Compositions and methods of use for modulating prekallikrein - Patent Application 20070123333

Abstract

Aspects of the present disclosure provide compounds, compositions and methods for modulating plasma prekallikrein (PKK) expression or activity. In some aspects, the compounds, compositions and methods of the present disclosure can be used to reduce the expression of PKK mRNA in cells or animals. In some aspects, the compounds, compositions and methods of the present disclosure can be used to reduce the expression of PKK protein in cells or animals.

Description

[Technical field]

[0001] [CROSS REFERENCE TO RELATED APPLICATIONS] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 251,571, filed October 1, 2021, U.S. Provisional Patent Application No. 63 / 252,554, filed October 5, 2021, U.S. Provisional Patent Application No. 63 / 270,504, filed October 21, 2021, U.S. Provisional Patent Application No. 63 / 283,175, filed November 24, 2021, and U.S. Provisional Patent Application No. 63 / 287,969, filed December 9, 2021. The disclosures of each of these prior applications are deemed to be part of the disclosure of this application and are incorporated by reference in their entirety into the disclosure of this application. [Background technology]

[0002] Plasma prekallikrein (PKK) is a glycoprotein involved in surface-dependent activation of blood coagulation, fibrinolysis, kinin production, and inflammation. PKK is encoded by the KLKB1 gene and is the precursor of plasma kallikrein (PK). PKK exists in plasma as a contact factor that forms a noncovalent complex with high molecular weight kininogen. PKK is converted to PK through cleavage of the internal Arg-Ile peptide bond by factor XIIa. PK is a component of the kinin-kallikrein pathway, which consists of several proteins that play roles in inflammation, blood pressure control, coagulation, and pain. PK liberates kinins from kininogen and also generates plasmin from plasminogen. For example, plasma kallikrein cleaves high molecular weight kininogen (HMWK) to generate bradykinin. The kinins, particularly bradykinin, then induce downstream effects including vasodilation and edema (see, e.g., Schmaier. J. Thromb. Haemost 14:28-39, 2016).

[0003] Certain mutations in PKK result in PKK deficiency, also known as Fletcher factor disease, a rare clotting factor deficiency characterized by a prolonged activated partial thromboplastin time (PTT). PKK deficiency has been associated with inflammatory and thrombotic disorders.

[0004] Mutations in PKK prevent the release of plasmin and kinins (e.g. bradykinin) and / or reduce fibrinolysis. This results in reduced vasodilation and increased thrombus formation, which in turn increases the likelihood of developing inflammatory or thrombotic diseases. Although individuals with PKK deficiency are often asymptomatic, they still exhibit a prolonged activated PTT and are at risk of developing the diseases listed above.

[0005] Inflammatory disorders occur when the immune system mistakenly attacks the body'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 wide variety of disorders and conditions characterized by inflammation. Examples include rheumatoid arthritis, allergies, asthma, autoimmune diseases, celiac disease, glomerulonephritis, hepatitis, inflammatory bowel disease, reperfusion injury, and transplant rejection. It is estimated that more than 1.36 million adults in the United States suffer from rheumatoid arthritis and 3 million suffer from inflammatory bowel disease.

[0006] Thrombosis is the formation of a blood clot inside a blood vessel, obstructing blood flow through the circulatory system. When a blood vessel is damaged, the body uses platelets and fibrin to form a clot to prevent blood loss. Under certain conditions, a blood clot can form in the body even when the blood vessel is not damaged. In healthy humans, a homeostatic balance exists between procoagulant (coagulant) and anticoagulant and fibrinolytic forces. Many genetic, acquired, and environmental factors can tip the balance toward coagulation, leading to the pathological formation of a blood clot in a vein (e.g., deep vein thrombosis), in an artery (e.g., myocardial infarction, ischemic stroke), or in the ventricle. A blood clot can obstruct blood flow at the site of formation or detach and embolize, blocking a distant blood vessel (e.g., pulmonary embolism, embolic stroke). In the United States alone, approximately 900,000 people are affected by blood clots each year, of which approximately 100,000 die from blood clot-related complications.

[0007] Hereditary angioedema (HAE) is a rare inflammatory disease characterized by repeated episodes of swelling around the head and extremities (Zuraw, BLN Engl. J. Med. 359:1027-36, 2008). Attacks of angioedema occur with unpredictable frequency and typically localize to the skin, stomach, oropharyngeal and laryngeal mucosa. Asphyxiation due to laryngeal swelling can be fatal. HAE is caused by a deficiency or dysfunction of the serine protease inhibitor C1-INH (Kaplan, AP et al. J. Allergy Clin. Immunol. 109:195-209, 2002). C1-INH is the major inhibitor of coagulation factors 12 and 11 (factor 11) of the intrinsic coagulation pathway and plasma kallikrein (Gigli, I. et al. J. Immunol. 104:574-581, 1970). C1-INH-mediated inhibition of plasma kallikrein and factor 12 inactivates the kallikrein pathway and reduces bradykinin (BK) levels. Deficiency or dysfunction of C1-INH leads to overproduction of BK, which is believed to be the mechanism by which HAE attacks occur. Type III HAE has been associated with mutations in the factor 12 gene, which encodes the coagulation protein factor 12 (Cichon, S. et al. Am. J. Hum. Genet. 79:1098-1104, 2006). At present, there is no cure for certain inflammatory or thrombotic conditions associated with dysregulation of PKK or other components of the kallikrein pathway, and therefore there is a need to find effective treatments for PKK-related diseases. [Prior art documents] [Non-patent literature]

[0008] [Non-Patent Document 1] Schmaier.J.Thromb.Haemost 14:28-39,2016 [Non-Patent Document 2] Zuraw,BLNEngl.J.Med.359:1027-36,2008 [Non-Patent Document 3] Kaplan,APet al.J.Allergy Clin.Immunol.109:195-209,2002 [Non-Patent Document 4] Gigli, I. et al. J. Immunol. 104:574-581, 1970 [Non-Patent Document 5] Cichon, S. et al. Am. J. Hum. Genet. 79:1098-1104, 2006 Summary of the Invention [Means for solving the problem]

[0009] The present disclosure provides compounds, compositions and methods for regulating 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 cells or animals.In certain embodiments, the compounds, compositions and methods can be used to reduce the amount of PKK protein in cells or animals.

[0010] In certain embodiments, the animal suffers from an inflammatory or thrombotic disease, disorder or condition, or a symptom thereof. In certain embodiments, the disease is hereditary angioedema (HAE), edema, angioedema, swelling, eyelid angioedema, ocular edema, macular edema, cerebral edema, thrombosis, embolism, thromboembolism, deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke, or infarction. Certain compounds, compositions, and methods provided herein are for reducing an inflammatory or thrombotic disease, disorder, or condition, or a symptom thereof, or hereditary angioedema (HAE), edema, angioedema, swelling, eyelid angioedema, ocular edema, macular edema, cerebral edema, thrombosis, embolism, thromboembolism, deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke, or infarction in an animal. In certain embodiments, the compounds and compositions provided herein are potent and tolerable and inhibit expression of PKK and can be used to treat, prevent, ameliorate, or slow the progression of an inflammatory or thrombotic disease, disorder or condition, or a symptom thereof, or hereditary angioedema (HAE), edema, angioedema, swelling, eyelid angioedema, ocular edema, macular edema, cerebral edema, thrombosis, embolism, thromboembolism, deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke, or infarction.

[0011] In certain embodiments, the compounds and compositions include one or more features that are effective for enhancing efficacy. In certain embodiments, the compounds and compositions include one or more features that are effective for enhancing tolerability. In certain embodiments, the compounds and compositions include 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 therapeutically significant than publicly disclosed compounds. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0012] It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the 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.

[0013] Any 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 records for sequence references, are expressly incorporated herein by reference in their entirety and in part as of the filing date of this application.

[0014] It is understood that the sequence set forth in each SEQ ID NO contained herein is independent of any modifications to the sugar moiety, internucleoside linkage, or nucleobase, even when presented in terms of modified compounds. Thus, a compound defined by a SEQ ID NO may independently contain one or more modifications to the sugar moiety, internucleoside linkage, or nucleobase. Oligomeric compounds referenced by compound number or reference ID number represent a combination of nucleobase sequence, chemical modifications, and motifs.

[0015] In this specification, 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 more than one (i.e., at least one) of the grammatical object of the article. For example, an "element" with "an" 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 specifically stated otherwise. In addition, the use of the term "including" and other forms, such as "includes" and "included," is not limiting and is used synonymously with the phrase "including, but not limited to."

[0016] definition Unless otherwise indicated, the following terms have the following meanings.

[0017] "Plasma prekallikrein" or "kallikrein B1" is used interchangeably with the term "PKK" and refers to either the nucleic acid or protein of PKK. Exemplary nucleotide and amino acid sequences of PKK can be found, for example, in GenBank Accession Nos. NM_000892.5 (incorporated herein as SEQ ID NO:1), NG_012095.2 truncated from positions 23529-54493 (incorporated herein as SEQ ID NO:2), XM_017008181.1 (incorporated herein as SEQ ID NO:3), NC_000004.12 truncated from positions 186215714-186258477 (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, such as 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 the diversity of the PKK gene, including variants shown in SNP databases. Numerous sequence variations within the PKK gene have been identified and can be found, for example, in NCBI dbSNP and UniProt (see, for example, ncbi.nlm.nih.gov / snp / ?term=PKK). "PKK mRNA" refers to the mRNA that codes for the PKK protein. PKK can refer to any of the above cases or the following cases.

[0018] "PKK specific inhibitor" refers to any agent capable of specifically inhibiting the expression or activity of PKK RNA and / or PKK protein 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.

[0019] "2'-O-Methoxyethyl" or "2'-MOE" refers to the modification 2'-O(CH2)2-OCH3. A 2'-O-methoxyethyl modified sugar is a modified sugar that has a 2'-O(CH2)2-OCH3 in place of the 2'-OH group of the ribosyl ring.

[0020] By "5' start site" is meant the nucleotide of a target nucleic acid or target region that is aligned with the 3'-most nucleoside of an antisense oligonucleotide.

[0021] By "3' termination site" is meant the nucleotide of a target nucleic acid or target region that is adjacent to the 5'-most nucleoside of an antisense oligonucleotide.

[0022] "About" means within ±10% of a given value. For example, if it is stated that "PKK was inhibited by about 70% by the compound," it indicates that PKK levels are inhibited within a range of 60% to 80%. When about is before a series of numbers or ranges, it is understood that "about" can modify each of the series of numbers or ranges.

[0023] "Administer" or "administering" refers to a route by which a compound or composition provided herein is introduced into an individual to perform its intended function. Examples of administration routes that can be used include, but are not limited to, parenteral administration, such as subcutaneous, intravenous or intramuscular injection or infusion.

[0024] "Ameliorate" refers to the improvement or reduction of at least one of the indicators, signs or symptoms of the relevant disease, disorder or condition. In certain embodiments, improvement includes the delay or slowing down of the progression or severity of one or more indicators of the condition or disease. The progression or severity of an indicator may be determined by subjective or objective measures, which are known to those skilled in the art.

[0025] "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.

[0026] By "antisense oligonucleotide" or "antisense strand" is meant an oligonucleotide that contains a region that is complementary to a target nucleic acid, eg, a PKK RNA, or a region thereof.

[0027] "Complementary" refers to a nucleobase sequence that is complementary to one or more nucleobase sequences of another oligonucleotide or nucleic acid or region thereof when the nucleobase sequence of the oligonucleotide or region is aligned in the opposite direction to the other oligonucleotide or nucleic acid or region thereof. Complementary nucleobases as described herein are limited to the combinations of adenine (A) and thymine (T), adenine (A) and uracil (U), and cytosine (C) and guanine (G), unless otherwise indicated. Complementary oligonucleotides and / or nucleic acids need not have nucleobase complementarity at each nucleoside and may contain one or more nucleobase mismatches. In contrast, "fully complementary" or "100% complementary" refers to an oligonucleotide in which there is a nucleobase match at each nucleoside and no nucleobase mismatches.

[0028] "Composition" or "pharmaceutical composition" refers to a mixture of substances suitable for administration to an individual. For example, a composition may include one or more compounds or salts thereof and a sterile aqueous solution.

[0029] "Co-administration" means administering two or more compounds in any manner such that both pharmacological actions of the compounds are experienced in a patient. Co-administration does not require that both compounds be administered in one pharmaceutical composition, in the same dosage form, by the same route of administration, or at the same time. The actions of both compounds need not be experienced simultaneously. Their actions need only overlap over a period of time, but not for an extended period of time. Co-administration includes concurrent or sequential administration of one or more compounds.

[0030] "Conjugate group" refers to a group of atoms attached to an oligonucleotide. The conjugate group is optionally attached to the oligonucleotide via a conjugate linker. The conjugate group may, for example, change the distribution, targeting or half-life of the compound in which it is incorporated. The conjugate group includes a targeting moiety.

[0031] "Conjugate linker" means a group of atoms that includes at least one bond that connects a linking moiety to an oligonucleotide.

[0032] "Identity" refers to, in relation to an oligonucleotide, the nucleic acid base sequence of one or more of the nucleic acid bases of the oligonucleotide or its region that matches the nucleic acid base sequence of another oligonucleotide or nucleic acid or its region. The identity of an oligonucleotide to another oligonucleotide or nucleic acid does not necessarily have to match each nucleic acid base, but may include one or more different nucleic acid bases. In contrast, "completely identical" or "100% identity" refers to, in relation to an oligonucleotide, that the oligonucleotide has the same nucleic acid bases as the other oligonucleotide or nucleic acid at each corresponding position and over its length.

[0033] "Individual" means a human or non-human animal selected to be the subject of treatment or therapy.

[0034] "Inhibiting expression or activity," with respect to a target nucleic acid or target protein, means reducing or blocking the expression or activity of the target relative to the expression or activity in an untreated or control sample, and does not necessarily indicate a complete abolition of expression or activity.

[0035] As used herein, the term "internucleoside bond" refers to the covalent bond between adjacent nucleosides in an oligonucleotide.As used herein, "modified internucleoside bond" refers to any internucleoside bond other than phosphodiester internucleoside bond."Phosphorothioate internucleoside bond" refers to the modified internucleoside bond in which one of the non-bridging oxygen atoms of phosphodiester internucleoside bond is replaced with a sulfur atom.

[0036] Representative internucleoside linkages with chiral centers include, but are not limited to, alkylphosphonates and phosphorothioates.Modified oligonucleotides containing internucleoside linkages with chiral centers can be prepared as a population of modified oligonucleotides containing stereorandom internucleoside linkages or as a population of modified oligonucleotides containing phosphorothioate linkages of specific stereochemical configuration, as described further below.Unless otherwise indicated, the chiral internucleoside linkages of the modified oligonucleotides described herein can be stereorandom or of specific stereochemical configuration.

[0037] The compounds of the present disclosure may contain proportions of atomic isotopes not found in nature at one or more of the atoms that constitute such compounds. For example, the compounds may contain radioactive isotopes, such as tritium ( 3 H), iodine-125( 125 I) or carbon-14( 14C). All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are included within the scope of the present disclosure.

[0038] The term "isotopic variant" refers to a therapeutic agent (e.g., a compound and / or modified oligonucleotide disclosed herein) that contains a proportion of an isotope not found in nature at one or more of the atoms that constitute such therapeutic agent. In certain embodiments, an "isotopic variant" of a therapeutic agent contains one or more isotopes in a proportion not found in nature, including 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( 129I) and iodine-131( 131 In certain embodiments, an "isotopic variant" of a therapeutic agent includes one or more isotopes in a ratio not found in nature, 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) are included, but are not limited to these.

[0039] For example, where feasible according to the judgment of one of skill in the art, in a therapeutic agent (e.g., a compound and / or modified oligonucleotide disclosed herein), any hydrogen may be, e.g., 2 H or any carbon can be, e.g. 13 C, or any nitrogen can be, e.g. 15 It can also be N, or any oxygen can be, for example, 18 It will be understood that the isotopic variant can also be O. In certain embodiments, an "isotopic variant" of a therapeutic agent contains deuterium (D) in a proportion not found in nature.

[0040] "Mismatched" or "non-complementary" refers to 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 the second oligonucleotide / nucleic acid are aligned in an antiparallel orientation. For example, a nucleobase (including but not limited to the universal nucleobases inosine and hypoxanthine) can hybridize with at least one nucleobase, but remains mismatched or non-complementary to the nucleobase to which it hybridizes. As another example, a nucleobase of a first oligonucleotide / nucleic acid that cannot hybridize to the corresponding nucleobase of a second oligonucleotide / nucleic acid when the first oligonucleotide / nucleic acid and the second oligonucleotide are aligned in an antiparallel orientation is a mismatched or non-complementary nucleobase.

[0041] "Modified oligonucleotide" means an oligonucleotide in which at least one sugar, nucleobase or internucleoside linkage has been modified.

[0042] "Modulation" refers to the alteration or adjustment of the characteristics of a cell, tissue, organ, or organism. For example, modulation of PKK RNA can mean increasing or decreasing the levels of PKK RNA and / or PKK protein in a cell, tissue, organ, or organism. A "modulator" produces a change in a cell, tissue, organ, or organism. For example, a PKK compound can be a modulator that reduces the amount of PKK RNA and / or PKK protein in a cell, tissue, organ, or organism.

