                 306 
               
               
                   
                   
                 fU.mC.fU.mG.fA.mA.fA. 
                   
                   
               
               
                   
                   
                 mG.fG.mG.fC.mA.fC.mA* 
                   
                   
               
               
                   
                   
                 mG*mG 
                   
                   
               
               
                   
               
               
                   
                   
                 H1.mC*mC*mU*mG*mU.mG. 
                 IS1001 
                 610 
               
               
                   
                   
                 mC.mC.fC.mU.fU.fU.fC. 
                   
                   
               
               
                   
                   
                 fA.mG.mA.mA.mA.mU.mU. 
                   
                   
               
               
                   
                   
                 mG.mG*mU*dQ 
                   
                   
               
               
                   
               
               
                   
                 RD2306 
                 mU*fC*mA.fC.mA.fU.mU. 
                 IA0813 
                 307 
               
               
                   
                   
                 fC.mA.fA.mU.fU.mC.fU. 
                   
                   
               
               
                   
                   
                 mU.fC.mU.fC.mC.fU.mC* 
                   
                   
               
               
                   
                   
                 mC*mA 
                   
                   
               
               
                   
               
               
                   
                   
                 H7.mG*mG*mA.mG.mG.mA. 
                 IS1002 
                 611 
               
               
                   
                   
                 mG.fA.mA.fG.fA.fA.fU. 
                   
                   
               
               
                   
                   
                 mU.mG.mA.mA.mU.mG.mU. 
                   
                   
               
               
                   
                   
                 mG*mA*dQ 
                   
                   
               
               
                   
               
               
                   
                 RD2307 
                 mA*fA*mG.fU.mG.fA.mA. 
                 IA0814 
                 308 
               
               
                   
                   
                 fA.mA.fA.mC.fU.mG.fA. 
                   
                   
               
               
                   
                   
                 mC.fA.mG.fC.mG.fA.mA* 
                   
                   
               
               
                   
                   
                 mC*mC 
                   
                   
               
               
                   
               
               
                   
                   
                 H1.mG*mG*mU.mU.mC.mG. 
                 IS1003 
                 612 
               
               
                   
                   
                 mC.mU.fG.mU.fC.fA.fG. 
                   
                   
               
               
                   
                   
                 fU.mU.mU.mU.mU.mC.mA. 
                   
                   
               
               
                   
                   
                 mC.mU*mU*dO 
                   
                   
               
               
                   
               
               
                   
                 RD2309 
                 mU*fC*mA.fA.mA.fG.mA. 
                 IA0816 
                 310 
               
               
                   
                   
                 fG.mU.fA.mA.fC.mC.fA. 
                   
                   
               
               
                   
                   
                 mG.fA.mG.fC.mU.fC.mC* 
                   
                   
               
               
                   
                   
                 mC*mU 
                   
                   
               
               
                   
               
               
                   
                   
                 Hl.mG*mG*mA.mG.mC.mU. 
                 IS1005 
                 614 
               
               
                   
                   
                 fC.mU.fG.fG.fU.fU.mA. 
                   
                   
               
               
                   
                   
                 mC.mU.mC.mU.mU.mU.mG* 
                   
                   
               
               
                   
                   
                 mA*dQ 
                   
                   
               
               
                   
               
               
                   
                 RD2308 
                 mA*fA*mU.fC.mC.fU.mA. 
                 IA0815 
                 309 
               
               
                   
                   
                 fG.mU.fU.mG.fG.mA.fG. 
                   
                   
               
               
                   
                   
                 mA.fA.mC.fC.mA.fU.mC* 
                   
                   
               
               
                   
                   
                 mC*mG 
                   
                   
               
               
                   
                   
                 H7.mG.mG*mA*mU.mG.mG. 
                 IS1004 
                 613 
               
               
                   
                   
                 mU.fU.mC.fU.fC.fC.fA. 
                   
                   
               
               
                   
                   
                 mA.mC.mU.mA.mG.mG.mA. 
                   
                   
               
               
                   
                   
                 mU*mU*dQ 
                   
                   
               
               
                   
               
               
                   
                 RD2310 
                 mU*fA*mC.fA.mG.fA.mU. 
                 IA0817 
                 311 
               
               
                   
                   
                 fU.mU.fA.mA.fA.mA.fU. 
                   
                   
               
               
                   
                   
                 mG.fC.mC.fA.mC.fU.mG* 
                   
                   
               
               
                   
                   
                 mC*mG 
                   
                   
               
               
                   
               
               
                   
                   
                 H1.mC*mG*mC.mA.mG.mU. 
                 IS1006 
                 615 
               
               
                   
                   
                 mG.mG.fC.mA.fU.fU.fU. 
                   
                   
               
               
                   
                   
                 fU.mA.mA.mA.mU.mC.mU. 
                   
                   
               
               
                   
                   
                 mG.mU*mA*dQ 
                   
                   
               
               
                   
               
               
                   
                 RD2311 
                 mu*fG*mU.fA.mA.fU.mU. 
                 IA0818 
                 312 
               
               
                   
                   
                 fC.mA.fA.mA.fG.mG.fA. 
                   
                   
               
               
                   
                   
                 mG.fC.mC.fU.mG.fG.mA* 
                   
                   
               
               
                   
                   
                 mG*mU 
                   
                   
               
               
                   
               
               
                   
                   
                 H1.mC*mU*mC.mC.mA.mG. 
                 IS1007 
                 616 
               
               
                   
                   
                 mG.fC.mU.fC.fC.fU.fU. 
                   
                   
               
               
                   
                   
                 mU.mG.mA.mA.mU.mU.mA. 
                   
                   
               
               
                   
                   
                 mC*mA*dQ 
                   
                   
               
               
                   
               
               
                   
                 RD2192 
                 mU*fA*mG.fU.mG.fU.mA. 
                 IA0819 
                 305 
               
               
                   
                   
                 fA.mU.fU.mC.fA.mA.fA. 
                   
                   
               
               
                   
                   
                 mG.fG.mA.fG.mC.fC.mU* 
                   
                   
               
               
                   
                   
                 mG*mG 
                   
                   
               
               
                   
               
               
                   
                   
                 H6.mC*mA*mG.mG.mC.mU. 
                 IS0925 
                 609 
               
               
                   
                   
                 mC.fC.mU.fU.fU.fG.fA. 
                   
                   
               
               
                   
                   
                 mA.mU.mU.mA.mC.mA.mC. 
                   
                   
               
               
                   
                   
                 mU*mA*dO 
                   
                   
               
               
                   
               
               
                   
                 RD2312 
                 mU*fU*mA.fG.mA.fC.mA. 
                 IA0820 
                 193 
               
               
                   
                   
                 fC.mC.fA.mG.fG.mU.fU. 
                   
                   
               
               
                   
                   
                 mG.fC.mU.fC.mC*fC*mU 
                   
                   
               
               
                   
                   
                 H1.mA*mG*mG.mG.mA.mG. 
                 IS1008 
                 617 
               
               
                   
                   
                 fC.mA.fA.fC.fC.fU.mG. 
                   