[0043] By "motif" is meant the pattern of unmodified and modified sugar moieties, nucleobases and / or internucleoside linkages in an oligonucleotide.

[0044] "Nucleic acid" refers to a molecule composed of monomeric nucleotides. Nucleic acids include, but are not limited to, ribonucleic acid (RNA), deoxyribonucleic acid (DNA), single-stranded nucleic acids, and double-stranded nucleic acids.

[0045] "Nucleobase" refers to a heterocyclic moiety that can pair with a base of another nucleic acid. As used herein, "natural nucleobase" refers to adenine (A), thymine (T), cytosine (C), uracil (U) and guanine (G). "Modified nucleobase" refers to a natural nucleobase that has been chemically modified. "Universal base" or "universal nucleobase" refers to a nucleobase other than natural and modified nucleobases, which can pair with any nucleobase.

[0046] "Nucleobase sequence" means the order of contiguous nucleobases in a nucleic acid or oligonucleotide, regardless of any sugar or internucleoside linkages.

[0047] "Nucleoside" refers to a compound comprising a nucleobase and a sugar moiety, each of which is independently unmodified or modified. "Modified nucleoside" refers to a nucleoside comprising a modified nucleobase and / or a modified sugar moiety. Modified nucleosides include abasic nucleosides in which the nucleobase is missing.

[0048] "Oligomeric compounds" refers to compounds that include one or more oligonucleotides and, optionally, one or more additional features, such as conjugate groups or terminal groups. Examples of oligomeric compounds include single-stranded and double-stranded compounds, such as oligonucleotides, antisense oligonucleotides, interfering RNA compounds (RNAi compounds), oligonucleotides that target microRNAs, occupancy-based compounds (e.g., compounds that block mRNA processing or translation, and splicing compounds). RNAi compounds include double-stranded compounds (e.g., small interfering RNA (siRNA) and double-stranded RNA (dsRNA)), as well as single-stranded compounds (e.g., single-stranded siRNA (ssRNA), single-stranded RNAi (ssRNAi), short hairpin RNA (shRNA) and microRNA mimics), which act, at least in part, through the RNA-induced silencing complex (RISC) pathway, which causes sequence-specific degradation and / or sequestration of target nucleic acids through a process known as RNA interference (RNAi). The term "RNAi compound" is meant to be synonymous with other terms used to describe nucleic acid compounds capable of mediating sequence-specific RNA interference, such as interfering RNA (iRNA), iRNA agent, RNAi agent, short interfering oligonucleotide, short interfering nucleic acid, short interfering modified oligonucleotide, chemically modified siRNA, etc. In addition, the term "RNAi" is meant to be synonymous with other terms used to describe sequence-specific RNA interference.

[0049] "Oligonucleotide" means a polymer of linked nucleosides, each of which, independent of one another, can be modified or unmodified.

[0050] The term "oligomeric duplex" refers to a duplex formed by two oligomeric compounds having complementary nucleobase sequences. Each oligomeric compound of an oligomeric duplex may also be referred to as a "duplex-forming oligomeric compound." The oligonucleotides of each oligomeric compound of an oligomeric duplex may contain non-complementary overhang-forming nucleosides. In some embodiments, the terms "duplex-forming oligomeric compound" and "modified oligonucleotide" are used interchangeably. In another embodiment, the terms "oligomeric duplex" and "compound" are used interchangeably.

[0051] "Parenteral administration" means administration by injection or infusion, including subcutaneous, intravenous, intramuscular, intraarterial, intraperitoneal, or intracranial, e.g., intrathecal or intraventricular, administration.

[0052] "Pharmaceutically acceptable carrier or diluent" means any substance suitable for use in administration to an individual. In certain embodiments, a pharma-ceutically acceptable carrier or diluent can be included in the compositions of the present disclosure, which aids in the administration and absorption of the compound by an individual, and does not cause significant adverse toxic effects to the patient. Non-limiting examples of pharma-ceutically acceptable excipients include water, NaCl, saline, and the like. For example, the pharma-ceutically acceptable carrier can be a sterile aqueous solution, such as PBS or water for injection. Those skilled in the art will recognize that other pharmaceutical excipients are also useful in the present disclosure.

[0053] "Pharmaceutically acceptable salts" means or refers to physiologically and pharma- ceutically acceptable salts of compounds, e.g., oligomeric compounds or oligonucleotides, i.e., salts that retain the desired biological activity of the parent compound and do not impart undesired toxicological effects.

[0054] As used herein, a pharma- ceutically acceptable salt is any salt of a compound provided herein that retains its biological properties and is not toxic or otherwise undesirable for medicinal use. Pharmaceutically acceptable salts of the therapeutic agents described herein include salts prepared with relatively non-toxic acids or bases, depending on the specific substituents found on the compounds or modified oligonucleotides described herein.

[0055] When a compound of the present disclosure contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of the compound with a sufficient amount of the desired base, either neat or in a suitable inert solvent.

[0056] When a compound of the present disclosure contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of the compound with a sufficient amount of the desired acid, either neat or in a suitable inert solvent.

[0057] That is, the compounds of the present disclosure may exist as salts, for example, salts with pharma- ceutically acceptable acids. Such salts may be derived from a variety of organic and inorganic counterions well known in the art. Such salts include (1) salts of organic or inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, sulfamic acid, acetic acid, trifluoroacetic acid, trichloroacetic acid, propionic acid, hexanoic acid, cyclopentylpropionic acid, glycolic acid, glutaric acid, pyruvic acid, lactic acid, malonic acid, succinic acid, sorbic acid, ascorbic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, picric acid, cinnamic acid, mandelic acid, phthalic acid, lauric acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphoric acid, camphorsulfonic acid, 4-methylbicyclo[2.2.or (2) acid addition salts formed with acids such as 2-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, benzoic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, cyclohexylsulfamic acid, quinic acid, muconic acid, or (3) acid addition salts formed with acids such as 2-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, benzoic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, cyclohexylsulfamic acid, quinic acid, muconic acid, or (4) acid addition salts formed with acids such as 2-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, benzoic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, cyclohexylsulfamic acid, quinic acid, muconic acid, or (5) acid addition salts formed with acids such as 2-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, benzoic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, cyclohexylsulfamic acid, quinic acid, muconic acid, or (6) acid addition salts formed with acids such as 2-oct-2-ene-1-carboxylic acid, glucoh or (b) is coordinated with an organic base, such as an aliphatic, alicyclic or aromatic organic amine, 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).

[0058] Pharmaceutically acceptable salts further include salts of sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like, and, when the compound contains a basic functional group, salts of non-toxic organic or inorganic acids, such as hydrohalides, e.g., hydrochlorides and hydrobromides, sulfates, phosphates, sulfamate, nitrates, acetates, trifluoroacetates, trichloroacetates, propionates, hexanoates, cyclopentylpropionates, glycolates, glutarates, pyruvates, lactates, malonates, succinates, sorbates, ascorbates, malates, maleates, fumarates, tartrates, citrates, benzoates, 3-(4-hydroxybenzoyl)benzoates, picrates, cinnamates, mandelates, phthal ... Examples of suitable salts include, but are not limited to, phosphate, 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 pharma- ceutically acceptable salts of the compounds and modified oligonucleotides disclosed herein are sodium or potassium salts. In some embodiments, the pharma- ceutically acceptable salts of the compounds and modified oligonucleotides disclosed herein are sodium salts.

[0059] The neutral form of the compound is preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in a 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, the compounds of the present disclosure contain both basic and acidic functional groups that allow the compounds to be converted into either base or acid addition salts. The neutral form of the compound 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 compound may differ from the various salt forms in certain physical properties, such as solubility in polar solvents, but unless otherwise indicated, the salts disclosed herein are equivalent to the parent form of the compound for the purposes of this disclosure.

[0060] By "pharmaceutical agent" is meant a chemical compound that produces a therapeutic effect when administered to an individual.

[0061] By "phosphorothioate linkage" is meant a modified phosphate linkage in which one of the non-bridging oxygen atoms is replaced with a sulfur atom.

[0062] "Part" refers to a certain number of consecutive (i.e. linked) nucleobases of a nucleic acid. In certain embodiments, a part is a certain number of consecutive nucleobases of a target nucleic acid. In certain embodiments, a part is a certain number of consecutive nucleobases of an oligonucleotide.

[0063] "Preventing" refers to delaying or forestalling the onset, development or progression of a disease, disorder or condition for a period of time.

[0064] "RNA interference compound" or "RNAi compound" refers to a compound that regulates a target nucleic acid and / or a target protein encoded by a target nucleic acid by acting, at least in part, through the RNA-induced silencing complex (RISC) pathway or Ago2, rather than through RNase H. RNAi compounds include, but are not limited to, double-stranded siRNA, single-stranded siRNA, and microRNA (including microRNA mimics).

[0065] By "sense oligonucleotide" or "sense strand" is meant 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.

[0066] "Specifically inhibit," with respect to a target nucleic acid or protein, means to reduce or block the expression or activity of the target nucleic acid or protein while minimizing or eliminating effects on non-target nucleic acids or proteins.

[0067] "Subunit", with respect to an oligonucleotide, means a nucleotide, nucleoside, nucleobase or sugar, or a modified nucleotide, nucleoside, nucleobase or sugar, as provided herein.

[0068] "Target nucleic acid," "target RNA," and "nucleic acid target" all refer to a nucleic acid that can be targeted by the compounds described herein.

[0069] "Target region" means a portion of a target nucleic acid to which one or more compounds are targeted.

[0070] By "targeting moiety" is meant a conjugate group that confers increased affinity for a given target, e.g., a molecule, a cell or cell type, a compartment, e.g., a cellular or organ compartment, a tissue, an organ, or a region of the body, e.g., compared to a compound lacking such a moiety.

[0071] "Terminal group" means a chemical group or group of atoms covalently attached to the end of an oligonucleotide.

[0072] "Therapeutically effective amount" or "effective amount" refers to an amount of a compound, pharmaceutical agent, or composition that provides a therapeutic effect to an individual. A "therapeutically effective amount" or "effective amount" is an amount of a compound sufficient to achieve its stated purpose (e.g., to treat, prevent, or ameliorate a disease, or to exert the action of administering the compound to alleviate one or more symptoms of a disease or condition) compared to the absence of the compound. An example of a "therapeutically effective amount" or "effective amount" is an amount sufficient to contribute to the treatment, prevention, amelioration, or alleviation of one or more symptoms of a disease. "Alleviation" of one or more symptoms (and grammatical equivalents of this phrase) means reducing the severity or frequency of the symptom(s) or eliminating the symptom(s). A "prophylactically effective amount" of a drug is an amount of drug that, when administered to a subject, has an intended prophylactic effect, e.g., prevents or delays the onset (or recurrence) of an injury, disease, condition or pathology, or reduces the likelihood of the onset (or recurrence) of an injury, disease, condition or pathology, or a symptom thereof. The term "therapeutically effective amount," as used herein, refers to an amount of a therapeutic agent sufficient to provide a therapeutic effect to an individual, e.g., to treat, prevent, or ameliorate a disease or disorder, or a symptom thereof, as described above. For example, for a 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 a "fold" improvement or a "fold" decrease. For example, a therapeutically effective amount can be at least 1.2-fold, 1.5-fold, 2-fold, 5-fold, or more, in effect, than a control.

[0073] The term "treating" or "treatment" refers to any objective or subjective parameter, such as relief, remission, reduction of symptoms, or any indication of successful treatment or improvement of an injury, disease, condition, or disease state, including making the injury, disease state, or disease state tolerable to the patient, slowing the rate of deterioration or decline, making the end point of deterioration less debilitating, improving the patient's physical or mental well-being. Treatment or improvement of symptoms can be based on objective or subjective parameters, including the results of a physical exam. The term "treating" and its variants may include prevention of an injury, disease state, condition, or disease. In an embodiment, treating is preventing. In an embodiment, treating does not include preventing.

[0074] "Treating" or "treatment", as used herein (and as well understood in the art), broadly includes any approach to obtain beneficial or desired results, including clinical results, in a subject's condition. Beneficial or desired clinical results may include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, reduction in the extent of the disease, stabilization of the condition (i.e., not worsening), prevention of the spread or spread of the disease, delay or slowing of the progression of the disease, improvement or mitigation of the condition, reduction in recurrence of the disease, and remission (whether partial or complete, detectable or undetectable). In other words, "treatment", as used herein, includes either curing, ameliorating, or preventing the disease. Treatment may prevent the onset of the disease, inhibit the spread of the disease, reduce the symptoms of the disease, completely or partially eliminate the underlying cause of the disease, shorten the duration of the disease, or a combination of these.

[0075] "Treating" and "treatment" as used herein include preventive treatment. The treatment method includes 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 will depend on various factors, such as the severity of the condition, the age of the patient, the concentration of the compound, the activity of the composition used in the treatment, or a combination thereof. It will also be apparent that the effective dosage of the agent used in the treatment or prevention may increase or decrease over a particular treatment or prevention regime. In some cases, chronic administration may be required. For example, the composition is administered to a subject in an amount and for a period sufficient to treat the patient.

[0076] "Treating" refers to the administration of a compound or pharmaceutical composition to an animal to alter or ameliorate a disease, disorder, or condition in the animal.

[0077] Certain compounds of the present disclosure have asymmetric carbon atoms (optical or chiral centers) or double bonds, and their enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisomers that may be defined in terms of absolute stereochemistry as (R) or (S) forms, or in the case of amino acids as (D) or (L) forms, and individual isomers are included within the scope of the present disclosure. The compounds of the present disclosure do not include isomers that are known in the art to be highly unstable and cannot be synthesized and / or isolated. The present disclosure is intended to include the compounds in racemic and optically pure form. Optically active (R) and (S) forms, or (D) and (L) forms, may be prepared using chiral synthons or chiral reagents or resolved using conventional techniques. When a compound described herein contains an olefinic bond or other geometrically asymmetric center, and unless otherwise specified, the compound is intended to include both the E and Z geometric isomers.

[0078] As used herein, the term "isomers" refers to compounds that have the same number and kinds of atoms, i.e., the same molecular weight, but differ in structural organization or arrangement of the atoms.

[0079] The term "tautomer," as used herein, refers to one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another.

[0080] It will be apparent to one of ordinary skill in the art that certain compounds of the present disclosure may exist in tautomeric forms, and all such tautomeric forms of the compounds are within the scope of the present disclosure.

[0081] Unless otherwise indicated, structures depicted herein are intended to include all stereochemical forms of the structure (i.e., the R and S configurations at each asymmetric center). Thus, single stereochemical isomers, as well as enantiomeric and diastereomeric mixtures of the compounds of the present disclosure, are included within the scope of the present disclosure.

[0082] As used herein, "chirally enriched population" refers to a plurality of molecules of the same molecular formula, in which the number or percentage of molecules in the population that contain a particular stereochemical configuration at a particular chiral center is greater than the number or percentage of molecules in the population that would be expected to contain the same particular stereochemical configuration at the same particular chiral center if the particular chiral center were stereorandom. A chirally enriched population of molecules that has multiple chiral centers in each molecule may contain one or more stereorandom chiral centers. In certain embodiments, the molecule is a modified oligonucleotide. In certain embodiments, the molecule is a compound that includes a modified oligonucleotide.

[0083] 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, hydrogen has been replaced by deuterium or tritium, or carbon has been replaced by 13 C or 14 Compounds having the structures of the present invention except for the substitution of a C-rich carbon are within the scope of this disclosure.

[0084] As used herein, "stereorandom chiral center" refers to a chiral center that has random stereochemical configuration with respect to a population of molecules of the same molecular formula. For example, in a population of molecules that includes stereorandom chiral centers, the number of molecules that have stereorandom chiral centers in the (S) configuration may be, but is not necessarily, the same as the number of molecules that have stereorandom chiral centers in the (R) configuration. The stereochemical configuration of a chiral center is considered random when it is the result of a synthetic method that is not designed to control the stereochemical configuration. In certain embodiments, the stereorandom chiral center is a stereorandom phosphorothioate internucleoside linkage.

[0085] Specific 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, expression of PKK is inhibited. In certain embodiments, translation of PKK is inhibited. In certain embodiments, activity of PKK is inhibited. In certain embodiments, expression, translation or activity of PKK is reduced by at least 10% compared to expression, translation or activity in an untreated sample or a control sample. For example, in certain embodiments, expression, translation or activity of PKK 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% compared to expression, translation or activity in an untreated sample or a control sample. In certain embodiments, the expression, translation or activity of PKK 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).

[0086] In certain aspects, the present disclosure relates to compounds targeting PKK nucleic acids. In certain embodiments, the PKK nucleic acids have the sequences shown in GENBANK Accession Nos. NM_000892.5 (herein incorporated as SEQ ID NO:1), NG_012095.2 truncated from 23529-54493 (herein incorporated as SEQ ID NO:2), XM_017008181.1 (herein incorporated as SEQ ID NO:3), NC_000004.12 truncated from 186215714-186258477 (herein incorporated as SEQ ID NO:4), NM_001318394.2 (herein incorporated as SEQ ID NO:5) and NM_001318396.2 (herein incorporated as SEQ ID NO:6).

[0087] 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.