                   
               
               
                   
                   
                 mG.mU.mG.mU.mC.mU.mA* 
                   
                   
               
               
                   
                   
                 mA*dQ 
                   
                   
               
               
                   
               
               
                   
                 RD2313 
                 mA*fU*mC.fC.mA.fG.mU. 
                 IA0821 
                 199 
               
               
                   
                   
                 fC.mC.fA.mU.fG.mU.fA. 
                   
                   
               
               
                   
                   
                 mC.fU.mC.fA.mG*fC*mG 
                   
                   
               
               
                   
               
               
                   
                   
                 H1.mC*mG*mC.mU.mG.mA. 
                 IS1009 
                 618 
               
               
                   
                   
                 fG.mU.fA.fC.fA.fU.mG. 
                   
                   
               
               
                   
                   
                 mG.mA.mC.mU.mG.mG.mA* 
                   
                   
               
               
                   
                   
                 mU*dQ 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 8 
               
             
            
               
                   
               
               
                 Average PKK Inhibition 
               
            
           
           
               
               
            
               
                   
                 Days 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
            
               
                 Compound 
                 4 
                 8 
                 15 
                 22 
                 29 
                 36 
                 43 
                 50 
                 57 
                 64 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
            
               
                 RD2305 
                 1 
                 0 
                 2 
                 37 
                 11 
                 5 
                 0 
                 0 
                 0 
                 0 
               
               
                 RD2306 
                 43 
                 60 
                 74 
                 88 
                 89 
                 84 
                 72 
                 70 
                 72 
                 63 
               
               
                 RD2307 
                 35 
                 54 
                 60 
                 69 
                 70 
                 79 
                 55 
                 54 
                 55 
                 50 
               
               
                 RD2309 
                 18 
                 58 
                 47 
                 69 
                 58 
                 71 
                 44 
                 54 
                 49 
                 45 
               
               
                 RD2308 
                 47 
                 32 
                 33 
                 42 
                 44 
                 45 
                 28 
                 24 
                 20 
                 18 
               
               
                 RD2310 
                 4 
                 37 
                 46 
                 64 
                 69 
                 72 
                 59 
                 62 
                 58 
                 53 
               
               
                 RD2311 
                 29 
                 55 
                 74 
                 85 
                 92 
                 92 
                 80 
                 75 
                 71 
                 63 
               
               
                 RD2192 
                 20 
                 −6 
                 −46 
                 26 
                 2 
                 18 
                 −4 
                 5 
                 −6 
                 0 
               
               
                 RD2312 
                 34 
                 42 
                 74 
                 78 
                 75 
                 72 
                 59 
                 51 
                 57 
                 54 
               
               
                 RD2313 
                 33 
                 50 
                 75 
                 90 
                 84 
                 93 
                 82 
                 82 
                 83 
                 84 
               
               
                   
               
            
           
         
       
     
     Example 4: Effect of Compounds Targeting Human PKK in Cynomolgus Monkeys 
     Compounds of interest, identified from in vitro gene expression screening, were evaluated in cynomolgus monkeys (Table 10). Prior to the study the monkeys were kept in quarantine during which the animals were observed daily for general health. Eight groups of 2 cynomolgus monkey each were injected with a single 4 mg/kg subcutaneous dose of oligonucleotide on Day 1 of the study. During the study period, the monkeys were observed daily for signs of illness or distress. Animals were bled on day −6 and on days 1 (prior to dosing), 4, 8, and 15 for serum collection and analysis. Future collections will be on days 22, 29, 36, 43, 50, 57, 64, 71, 78 and 85. In a second set of experiments, animals were bled on day −6 and days 1 (prior to dosing), 4, 8, 15 and 22 for serum collection and analysis. Future collections for the second set of experiments will be on days 29, 36, 43, 50, 57, 64, 71, 78 and 85. In a third set of experiments, animals were bled on day −6 and days 1 (prior to dosing), 4, 8, 15, 22, 29 and 36 for serum collection and analysis. Future collections for the third set of experiments will be on days 43, 50, 57, 64, 71, 78 and 85. In a fourth set of experiments, animals were bled on day −6 and days 1 (prior to dosing), 4, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78 and 85 for serum collection and analysis. The protocols described were approved by the Institutional Animal Care and Use Committee (IACUC). Circulating PKK levels were quantified using an ELISA specific for human angiotensinogen (and cross-reactive with cynomolgus), according to manufacturer&#39;s protocol (IBL America #27412). PKK inhibition data were expressed as percent of baseline value (Day 1 prior to dosing) and as an average of the group for each compound. Results from the four sets of experiments are shown in Tables 11, 12, 13 and 14. Clinical chemistry was performed on Day −1 or Day −6 and Day 63 or 64 and Day 92. There were no test article-related effects on body weight (Table 15) and all serum chemistry values were within reference ranges (Table 16 and 17). 
     
       
         
           
               
             
               
                 TABLE 9 
               
             
            
               
                   
               
               
                 Compound Sequence 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                 Seq 
                 SEQ 
                   
                   
                   
                   
               
               
                   
                 ID 
                 ID 
                   
                   
                   
                   
               
               
                   
                 NO: 1 
                 NO: 1 
                 Antisense 
                 SEQ 
                 Sense 
                 SEQ 
               
               
                 Compound 
                 Start 
                 Stop 
                 Sequence 
                 ID 
                 Sequence 
                 ID 
               
               
                 Number 
                 Site 
                 Site 
                 (5′-3′) 
                 NO: 
                 (5′-3′) 
                 NO: 
               
               
                   
               
               
                 RD2423 
                 1546 
                 1568 
                 UGUAAUU 
                 312 
                 CUCCAGG 
                 619 
               
               
                   
                   
                   
                 CAAAGGA 
                   
                 CUCCUUU 
                   
               
               
                   
                   
                   
                 GCCUGGA 
                   
                 GAAUUAC 
                   
               
               
                   
                   
                   
                 GU 
                   
                 A 
                   
               
               
                   
               
               
                 RD2436 
                 1546 
                 1568 
                 UGUAAUU 
                 312 
                 UCUCCAG 
                 616 
               
               
                   
                   
                   
                 CAAAGGA 
                   
                 GCUCCUU 
                   
               
               
                   
                   
                   
                 GCCUGGA 
                   
                 UGAAUUA 
                   
               
               
                   
                   
                   
                 GU 
                   
                 CA 
                   
               
               
                   
               
               
                 RD2437 
                 1546 
                 1568 
                 UGUAAUU 
                 312 
                 UCUCCAG 
                 620 
               
               
                   
                   
                   
                 CAAAGGA 
                   
                 GCUCCUU 
                   
               
               
                   
                   
                   
                 GCCUGGA 
                   
                 UGAAUUA 
                   
               
               
                   
                   
                   
                 GU 
                   
                 CAU 
                   
               
               
                   
               
               
                 RD2438 
                 1546 
                 1568 
                 UGUAAUU 
                 312 
                 UCCAGGC 
                 468 
               
               
                   
                   
                   
                 CAAAGGA 
                   
                 UCCUUUG 
                   
               
               
                   
                   
                   
                 GCCUGGA 
                   
                 AAUUACA 
                   
               
               
                   
                   
                   
                 GU 
                   
                   
                   
               
               
                   
               
               
                 RD2439 
                 988 
                 1010 
                 UCACAUU 
                 307 
                 UGGAGGA 
                 622 
               
               
                   
                   
                   
                 CAAUUCU 
                   
                 GAAGAAU 
                   
               
               
                   
                   
                   
                 UCUCCUC 
                   
                 UGAAUGU 
                   
               
               
                   
                   
                   
                 CA 
                   
                 GA 
                   
               
               
                   
               
               
                 RD2440 
                 988 
                 1010 
                 UCACAUU 
                 307 
                 UGGAGGA 
                 623 
               
               
                   
                   
                   
                 CAAUUCU 
                   
                 GAAGAAU 
                   
               
               
                   
                   
                   
                 UCUCCUC 
                   
                 UGAAUGU 
                   
               
               
                   
                   
                   
                 CA 
                   
                 GAU 
                   
               
               
                   
               
               
                 RD2442 
                 1569 
                 1591 
                 UCAUAUU 
                 313 
                 CUGAAUU 
                 624 
               
               
                   
                   
                   
                 GGUUUUU 
                   
                 CCAAAAA 
                   
               
               
                   
                   
                   
                 GGAAUUC 
                   
                 CCAAUAU 
                   
               
               
                   
                   
                   
                 AG 
                   
                 GA 
                   
               
               
                   
               
               
                 RD2492 
                 1548 
                 1568 
                 UGUAAUU 
                 164 
                 UUCCUUU 
                 625 
               
               
                   
                   
                   
                 CAAAGGA 
                   
                 GAAUUAC 
                   
               
               
                   
                   
                   
                 GCCUGGA 
                   
                 A 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 10 
               
             
            
               
                   
               
               
                 Compound Chemistry 
               
            
           
           
               
               
               
               
            
               
                   
                   
                   
                 SEQ 
               
               
                   
                 Modified Strands 
                 Ref ID 
                 ID 
               
               
                 Compound 
                 (5′-3′) 
                 NO: 
                 NO: 
               
               
                   
               
               
                 RD2423 
                 mu*fG*mU.fA.mA.fU. 
                 IA0818 
                 312 
               
               
                   
                 mU.fC.mA.fA.mA.fG. 
                   
                   
               
               
                   
                 mG.fA.mG.fC.mC.fU. 
                   
                   
               
               
                   
                 mG.fG.mA*mG*mU 
                   
                   
               
               
                   
               
               
                   
                 H9*mU*mC.mC.mA.mG. 
                 IS1058 
                 619 
               
               
                   
                 mG.fC.mU.fC.fC.fU. 
                   
                   
               
               
                   
                 fU.mU.mG.mA.mA.mU. 
                   
                   
               
               
                   
                 mU.mA.mC*mA*dQ 
                   
                   
               
               
                   
               
               
                 RD2436 
                 mu*fG*mU.fA.mA.fU. 
                 IA0818 
                 312 
               
               
                   
                 mU.fC.mA.fA.mA.fG. 
                   
                   
               
               
                   
                 mG.fA.mG.fC.mC.fU. 
                   
                   
               
               
                   
                 mG.fG.mA*mG*mU 
                   
                   
               
               
                   
               
               
                   
                 H2*mC*mU.mC.mC.mA. 
                 IS1066 
                 616 
               
               
                   
                 mG.mG.fC.mU.fC.fC. 
                   
                   
               
               
                   
                 fU.fU.mU.mG.mA.mA. 
                   
                   
               
               
                   
                 mU.mU.mA.mC*mA*dQ 
                   
                   
               
               
                   
               
               
                 RD2437 
                 mu*fG*mU.fA.mA.fU. 
                 IA0818 
                 312 
               
               
                   
                 mU.fC.mA.fA.mA.fG. 
                   
                   
               
               
                   
                 mG.fA.mG.fC.mC.fU. 
                   
                   
               
               
                   
                 mG.fG.mA*mG*mU 
                   
                   
               
               
                   
               
               
                   
                 H2*mC*mU.mC.mC.mA. 
                 IS1067 
                 620 
               
               
                   
                 mG.mG.fC.mU.fC.fC. 
                   
                   
               
               
                   
                 fU.fU.mU.mG.mA.mA. 
                   
                   
               
               
                   
                 mU.mU.mA.mC.mA*mU* 
                   
                   
               
               
                   
                 dQ 
                   
                   
               
               
                   
               
               
                 RD2438 
                 mu*fG*mU.fA.mA.fU. 
                 IA0818 
                 312 
               
               
                   
                 mU.fC.mA.fA.mA.fG. 
                   
                   
               
               
                   
                 mG.fA.mG.fC.mC.fU. 
                   
                   
               
               
                   
                 mG.fG.mA*mG*mU 
                   
                   
               
               
                   
               
               
                   
                 H2*mC*mC.mA.mG.mG. 
                 IS1068 
                 468 
               
               
                   
                 fC.mU.fC.fC.fU.fU. 
                   
                   
               
               
                   
                 mU.mG.mA.mA.mU.mU. 
                   
                   
               
               
                   
                 mA.mC*mA*dQ 
                   
                   
               
               
                   
               
               
                 RD2439 
                 mU*fC*mA.fC.mA.fU. 
                 IA0813 
                 307 
               
               
                   
                 mU.fC.mA.fA.mU.fU. 
                   
                   
               
               
                   
                 mC.fU.mU.fC.mU.fC. 
                   
                   
               
               
                   
                 mC.fU.mC*mC*mA 
                   
                   
               
               
                   
               
               
                   
                 H2*mG*mG.mA.mG.mG. 
                 IS1069 
                 622 
               
               
                   
                 mA.mG.fA.mA.fG.fA. 
                   
                   
               
               
                   
                 fA.fU.mU.mG.mA.mA. 
                   
                   
               
               
                   
                 mU.mG.mU.mG*mA*dQ 
                   
                   
               
               
                   
               
               
                 RD2440 
                 mU*fC*mA.fC.mA.fU. 
                 IA0813 
                 307 
               
               
                   
                 mU.fC.mA.fA.mU.fU. 
                   
                   
               
               
                   
                 mC.fU.mU.fC.mU.fC. 
                   
                   
               
               
                   
                 mC.fU.mC*mC*mA 
                   
                   
               
               
                   
               
               
                   
                 H2*mG*mG.mA.mG.mG. 
                 IS1070 
                 623 
               
               
                   
                 mA.mG.fA.mA.fG.fA. 
                   
                   
               
               
                   
                 fA.fU.mU.mG.mA.mA. 
                   
                   
               
               
                   
                 mU.mG.mU.mG.mA*mU* 
                   
                   
               
               
                   
                 dQ 
                   
                   
               
               
                   
               
               
                 RD2442 
                 mU*fC*mA.fU.mA.fU. 
                 IA0828 
                 313 
               
               
                   
                 mU.fG.mG.fU.mU.fU. 
                   
                   
               
               
                   
                 mU.fU.mG.fG.mA.fA. 
                   