[0088] Certain embodiments provide compounds comprising a modified oligonucleotide having a nucleobase sequence that includes 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, or at least 23 consecutive nucleobases of any of the nucleobase sequences of SEQ ID NOs: 10-313, 626, 627, and 628 (e.g., a modified oligonucleotide having a length of 14-30, e.g., 14-23, linked nucleosides).

[0089] Certain embodiments provide compounds comprising a modified oligonucleotide having a nucleobase sequence comprising any one of SEQ ID NOs: 10-313, 626, 627, and 628 (e.g., a modified oligonucleotide having a length of 14-30, e.g., 14-23, linked nucleosides).

[0090] 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.

[0091] 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.

[0092] Certain embodiments provide a compound comprising a first modified oligonucleotide (e.g., a first modified oligonucleotide having a length of 14 to 30, e.g., 14 to 23 nucleosides linked together) having a nucleobase sequence including 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, or at least 23 consecutive nucleobases of any of the nucleobase sequences of SEQ ID NOs: 10 to 631, and a second modified oligonucleotide (e.g., a second modified oligonucleotide having a length of 14 to 30, e.g., 14 to 23 nucleosides linked together) having a region complementary to the first modified oligonucleotide.

[0093] In certain embodiments, the compound comprises a first modified oligonucleotide 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, or at least 23 consecutive nucleobases of any of the nucleobase sequences shown in Tables 2-4, 6, and 8 (e.g., a first modified oligonucleotide having a length of 14 to 30, e.g., 14 to 23, nucleosides linked together), and a second modified oligonucleotide having a region complementary to the first modified oligonucleotide (e.g., a second modified oligonucleotide having a length of 14 to 30, e.g., 14 to 23, nucleosides linked together).

[0094] Certain embodiments provide a compound comprising a first modified oligonucleotide having a nucleobase sequence including any one of SEQ ID NOs: 10 to 631 (e.g., a first modified oligonucleotide having a length of 14 to 30, e.g., 14 to 23, nucleosides linked together) and a second modified oligonucleotide having a region complementary to the first modified oligonucleotide (e.g., a second modified oligonucleotide having a length of 14 to 30, e.g., 14 to 23, nucleosides linked together).

[0095] Certain embodiments provide a compound comprising a first modified oligonucleotide having a nucleic acid base sequence selected from any one of SEQ ID NOs: 10 to 631, and a second modified oligonucleotide having a length of 19 to 23 linked nucleosides, the second modified oligonucleotide having a region complementary to the first modified oligonucleotide.

[0096] In certain embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide having a length of 14-30, e.g., 14-23 linked nucleosides) having a nucleobase sequence that includes 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 consecutive nucleobases of any of the nucleobase sequences of SEQ ID NOs: 307, 312, or 626. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide having a length of 14-30, e.g., 14-23 linked nucleosides) having a nucleobase sequence that includes 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 consecutive nucleobases of any of the nucleobase sequences of SEQ ID NOs: 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.

[0097] In certain embodiments, the modified oligonucleotide or first modified oligonucleotide of any of the above compounds has at least 80%, at least 85%, at least 90% or at least 95% complementarity or identity over its length with SEQ ID NO: 1, 3, 5 or 6. In certain embodiments, the modified oligonucleotide or first modified oligonucleotide has at least one, at least two, at least three mismatches with a region of SEQ ID NO: 1, 3, 5 or 6. In certain embodiments, the region of complementarity between the first modified oligonucleotide, i.e., the first strand, and the second modified oligonucleotide, i.e., the second strand, is 14-30 nucleosides long. In certain embodiments, the region of complementarity between the first modified oligonucleotide, i.e., the first strand, and the second modified oligonucleotide, i.e., the second strand, is 14-23 nucleosides long. In certain embodiments, the complementary region between the first modified oligonucleotide, i.e., the first strand, and the second modified oligonucleotide, i.e., the second strand, is 19-23 nucleosides long. In certain embodiments, the complementary region between the first modified oligonucleotide, i.e., the first strand, and the second modified oligonucleotide, i.e., the second strand, is 21-23 nucleosides long. In certain embodiments, the first modified oligonucleotide is fully complementary to the second modified oligonucleotide.

[0098] In certain embodiments, the modified oligonucleotide or the first modified oligonucleotide of any of the above compounds comprises at least one modification selected from the group consisting of modified internucleoside linkages, modified sugars, and modified nucleobases. In certain embodiments, the second modified oligonucleotide of any of the above compounds comprises at least one modification selected from the group consisting of modified internucleoside linkages, modified sugars, and modified nucleobases. 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 the methylphosphonate internucleoside linkage is at the 3' end of the first or second modified oligonucleotide or at the 5' end of the first modified oligonucleotide. In certain embodiments, the modified sugar comprises a modification selected from the group consisting of halogens, alkoxy groups, and bicyclic sugars. 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 halogen, alkoxy group, and 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 10 or fewer 2'-F sugar modifications. In certain embodiments, the second modified oligonucleotide comprises 5 or fewer 2'-F sugar modifications.

[0099] In certain embodiments, the compound of any of the above embodiments 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 a second modified oligonucleotide or a sense oligonucleotide. In certain embodiments, the one or more GalNAc are attached to the 2' or 3' position of the ribosyl ring. In certain embodiments, the one or more GalNAc are attached to the 5' nucleoside of the modified oligonucleotide. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is selected from the following formula, or a salt, solvate, or hydrate thereof, where R is a portion of the modified oligonucleotide other than the 5' nucleoside. [ka] [ka] [ka] [ka]

[0100] In certain embodiments, R' is O. In certain embodiments, R' is S. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of Formula I and R' is O. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of Formula I and R' is S. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of Formula II and R' is O. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of Formula II and R' is S. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of Formula III and R' is O. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of Formula III and R' is S. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of Formula IV and R' is O. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of Formula IV and R' is S. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of formula V and R' is O. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of formula V and R' is S. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of formula VI and R' is O. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of formula VI and R' is S. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of formula VII and R' is O. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of formula VII and R' is S. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of formula VIII and R' is O. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of formula VIII and R' is S.

[0101] Certain embodiments provide a compound comprising a first modified oligonucleotide selected from any one of Reference ID Numbers IA0812-821 and a second modified oligonucleotide having a length of 14 to 21 linked nucleosides, the second modified oligonucleotide being fully complementary to the first modified oligonucleotide.

[0102] Certain embodiments provide a compound comprising a first modified oligonucleotide consisting of IA0813 and a second modified oligonucleotide consisting of IS1002.

[0103] Certain embodiments provide a compound comprising a first modified oligonucleotide consisting of IA0818 and a second modified oligonucleotide consisting of IS1007.

[0104] Certain embodiments provide a compound comprising a first modified oligonucleotide consisting of IA0818 and a second modified oligonucleotide consisting of IS1068.

[0105] Certain embodiments provide a compound comprising a first modified oligonucleotide selected from any one of Reference ID Numbers IA0864-866 and a second modified oligonucleotide having a length of 14 to 21 linked nucleosides, the second modified oligonucleotide being fully complementary to the first modified oligonucleotide.

[0106] Certain embodiments provide a compound comprising a first modified oligonucleotide selected from Reference ID Nos. IA0818 and IA0864 and a second modified oligonucleotide selected from Reference ID Nos. IS1058 and IS1059.

[0107] 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.

[0108] 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.

[0109] In certain embodiments, the compound of any of the above embodiments is in the form of a pharma- ceutically acceptable salt. In certain embodiments, the pharma- ceutically acceptable salt is a sodium salt. In certain embodiments, the pharma- ceutically acceptable salt is a potassium salt.

[0110] An embodiment provided by the present invention is a modified oligonucleotide according to the chemical structure: [ka] or a pharmaceutically acceptable salt or stereoisomer thereof. In certain embodiments, reference ID number IA0818 is a modified oligonucleotide according to the above chemical structure, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0111] An embodiment provided by the present invention is a modified oligonucleotide according to the chemical structure: [ka] or a pharmaceutically acceptable salt or stereoisomer thereof. In certain embodiments, reference ID number IS1058 is a modified oligonucleotide according to the above chemical structure, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0112] An embodiment provided by the present invention is a modified oligonucleotide according to the chemical structure: [ka] or a pharmaceutically acceptable salt or stereoisomer thereof. In certain embodiments, reference ID number IA0864 is a modified oligonucleotide according to the above chemical structure, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0113] An embodiment provided by the present invention is a modified oligonucleotide according to the chemical structure: [ka] or a pharmaceutically acceptable salt or stereoisomer thereof. In certain embodiments, Reference ID No. IS1059 is a modified oligonucleotide according to the above chemical structure, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0114] In certain embodiments, the pharma- ceutically acceptable salt of the modified oligonucleotides provided herein is a sodium or potassium salt.

[0115] An embodiment provided herein is a sodium salt of a modified oligonucleotide according to the chemical structure: [ka] or a stereoisomer thereof. In certain embodiments, reference ID number IA0818 is a modified oligonucleotide according to the above chemical structure or a stereoisomer thereof.

[0116] An embodiment provided herein is a sodium salt of a modified oligonucleotide according to the chemical structure: [ka] or a stereoisomer thereof. In certain embodiments, Reference ID No. IS1058 is a modified oligonucleotide according to the above chemical structure or a stereoisomer thereof.

[0117] An embodiment provided herein is a sodium salt of a modified oligonucleotide according to the chemical structure: [ka] or a stereoisomer thereof. In certain embodiments, reference ID number IA0864 is a modified oligonucleotide according to the above chemical structure or a stereoisomer thereof.

[0118] An embodiment provided herein is a sodium salt of a modified oligonucleotide according to the chemical structure: [ka] or a stereoisomer thereof. In certain embodiments, Reference ID No. IS1059 is a modified oligonucleotide according to the above chemical structure or a stereoisomer thereof.

[0119] An embodiment provided herein is a compound according to the chemical structure: [ka] or a pharmaceutically acceptable salt or stereoisomer thereof. In certain embodiments, compound number RD2423 is a compound according to the above chemical structure, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0120] An embodiment provided herein is a compound according to the chemical structure: [ka] or a pharmaceutically acceptable salt or stereoisomer thereof. In certain embodiments, compound number RD2424 is a compound according to the above chemical structure, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0121] In certain embodiments, a pharma- ceutically acceptable salt of a compound provided herein is a sodium or potassium salt.

[0122] An embodiment provided herein is a sodium salt of a compound according to the following chemical structure: [ka] or a stereoisomer thereof. In certain embodiments, compound number RD2423 is a compound according to the above chemical structure or a stereoisomer thereof.

[0123] An embodiment provided herein is a sodium salt of a compound according to the following chemical structure: [ka] or a stereoisomer thereof. In certain embodiments, compound number RD2424 is a compound according to the above chemical structure or a stereoisomer thereof.

[0124] In certain embodiments, the present invention provides a population of modified oligonucleotides, in which any of the phosphorothioate internucleoside linkages of the modified oligonucleotides are stereorandom. In certain embodiments, the present invention provides a population of compounds in which any of the phosphorothioate internucleoside linkages of the modified oligonucleotides are stereorandom.

[0125] Certain embodiments provide a composition comprising a compound of any one of the above embodiments and a pharma- ceutically acceptable carrier.

[0126] Certain embodiments provide a composition comprising a compound of any of the above embodiments for use in therapy.

[0127] Certain embodiments provide a method of treating, preventing or ameliorating a disease, disorder or condition associated with dysregulation of the PKK and / or kallikrein pathway in an individual, comprising administering to the individual a compound that targets PKK to treat, prevent or ameliorate the disease, disorder or condition. In certain embodiments, a compound or composition of any of the above embodiments is administered to the 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, eyelid angioedema, ocular edema, macular edema, cerebral edema, thrombosis, embolism, thromboembolism, deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke or infarction. In certain embodiments, administering the compound inhibits, reduces or ameliorates an inflammatory or thrombotic disease, disorder or condition, or a symptom thereof. In certain embodiments, administration of the compound inhibits, reduces or ameliorates hereditary angioedema (HAE), edema, angioedema, swelling, eyelid angioedema, ocular edema, macular edema, cerebral edema, thrombosis, embolism, thromboembolism, deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke or infarction, or symptoms thereof.

[0128] In certain embodiments, a compound of any of the above embodiments, or a composition comprising the compound, is administered to an individual in a therapeutically effective amount. In certain embodiments, a composition comprising the compound of any of the above embodiments is administered to an individual at a dosage level sufficient to deliver about 1-100 mg per kg of body weight of the individual. In certain embodiments, a compound of any of the above embodiments, or a composition comprising the compound, 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 per day, up to that dosage level or dose.

[0129] In certain embodiments, a composition comprising a compound of any of the above embodiments is administered to an individual once a day, once a week, once a month, once a quarter, or once a year. In certain embodiments, a compound of any of the above embodiments, or a composition comprising the compound, is administered to an individual about once a quarter (i.e., once every three months) to about once a year. In certain embodiments, a compound of any of the above embodiments, or a composition comprising the compound, is administered to an individual about once a quarter, about once every six months, or about once a year.

[0130] Certain embodiments provide a method for inhibiting the expression of PKK in a cell, comprising contacting the cell with a compound that targets PKK, thereby inhibiting the 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 inflammatory or thrombotic disease, disorder or condition, or symptoms thereof.In certain embodiments, the individual has or is at risk of having hereditary angioedema (HAE), edema, angioedema, swelling, eyelid angioedema, ocular edema, macular edema, cerebral edema, thrombosis, embolism, thromboembolism, deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke or infarction.

[0131] Certain embodiments provide a method for reducing or suppressing inflammatory or thrombotic disease, disorder or condition, or its symptoms in an individual, comprising administering a compound that targets PKK to the individual, thereby reducing or suppressing inflammatory or thrombotic disease, disorder or condition, or its symptoms in the individual.In certain embodiments, the individual has or is at risk of having hereditary angioedema (HAE), edema, angioedema, swelling, eyelid angioedema, ocular edema, macular edema, cerebral edema, thrombosis, embolism, thromboembolism, deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke or infarction.In certain embodiments, the compound is a compound that targets PKK.In certain embodiments, the compound is any of the above compounds.In certain embodiments, the compound or composition is administered parenterally.

[0132] Certain embodiments provide for the use of compound targeting PKK for the treatment, prevention or improvement of disease, disorder or pathology related to PKK.In certain embodiments, the disease, disorder or pathology is inflammatory disease, thrombotic disease, hereditary angioedema (HAE), edema, angioedema, swelling, eyelid angioedema, ocular edema, macular edema, cerebral edema, thrombosis, embolism, thromboembolism, deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke or infarction.In certain embodiments, the compound is a compound targeting PKK.In certain embodiments, the compound is any of the above-mentioned compounds.

[0133] Certain embodiments provide the use of the compound that targets PKK for the manufacture of medicine for treating, preventing or improving the disease, disorder or pathology associated with PKK.In certain embodiments, the disease, disorder or pathology is inflammatory disease, thrombotic disease, hereditary angioedema (HAE), edema, angioedema, swelling, eyelid angioedema, ocular edema, macular edema, cerebral edema, thrombosis, embolism, thromboembolism, deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke or infarction.In certain embodiments, the compound is a compound that targets PKK.In certain embodiments, the compound is any of the above-mentioned compounds.

[0134] Certain Indications In certain aspects, the present disclosure relates to a method for inhibiting the expression of PKK, which may be useful for treating, preventing or ameliorating diseases, disorders or conditions associated with PKK in an individual by administering 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, oligomeric compound or oligonucleotide that targets PKK.

[0135] In certain aspects, the present disclosure relates to treating, preventing or ameliorating a disease, disorder or condition associated with PKK. In certain embodiments, the disease, disorder or condition associated with PKK that can be treated, prevented and / or ameliorated by the methods provided herein includes inflammatory disease, thrombotic disease, hereditary angioedema (HAE), edema, angioedema, swelling, eyelid angioedema, ocular edema, macular edema, cerebral edema, thrombosis, embolism, thromboembolism, deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke or infarction. Certain compounds provided herein are directed to compounds and compositions that reduce inflammatory diseases, thrombotic diseases, hereditary angioedema (HAE), edema, angioedema, swelling, eyelid angioedema, ocular edema, macular edema, cerebral edema, thrombosis, embolism, thromboembolism, deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke or infarction in an animal.

[0136] In certain embodiments, the method for treating, preventing or ameliorating a disease, disorder or condition associated with PKK in an individual comprises administering a compound comprising a PKK-specific inhibitor to the individual, 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 an inflammatory disease or a thrombotic disease.In certain embodiments, the compound comprises an antisense oligonucleotide that targets PKK.In certain embodiments, the compound comprises an oligonucleotide that targets PKK. In certain embodiments, the compound comprises a modified oligonucleotide 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 consecutive nucleobases of any of the nucleobase sequences of SEQ ID NOs: 10-313, 626, 627, and 628 (e.g., a modified oligonucleotide having a length of 14-30, e.g., a modified oligonucleotide having a length of 14-23 nucleosides linked together). In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence comprising any one of the nucleobase sequences of SEQ ID NOs: 10-313, 626, 627, and 628 (e.g., a modified oligonucleotide having a length of 14-30, e.g., a modified oligonucleotide having a length of 14-23 nucleosides linked together). In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence selected from any one of the nucleobase sequences of SEQ ID NOs: 10-313, 626, 627, and 628. In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence comprising any one of SEQ ID NOs: 307, 312, and 626 (e.g., a modified oligonucleotide having a length of 14-30, e.g., 14-23 linked nucleosides). In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence comprising any one of SEQ ID NOs: 307, 312, and 626.

[0137] In any of the above embodiments, the compound can be single-stranded or double-stranded. In certain embodiments, the single-stranded compound can be 14-30, 14-23, 14-20, 16-20, or 14-16 linked nucleosides in length. In certain embodiments, the 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, the double-stranded compound can include two oligonucleotides of the same or different length, as described elsewhere herein. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide having a length of 14-30, e.g., 14-23 linked nucleosides) having a nucleobase sequence that includes 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 consecutive nucleobases of the nucleobase sequence of SEQ ID NO: 307, 312, or 626. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide having a length of 14-30, e.g., 14-23 linked nucleosides) having a nucleobase sequence that includes 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 consecutive nucleobases of the nucleobase sequence of SEQ ID NO: 468, 611, 616, 619, or 629. In certain embodiments, the 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, the 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.

[0138] In any of the above embodiments, the compound can be an antisense oligonucleotide or oligomer compound. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleic acid base sequence including 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 consecutive nucleic acid bases of any of the nucleic acid base sequences of SEQ ID NOs: 10-631 (e.g., a first modified oligonucleotide having a length of 14-30, e.g., a first modified oligonucleotide having a length of 14-23 nucleosides linked together), and a second modified oligonucleotide having a region complementary to the first modified oligonucleotide (e.g., a second modified oligonucleotide having a length of 14-30, e.g., a second modified oligonucleotide having a length of 14-23 nucleosides linked together). In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleic acid base sequence comprising any one of SEQ ID NOs: 10-313, 626, 627, and 628 (e.g., a first modified oligonucleotide having a length of 14-30, e.g., 14-23 nucleosides linked together), and a second modified oligonucleotide having a region complementary to the first modified oligonucleotide (e.g., a second modified oligonucleotide having a length of 14-30, e.g., 14-23 nucleosides linked together). In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleic acid base sequence selected from any one of SEQ ID NOs: 10-631, and a second modified oligonucleotide having a length of 19-23 nucleosides linked together, the second modified oligonucleotide having a region complementary to the first modified oligonucleotide. In certain embodiments, the compound is administered parenterally to the individual. In certain embodiments, administration of the compound ameliorates, maintains or prevents inflammatory disease, thrombotic disease, hereditary angioedema (HAE), edema, angioedema, swelling, eyelid angioedema, ocular edema, macular edema, cerebral edema, thrombosis, embolism, thromboembolism, deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke or infarction in an animal.

[0139] In certain embodiments, the method of treating, preventing or improving inflammatory disease, thrombotic disease, hereditary angioedema (HAE), edema, angioedema, swelling, eyelid angioedema, ocular edema, macular edema, cerebral edema, thrombosis, embolism, thromboembolism, deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke or infarction in an animal comprises administering a compound comprising a PKK-specific inhibitor to the individual, thereby treating, preventing or improving inflammatory disease, thrombotic disease, hereditary angioedema (HAE), edema, angioedema, swelling, eyelid angioedema, ocular edema, macular edema, cerebral edema, thrombosis, embolism, thromboembolism, deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke or infarction.In certain embodiments, the compound comprises an antisense oligonucleotide that targets PKK.In certain embodiments, the compound comprises an oligonucleotide that targets PKK. In certain embodiments, the compound comprises a modified oligonucleotide 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 consecutive nucleobases of any of the nucleobase sequences of SEQ ID NOs: 10-313, 626, 627, and 628 (e.g., a modified oligonucleotide having a length of 14-30, e.g., a modified oligonucleotide having a length of 14-23 nucleosides linked together). In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence comprising any one of the nucleobase sequences of SEQ ID NOs: 10-313, 626, 627, and 628 (e.g., a modified oligonucleotide having a length of 14-30, e.g., a modified oligonucleotide having a length of 14-23 nucleosides linked together). In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence selected from any one of the nucleobase sequences of SEQ ID NOs: 10-313, 626, 627, and 628. In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence comprising any one of SEQ ID NOs: 307, 312, and 626 (e.g., a modified oligonucleotide having a length of 14 to 30, e.g., 14 to 23 linked nucleosides.In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence selected from any one of SEQ ID NOs: 307, 312, and 626. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide having a length of 14-30, e.g., 14-23 linked nucleosides) having a nucleobase sequence that includes 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 NOs: 307, 312, or 626. In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence that includes 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 consecutive nucleobases of the nucleobase sequence of SEQ ID NO: 468, 611, 616, 619, or 629 (e.g., a modified oligonucleotide having a length of 14 to 30, e.g., 14 to 23 linked nucleosides). In certain embodiments, the 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, the 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 the nucleobase sequence of SEQ ID NO: 626 and a second modified oligonucleotide having the nucleobase sequence of SEQ ID NO: 629. In any of the above embodiments, the compound can be single-stranded or double-stranded. In any of the above embodiments, the compound can be an antisense oligonucleotide or an oligomeric compound.In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence including 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, or at least 23 consecutive nucleobases of any of the nucleobase sequences of SEQ ID NOs: 10-631 (e.g., a first modified oligonucleotide having a length of 14 to 30, e.g., 14 to 23, nucleosides linked together), and a second modified oligonucleotide having a region complementary to the first modified oligonucleotide (e.g., a second modified oligonucleotide having a length of 14 to 30, e.g., 14 to 23, nucleosides linked together). In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleic acid base sequence comprising any one of SEQ ID NOs: 10 to 631 (e.g., a first modified oligonucleotide having a length of 14 to 30, e.g., 14 to 23 nucleosides linked together) and a second modified oligonucleotide having a region complementary to the first modified oligonucleotide (e.g., a second modified oligonucleotide having a length of 14 to 30, e.g., 14 to 23 nucleosides linked together). In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleic acid base sequence selected from any one of SEQ ID NOs: 10 to 631 and a second modified oligonucleotide having a length of 19 to 23 nucleosides linked together, the second modified oligonucleotide having a region complementary to the first modified oligonucleotide. In certain embodiments, administering the compound improves, maintains or prevents inflammatory disease, thrombotic disease, hereditary angioedema (HAE), edema, angioedema, swelling, eyelid angioedema, ocular edema, macular edema, cerebral edema, thrombosis, embolism, thromboembolism, deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke or infarction in an animal. In certain embodiments, the individual is identified as having or at risk of having a disease associated with PKK.

[0140] In certain embodiments, the method of inhibiting the expression of PKK in an individual who is or is at risk of developing a disease, disorder or condition associated with PKK comprises administering to the individual a compound comprising a PKK-specific inhibitor, thereby inhibiting the expression of PKK in the individual.In certain embodiments, administering the compound inhibits the 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 is or is at risk of developing an inflammatory disease, a thrombotic disease, hereditary angioedema (HAE), edema, angioedema, swelling, eyelid angioedema, ocular edema, macular edema, cerebral edema, thrombosis, embolism, thromboembolism, deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke or infarction.In certain embodiments, the compound comprises an antisense oligonucleotide that targets PKK.In certain embodiments, the compound comprises an oligonucleotide that targets PKK. In certain embodiments, the compound comprises a modified oligonucleotide 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 consecutive nucleobases of any of the nucleobase sequences of SEQ ID NOs: 10-313, 626, 627, and 628 (e.g., a modified oligonucleotide having a length of 14-30, e.g., a modified oligonucleotide having a length of 14-23 nucleosides linked together). In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence comprising any one of the nucleobase sequences of SEQ ID NOs: 10-313, 626, 627, and 628 (e.g., a modified oligonucleotide having a length of 14-30, e.g., a modified oligonucleotide having a length of 14-23 nucleosides linked together). In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence selected from any one of the nucleobase sequences of SEQ ID NOs: 10-313, 626, 627, and 628.In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence selected from any one of SEQ ID NOs: 307, 312, and 626 (e.g., a modified oligonucleotide having a length of 14-30, e.g., 14-23 linked nucleosides). In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence selected from any one of SEQ ID NOs: 307, 312, and 626. In certain embodiments, the compound comprises a modified oligonucleotide 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 consecutive nucleobases of the nucleobase sequence of SEQ ID NOs: 307, 312, or 626 (e.g., a modified oligonucleotide having a length of 14-30, e.g., 14-23 linked nucleosides). In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence that includes 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 consecutive nucleobases of the nucleobase sequence of SEQ ID NO: 468, 611, 616, 619, or 629 (e.g., a modified oligonucleotide having a length of 14 to 30, e.g., 14 to 23 linked nucleosides). In certain embodiments, the 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, the 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 the nucleobase sequence of SEQ ID NO:626 and a second modified oligonucleotide having the nucleobase sequence of SEQ ID NO:629.In any of the above embodiments, the compound can be single-stranded or double-stranded. In any of the above embodiments, the compound can be an antisense oligonucleotide or oligomeric compound. In certain embodiments, the compound includes a first modified oligonucleotide (e.g., a first modified oligonucleotide having a length of 14 to 30, e.g., 14 to 23 nucleosides linked together) having a nucleobase sequence including 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 consecutive nucleobases of any of the nucleobase sequences of SEQ ID NOs: 10 to 631, and a second modified oligonucleotide (e.g., a second modified oligonucleotide having a length of 14 to 30, e.g., 14 to 23 nucleosides linked together) having a region complementary to the first modified oligonucleotide. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleic acid base sequence comprising any one of SEQ ID NOs: 10 to 631 (e.g., a first modified oligonucleotide having a length of 14 to 30, e.g., 14 to 23 nucleosides linked together) and a second modified oligonucleotide having a region complementary to the first modified oligonucleotide (e.g., a second modified oligonucleotide having a length of 14 to 30, e.g., 14 to 23 nucleosides linked together). In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleic acid base sequence selected from any one of SEQ ID NOs: 10 to 631 and a second modified oligonucleotide having a length of 19 to 23 nucleosides linked together, the second modified oligonucleotide having a region complementary to the first modified oligonucleotide. In certain embodiments, the compound is administered parenterally to the individual. In certain embodiments, administration of the compound ameliorates, maintains or prevents inflammatory diseases, thrombotic diseases, hereditary angioedema (HAE), edema, angioedema, swelling, eyelid angioedema, ocular edema, macular edema, cerebral edema, thrombosis, embolism, thromboembolism, deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke or infarction.

[0141] In certain embodiments, the method of inhibiting the expression of PKK in a cell comprises contacting the cell with a compound comprising a PKK-specific inhibitor, thereby inhibiting the expression of PKK in the cell.In certain embodiments, the cell is a hepatocyte.In certain embodiments, the cell is a cell in the liver.In certain embodiments, the cell is a cell in the liver of an individual who has or is at risk of having inflammatory disease, thrombotic disease, hereditary angioedema (HAE), edema, angioedema, swelling, eyelid angioedema, ocular edema, macular edema, cerebral edema, thrombosis, embolism, thromboembolism, deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke or infarction.In certain embodiments, the compound comprises an antisense oligonucleotide that targets PKK.In certain embodiments, the compound comprises an oligonucleotide that targets PKK. In certain embodiments, the compound comprises a modified oligonucleotide 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 consecutive nucleobases of any of the nucleobase sequences of SEQ ID NOs: 10-313, 626, 627, and 628 (e.g., a modified oligonucleotide having a length of 14-30, e.g., a modified oligonucleotide having a length of 14-23 nucleosides linked together). In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence comprising any one of the nucleobase sequences of SEQ ID NOs: 10-313, 626, 627, and 628 (e.g., a modified oligonucleotide having a length of 14-30, e.g., a modified oligonucleotide having a length of 14-23 nucleosides linked together). In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence selected from any one of the nucleobase sequences of SEQ ID NOs: 10-313, 626, 627, and 628. In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence comprising any one of SEQ ID NOs: 307, 312, and 626 (e.g., a modified oligonucleotide having a length of 14 to 30, e.g., 14 to 23 linked nucleosides.In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence selected from any one of SEQ ID NOs: 307, 312, and 626. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide having a length of 14-30, e.g., 14-23 linked nucleosides) having a nucleobase sequence that includes 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 NOs: 307, 312, or 626. In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence that includes 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 consecutive nucleobases of the nucleobase sequence of SEQ ID NO: 468, 611, 616, 619, or 629 (e.g., a modified oligonucleotide having a length of 14 to 30, e.g., 14 to 23 linked nucleosides). In certain embodiments, the 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, the 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 the nucleobase sequence of SEQ ID NO:626 and a second modified oligonucleotide having the nucleobase sequence of SEQ ID NO:629.

[0142] In any of the above embodiments, the compound can be single-stranded or double-stranded. In any of the above embodiments, the compound can be an antisense oligonucleotide or oligomeric compound. In certain embodiments, the compound includes a first modified oligonucleotide (e.g., a first modified oligonucleotide having a length of 14 to 30, e.g., 14 to 23 nucleosides linked together) having a nucleobase sequence including 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 consecutive nucleobases of any of the nucleobase sequences of SEQ ID NOs: 10 to 631, and a second modified oligonucleotide (e.g., a second modified oligonucleotide having a length of 14 to 30, e.g., 14 to 23 nucleosides linked together) having a region complementary to the first modified oligonucleotide. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleic acid base sequence comprising any one of SEQ ID NOs: 10 to 631 (e.g., a first modified oligonucleotide having a length of 14 to 30, e.g., 14 to 23 nucleosides linked together) and a second modified oligonucleotide having a region complementary to the first modified oligonucleotide (e.g., a second modified oligonucleotide having a length of 14 to 30, e.g., 14 to 23 nucleosides linked together). In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleic acid base sequence selected from any one of SEQ ID NOs: 10 to 631 and a second modified oligonucleotide having a length of 19 to 23 nucleosides linked together, the second modified oligonucleotide having a region complementary to the first modified oligonucleotide.

[0143] In certain embodiments, a method of reducing or inhibiting an inflammatory disease, a thrombotic disease, hereditary angioedema (HAE), edema, angioedema, swelling, eyelid angioedema, ocular edema, macular edema, cerebral edema, thrombosis, embolism, thromboembolism, deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke, or infarction in an individual who has or is at risk for a disease associated with PKK comprises reducing or inhibiting an inflammatory disease, a thrombotic disease, hereditary angioedema (HAE), edema, angioedema, swelling, eyelid angioedema, ocular edema, macular edema, cerebral edema, thrombosis, embolism, thromboembolism, deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke, or infarction in the individual by administering to the individual a compound comprising a PKK-specific inhibitor. In certain embodiments, the individual is at risk of having or will have inflammatory disease, thrombotic disease, hereditary angioedema (HAE), edema, angioedema, swelling, eyelid angioedema, ocular edema, macular edema, cerebral edema, thrombosis, embolism, thromboembolism, deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke or infarction.In certain embodiments, the compound comprises the antisense oligonucleotide that targets PKK.In certain embodiments, the compound comprises the oligonucleotide that targets PKK. In certain embodiments, the compound comprises a modified oligonucleotide 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 consecutive nucleobases of any of the nucleobase sequences of SEQ ID NOs: 10-313, 626, 627, and 628 (e.g., a modified oligonucleotide having a length of 14-30, e.g., a modified oligonucleotide having a length of 14-23 nucleosides linked together). In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence comprising any one of the nucleobase sequences of SEQ ID NOs: 10-313, 626, 627, and 628 (e.g., a modified oligonucleotide having a length of 14-30, e.g., a modified oligonucleotide having a length of 14-23 nucleosides linked together). In certain embodiments, the compound comprises a modified oligonucleotide selected from any one of the nucleobase sequences of SEQ ID NOs: 10-313, 626, 627, and 628.In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence comprising any one of SEQ ID NOs: 307, 312, and 626 (e.g., a modified oligonucleotide having a length of 14-30, e.g., 14-23 linked nucleosides). In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence selected from any one of SEQ ID NOs: 307, 312, and 626. In certain embodiments, the compound comprises a modified oligonucleotide 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 consecutive nucleobases of the nucleobase sequence of SEQ ID NOs: 307, 312, or 626 (e.g., a modified oligonucleotide having a length of 14-30, e.g., 14-23 linked nucleosides). In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence that includes 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 consecutive nucleobases of the nucleobase sequence of SEQ ID NO: 468, 611, 616, 619, or 629 (e.g., a modified oligonucleotide having a length of 14 to 30, e.g., 14 to 23 linked nucleosides). In certain embodiments, the 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, the 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 the nucleobase sequence of SEQ ID NO:626 and a second modified oligonucleotide having the nucleobase sequence of SEQ ID NO:629.In any of the above embodiments, the compound can be single-stranded or double-stranded. In any of the above embodiments, the compound can be an antisense oligonucleotide or oligomeric compound. In certain embodiments, the compound includes a first modified oligonucleotide (e.g., a first modified oligonucleotide having a length of 14 to 30, e.g., 14 to 23 nucleosides linked together) having a nucleobase sequence including 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 consecutive nucleobases of any of the nucleobase sequences of SEQ ID NOs: 10 to 631, and a second modified oligonucleotide (e.g., a second modified oligonucleotide having a length of 14 to 30, e.g., 14 to 23 nucleosides linked together) having a region complementary to the first modified oligonucleotide. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence comprising any one of SEQ ID NOs: 10-631 (e.g., a first modified oligonucleotide having a length of 14-30, e.g., 14-23 nucleosides linked together) and a second modified oligonucleotide having a region complementary to the first modified oligonucleotide (e.g., a second modified oligonucleotide having a length of 14-30, e.g., 14-23 nucleosides linked together). In certain embodiments, the 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 having a length of 19-23 nucleosides linked together, the second modified oligonucleotide having a region complementary to the first modified oligonucleotide. In certain embodiments, the compound is administered parenterally to the individual. In certain embodiments, the individual is identified as having or at risk of having a disease, disorder, or condition associated with PKK.