                   
               
               
                   
                 mU.fU.mC*mA*mG 
                   
                   
               
               
                   
               
               
                   
                 H9*mU*mG.mA.mA.mU. 
                 IS1072 
                 624 
               
               
                   
                 mU.mC.fC.mA.fA.fA. 
                   
                   
               
               
                   
                 fA.fA.mC.mC.mA.mA. 
                   
                   
               
               
                   
                 mU.mA.mU.mG*mA*dO 
                   
                   
               
               
                   
               
               
                 RD2492 
                 mU*fG*mU.fA.mA.fU. 
                 IA0867 
                 164 
               
               
                   
                 mU.fC.mA.fA.mA.fG. 
                   
                   
               
               
                   
                 mG.fA*mG*fC*mC*fU* 
                   
                   
               
               
                   
                 mG*fG*mA 
                   
                   
               
               
                   
               
               
                   
                 H2*mU.fC.fC.fU.fU. 
                 IS1074 
                 625 
               
               
                   
                 mU.mG.mA.mA.mU.mU. 
                   
                   
               
               
                   
                 mA.mC.mA*dQ 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 11 
               
             
            
               
                   
               
               
                 Average PKK Inhibition 
               
            
           
           
               
               
            
               
                   
                 Days 
               
            
           
           
               
               
               
               
               
            
               
                   
                 Compound 
                 4 
                 8 
                 15 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
            
               
                   
                 RD2423 
                 28 
                 52 
                 66 
               
               
                   
                 RD2436 
                 22 
                 43 
                 67 
               
               
                   
                 RD2437 
                 62 
                 45 
                 66 
               
               
                   
                 RD2438 
                 21 
                 50 
                 77 
               
               
                   
                 RD2439 
                 26 
                 43 
                 55 
               
               
                   
                 RD2440 
                 21 
                 31 
                 46 
               
               
                   
                 RD2442 
                 20 
                 41 
                 71 
               
               
                   
                 RD2492 
                 23 
                 37 
                 55 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 12 
               
             
            
               
                   
               
               
                 Average PKK Inhibition 
               
            
           
           
               
               
               
            
               
                   
                 Days 
                   
               
            
           
           
               
               
               
               
               
               
            
               
                   
                 Compound 
                 4 
                 8 
                 15 
                 22 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
               
            
               
                   
                 RD2423 
                 26 
                 51 
                 79 
                 85 
               
               
                   
                 RD2436 
                 20 
                 40 
                 69 
                 76 
               
               
                   
                 RD2437 
                 5 
                 33 
                 64 
                 75 
               
               
                   
                 RD2438 
                 30 
                 49 
                 74 
                 81 
               
               
                   
                 RD2439 
                 4 
                 36 
                 58 
                 64 
               
               
                   
                 RD2440 
                 4 
                 27 
                 46 
                 39 
               
               
                   
                 RD2442 
                 9 
                 39 
                 63 
                 70 
               
               
                   
                 RD2492 
                 17 
                 33 
                 52 
                 54 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 13 
               
             
            
               
                   
               
               
                 Average PKK Inhibition 
               
            
           
           
               
               
               
            
               
                   
                 Days 
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                 Compound 
                 4 
                 8 
                 15 
                 22 
                 29 
                 36 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                 RD2423 
                 26 
                 51 
                 79 
                 85 
                 85 
                 84 
               
               
                   
                 RD2436 
                 20 
                 40 
                 69 
                 76 
                 77 
                 79 
               
               
                   
                 RD2437 
                 5 
                 33 
                 64 
                 75 
                 77 
                 79 
               
               
                   
                 RD2438 
                 30 
                 49 
                 74 
                 81 
                 76 
                 76 
               
               
                   
                 RD2439 
                 4 
                 36 
                 58 
                 64 
                 63 
                 — 
               
               
                   
                 RD2440 
                 4 
                 27 
                 46 
                 39 
                 47 
                 — 
               
               
                   
                 RD2442 
                 9 
                 39 
                 63 
                 70 
                 67 
                 — 
               
               
                   
                 RD2492 
                 17 
                 33 
                 52 
                 54 
                 52 
                 — 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 14 
               
             
            
               
                   
               
               
                 Average PKK Inhibition 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                   
                 Day 
                 Day 
                 Day 
                 Day 
                 Day 
                 Day 
                 Day 
                 Day 
                 Day 
                 Day 
                 Day 
                 Day 
                 Day 
               
               
                 Compound 
                 4 
                 8 
                 15 
                 22 
                 29 
                 36 
                 43 
                 50 
                 57 
                 64 
                 71 
                 78 
                 85 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                 RD2423 
                 14 
                 41 
                 74 
                 88 
                 91 
                 90 
                 88 
                 92 
                 81 
                 85 
                 87 
                 80 
                 68 
               
               
                 RD2436 
                 20 
                 40 
                 69 
                 76 
                 77 
                 79 
                 73 
                 77 
                 76 
                 69 
                 61 
                 64 
                 37 
               
               
                 RD2437 
                 5 
                 33 
                 64 
                 75 
                 77 
                 79 
                 70 
                 80 
                 79 
                 71 
                 70 
                 68 
                 54 
               
               
                 RD2438 
                 30 
                 49 
                 74 
                 81 
                 76 
                 76 
                 68 
                 71 
                 60 
                 52 
                 42 
                 36 
               
               
                 RD2439 
                 4 
                 36 
                 58 
                 64 
                 63 
                 58 
                 65 
                 66 
               
               
                 RD2440 
                 4 
                 27 
                 46 
                 39 
                 47 
               
               
                 RD2442 
                 9 
                 39 
                 63 
                 70 
                 67 
                 73 
                 72 
                 72 
                 71 
                 59 
                 60 
                 62 
                 56 
               
               
                 RD2492 
                 17 
                 33 
                 52 
                 54 
                 52 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 15 
               
             
            
               
                   
               
               
                 Body Weight (kg) 
               
            
           
           
               
               
               
               
               
            
               
                   
                 Compound 
                 Day −1 
                 Day 63 
                 Day 91 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
            
               
                   
                 RD2423 Cyno#1 
                 2.4 
                 2.4 
                 2.4 
               
               
                   
                 RD2423 Cyno#2 
                 2.6 
                 2.6 
                 2.7 
               
               
                   
                 RD2436 Cyno#1 
                 2.9 
                 3.1 
                 3.2 
               
               
                   
                 RD2436 Cyno#2 
                 2.5 
                 2.6 
                 2.7 
               
               
                   
                 RD2437 Cyno#1 
                 3.1 
                 3.2 
                 3.2 
               
               
                   
                 RD2437 Cyno#2 
                 2.6 
                 2.7 
                 2.9 
               
               
                   
                 RD2438 Cyno#1 
                 3.2 
                 3.2 
                 3.4 
               
               
                   
                 RD2438 Cyno#2 
                 2.5 
                 2.6 
                 2.6 
               
               
                   
                 RD2439 Cyno#1 
                 3.6 
                 4.1 
                 N/A 
               
               
                   
                 RD2439 Cyno#2 
                 2.7 
                 2.8 
                 N/A 
               
               
                   