[0144] Certain embodiments are directed to compounds that comprise PKK specific inhibitors, and are used to treat diseases, disorders or conditions associated with PKK.In certain embodiments, the disease, disorder or condition is inflammatory disease, thrombotic disease, hereditary angioedema (HAE), edema, angioedema, swelling, eyelid angioedema, ocular edema, macular edema, cerebral edema, thrombosis, embolism, thromboembolism, deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke or infarction.In certain embodiments, the compound comprises antisense oligonucleotides that target PKK.In certain embodiments, the compound comprises oligonucleotides that target PKK. In certain embodiments, the compound comprises a modified oligonucleotide 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 consecutive nucleobases of any of the nucleobase sequences of SEQ ID NOs: 10-313, 626, 627, and 628 (e.g., a modified oligonucleotide having a length of 14-30, e.g., a modified oligonucleotide having a length of 14-23 nucleosides linked together). In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence comprising any one of the nucleobase sequences of SEQ ID NOs: 10-313, 626, 627, and 628 (e.g., a modified oligonucleotide having a length of 14-30, e.g., a modified oligonucleotide having a length of 14-23 nucleosides linked together). In certain embodiments, the compound comprises a modified oligonucleotide selected from any one of the nucleobase sequences of SEQ ID NOs: 10-313, 626, 627, and 628. In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence comprising any one of SEQ ID NOs: 307, 312, and 626 (e.g., a modified oligonucleotide having a length of 14-30, e.g., 14-23 linked nucleosides). In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence selected from any one of SEQ ID NOs: 307, 312, and 626.In certain embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide having a length of 14-30, e.g., 14-23 linked nucleosides) having a nucleobase sequence that includes 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 consecutive nucleobases of the nucleobase sequence of SEQ ID NO: 307, 312, or 626. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide having a length of 14-30, e.g., 14-23 linked nucleosides) having a nucleobase sequence that includes 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 consecutive nucleobases of the nucleobase sequence of SEQ ID NO: 468, 611, 616, 619, or 629. In certain embodiments, the 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, the 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 above embodiments, the compound can be single-stranded or double-stranded. In any of the above embodiments, the compound can be an antisense oligonucleotide or an oligomeric compound.In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence including 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, or at least 23 consecutive nucleobases of any of the nucleobase sequences of SEQ ID NOs: 10-631 (e.g., a first modified oligonucleotide having a length of 14 to 30, e.g., 14 to 23, nucleosides linked together), and a second modified oligonucleotide having a region complementary to the first modified oligonucleotide (e.g., a second modified oligonucleotide having a length of 14 to 30, e.g., 14 to 23, nucleosides linked together). In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleic acid base sequence comprising any one of SEQ ID NOs: 10 to 631 (e.g., a first modified oligonucleotide having a length of 14 to 30, e.g., 14 to 23 nucleosides linked together) and a second modified oligonucleotide having a region complementary to the first modified oligonucleotide (e.g., a second modified oligonucleotide having a length of 14 to 30, e.g., 14 to 23 nucleosides linked together). In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleic acid base sequence selected from any one of SEQ ID NOs: 10 to 631 and a second modified oligonucleotide having a length of 19 to 23 nucleosides linked together, the second modified oligonucleotide having a region complementary to the first modified oligonucleotide. In certain embodiments, the compound is administered parenterally to the individual.

[0145] Certain embodiments are directed to compounds that comprise PKK-specific inhibitors, and are used to reduce or inhibit inflammatory disease, thrombotic disease, hereditary angioedema (HAE), edema, angioedema, swelling, eyelid angioedema, ocular edema, macular edema, cerebral edema, thrombosis, embolism, thromboembolism, deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke or infarction.In certain embodiments, the compounds comprise antisense oligonucleotides that target PKK.In certain embodiments, the compounds comprise oligonucleotides that target PKK. In certain embodiments, the compound comprises a modified oligonucleotide 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 consecutive nucleobases of any of the nucleobase sequences of SEQ ID NOs: 10-313, 626, 627, and 628 (e.g., a modified oligonucleotide having a length of 14-30, e.g., a modified oligonucleotide having a length of 14-23 nucleosides linked together). In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence comprising any one of the nucleobase sequences of SEQ ID NOs: 10-313, 626, 627, and 628 (e.g., a modified oligonucleotide having a length of 14-30, e.g., a modified oligonucleotide having a length of 14-23 nucleosides linked together). In certain embodiments, the compound comprises a modified oligonucleotide selected from any one of the nucleobase sequences of SEQ ID NOs: 10-313, 626, 627, and 628. In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence comprising any one of SEQ ID NOs: 307, 312, and 626 (e.g., a modified oligonucleotide having a length of 14-30, e.g., 14-23 linked nucleosides). In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence selected from any one of SEQ ID NOs: 307, 312, and 626.In certain embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide having a length of 14-30, e.g., 14-23 linked nucleosides) having a nucleobase sequence that includes 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 consecutive nucleobases of the nucleobase sequence of SEQ ID NO: 307, 312, or 626. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide having a length of 14-30, e.g., 14-23 linked nucleosides) having a nucleobase sequence that includes 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 consecutive nucleobases of the nucleobase sequence of SEQ ID NO: 468, 611, 616, 619, or 629. In certain embodiments, the 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, the 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 above embodiments, the compound can be single-stranded or double-stranded. In any of the above embodiments, the compound can be an antisense oligonucleotide or an oligomeric compound.In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence including 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, or at least 23 consecutive nucleobases of any of the nucleobase sequences of SEQ ID NOs: 10-631 (e.g., a first modified oligonucleotide having a length of 14 to 30, e.g., 14 to 23, nucleosides linked together), and a second modified oligonucleotide having a region complementary to the first modified oligonucleotide (e.g., a second modified oligonucleotide having a length of 14 to 30, e.g., 14 to 23, nucleosides linked together). In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleic acid base sequence comprising any one of SEQ ID NOs: 10 to 631 (e.g., a first modified oligonucleotide having a length of 14 to 30, e.g., 14 to 23 nucleosides linked together) and a second modified oligonucleotide having a region complementary to the first modified oligonucleotide (e.g., a second modified oligonucleotide having a length of 14 to 30, e.g., 14 to 23 nucleosides linked together). In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleic acid base sequence selected from any one of SEQ ID NOs: 10 to 631 and a second modified oligonucleotide having a length of 19 to 23 nucleosides linked together, the second modified oligonucleotide having a region complementary to the first modified oligonucleotide.

[0146] Certain embodiments are directed to the use of a compound comprising a PKK-specific inhibitor in the manufacture or preparation of a medicament for treating a disease, disorder or condition associated with PKK. Certain embodiments are directed to the use of a compound comprising a PKK-specific inhibitor in the preparation of a medicament for treating a disease, disorder or condition associated with PKK. In certain embodiments, the disease is an inflammatory disease or a thrombotic disease. In certain embodiments, the disease is hereditary angioedema (HAE), edema, angioedema, swelling, eyelid angioedema, ocular edema, macular edema, cerebral edema, thrombosis, embolism, thromboembolism, deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke or infarction. In certain embodiments, the compound comprises an antisense oligonucleotide targeting PKK. In certain embodiments, the compound comprises an oligonucleotide targeting PKK. In certain embodiments, the compound comprises a modified oligonucleotide 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 consecutive nucleobases of any of the nucleobase sequences of SEQ ID NOs: 10-313, 626, 627, and 628 (e.g., a modified oligonucleotide having a length of 14-30, e.g., a modified oligonucleotide having a length of 14-23 nucleosides linked together). In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence comprising any one of the nucleobase sequences of SEQ ID NOs: 10-313, 626, 627, and 628 (e.g., a modified oligonucleotide having a length of 14-30, e.g., a modified oligonucleotide having a length of 14-23 nucleosides linked together). In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence selected from any one of the nucleobase sequences of SEQ ID NOs: 10-313, 626, 627, and 628. In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence comprising any one of SEQ ID NOs: 307, 312, and 626 (e.g., a modified oligonucleotide having a length of 14 to 30, e.g., 14 to 23 linked nucleosides.In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence selected from any one of SEQ ID NOs: 307, 312, and 626. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide having a length of 14-30, e.g., 14-23 linked nucleosides) having a nucleobase sequence that includes 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 NOs: 307, 312, or 626. In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence that includes 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 consecutive nucleobases of the nucleobase sequence of SEQ ID NO: 468, 611, 616, 619, or 629 (e.g., a modified oligonucleotide having a length of 14 to 30, e.g., 14 to 23 linked nucleosides). In certain embodiments, the 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, the 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 the nucleobase sequence of SEQ ID NO: 626 and a second modified oligonucleotide having the nucleobase sequence of SEQ ID NO: 629. In any of the above embodiments, the compound can be single-stranded or double-stranded. In any of the above embodiments, the compound can be an antisense oligonucleotide or an oligomeric compound.In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence including 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, or at least 23 consecutive nucleobases of any of the nucleobase sequences of SEQ ID NOs: 10-631 (e.g., a first modified oligonucleotide having a length of 14 to 30, e.g., 14 to 23, nucleosides linked together), and a second modified oligonucleotide having a region complementary to the first modified oligonucleotide (e.g., a second modified oligonucleotide having a length of 14 to 30, e.g., 14 to 23, nucleosides linked together). In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleic acid base sequence comprising any one of SEQ ID NOs: 10 to 631 (e.g., a first modified oligonucleotide having a length of 14 to 30, e.g., 14 to 23 nucleosides linked together) and a second modified oligonucleotide having a region complementary to the first modified oligonucleotide (e.g., a second modified oligonucleotide having a length of 14 to 30, e.g., 14 to 23 nucleosides linked together). In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleic acid base sequence selected from any one of SEQ ID NOs: 10 to 631 and a second modified oligonucleotide having a length of 19 to 23 nucleosides linked together, the second modified oligonucleotide having a region complementary to the first modified oligonucleotide.

[0147] Certain embodiments are directed to the use of the compound comprising PKK specific inhibitor in the manufacture or preparation of medicament for reducing or suppressing inflammatory disease, thrombotic disease in individuals who are or are at risk of developing inflammatory disease or thrombotic disease associated with PKK.In certain embodiments, the inflammatory disease or thrombotic disease is hereditary angioedema (HAE), edema, angioedema, swelling, eyelid angioedema, ocular edema, macular edema, cerebral edema, thrombosis, embolism, thromboembolism, deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke or infarction.Certain embodiments are directed to the use of the compound comprising PKK specific inhibitor in the preparation of medicament for treating disease associated with PKK. In certain embodiments, the disease is inflammatory disease, thrombotic disease, hereditary angioedema (HAE), edema, angioedema, swelling, eyelid angioedema, ocular edema, macular edema, cerebral edema, thrombosis, embolism, thromboembolism, deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke or infarction.In certain embodiments, the compound comprises the antisense oligonucleotide that targets PKK.In certain embodiments, the compound comprises the oligonucleotide that targets PKK. In certain embodiments, the compound comprises a modified oligonucleotide 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 consecutive nucleobases of any of the nucleobase sequences of SEQ ID NOs: 10-313, 626, 627, and 628 (e.g., a modified oligonucleotide having a length of 14-30, e.g., a modified oligonucleotide having a length of 14-23 nucleosides linked together). In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence comprising any one of the nucleobase sequences of SEQ ID NOs: 10-313, 626, 627, and 628 (e.g., a modified oligonucleotide having a length of 14-30, e.g., a modified oligonucleotide having a length of 14-23 nucleosides linked together). In certain embodiments, the compound comprises a modified oligonucleotide selected from any one of the nucleobase sequences of SEQ ID NOs: 10-313, 626, 627, and 628.In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence comprising any one of SEQ ID NOs: 307, 312, and 626 (e.g., a modified oligonucleotide having a length of 14-30, e.g., 14-23 linked nucleosides). In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence selected from any one of SEQ ID NOs: 307, 312, and 626. In certain embodiments, the compound comprises a modified oligonucleotide 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 consecutive nucleobases of the nucleobase sequence of SEQ ID NOs: 307, 312, or 626 (e.g., a modified oligonucleotide having a length of 14-30, e.g., 14-23 linked nucleosides). In certain embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence that includes 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 consecutive nucleobases of the nucleobase sequence of SEQ ID NO: 468, 611, 616, 619, or 629 (e.g., a modified oligonucleotide having a length of 14 to 30, e.g., 14 to 23 linked nucleosides). In certain embodiments, the 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, the 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 the nucleobase sequence of SEQ ID NO:626 and a second modified oligonucleotide having the nucleobase sequence of SEQ ID NO:629.In any of the above embodiments, the compound can be single-stranded or double-stranded. In any of the above embodiments, the compound can be an antisense oligonucleotide or oligomeric compound. In certain embodiments, the compound includes a first modified oligonucleotide (e.g., a first modified oligonucleotide having a length of 14 to 30, e.g., 14 to 23 nucleosides linked together) having a nucleobase sequence including 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 consecutive nucleobases of any of the nucleobase sequences of SEQ ID NOs: 10 to 631, and a second modified oligonucleotide (e.g., a second modified oligonucleotide having a length of 14 to 30, e.g., 14 to 23 nucleosides linked together) having a region complementary to the first modified oligonucleotide. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleic acid base sequence comprising any one of SEQ ID NOs: 10 to 631 (e.g., a first modified oligonucleotide having a length of 14 to 30, e.g., 14 to 23 nucleosides linked together) and a second modified oligonucleotide having a region complementary to the first modified oligonucleotide (e.g., a second modified oligonucleotide having a length of 14 to 30, e.g., 14 to 23 nucleosides linked together). In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleic acid base sequence selected from any one of SEQ ID NOs: 10 to 631 and a second modified oligonucleotide having a length of 19 to 23 nucleosides linked together, the second modified oligonucleotide having a region complementary to the first modified oligonucleotide.

[0148] In any of the above methods or uses, the compound can be an oligomeric compound. In any of the above methods or uses, the compound can be single-stranded or double-stranded. In any of the above methods or uses, the compound can target 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, the modified oligonucleotide is 8-80 nucleosides linked in length, 10-30 nucleosides linked in length, 14-30 nucleosides linked in length, 14-23 nucleosides linked in length, or 19-23 nucleosides linked in length. In certain embodiments, the modified oligonucleotide is at least 80%, at least 85%, at least 90%, at least 95% or 100% complementary over its length to any of the nucleobase sequences set forth in SEQ ID NO: 1, 3, 5 or 6. In certain embodiments, the 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 5-methylcytosine. In any of the above embodiments, each modified oligonucleotide is independently 12-30, 14-30, 14-25, 14-24, 14-23, 16-23, 17-23, 18-23, 19-23, 19-22, or 19-20 linked nucleosides in length. In certain embodiments, the modified oligonucleotide has at least 1, at least 2, or at least 3 mismatches to a region of SEQ ID NO: 1, 3, 5, or 6.

[0149] In any of the above methods or uses, the compound comprises a first and a second modified oligonucleotide, and there is a region of complementarity between the first modified oligonucleotide and the second modified oligonucleotide. In certain embodiments, the region of complementarity between the first and second oligonucleotides is 14-23, 19-23, or 21-23 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 the group consisting of 2'-MOE, 2'-F, and 2'-OMe, or a combination thereof. In certain embodiments, the first or second modified oligonucleotide comprises 10 or fewer 2'-F sugar modifications. In certain embodiments, the first or second modified oligonucleotide comprises 5 or fewer 2'-F sugar modifications.

[0150] In any of the above methods or uses, the compound 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 GalNAcs. In certain embodiments, the one or more GalNAcs are attached to the 2' or 3' position of the ribosyl ring. In certain embodiments, the one or more GalNAcs are attached to the 5' nucleoside of the modified oligonucleotide. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is selected from Formulae I-VIII, or a salt, solvate, or hydrate thereof, where R is a 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 of formula II and R' is O. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of formula II and R' is S. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of formula III and R' is O. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of formula III and R' is S. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of formula IV and R' is O. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of formula IV and R' is S. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of formula V and R' is O. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of formula V and R' is S. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of formula VI and R' is O. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of Formula VI and R' is S.In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of Formula VII and R' is O. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of Formula VII and R' is S. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of Formula VIII and R' is O. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of Formula VIII and R' is S.

[0151] In any of the above methods or uses, the compound comprises a first modified oligonucleotide selected from any one of Reference ID Nos. IA0812-821 and a second modified oligonucleotide having a length of 14-21 nucleosides linked together, the second modified oligonucleotide being 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.

[0152] In any of the above methods or uses, the compound comprises a first modified oligonucleotide selected from any one of Reference ID Nos. IA0864-866 and a second modified oligonucleotide having a length of 14-21 nucleosides linked together, the second modified oligonucleotide being 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 Reference ID Nos. IA0818 and IA0864 and a second modified oligonucleotide selected from Reference 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.