                 RD2440 Cyno#1 
                 3.9 
                 4.3 
                 N/A 
               
               
                   
                 RD2440 Cyno#2 
                 2.3 
                 2.4 
                 N/A 
               
               
                   
                 RD2442 Cyno#1 
                 4.4 
                 4.5 
                 4.6 
               
               
                   
                 RD2442 Cyno#2 
                 2.3 
                 2.4 
                 2.5 
               
               
                   
                 RD2492 Cyno#1 
                 4 
                 4 
                 N/A 
               
               
                   
                 RD2492 Cyno#2 
                 2.3 
                 2.3 
                 N/A 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 16 
               
             
            
               
                   
               
               
                 Liver Function Markers 
               
            
           
           
               
               
               
               
               
            
               
                   
                 ALT (U/L) 
                 AST (U/L) 
                 Bilirubin (mg/dL) 
                 Albumin (g/dL) 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                   
                 Day 
                 Day 
                 Day 
                 Day 
                 Day 
                 Day 
                 Day 
                 Day 
                 Day 
                 Day 
                 Day 
                 Day 
               
               
                 Compound 
                 −6 
                 64 
                 92 
                 −6 
                 64 
                 92 
                 −6 
                 64 
                 92 
                 −6 
                 64 
                 92 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                 RD2423 Cyno#1 
                 47 
                 47 
                 51 
                 53 
                 46 
                 46 
                 0.25 
                 0.26 
                 0.28 
                 4.3 
                 4.5 
                 4.5 
               
               
                 RD2423 Cyno#2 
                 76 
                 75 
                 58 
                 69 
                 65 
                 46 
                 0.15 
                 0.36 
                 0.27 
                 4.0 
                 4.3 
                 3.9 
               
               
                 RD2436 Cyno#1 
                 25 
                 22 
                 25 
                 45 
                 48 
                 39 
                 0.24 
                 0.34 
                 0.32 
                 4.5 
                 4.3 
                 4.1 
               
               
                 RD2436 Cyno#2 
                 65 
                 73 
                 78 
                 64 
                 41 
                 42 
                 0.19 
                 0.23 
                 0.25 
                 4.4 
                 4.5 
                 4.5 
               
               
                 RD2437 Cyno#1 
                 41 
                 40 
                 51 
                 39 
                 43 
                 43 
                 0.24 
                 0.28 
                 0.27 
                 4.3 
                 4.5 
                 4.4 
               
               
                 RD2437 Cyno#2 
                 55 
                 51 
                 50 
                 55 
                 57 
                 48 
                 0.14 
                 0.24 
                 0.26 
                 4.5 
                 4.6 
                 4.4 
               
               
                 RD2438 Cyno#1 
                 66 
                 64 
                 64 
                 101 
                 62 
                 50 
                 0.18 
                 0.17 
                 0.17 
                 4.2 
                 4.5 
                 4.2 
               
               
                 RD2438 Cyno#2 
                 25 
                 21 
                 25 
                 38 
                 33 
                 33 
                 0.33 
                 0.44 
                 0.53 
                 4.8 
                 4.6 
                 4.5 
               
               
                 RD2439 Cyno#1 
                 80 
                 64 
                 N/A 
                 87 
                 48 
                 N/A 
                 0.16 
                 0.16 
                 N/A 
                 4.4 
                 4.6 
                 N/A 
               
               
                 RD2439 Cyno#2 
                 105 
                 88 
                 N/A 
                 49 
                 54 
                 N/A 
                 0.15 
                 0.23 
                 N/A 
                 4.5 
                 4.4 
                 N/A 
               
               
                 RD2440 Cyno#1 
                 66 
                 48 
                 N/A 
                 115 
                 52 
                 N/A 
                 0.32 
                 0.30 
                 N/A 
                 4.4 
                 4.6 
                 N/A 
               
               
                 RD2440 Cyno#2 
                 50 
                 58 
                 N/A 
                 45 
                 48 
                 N/A 
                 0.25 
                 0.39 
                 N/A 
                 4.8 
                 5.0 
                 N/A 
               
               
                 RD2442 Cyno#1 
                 66 
                 61 
                 69 
                 54 
                 38 
                 55 
                 0.17 
                 0.17 
                 0.30 
                 4.1 
                 4.2 
                 4.1 
               
               
                 RD2442 Cyno#2 
                 63 
                 70 
                 70 
                 51 
                 54 
                 56 
                 0.21 
                 0.23 
                 0.17 
                 4.3 
                 4.4 
                 4.3 
               
               
                 RD2492 Cyno#1 
                 57 
                 39 
                 N/A 
                 84 
                 38 
                 N/A 
                 0.12 
                 0.17 
                 N/A 
                 4.2 
                 4.2 
                 N/A 
               
               
                 RD2492 Cyno#2 
                 92 
                 78 
                 N/A 
                 72 
                 85 
                 N/A 
                 0.18 
                 0.27 
                 N/A 
                 4.7 
                 4.5 
                 N/A 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 17 
               
             
            
               
                   
               
               
                 Kidney Function Markers 
               
            
           
           
               
               
               
            
               
                   
                 BUN (mg/dL) 
                 Creatinine (mg/dL) 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                 Day 
                 Day 
                 Day 
                 Day 
                 Day 
                 Day 
               
               
                 Compound 
                 −6 
                 64 
                 92 
                 −6 
                 64 
                 92 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                 RD2423 Cyno#1 
                 24 
                 20 
                 18 
                 0.51 
                 0.62 
                 0.58 
               
               
                 RD2423 Cyno#2 
                 34 
                 30 
                 28 
                 0.51 
                 0.61 
                 0.55 
               
               
                 RD2436 Cyno#1 
                 27 
                 26 
                 23 
                 0.48 
                 0.49 
                 0.47 
               
               
                 RD2436 Cyno#2 
                 22 
                 19 
                 19 
                 0.46 
                 0.51 
                 0.56 
               
               
                 RD2437 Cyno#1 
                 31 
                 24 
                 21 
                 0.61 
                 0.71 
                 0.75 
               
               
                 RD2437 Cyno#2 
                 25 
                 21 
                 23 
                 0.48 
                 0.48 
                 0.43 
               
               
                 RD2438 Cyno#1 
                 23 
                 27 
                 20 
                 0.46 
                 0.64 
                 0.61 
               
               
                 RD2438 Cyno#2 
                 21 
                 18 
                 22 
                 0.50 
                 0.47 
                 0.46 
               
               
                 RD2439 Cyno#1 
                 21 
                 21 
                 N/A 
                 0.53 
                 0.63 
                 N/A 
               
               
                 RD2439 Cyno#2 
                 28 
                 27 
                 N/A 
                 0.39 
                 0.36 
                 N/A 
               
               
                 RD2440 Cyno#1 
                 23 
                 24 
                 N/A 
                 0.53 
                 0.74 
                 N/A 
               
               
                 RD2440 Cyno#2 
                 24 
                 19 
                 N/A 
                 0.32 
                 0.44 
                 N/A 
               
               
                 RD2442 Cyno#1 
                 30 
                 26 
                 25 
                 0.57 
                 0.75 
                 0.62 
               
               
                 RD2442 Cyno#2 
                 28 
                 30 
                 27 
                 0.50 
                 0.61 
                 0.59 
               
               
                 RD2492 Cyno#1 
                 23 
                 22 
                 N/A 
                 0.52 
                 0.59 
                 N/A 
               
               
                 RD2492 Cyno#2 
                 33 
                 26 
                 N/A 
                 0.66 
                 0.44 
                 N/A 
               
               
                   
               
            
           
         
       
     
     Example 5: Effect of Compounds Targeting Human PKK in Cynomolgus Monkeys 
     Compounds of interest were evaluated in cynomolgus monkeys (Table 19). Prior to the study the monkeys were kept in quarantine during which the animals were observed daily for general health. Eight groups of 2 cynomolgus monkey each were injected with a single 4 mg/kg subcutaneous dose of oligonucleotide on Day 1 of the study. During the study period, the monkeys were observed daily for signs of illness or distress. Animals were bled on day −6 and on days 1 (prior to dosing), 8, 15 and 22 for serum collection and analysis. Future collections will be on days 29, 36, 43, 50, 57, 64 and 71. In a second set of experiments, animals were bled on day −6 and days 1 (prior to dosing), 8, 15, 22, 29, 36, 43, 50, 57, 64 and 71. The protocols described were approved by the Institutional Animal Care and Use Committee (IACUC). Circulating PKK levels were quantified using an ELISA specific for human angiotensinogen (and cross-reactive with cynomolgus), according to manufacturer&#39;s protocol (IBL America #27412). PKK inhibition data were expressed as percent of baseline value (Day 1 prior to dosing) and as an average of the group for each compound. Results from the two sets of experiments are shown in Tables 20 and 21. Clinical chemistry was performed on Day −1 or Day −6 and Day 64 and Day 92. There were no test article-related effects on body weight (Table 22) and all serum chemistry values were within reference ranges (Tables 23 and 24). 
     
       
         
           
               
             
               
                 TABLE 18 
               
             
            
               
                   
               
               
                 Compound Sequence 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                 Seq 
                 SEQ 
                   
                   
                   
                   
               
               
                   
                 ID 
                 ID 
                 Anti- 
                   
                   
                   
               
               
                   
                 NO: 
                 NO: 
                 sense 
                   
                 Sense 
                   
               
               
                 Com- 
                 1 
                 1 
                 Se- 
                 SEQ 
                 Se- 
                 SEQ 
               
               
                 pound 
                 Start 
                 Stop 
                 quence 
                 ID 
                 quence 
                 ID 
               
               
                 Number 
                 Site 
                 Site 
                 (5′-3′) 
                 NO: 
                 (5′-3′) 
                 NO:  
               
               
                   
               
               
                 RD2424 
                 630 
                 652 
                 UGAGAA 
                 626 
                 UAACGU 
                 629 
               
               
                   
                   
                   
                 UCCAGA 
                   
                 GGAAUC 
                   
               
               
                   
                   
                   
                 UUCCAC 
                   
                 UGGAUU 
                   
               
               
                   
                   
                   
                 GUUAC 
                   
                 CUCA 
                   
               
               
                   
               
               
                 RD2425 
                 689 
                 711 
                 UCAAGA 
                 627 
                 UGAACA 
                 630 
               
               
                   
                   
                   
                 UGCUGG 
                   
                 CUCUUC 
                   
               
               
                   
                   
                   
                 AAGAUG 
                   
                 AGCAUC 
                   
               
               
                   
                   
                   
                 UUCAU 
                   
                 UUGA 
                   
               
               
                   
               
               
                 RD2426 
                 1183 
                 1205 
                 ACAAUC 
                 628 
                 CUCUGG 
                 631 
               
               
                   
                   
                   
                 UCAAAG 
                   
                 UUACUC 
                   
               
               
                   
                   
                   
                 AGUAAC 
                   
                 UUUGAG 
                   
               
               
                   
                   
                   
                 CAGAG 
                   
                 AUUGU 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 19 
               
             
            
               
                   
               
               
                 Compound Chemistry 
               
            
           
           
               
               
               
               
            
               
                   
                 Modified 
                   
                 SEQ 
               
               
                   
                 Strands 
                 Ref ID 
                 ID 
               
               
                 Compound 
                 (5′-3′) 
                 NO: 
                 NO: 
               
               
                   
               
               
                 RD2424 
                 mu*fG*mA.fG.mA.fA. 
                 IA0864 
                 626 
               
               
                   
                 mU.fC.mC.fA.mG.fA. 
                   
                   
               
               
                   
                 mU.fU.mC.fC.mA.fC. 
                   
                   
               
               
                   
                 mG.fU.mU*mA*mC 
                   
                   
               
               
                   
               
               
                   
                 H4*mA*mA.mC.mG.mU. 
                 IS1059 
                 629 
               
               
                   
                 mG.fG.mA.fA.fU.fC. 
                   
                   
               
               
                   
                 fU.mG.mG.mA.mU.mU. 
                   
                   
               
               
                   
                 mC.mU.mC*mA*dQ 
                   
                   
               
               
                   
               
               
                 RD2425 
                 mU*fC*mA.fA.mG.fA. 
                 IA0865 
                 627 
               
               
                   
                 mU.fG.mC.fU.mG.fG. 
                   
                   
               
               
                   
                 mA.fA.mG.fA.mU.fG. 
                   
                   
               
               
                   
                 mU.fU.mC*mA*mU 
                   
                   
               
               
                   
               
               
                   
                 H4*mG*mA.mA.mC.mA. 
                 IS1060 
                 630 
               
               
                   
                 mU.fC.mU.fU.fC.fC. 
                   
                   
               
               
                   
                 fA.mG.mC.mA.mU.mC. 
                   
                   
               
               
                   
                 mU.mU.mG*mA*dO 
                   
                   
               
               
                   
               
               
                 RD2426 
                 mA*fC*mA.fA.mU.fC. 
                 IA0866 
                 628 
               
               
                   
                 mU.fC.mA.fA.mA.fG. 
                   
                   
               
               
                   
                 mA.fG.mU.fA.mA.fC. 
                   
                   
               
               
                   
                 mC.fA.mG*mA*mG 
                   
                   
               
               
                   
               
               
                   
                 H9*mU*mC.mU.mG.mG. 
                 IS1061 
                 631 
               
               
                   
                 mU.mU.fA.mC.fU.fC. 
                   
                   
               
               
                   
                 fU.fU.mU.mG.mA.mG. 
                   