[0153] In certain embodiments, the compound comprises a first modified oligonucleotide selected from reference ID numbers IA0818 and IA0864, ​​and a second modified oligonucleotide selected from reference ID numbers 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.

[0154] In certain embodiments, the compound is in the form of a pharmaceutically acceptable salt.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, the composition comprises the compound of any one of the above embodiments and a pharmaceutically acceptable carrier.

[0155] In any of the above methods or uses, the compound of any of the above embodiments, or a composition comprising the compound, is administered to the individual in a therapeutically effective amount. In certain embodiments, the compound of any of the above embodiments, or a composition comprising the compound, is administered to the individual at a dosage level sufficient to deliver about 1-100 mg per kg of the individual's body weight. In certain embodiments, the compound of any of the above embodiments, or a composition comprising the compound, is administered to the 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 per day, up to that dosage level or dose.

[0156] In any of the above methods or uses, the compound of any of the above embodiments, or a composition comprising the compound, is administered to an individual once a day, once a week, once a month, once a quarter, or once a year. In certain embodiments, the compound of any of the above embodiments, or a composition comprising the compound, is administered to an individual about once a quarter (i.e., once every three months) to about once a year. In certain embodiments, the compound of any of the above embodiments, or a composition comprising the compound, is administered to an individual about once a quarter, about once every six months, or about once a year.

[0157] Certain compounds In certain aspects, the present disclosure relates to compounds that comprise or consist of oligomeric compounds, hi certain embodiments, the oligomeric compounds comprise a nucleobase sequence that is complementary to the nucleobase sequence of a target nucleic acid.

[0158] In certain aspects, the present disclosure relates to compounds that comprise or consist of modified oligonucleotides, which in certain embodiments have a nucleobase sequence that is complementary to the nucleobase sequence of a target nucleic acid.

[0159] In certain aspects, the disclosure relates to compounds that comprise or consist of antisense oligonucleotides, which in certain embodiments have a nucleobase sequence that is complementary to the nucleobase sequence of a target nucleic acid.

[0160] In certain aspects, the present disclosure relates to a compound that is a single-stranded compound. In certain embodiments, the single-stranded compound comprises an oligomeric compound or is composed of an oligomeric compound. In certain embodiments, such an oligomeric compound comprises an oligonucleotide and optionally a conjugate group or is composed 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 the single-stranded compound comprises a self-complementary nucleobase sequence.

[0161] 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 complementary to the target nucleic acid, and the second oligonucleotide has a region complementary 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 complementary to the 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 complementary to the target nucleic acid, and the second modified oligonucleotide has a region complementary to the first modified oligonucleotide. In certain embodiments, the oligonucleotide or modified oligonucleotide of the double-stranded compound is an RNA oligonucleotide. In such embodiments, the thymine nucleobase in the modified oligonucleotide is replaced with a uracil nucleobase.

[0162] In certain embodiments, the compounds described herein comprise a conjugate group.In certain embodiments, the first oligonucleotide or the first modified oligonucleotide of the double-stranded compound comprises a conjugate group.In certain embodiments, the second oligonucleotide or the second modified oligonucleotide of the double-stranded compound comprises a conjugate group.In certain embodiments, the first oligonucleotide or the first modified oligonucleotide and the second oligonucleotide or the second modified oligonucleotide of the double-stranded compound each comprise a conjugate group.

[0163] In certain embodiments, the compound is 14-30 linked nucleosides in length. In certain embodiments, the first oligonucleotide or the first modified oligonucleotide of the double-stranded compound is 14-30 linked nucleosides in length. In certain embodiments, the second oligonucleotide or the second modified oligonucleotide is 14-30 linked nucleosides in length. In certain embodiments, the oligonucleotide or the modified oligonucleotide of the double-stranded compound has a blunt end at one or both ends of the compound. In certain embodiments, the oligonucleotide or the modified oligonucleotide of the double-stranded compound includes non-complementary overhang-forming nucleosides at one or both ends of the compound.

[0164] In certain embodiments, the 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 the 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.

[0165] Examples of single-stranded and double-stranded compounds include, but are not limited to, oligonucleotides, antisense oligonucleotides, siRNAs, oligonucleotides targeting microRNAs, occupancy-based compounds (e.g., compounds that block mRNA processing or translation, and splicing compounds), and single-stranded RNAi compounds (e.g., small hairpin RNAs (shRNAs), single-stranded siRNAs (ssRNAs), and microRNA mimics).

[0166] In certain embodiments, the compounds described herein, when written in the 5'→3' orientation, have a nucleobase sequence that comprises the reverse complement of a target region of a target nucleic acid to which the compound is targeted.

[0167] In certain embodiments, the compounds described herein include oligonucleotides having a length of 12-30 linked subunits. In certain embodiments, the compounds described herein include oligonucleotides having a length of 12-23 linked subunits. In certain embodiments, the compounds described herein include oligonucleotides having a length of 14-30 linked subunits. In certain embodiments, the compounds described herein include oligonucleotides having a length of 14-23 linked subunits. In certain embodiments, the compounds described herein include oligonucleotides having a length of 15-30 linked subunits. In certain embodiments, the compounds described herein include oligonucleotides having a length of 15-23 linked subunits. In certain embodiments, the compounds described herein include oligonucleotides having a length of 16-30 linked subunits. In certain embodiments, the compounds described herein include oligonucleotides having a length of 16-23 linked subunits. In certain embodiments, the compounds described herein include oligonucleotides having a length of 17-30 linked subunits. In certain embodiments, the compounds described herein include oligonucleotides having a length of 17-23 linked subunits. In certain embodiments, the compounds described herein include oligonucleotides having a length of 18-30 linked subunits. In certain embodiments, the compounds described herein include oligonucleotides having a length of 18-23 linked subunits. In certain embodiments, the compounds described herein include oligonucleotides having a length of 19-30 linked subunits. In certain embodiments, the compounds described herein include oligonucleotides having a length of 19-23 linked subunits.In other words, each of these oligonucleotides may have between 12 and 30 subunits linked together, between 12 and 23 subunits linked together, between 14 and 30 subunits linked together, between 14 and 23 subunits linked together, between 15 and 30 subunits linked together, between 15 and 23 subunits linked together, between 16 and 30 subunits linked together, between 16 and 23 subunits linked together, between 17 and 30 subunits linked together, between 17 and 23 subunits linked together, between 18 and 30 subunits linked together, between 18 and 23 subunits linked together, between 19 and 30 subunits linked together, or between 19 and 23 subunits linked together. In certain embodiments, the compounds described herein include oligonucleotides that are 14 subunits linked in length. In certain embodiments, the compounds described herein include oligonucleotides that are 16 subunits linked in length. In certain embodiments, the compounds described herein include oligonucleotides that are 17 subunits linked in length. In certain embodiments, the compounds described herein include oligonucleotides with a length of 18 linked subunits. In certain embodiments, the compounds described herein include oligonucleotides with a length of 19 linked subunits. In certain embodiments, the compounds described herein include oligonucleotides with a length of 20 linked subunits. In certain embodiments, the compounds described herein include oligonucleotides with a length of 21 linked subunits. In certain embodiments, the compounds described herein include oligonucleotides with a length of 22 linked subunits. In certain embodiments, the compounds described herein include oligonucleotides with a length of 23 linked subunits.In another embodiment, the compounds described herein include oligonucleotides having 8-80, 12-50, 13-30, 13-50, 14-30, 14-50, 15-30, 15-50, 16-30, 16-50, 17-30, 17-50, 18-23, 18-24, 18-25, 18-50, 19-23, 19-30, 19-50, 20-23, or 20-30 linked subunits. In certain such embodiments, the compounds described herein include oligonucleotides that are 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.

[0168] In certain embodiments, the compound may further comprise an additional moiety, such as a conjugate group or a delivery moiety. In certain embodiments, such a compound is an oligomeric compound, and the additional moiety is attached to the oligonucleotide. In certain embodiments, the conjugate group is attached to the nucleoside of the oligonucleotide.

[0169] In certain embodiments, the compound may be shortened or truncated, for example, one or more subunits may be deleted from the 5' end of the oligonucleotide (5' truncation) or from the 3' end (3' truncation).

[0170] In certain embodiments, the compound may be extended. For example, one or more subunits may be attached to the 3'-end or 5'-end of the 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 the 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 the oligonucleotide. In certain embodiments, at least one or more subunits may be attached to the 3' or 5' end of an oligonucleotide of a double-stranded compound to form a 3' overhang and / or a 5' 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 both 5' ends of the oligonucleotide of the 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 subunits) is attached to both 3' ends of the oligonucleotide of the double stranded compound. In certain embodiments, the subunits are attached to both oligonucleotides of a double-stranded compound at the same end (e.g., the subunit is attached to the 3' end of one oligonucleotide and the subunit is attached to the 5' end of the other oligonucleotide). In certain embodiments, when the 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 different. In certain embodiments, when the 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 the 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 the subunits are attached to both oligonucleotides of a double-stranded compound at the same end, may be found at one or both ends of the double-stranded compound. In certain embodiments, the subunits attached to the 3' end and / or the 5' end are modified.

[0171] In certain embodiments, the compounds described herein are oligonucleotides. In certain embodiments, the compounds described herein are modified oligonucleotides. In certain embodiments, the compounds described herein are antisense oligonucleotides. In certain embodiments, the compounds described herein are oligomeric compounds. In certain embodiments, the compounds described herein are RNAi compounds. In certain embodiments, the compounds described herein are siRNA compounds.

[0172] In certain embodiments, the compounds described herein are oligonucleotide sequences that target PKK and can include any of the sequences described herein, hi certain embodiments, the compounds can be double-stranded.

[0173] In certain embodiments, the compound comprises an oligonucleotide comprising at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23 consecutive nucleobase portions of any one of SEQ ID NOs: 10-313, 626, 627, and 628. In certain embodiments, the compound comprises an oligonucleotide comprising at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23 consecutive nucleobase portions of SEQ ID NOs: 307, 312, or 626. In certain embodiments, the compound comprises a second oligonucleotide. In certain embodiments, the compound comprises an oligonucleotide comprising at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23 consecutive nucleobase portions of SEQ ID NOs: 468, 611, 616, 619, or 629. In certain embodiments, the compound comprises a first oligonucleotide comprising at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23 consecutive nucleobase portions of SEQ ID NO:312 and a second oligonucleotide comprising at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23 consecutive nucleobase portions of SEQ ID NO:619. In certain embodiments, the compound comprises a first oligonucleotide comprising at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23 consecutive nucleobase portions of SEQ ID NO:626 and a second oligonucleotide comprising at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23 consecutive nucleobase portions of SEQ ID NO:629.

[0174] In certain embodiments, the compound comprises a ribonucleotide in which the oligonucleotide has a uracil (U) in place of a thymine (T) in any of the sequences shown herein. In certain embodiments, the compound comprises a deoxyribonucleotide in which the oligonucleotide has a thymine (T) in place of a uracil (U) in any of the sequences shown herein.

[0175] A specific mechanism In certain embodiments, the compounds described herein comprise or consist of modified oligonucleotides. In certain embodiments, the compounds described herein comprise or consist of antisense oligonucleotides. In certain embodiments, the compounds comprise or consist of oligomeric compounds. In certain embodiments, the compounds described herein can hybridize to target nucleic acids. In certain embodiments, the compounds described herein selectively act on one or more target nucleic acids. Such compounds comprise nucleobase sequences that hybridize to one or more target nucleic acids to provide one or more desired activities, and do not hybridize to one or more non-target nucleic acids or do not hybridize to one or more non-target nucleic acids in a manner that provides less desirable activities.

[0176] In certain embodiments, the hybridization of the compound described herein to the target nucleic acid recruits one or more proteins that cleave the target nucleic acid. For example, certain compounds described herein or parts of the compounds are incorporated into the RNA-induced silencing complex (RISC), which ultimately cleaves the target nucleic acid. For example, certain compounds described herein cause the target nucleic acid to be cleaved by Argonaute. The compound that is incorporated into RISC is an RNAi compound. The RNAi compound can be double-stranded (siRNA) or single-stranded (ssRNA).

[0177] In certain embodiments, the hybridization of the compounds described herein to a target nucleic acid does not recruit a protein that cleaves the target nucleic acid. In certain such embodiments, the hybridization of the compounds to a target nucleic acid alters the splicing of the target nucleic acid. In certain embodiments, the hybridization of the compounds to a target nucleic acid inhibits the binding interaction of the target nucleic acid with a protein or other nucleic acid. In certain such embodiments, the hybridization of the compounds to a target nucleic acid alters RNA processing. In certain such embodiments, the hybridization of the compounds to a target nucleic acid alters the translation of the target nucleic acid.

[0178] The activity of a compound hybridized to a target nucleic acid may be observed directly or indirectly. In certain embodiments, observing or detecting an activity involves observing or detecting a change in the amount of a target nucleic acid or a protein encoded by such a target nucleic acid, a change in the ratio of splice variants of a nucleic acid or protein, and / or a change in a phenotype in a cell or animal.

[0179] Certain modifications In certain aspects, the present disclosure relates to a compound that comprises or consists of an oligonucleotide. The oligonucleotide is composed of linked nucleosides. In certain embodiments, the oligonucleotide may be unmodified RNA or DNA or may be modified. In certain embodiments, the oligonucleotide is a modified oligonucleotide. In certain embodiments, the modified oligonucleotide comprises at least one modified sugar, modified nucleobase, or modified internucleoside linkage compared to unmodified RNA or DNA. In certain embodiments, the oligonucleotide has a modified nucleoside. The modified nucleoside may comprise a modified sugar, a modified nucleobase, or both a modified sugar and a modified nucleobase. The modified oligonucleotide may also comprise terminal modifications, such as 5'-terminal modifications and 3'-terminal modifications.

[0180] Sugar modifications and motifs In certain embodiments, the modified sugar is a substituted furanosyl sugar or a non-bicyclic modified sugar. In certain embodiments, the modified sugar is a bicyclic or tricyclic modified sugar. In certain embodiments, the modified sugar is a sugar substitute. The sugar substitute may include one or more substitutions described herein.

[0181] In certain embodiments, the 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 substituents, including, but not limited to, substituents at the 2', 3', 4', and 5' positions.

[0182] In certain embodiments, the 2'-position substituent includes, but is not limited to, F and OCH3 ("OMe", "O-methyl" or "methoxy"). In certain embodiments, suitable 2'-position substituents for non-bicyclic modified sugars include, but are not limited to, halo, allyl, amino, azido, SH, CN, OCN, CF3, OCF3, F, Cl, Br, SCH3, SOCH3, SO2CH3, ONO2, NO2, N3, and NH2. In certain embodiments, the 2'-position substituent includes, but is not limited to, O-(C1-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, but are not limited thereto, wherein the alkyl, alkenyl and alkynyl can be substituted or unsubstituted C1-C 10 Alkyl or C2-C 10It can also be alkenyl and alkynyl. In certain embodiments, the substituents at the 2' position include, but are not limited to, alkaryl, aralkyl, O-alkaryl and O-aralkyl. In certain embodiments, these 2' substituents can be further substituted with one or more substituents independently selected from hydroxyl, alkoxy, carboxy, benzyl, phenyl, nitro(NO2), thiol, thioalkoxy, thioalkyl, halogen, alkyl, aryl, alkenyl and alkynyl. In certain embodiments, the substituents at the 2' position include, but are not limited to, O[(CH2) n O] m CH3, O(CH2) n OCH3, O(CH2) n CH3, O(CH2) n ONH2, O(CH2) n NH2, O(CH2) n SCH3 and O(CH2) n ON [(CH2) n CH3)]2, where n and m are independently 1 to about 10. In certain embodiments, the substituent at the 2' position includes, but is not limited to, OCH2CH2OCH3 ("MOE"), O(CH2)2ON(CH3)2 ("DMAOE"), O(CH2)2O(CH2)2N(CH3)2 ("DMAEOE"), and OCH2C(=O)-N(H)CH3 ("NMA").

[0183] In certain embodiments, suitable 4'-position substituents for non-bicyclic modified sugars include, but are not limited to, alkoxy (e.g., methoxy), alkyl, and those described in WO 2015 / 106128 to Manoharan et al. In certain embodiments, suitable 5'-position substituents for non-bicyclic modified sugars include, but are not limited to, methyl ("Me") (R or S), vinyl, and methoxy. In certain embodiments, the 2', 4', and 5'-position substituents described herein can also be attached to other specific positions on the sugar. In certain embodiments, such substituents can be attached to the 3'-position of the sugar of the 3'-terminal nucleoside, or the 5'-position of the 5'-terminal nucleoside. In certain embodiments, non-bicyclic modified sugars can include more than one non-bridged sugar substituent. In certain such embodiments, non-bicyclic modified sugar substituents include, but are not limited to, 5'-Me-2'-F, 5'-Me-2'-OMe (including both the R and S isomers). In certain embodiments, modified sugar substituents include those described in WO 2008 / 101157 by Migawa et al. and US 2013 / 0203836 by Rajeev et al.

[0184] In certain embodiments, the modified sugar is a bicyclic sugar. A bicyclic sugar is a modified sugar that includes two rings, with the bicyclic structure being formed by a bridge connecting two of the atoms in the first ring to form the second ring. In certain embodiments, the bicyclic sugar includes a bridge substituent that bridges two of the atoms of the furanosyl ring to form the second ring. In certain embodiments, the bicyclic sugar does not include a furanosyl moiety. A "bicyclic nucleoside" ("BNA") is a nucleoside that has a bicyclic sugar. In certain embodiments, the bicyclic sugar includes a bridge between the 4' and 2' furanose ring atoms. In certain embodiments, the bicyclic sugar includes a bridge between the 5' and 3' furanose ring atoms. In certain such embodiments, the furanose ring is a ribose ring. In certain embodiments, the substituents bridging 4' and 2' include 4'-CH2-2', 4'-(CH2)2-2', 4'-(CH2)3-2', 4'-CH2-O-2' ("LNA"), 4'-CH2-S-2', 4'-(CH2)2-O-2' ("ENA"), 4'-CH(CH3)-O-2' ("constrained ethyl" or "cEt" when in the S configuration), 4'-CH2-O-CH2-2', 4'-CH2-N(R)-2', 4'-CH(CHOCH3)-O-2' ("constrained MOE" or "cMOE") and analogs thereof (e.g., U.S. Pat. No. 7,399,845), 4'-C(CH3)(CH3)-O-2' and analogs thereof (e.g., U.S. Pat. No. 8,278,283), 4'-CH2-N(OCH3)-2' and analogs thereof (e.g., U.S. Pat. No. 8,278,425), 4'-CH2-ON(CH3)-2' (e.g., U.S. Patent Application Publication No. 2004 / 0171570), 4'-CH2-N(R)-O-2' (wherein R is H, C1-C 12alkyl or a protecting group) (e.g., U.S. Pat. No. 7,427,672), 4'-CH2-C(H)(CH3)-2' (e.g., Chattopadhyaya el al., J. Org. Chem., 2009, 74, 118-134), and 4'-CH2-C(=CH2)-2' and analogs thereof (e.g., U.S. Pat. No. 8,278,426). The entire contents of each of the above are incorporated herein by reference. Additional representative U.S. patents and published U.S. patent applications that teach the preparation of bicyclic nucleonucleotides include, but are not limited to, 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, Nos. 7,569,686, 7,741,457, 8,022,193, 8,030,467, 8,278,425, 8,278,426, 8,278,283, US2008 / 0039618, US2009 / 0012281, US2013 / 0190383, and WO2013 / 036868, the entire contents of each of which are incorporated herein by reference. Any of the above bicyclic nucleosides can be prepared with one or more stereochemical sugar configurations, including, for example, α-L-ribofuranose and β-D-ribofuranose (see, e.g., WO99 / 14226). Certain bicyclic nucleosides herein are in the β-D configuration, unless otherwise indicated.

[0185] In certain embodiments, the modified sugar is a sugar substitute. In certain embodiments, the sugar substitute has an oxygen atom replaced with, for example, a sulfur atom, a carbon atom, or a nitrogen atom. In certain such embodiments, the sugar substitute may also include bridged and / or non-bridged substituents as described herein. In certain such embodiments, the sugar substitute includes a ring having more than five atoms. In certain such embodiments, the sugar substitute includes a cyclobutyl moiety in place of the pentofuranosyl sugar. In certain embodiments, the sugar substitute includes a six-membered ring in place of the pentofuranosyl sugar. In certain embodiments, the sugar substitute includes a tetrahydropyran ("THP") in place of the pentofuranosyl sugar. In certain embodiments, the sugar substitute includes a morpholino in place of the pentofuranosyl sugar. Representative United States patents which 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, and 5,591,722. Nos. 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 which are incorporated herein by reference.

[0186] In some embodiments, the surrogate sugar comprises an acyclic moiety. In certain embodiments, the surrogate sugar is an unlocked nucleic acid ("UNA"). A UNA is an acyclic unlocked nucleic acid in which any of the sugar bonds are removed to form an unlocked "sugar" residue. In one example, a UNA also includes a monomer in which the C1'-C4' bond (i.e., the carbon-oxygen-carbon covalent bond between the C1' and C4' carbons) is removed. In another example, the C2' and C3' bond (i.e., the carbon-carbon covalent bond between the C2' and C3' carbons) of the sugar is removed. Representative U.S. publications teaching the preparation of UNAs include, but are not limited to, U.S. Patent No. 8,314,227, and U.S. Patent Application Publication Nos. 2013 / 0096289, 2013 / 0011922, and 2011 / 0313020, the entire contents of each of which are incorporated herein by reference. In certain embodiments, sugar surrogates include peptide nucleic acids ("PNAs"), acyclic butyl nucleic acids (see, e.g., Kumar et al., Org. Biomol. Chem., 2013, 11, 5853-5865), and the nucleosides and oligonucleotides described in Manoharan et al., US 2013 / 130378, the entire contents of which are incorporated herein by reference. Many other bicyclic sugars, tricyclic sugars, and sugar surrogate ring systems are known in the art that can be used in modified nucleosides.

[0187] In certain aspects, the present disclosure relates to compounds comprising at least one oligonucleotide, the nucleosides of which contain one or more modified and / or unmodified sugars arranged in a predetermined pattern or "sugar motif" along the oligonucleotide or region thereof. In certain instances, such sugar motifs include, but are not limited to, any of the sugar modification patterns described herein.

[0188] In certain embodiments, the oligonucleotide comprises a gapmer sugar motif. A gapmer oligonucleotide comprises or consists of a region having two outer "wing" regions and a central or internal "gap" region. The gap and wing regions form a contiguous sequence of nucleosides, with the majority of nucleoside sugars of each wing being different 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 having gapmer sugar motifs are described, for example, in U.S. Pat. No. 8,790,919, the entire contents of which are incorporated herein by reference.

[0189] In certain embodiments, one or both of the oligonucleotides of the double-stranded compound contain a triplex sugar motif. An oligonucleotide with a triplex sugar motif contains three identical sugar modifications on three consecutive nucleosides. In certain embodiments, the triplex is located at or near the cleavage site of the oligonucleotide. In certain embodiments, the oligonucleotide of the double-stranded compound may contain two or more triplex sugar motifs. In certain embodiments, the identical sugar modification of the triplex sugar motif is a 2'-F modification. Compounds with triplex sugar motifs are disclosed, for example, in U.S. Pat. No. 10,668,170, the entire contents of which are incorporated herein by reference.

[0190] In certain embodiments, one or both of the oligonucleotides of the double-stranded compound contain a quadruplex sugar motif. An oligonucleotide having a quadruplex sugar motif contains four identical sugar modifications on four consecutive nucleosides. In certain embodiments, the quadruplex is located at or near the cleavage site. In certain embodiments, the oligonucleotide of the double-stranded compound may contain two or more quadruplex sugar motifs. In certain embodiments, the identical sugar modification of the quadruplex sugar motif is a 2'-F modification. In a double-stranded compound having a double-stranded region that is 19-23 nucleotides in length, the cleavage site of the antisense oligonucleotide is typically around the 10th, 11th, and 12th positions from the 5' end. In certain embodiments, the quadruplex sugar motif is at the 8th, 9th, 10th, 11th position, 9th, 10th, 11th, 12th position, 10th, 11th, 12th position, 11th, 12th, 13th position, 11th, 12th, 13th, 14th position, or 12th, 13th, 14th, 15th positions of the sense oligonucleotide, counting from the first nucleoside at the 5' end of the sense oligonucleotide or from the first paired nucleotide in the double-stranded region toward the 5' end of the sense oligonucleotide. In certain embodiments, the quadruplex sugar motif is at the 8th, 9th, 10th, 11th position, 9th, 10th, 11th, 12th position, 10th, 11th, 12th position, 11th, 12th, 13th position, 11th, 12th, 13th, 14th position, or 12th, 13th, 14th, 15th position of the antisense oligonucleotide, counting from the first nucleoside at the 5' end of the antisense oligonucleotide or from the first paired nucleotide in the double-stranded region toward the 5' end of the antisense oligonucleotide. The cleavage site may vary depending on the length of the double-stranded region of the double-stranded compound and the position of the quadruplex may vary accordingly.

[0191] In certain embodiments, the oligonucleotide comprises an alternating sugar motif. In certain embodiments, one or both of the 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, where one or more consecutive nucleosides comprising a first sugar modification alternate 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, the alternating motif can be "ABABABABABAB...", "AABBAABBAABB...", "AABAABAABAAB...", "AAABAAABAAAB...", "AAABBBAAABBB..." or "ABCABCABCABC...", etc., where A, B and C each represent one type of modification for that nucleoside. In certain embodiments, the alternating sugar motif is repeated 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 consecutive nucleobases along the oligonucleotide. In certain embodiments, the alternating sugar motif is composed of two different sugar modifications. In certain embodiments, the alternating sugar motif comprises a 2'-OMe and a 2'-F sugar modification.

[0192] In certain embodiments, each nucleoside of an oligonucleotide is independently modified with one or more sugar modifications as described herein.In certain embodiments, each oligonucleotide of a double-stranded compound independently has one or more sugar motifs as described herein.In certain embodiments, the oligonucleotide that includes a sugar motif is fully modified, in that each nucleoside other than the nucleoside that includes the sugar motif includes a sugar modification.

[0193] Nucleobase modifications and motifs In certain embodiments, the compound described herein comprises modified oligonucleotide.In certain embodiments, modified oligonucleotide comprises one or more nucleosides that comprise modified nucleobase.In certain embodiments, modified oligonucleotide comprises one or more nucleosides that do not comprise nucleobase, and this nucleoside is called abasic nucleoside.

[0194] In certain embodiments, the modified nucleobase is 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, the modified nucleobases are 2-aminopropyladenine, 5-hydroxymethylcytosine, 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—CH3) uracil, 5-propynylcytosine, 6-azo uracil, 6-azo cytosine, 6-azo thymine, 5-ribosyluracil (pseudouracil), 4-thiouracil, 8-halopurine, 8-aminopurine, 8-thiolpurine, 8-thioalkylpurine, 8-hydroxylpurine, 8-aza Selected from purine 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-extended bases, and fluorinated bases. Further modified nucleobases include tricyclic pyrimidines, such as 1,3-diazaphenoxazin-2-one, 1,3-diazaphenothiazin-2-one, and 9-(2-aminoethoxy)-1,3-diazaphenoxazin-2-one (G clamp).Modified nucleobases may also include bases in which the purine or pyrimidine base is replaced with other heterocycles, such as 7-deaza-adenine, 7-deazaguanosine, 2-aminopyridine, and 2-pyridone.

[0195] Further nucleobases include those described 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, JL, Ed., John Wiley & Sons, 1990, 858-859, Englisch et al., Angewandte Chemie, International Edition, 1991, 30, 613, Sanghvi, YS, Chapter 15, dsRNA Research and Applications, pages 289-302, Antisense Research and Applications, Crooke, ST and Lebleu, B., Eds., CRC Press, 1993, 273-288, Antisense Drug Technology, Crooke ST, Ed., CRC Press, 2008, 163-166 and 442-443 (Chapters 6 and 15), each of which is incorporated herein by reference.

[0196] Publications which teach the preparation of certain of the above and other modified nucleobases include, but are not limited to, U.S. Patent Application Publication Nos. 2003 / 0158403 and 2003 / 0175906, U.S. Patent Nos. 4,845,205, 5,130,302, 5,134,066, 5,175,273, 5,367,066, 5,432,272, and 5,432,272. No. 5,434,257, No. 5,457,187, No. 5,459,255, No. 5,484,908, No. 5,502,177, No. 5,525,711, No. 5, No. 552,540, No. 5,587,469, No. 5,594,121, No. 5,596,091, No. 5,614,617, No. 5,645,985, No. 5,681,941 No. 5,811,534, No. 5,750,692, No. 5,948,903, No. 5,587,470, No. 5,457,191, No. 5,763,588, No. 5, No. 830,653, No. 5,808,027, No. 6,005,096, No. 6,015,886, No. 6,147,200, No. 6,166,197, No. 6,166,199 Nos. 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 contents of each of which are incorporated herein by reference in their entirety.

[0197] In certain embodiments, the compounds described herein comprise oligonucleotides. In certain embodiments, the oligonucleotides comprise modified and / or unmodified nucleobases arranged in a predetermined pattern or motif along the oligonucleotide or a region thereof. In certain embodiments, each nucleobase is modified. In certain embodiments, none of the nucleobases is 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 the modified oligonucleotide are 5-methylcytosine.

[0198] In certain embodiments, the modified oligonucleotide comprises a modified nucleobase block. In certain such embodiments, the block is at the 3' end of the oligonucleotide. In certain embodiments, the block is within 3 nucleosides from 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 from the 5' end of the oligonucleotide.

[0199] Internucleoside linkage modifications and motifs The 3'→5' phosphodiester bond is the natural internucleoside bond of RNA and DNA. In certain embodiments, the compounds described herein have one or more modified internucleoside linkages, i.e., non-natural internucleoside linkages. Certain non-natural internucleoside linkages can provide desirable properties, such as enhanced cellular uptake, enhanced affinity for target nucleic acids, and increased stability in the presence of nucleases. Representative modified internucleoside linkages that contain phosphorus include, but are not limited to, phosphotriesters, alkylphosphonates (e.g., methylphosphonates), phosphoramidates, and phosphorothioates ("P=S") and phosphorodithioates ("HS-P=S"). Representative phosphorus-free internucleoside linkage groups include, but are not limited to, methylenemethylimino (-CH2-N(CH3)-O-CH2), thiodiester, thionocarbamate (-OC(=O)(NH)-S-), siloxane (-O-SiH2-O-) and N,N'-dimethylhydrazine (-CH2-N((CH3)-N((CH3)-). Methods for preparing phosphorus-containing and phosphorus-free internucleoside linkages are well known to those of skill in the art. Neutral internucleoside linkages include phosphotriester, methylphosphonate, MMI(3'- Examples of neutral internucleoside linkages include, but are not limited to, CH2-N(CH3)-O-5'), amide-3 (3'-CH2-C(=O)-N(H)-5'), amide-4 (3'-CH2-N(H)-C(=O)-5'), formacetal (3'-O-CH2-O-5'), methoxypropyl, and thioformacetal (3'-S-CH2-O-5'). Additional neutral internucleoside linkages include nonionic linkages including siloxanes (dialkylsiloxanes), carboxylates, carboxamides, sulfides, sulfonates, and amides (see, e.g., Carbohydrate Modifications in Antisense Research; YS Sanghvi and PD Cook, Eds., ACS Symposium Series 580; Chapters 3 and 4, 40-65).Additional neutral internucleoside linkages include non-ionic linkages containing a mixture of N, O, S and CH2 moieties.

[0200] In certain embodiments, the compound provided by the present invention comprises at least one modified internucleoside bond.Modified internucleoside bond can be located at any position of oligonucleotide.In double-stranded compounds, modified internucleoside bond can be located at the sense oligonucleotide, antisense oligonucleotide or both oligonucleotides of the double-stranded compound.

[0201] In certain embodiments, the internucleoside linkage modifications may be present at all of the nucleosides of the oligonucleotide. In certain embodiments, the internucleoside linkage modifications may be present in an alternating pattern along the oligonucleotide. In certain embodiments, essentially all of the internucleoside linkage groups are phosphate internucleoside linkages (P=O). In certain embodiments, each internucleoside linkage group of the modified oligonucleotide is phosphorothioate (P=S). In certain embodiments, each internucleoside linkage group of the modified oligonucleotide is independently selected from phosphorothioate internucleoside linkages and phosphate internucleoside linkages. In certain embodiments, the pattern of internucleoside linkage modifications of each oligonucleotide of the double-stranded compound is the same. In certain embodiments, the pattern of internucleoside linkage modifications of each oligonucleotide of the double-stranded compound is different. In certain embodiments, the 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 of the 5'-terminus and 3'-terminus. In certain such embodiments, the modified internucleoside linkages are phosphorothioate internucleoside linkages or alkylphosphonate internucleoside linkages. In certain such embodiments, the antisense oligonucleotide comprises at least two modified internucleoside linkages at either or both of the 5'-terminus and 3'-terminus. In certain such embodiments, the modified internucleoside linkages are phosphorothioate internucleoside linkages or alkylphosphonate internucleoside linkages.

[0202] In certain embodiments, the double-stranded compound comprises an overhang region. In certain embodiments, the double-stranded compound comprises a phosphorothioate internucleoside bond modification or an alkylphosphonate internucleoside bond modification in the overhang region. In certain embodiments, the double-stranded compound comprises a phosphorothioate internucleoside bond or an alkylphosphonate internucleoside bond that connects the overhang nucleotide to the paired nucleotide next to the overhang nucleotide. For example, there may be at least two phosphorothioate internucleoside bonds between the three terminal nucleosides, two of which are overhang nucleosides, and the third nucleoside is the paired nucleoside next to the overhang nucleoside. These three terminal 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.