                   
               
               
                   
                 mA.mU.mU.mG*mU*dQ 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 20 
               
             
            
               
                   
               
               
                 Average PKK Inhibition 
               
            
           
           
               
               
            
               
                   
                 Days 
               
            
           
           
               
               
               
               
               
            
               
                   
                 Compound 
                 8 
                 15 
                 22 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
            
               
                   
                 RD2424 
                 53 
                 80 
                 87 
               
               
                   
                 RD2425 
                 31 
                 60 
                 69 
               
               
                   
                 RD2426 
                 30 
                 54 
                 58 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 22 
               
             
            
               
                   
               
               
                 Body Weight (kg) 
               
            
           
           
               
               
               
               
               
            
               
                   
                 Compound 
                 Day −1 
                 Day 64 
                 Day 92 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
            
               
                   
                 RD2424 Cyno#1 
                 3.1 
                 3.1 
                 3.1 
               
               
                   
                 RD2424 Cyno#2 
                 3.2 
                 3.6 
                 3.7 
               
               
                   
                 RD2425 Cyno#1 
                 2.9 
                 3.3 
                 N/A 
               
               
                   
                 RD2425 Cyno#2 
                 3.1 
                 3.5 
                 N/A 
               
               
                   
                 RD2426 Cyno#1 
                 3.5 
                 3.9 
                 N/A 
               
               
                   
                 RD2426 Cyno#2 
                 2.8 
                 3.2 
                 N/A 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 21 
               
             
            
               
                   
               
               
                 Average PKK Inhibition 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
            
               
                   
                 Day 
                 Day 
                 Day 
                 Day 
                 Day 
                 Day 
                 Day 
                 Day 
                 Day 
                 Day 
               
               
                 Compound 
                 8 
                 15 
                 22 
                 29 
                 36 
                 43 
                 50 
                 57 
                 64 
                 71 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
            
               
                 RD2424 
                 71 
                 87 
                 94 
                 91 
                 91 
                 84 
                 88 
                 80 
                 79 
                 74 
               
               
                 RD2425 
                 42 
                 60 
                 76 
                 73 
                 80 
                 75 
                 72 
                 72 
                 68 
               
               
                 RD2426 
                 30 
                 54 
                 58 
                 57 
                   
                 57 
                 65 
                 58 
                 58 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 23 
               
             
            
               
                   
               
               
                 Liver Function Markers 
               
            
           
           
               
               
               
               
               
            
               
                   
                 ALT (U/L) 
                 AST (U/L) 
                 Bilirubin (mg/dL) 
                 Albumin (g/dL) 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                   
                 Day 
                 Day 
                 Day 
                 Day 
                 Day 
                 Day 
                 Day 
                 Day 
                 Day 
                 Day 
                 Day 
                 Day 
               
               
                 Compound 
                 −6 
                 64 
                 92 
                 −6 
                 64 
                 92 
                 −6 
                 64 
                 92 
                 −6 
                 64 
                 92 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                 RD2424 Cyno#1 
                 58 
                 N/A 
                 65 
                 50 
                 N/A 
                 45 
                 &lt;0.2 
                 N/A 
                 &lt;0.2 
                 4.3 
                 N/A 
                 4.4 
               
               
                 RD2424 Cyno#2 
                 50 
                 N/A 
                 42 
                 34 
                 N/A 
                 32 
                 0.3 
                 N/A 
                 0.2 
                 4.5 
                 N/A 
                 4.5 
               
               
                 RD2425 Cyno#1 
                 57 
                 49 
                 N/A 
                 49 
                 38 
                 N/A 
                 0.2 
                 &lt;0.2 
                 N/A 
                 4.2 
                 4.2 
                 N/A 
               
               
                 RD2425 Cyno#2 
                 37 
                 42 
                 N/A 
                 39 
                 39 
                 N/A 
                 0.4 
                 0.2 
                 N/A 
                 4.5 
                 4.5 
                 N/A 
               
               
                 RD2426 Cyno#1 
                 46 
                 40 
                 N/A 
                 46 
                 40 
                 N/A 
                 0.2 
                 0.3 
                 N/A 
                 4.2 
                 4.6 
                 N/A 
               
               
                 RD2426 Cyno#2 
                 68 
                 52 
                 N/A 
                 68 
                 52 
                 N/A 
                 0.3 
                 &lt;0.2 
                 N/A 
                 4.4 
                 4.4 
                 N/A 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 24 
               
             
            
               
                   
               
               
                 Kidney Function Markers 
               
            
           
           
               
               
               
            
               
                   
                 BUN (mg/dL) 
                 Creatinine (mg/dL) 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                 Day 
                 Day 
                 Day 
                 Day 
                 Day 
                 Day 
               
               
                 Compound 
                 −6 
                 64 
                 92 
                 −6 
                 64 
                 92 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                 RD2424 Cyno#1 
                 22 
                 N/A 
                 14 
                 0.5 
                 N/A 
                 0.5 
               
               
                 RD2424 Cyno#2 
                 22 
                 N/A 
                 18 
                 0.8 
                 N/A 
                 0.8 
               
               
                 RD2425 Cyno#1 
                 21 
                 15 
                 N/A 
                 0.4 
                 0.4 
                 N/A 
               
               
                 RD2425 Cyno#2 
                 28 
                 22 
                 N/A 
                 0.6 
                 0.5 
                 N/A 
               
               
                 RD2426 Cyno#1 
                 23 
                 20 
                 N/A 
                 0.6 
                 0.6 
                 N/A 
               
               
                 RD2426 Cyno#2 
                 31 
                 26 
                 N/A 
                 0.7 
                 0.5 
                 N/A 
               
               
                   
               
            
           
         
       
     
     Example 6: Effect of Compounds Targeting Human PKK in Lewis Rats 
     Female Lewis rats (5 females/group, 8 weeks of age) were given single subcutaneous SC injections of 0 (Vehicle Control (phosphate buffered saline (PBS)), 200 mg/kg RD2423 or 200 mg/kg RD2438 at a dose volume of mL/kg to groups 1-3, respectively, on Day 1. Observations included viability, clinical signs and body weight (Days 1 and 10). Blood samples were collected for clinical chemistry (Day 0 (predose), 3 and 10), hematology (Day 10) and coagulation (Day 10). On Day 10, heart, liver, and both kidneys were harvested from each rat and fixed in 10% neutral buffered formalin after weighing. 
     Results: There were no drug-related effects on viability, clinical observations, body weight or organ weight (heart, liver, and kidneys), clinical chemistry, hematology or coagulation (prothrombin clotting time) parameters. A single subcutaneous administration of 200 mg/kg of compounds RD2423 or RD2438 to female Lewis rats was well tolerated. 
     
       
         
           
               
               
            
               
                   
                 SEQ ID NO: 1 
               
               
                   
                 AGTGCCACATTAGAACAGCTTGAAGACCGTTCATTT 
               
               
                   
               
               
                   
                 TTAAGTGACAAGAGACTCACCTCCAAGAAGCAATT 
               
               
                   
               
               
                   
                 GTGTTTTCAGAATGATTTTATTCAAGCAAGCAACT 
               
               
                   
               
               
                   
                 TATTTCATTTCCTTGTTTGCTACAGTTTCCTGTGG 
               
               
                   
               
               
                   
                 ATGTCTGACTCAACTCTATGAAAACGCCTTCTTCA 
               
               
                   
               
               
                   
                 GAGGTGGGGATGTAGCTTCCATGTACACCCCAAAT 
               
               
                   
               
               
                   
                 GCCCAATACTGCCAGATGAGGTGCACATTCCACCC 
               
               
                   
               
               
                   
                 AAGGTGTTTGCTATTCAGTTTTCTTCCAGCAAGTT 
               
               
                   
               
               
                   
                 CAATCAATGACATGGAGAAAAGGTTTGGTTGCTTC 
               
               
                   
               
               
                   
                 TTGAAAGATAGTGTTACAGGAACCCTGCCAAAAGT 
               
               
                   
               
               
                   
                 ACATCGAACAGGTGCAGTTTCTGGACATTCCTTGA 
               
               
                   
               
               
                   
                 AGCAATGTGGTCATCAAATAAGTGCTTGCCATCGA 
               
               
                   
               
               
                   
                 GACATTTATAAAGGAGTTGATATGAGAGGAGTCAA 
               
               
                   
               
               
                   
                 TTTTAATGTGTCTAAGGTTAGCAGTGTTGAAGAAT 
               
               
                   
               
               
                   
                 GCCAAAAAAGGTGCACCAGTAACATTCGCTGCCAG 
               
               
                   
               
               
                   
                 ITTTTTTCATATGCCACGCAAACATTTCACAAGGC 
               
               
                   
               
               
                   
                 AGAGTACCGGAACAATTGCCTATTAAAGTACAGTC 
               
               
                   
               
               
                   
                 CCGGAGGAACACCTACCGCTATAAAGGTGCTGAGT 
               
               
                   
               
               
                   
                 AACGTGGAATCTGGATTCTCACTGAAGCCCTGTGC 
               
               
                   
               
               
                   
                 CCTTTCAGAAATTGGTTGCCACATGAACATCTTCC 
               
               
                   
               
               
                   
                 AGCATCTTGCGTTCTCAGATGTGGATGTTGCCAGG 
               
               
                   
               
               
                   
                 GTTCTCACTCCAGATGCTTTTGTGTGTCGGACCAT 
               
               
                   
               
               
                   
                 CTGCACCTATCACCCCAACTGCCTCTTCTTTACAT 
               
               
                   
               
               
                   
                 TCTATACAAATGTATGGAAAATCGAGTCACAAAGA 
               
               
                   
               
               
                   
                 AATGTTTGTCTTCTTAAAACATCTGAAAGTGGCAC 
               
               
                   
               
               
                   
                 ACCAAGTTCCTCTACTCCTCAAGAAAACACCATAT 
               
               
                   
               
               
                   
                 CTGGATATAGCCTTTTAACCTGCAAAAGAACTTTA 
               
               
                   
               
               
                   
                 CCTGAACCCTGCCATTCTAAAATTTACCCGGGAGT 
               
               
                   
               
               
                   
                 TGACTTTGGAGGAGAAGAATTGAATGTGACTTTTG 
               
               
                   
               
               
                   
                 TTAAAGGAGTGAATGTTTGCCAAGAGACTTGCACA 
               
               
                   
               
               
                   
                 AAGATGATTCGCTGTCAGTTTTTCACTTATTCTTT 
               
               
                   
               
               
                   
                 ACTCCCAGAAGACTGTAAGGAAGAGAAGTGTAAGT 
               
               
                   
               
               
                   
                 GTTTCTTAAGATTATCTATGGATGGTTCTCCAACT 
               
               
                   
               
               
                   
                 AGGATTGCGTATGGGACACAAGGGAGCTCTGGTTA 
               
               
                   
               
               
                   
                 CTCTTTGAGATTGTGTAACACTGGGGACAACTCTG 
               
               
                   
               
               
                   
                 TCTGCACAACAAAAACAAGCACACGCATTGTTGGA 
               
               
                   
               
               
                   
                 GGAACAAACTCTTCTTGGGGAGAGTGGCCCTGGCA 
               
               
                   
               
               
                   
                 GGTGAGCCTGCAGGTGAAGCTGACAGCTCAGAGGC 
               
               
                   
               
               
                   
                 ACCTGTGTGGAGGGTCACTCATAGGACACCAGTGG 
               
               
                   
               
               
                   
                 GTCCTCACTGCTGCCCACTGCTTTGATGGGCTTCC 
               
               
                   
               
               
                   
                 CCTGCAGGATGTTTGGCGCATCTATAGTGGCATTT 
               
               
                   
               
               
                   
                 TAAATCTGTCAGACATTACAAAAGATACACCTTTC 
               
               
                   
               
               
                   
                 TCACAAATAAAAGAGATTATTATTCACCAAAACTA 
               
               
                   
               
               
                   
                 TAAAGTCTCAGAAGGGAATCATGATATCGCCTTGA 
               
               
                   
               
               
                   
                 TAAAACTCCAGGCTCCTTTGAATTACACTGAATTC 
               
               
                   
               
               
                   
                 CAAAAACCAATATGCCTACCTTCCAAAGGTGACAC 
               
               
                   
               
               
                   
                 AAGCACAATTTATACCAACTGTTGGGTAACCGGAT 
               
               
                   
               
               
                   
                 GGGGCTTCTCGAAGGAGAAAGGTGAAATCCAAAAT 
               
               
                   
               
               
                   
                 ATTCTACAAAAGGTAAATATTCCTTTGGTAACAAA 
               
               
                   
               
               
                   
                 TGAAGAATGCCAGAAAAGATATCAAGATTATAAAA 
               
               
                   
               
               
                   
                 TAACCCAACGGATGGTCTGTGCTGGCTATAAAGAA 
               
               
                   
               
               
                   
                 GGGGGAAAAGATGCTTGTAAGGGAGATTCAGGTGG 
               
               
                   
               
               
                   
                 TCCCTTAGTTTGCAAACACAATGGAATGTGGCGTT 
               
               
                   
               
               
                   
                 TGGTGGGCATCACCAGCTGGGGTGAAGGCTGTGCC 
               
               
                   
               
               
                   
                 CGCAGGGAGCAACCTGGTGTCTACACCAAAGTCGC 
               
               
                   
               
               
                   
                 TGAGTACATGGACTGGATTTTAGAGAAAACACAGA 
               
               
                   
               
               
                   
                 GCAGTGATGGAAAAGCTCAGATGCAGTCACCAGCA 
               
               
                   
               
               
                   
                 TGAGAAGCAGTCCAGAGTCTAGGCAATTTTTACAA 
               
               
                   
               
               
                   
                 CCTGAGTTCAAGTCAAATTCTGAGCCTGGGGGGTC 
               
               
                   
               
               
                   
                 CTCATCTGCAAAGCATGGAGAGTGGCATCTTCTTT 
               
               
                   
               
               
                   
                 GCATCCTAAGGACGAAAAACACAGTGCACTCAGAG 
               
               
                   
               
               
                   
                 CTGCTGAGGACAATGTCTGGCTGAAGCCCGCTTTC 
               
               
                   
               
               
                   
                 AGCACGCCGTAACCAGGGGCTGACAATGCGAGGTC 
               
               
                   
               
               
                   
                 GCAACTGAGATCTCCATGACTGTGTGTTGTGAAAT 
               
               
                   
               
               
                   
                 AAAATGGTGAAAGATCA