[0203] In certain embodiments, the modified oligonucleotide comprises one or more internucleoside linkages with a chiral center. Exemplary chiral internucleoside linkages include, but are not limited to, alkyl phosphonates and phosphorothioates. Modified oligonucleotides comprising internucleoside linkages with a chiral center can be prepared as a population of modified oligonucleotides comprising stereorandom internucleoside linkages or as a population of modified oligonucleotides comprising phosphorothioate linkages of a specific stereochemical configuration. In certain embodiments, the population of modified oligonucleotides comprises phosphorothioate internucleoside linkages, all of which are stereorandom. Such modified oligonucleotides can be produced using a synthesis method in which the stereochemical configuration of each phosphorothioate linkage is randomly selected. As will be appreciated by those skilled in the art, each individual phosphorothioate of each individual oligonucleotide molecule has a defined stereochemical configuration. In certain embodiments, the population of modified oligonucleotides is enriched for modified oligonucleotides that contain one or more specific phosphorothioate internucleoside linkages that are in a specific stereochemical arrangement that is selected independently. In certain embodiments, the specific phosphorothioate linkages in the specific arrangement are present in at least 65% of the molecules in the population. In certain embodiments, the specific phosphorothioate linkages in the specific arrangement are present in at least 70% of the molecules in the population. In certain embodiments, the specific phosphorothioate linkages in the specific arrangement are present in at least 80% of the molecules in the population. In certain embodiments, the specific phosphorothioate linkages in the specific arrangement are present in at least 90% of the molecules in the population. In certain embodiments, the specific phosphorothioate linkages in the specific arrangement are present in at least 99% of the molecules in the population.Such modified oligonucleotide enriched populations can be produced using synthetic methods known in the art, such as those described in Oka et al., JACS 125, 8307 (2003), Wan et al. Nuc. Acid. Res. 42, 13456 (2014) and WO2017 / 015555. In certain embodiments, the modified oligonucleotide population is enriched in modified oligonucleotides having at least one phosphorothioate in the (Sp) configuration among the phosphorothioates shown. In certain embodiments, the modified oligonucleotide population is enriched in modified oligonucleotides having at least one phosphorothioate in the (Rp) configuration.

[0204] Conjugate Group In certain embodiments, the compounds described herein comprise or consist of one or more oligonucleotides and, optionally, one or more conjugate groups. The conjugate groups may be attached to either or both ends of the oligonucleotide and / or to any internal position. In certain embodiments, the conjugate groups may be attached at the 3' end of the oligonucleotide. In certain embodiments, the conjugate groups may be attached at the 5' end of the oligonucleotide. In certain embodiments, the oligonucleotide may be covalently attached to one or more conjugate groups.

[0205] In certain embodiments, the conjugate group is a terminal group attached to either or both ends of the oligonucleotide.In certain such embodiments, the terminal group is attached at the 3' end of the oligonucleotide.In certain such embodiments, the terminal group is attached at the 5' end of the oligonucleotide.In certain embodiments, the terminal group includes, but is not limited to, a capping group, a phosphate moiety, a protecting group, a modified or unmodified nucleoside, and two or more nucleosides that are independently modified or unmodified, such as an overhang.

[0206] In certain embodiments, the conjugate group modifies one or more of the properties of the oligonucleotide to which it is attached, including but not limited to its pharmacodynamics, pharmacokinetics, stability, activity, half-life, binding, absorption, tissue distribution, cellular distribution, cellular uptake, charge and clearance.In certain embodiments, the conjugate group enhances the affinity of the compound to a certain target, for example, a molecule, a cell or cell type, a compartment, for example, a cellular or organ compartment, a tissue, an organ or an area of ​​the body, for example, compared to a compound that does not have such a conjugate group.In certain embodiments, the conjugate group provides the oligonucleotide to which it is attached with a new property, for example, a fluorophore group or a reporter group that makes the oligonucleotide detectable.

[0207] In certain embodiments, conjugate groups include, but are not limited to, intercalators, reporter molecules, polyamines, polyamides, peptides, glycans, vitamin moieties, polyethylene glycols, thioethers, polyethers, cholesterol, thiocholesterol, cholic acid moieties, folic acid, lipids, phospholipids, biotin, phenazine, phenanthridine, anthraquinone, adamantane, acridine, fluoresceins, rhodamines, coumarins, fluorophores, and dyes.

[0208] In certain embodiments, the conjugate group includes an active drug substance, such as aspirin, warfarin, phenylbutazone, ibuprofen, suprofen, fenbufen, ketoprofen, (S)-(+)-pranoprofen, carprofen, dansylsarcosine, 2,3,5-triiodobenzoic acid, fingolimod, flufenamic acid, folinic acid, benzothiadiazide, chlorothiazide, diazepines, indomethacin, barbiturates, cephalosporins, sulfa drugs, antidiabetics, antibacterial agents, or antibiotics.

[0209] In certain embodiments, the conjugate group is a targeting moiety.In certain embodiments, the targeting moiety includes, but is not limited to, lectin, glycoprotein, lipid, protein, peptide, peptidomimetic, receptor ligand, antibody, thyrotropin, melanotropin, surfactant protein A, glycan, glycan derivative, modified glycan, glycan cluster, polysaccharide, modified polysaccharide or polysaccharide derivative, mucin glycan, polyvalent lactose, polyvalent galactose, N-acetyl-galactosamine (GalNAc), N-acetylglucosamine, polyvalent mannose, polyvalent fucose, glycosylated polyamino acid, polyvalent galactose, transferrin, bisphosphonate, polyglutamic acid, polyaspartic acid, lipid, cholesterol, steroid, bile acid, folic acid, vitamin B12, vitamin A, biotin, or RGD peptide or RGD peptide mimic.

[0210] In certain embodiments, the conjugate group may be any of the conjugate groups described in the following references, e.g., 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), thioethers, e.g., hexyl-S-tritylthiol (e.g., Manoharan et al., αnn. 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, 19 ...esters, e.g., thioesters, e.g., thioesters, e.g., thioesters, e.g., thioesters, e.g., thioesters, e.g., thioesters, e.g., thioesters, e.g., Res., 1992,20:533-538), aliphatic chains such as dodecanediol 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 such as 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, 1995,36:3651-3654). Res., 1990,18:3777-3783), polyamine or polyethylene glycol chains (e.g., Manoharan et al., Nucleosides & 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-carbonyloxycholesterol moieties (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 glycans (e.g., Maier et al., Bioconjugate Chemistry, 2003, 14, 18-29; Rensen et al. al., J. Med. Chem. 2004, 47, 5798-5808, WO2009 / 073809, U.S. Patent Nos. 8,106,022, 8,450,467 and 8,828,957, WO2014 / 179445, WO2014 / 179620, and U.S. Patent Nos. 9,127,276, 9,181,549 and 10,844,379), each of which is incorporated herein by reference in its entirety.

[0211] The conjugate group may be attached to the oligonucleotide via a conjugate linker. In certain embodiments, the conjugate linker comprises a chain structure, such as a hydrocarbyl chain, or an oligomer consisting of repeating units or a combination of such repeating units. In certain embodiments, the conjugate linker comprises one or more groups selected from alkyl, amino, oxo, amide, disulfide, polyethylene glycol, ether, thioether, and hydroxylamino. In certain embodiments, the conjugate linker comprises at least one phosphorus group. In certain embodiments, the conjugate linker comprises at least one phosphate group. In certain embodiments, the conjugate linker comprises at least one neutral linking group. In certain embodiments, the conjugate linker includes, but is not limited to, pyrrolidine, 8-amino-3,6-dioxaoctanoic acid (ADO), succinimidyl 4-(N-maleimidophenyl)cyclohexane-1-carboxylate (SMCC), and 6-aminohexanoic acid (AHEX or AHA). Other conjugate linkers include substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C2-C 10 Alkenyl, or substituted or unsubstituted C2-C 10A non-limiting list of preferred substituents in this case includes, but is not limited to, alkynyl, hydroxyl, amino, alkoxy, carboxy, benzyl, phenyl, nitro, thiol, thioalkoxy, halogen, alkyl, aryl, alkenyl, and alkynyl. In certain embodiments, the conjugate linker comprises 1-10 linker nucleosides. In certain embodiments, such linker nucleosides may comprise modified or unmodified nucleosides. It is typically desirable for the linker nucleosides to be cleaved from the compound after the compound has reached the target tissue. Thus, the linker nucleosides of the present invention can be linked to each other and to the remainder of the compound via cleavable bonds. In the present invention, the linker nucleosides are not considered to be part of the oligonucleotide. Thus, in embodiments where a compound comprises an oligonucleotide consisting of a predetermined number or range of linked nucleosides and / or a predetermined percentage of complementarity to a reference nucleic acid, and the compound also comprises a conjugate group that includes a conjugate linker that includes linker nucleosides, these linker nucleosides are not counted toward the length of the oligonucleotide and are not used in determining the percentage of complementarity of the oligonucleotide to the reference nucleic acid.

[0212] In certain embodiments, conjugate groups and conjugate linkers, as well as other modifications, include those described in US5,994,517, US6,300,319, US6,660,720, US6,906,182, US7,262,177, US7,491,805, US8,106,022, US7,723,509, US9,127,276, US2006 / 0148740, US2011 / 0123520, WO2013 / 033230, WO2012 / 037254, Biessen et al., J. Med. Chem. 1995, 38, 1846-1852, Lee et al., Bioorganic & 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. 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. al., Int J Pep Protein Res, 1983, 22, 539-548, Lee et al. 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. al., Glycohiol, 2001, 11, 821-829, Rensen et al. al., J Biol Chem,2001,276,37577-37584、Lee et al.,Methids Enzymol,2003,362,38-43、Westerlind et al.,Glycoconj J,2004,21,227-241、Lee Meorg Me et al.,Bio 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-Meorg et.5231、 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 et.al.,Biessen、 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、Rensense et al.,Throm Varterios 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、Ac02se Nucleic Devic,Antisen12,103-128, Merwin et al., Bioconjug Chem, 1994, 5, 612-620, Tomiya et al., Bioorg Med Chem, 2013, 21, 5275-5281, International Publication No. 1998 / 013381, same as No. 2011 / 038356, same as No. 1997 / 046098, same as No. 2008 / 098788, same as No. 2004 / 101619, same as No. 2 No. 012 / 037254, same as No. 2011 / 120053, same as No. 2011 / 100131, same as No. 2011 / 163121, same as No. 2012 / 177947, same as No. 2013 / 033230, same as No. 2013 / 075035, same as No. 2 012 / 083185, 2012 / 083046, 2009 / 082607, 2009 / 134487, 2010 / 144740, 2010 / 148013, 1997 / 020563, 2010 / 088537, 2002 / 043771, 2010 / 129709, 2012 / 068187, 2009 / 126933, 2004 / 024757, 2010 / 054406, 2 No. 012 / 089352, same as No. 2012 / 089602, same as No. 2013 / 166121, same as No. 2013 / 165816, US Patent No. 4,751,219, same as No. 7,582,744, same as No. 8,552,163, same as No. 8,1 No. 37,695, same as No. 6,908,903, same as No. 6,383,812, same as No. 7,262,177, same as No. 6,525,031, same as No. 5,994,517, same as No. 6,660,720, same as No. 6,300,319, same as No. 7,72 No. 3,509, same as No. 8,106,022, same as No. 7,491,805, same as No. 7,491,805, same as No. 8,541,548, same as No. 8,344,125, same as No. 8,313,772, same as No. 8,349,308, same as No. 8,450,467, same as No. 8,501,930, same as No. 8,158,601, same as No. 7,262,177, same as No. 6,906,182, same as No. 6,620,916, same as No. 8,435,491, same as No. 8,404,862, same as No. 7,851,615, U.S. Patent Application Publication Nos. 2011 / 0097264, 2011 / 0097265, 2013 / 0004427, 2003 / 0119724, 2011 / 0207799, 2012 / 0035115, 2012 / 0230938, 2005 / 0164235, 2006 / 0183886, 2012 / 0136042, 2012 / 0095075, 2013 / 0109817, 2014 / 0109821, 2015 / 0109822, 2016 / 0109823, 2017 / 0109824, 2018 / 0109825, 2019 / 0109826, 2019 / 0109827, 2019 / 0109829, 2020 / 0109828, 2020 / 0109829, 2021 / 0109829, 2022 / 0109829, 2023 / 0109829, 2024 / 0109829, 2025 / 0109829, 2026 / 0109829, 2027 / 0109829, 2028 / 0109829, 2029 / 0119724, 2011 / 0207799, 2012 / 0035115, 2012 / 0230938, 2005 / 0164235, 2006 / These include, but are not limited to, those described in the following references: 2006 / 0148740, 2008 / 0206869, 2012 / 0165393, 2012 / 0101148, 2013 / 0121954, 2011 / 0123520, 2003 / 0077829, 2008 / 0108801, and 2009 / 0203132, each of which is incorporated herein by reference in its entirety.

[0213] A specific targeting part In certain embodiments, the compounds provided herein include a conjugate group. In certain embodiments, the oligonucleotides provided herein include a conjugate group. In certain embodiments, the conjugate group is a targeting moiety. In certain embodiments, the targeting moiety includes one or more GalNAcs. In certain embodiments, the one or more GalNAcs are attached to one or more positions of the furanose ring. In certain embodiments, the one or more GalNAcs are attached to the 2' or 3' positions of the furanose ring. In certain embodiments, the furanose ring is a subunit of the oligonucleotide. In certain embodiments, the furanose ring is the sugar of the 5' nucleoside of an oligonucleotide. In certain embodiments, the furanose ring is the sugar of the 5' nucleoside of a sense oligonucleotide. In certain embodiments, the compound or oligonucleotide includes one or more subunits of the following formula, or a salt, solvate, or hydrate thereof: [ka] During the ceremony, R 1 is H, adenine, guanine, thymine, cytosine, uracil, carbocyclyl, heterocyclyl, aryl, heteroaryl or a nucleobase analogue; R 2 is an oligonucleotide sequence of the invention, 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, a urea, O, S, S(=O), S(=O)2, NH, a substituted N group, an alkyl, an alkenyl, a dienyl, an alkynyl, a heteroalkyl, a phosphate; R 3 is H, -C=(O)-NH-(CH2CH2O) j -GalNAc or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc; R 4 is H, -C=(O)-NH-(CH2CH2O) k -GalNAc or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc; R 5 is -C=(O)-NH-(CH2CH2O) m -GalNAc or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc; R 6 is -C=(O)-NH-(CH2CH2O) n -GalNAc or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc; W and Q are each independently O, NH, CH2, or CH2O; S 1 and S 2 are each independently C(R 7) or N, wherein R 7 each instance of is independently H, alkyl, heteroalkyl, or halogen; j is an integer between 1 and 10, inclusive; k is an integer between 1 and 10, inclusive; m is an integer from 1 to 10, inclusive; n is an integer from 1 to 10 (inclusive).

[0214] 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.

[0215] In certain embodiments, L 1 and L 2 is the same.

[0216] In certain embodiments, L 1 and L 2 are each independently alkyl; R 3 is H, -C=(O)-NH-(CH2CH2O) j -GalNAc or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc; R 4 is H, -C=(O)-NH-(CH2CH2O) k -GalNAc or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc; R 5 is -C=(O)-NH-(CH2CH2O) m -GalNAc or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc; R 6 is -C=(O)-NH-(CH2CH2O) n-GalNAc or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc.

[0217] In certain embodiments, L 1 and L 2 are each independently alkyl-C(=O)-NH-alkyl; R 3 is H, -C=(O)-NH-(CH2CH2O) j -GalNAc or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc; R 4 is H, -C=(O)-NH-(CH2CH2O) k -GalNAc or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc; R 5 is -C=(O)-NH-(CH2CH2O) m -GalNAc or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc; R 6 is -C=(O)-NH-(CH2CH2O) n -GalNAc or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc.

[0218] In certain embodiments, R 4 is H.

[0219] In certain embodiments, L 1 and L 2 are each independently alkyl; R 3 is -C=(O)-NH-(CH2CH2O) j -GalNAc or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc; R 4 is H and R 5 is -C=(O)-NH-(CH2CH2O) m -GalNAc or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc; R 6 is -C=(O)-NH-(CH2CH2O) n-GalNAc or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc.

[0220] In certain embodiments, L 1 and L 2 are each independently alkyl-C(=O)-NH-alkyl; R 3 is -C=(O)-NH-(CH2CH2O) j -GalNAc or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc; R 4 is H and R 5 is -C=(O)-NH-(CH2CH2O) m -GalNAc or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc; R 6 is -C=(O)-NH-(CH2CH2O) n -GalNAc or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc.

[0221] In certain embodiments, R 3 is -C=(O)-NH-(CH2CH2O) j -GalNAc, R 4 is H and R 5 is -C=(O)-NH-(CH2CH2O) m -GalNAc, R 6 is -C=(O)-NH-(CH2CH2O) n -GalNAc.

[0222] In certain embodiments, R 3 is -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc, R 4 is H and R 5 is -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc, R 6 is -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc.

[0223] In certain embodiments, the compound or oligonucleotide comprises one or more subunits of the following formula, or a salt, solvate or hydrate thereof: [ka] During the ceremony, R 9 is H, adenine, guanine, thymine, cytosine or uracil, or adenine, guanine, thymine, cytosine or uracil, respectively, containing a protecting group (PG), a modified nucleobase, an optionally substituted alkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted carbocyclyl, an optionally substituted heterocyclyl, or a nucleobase analog; L is a bond, a phosphodiester bond, a phosphorothioate bond, a triazole, a tetrazole, an amide, a reverse amide, a carbamate, a carbonate, a urea, an alkyl, or a heteroalkyl; R 2 is an oligonucleotide sequence of the invention, Y1 is O, CH2, CH2O or optionally substituted NH; Y2 is O, CH2, CH2O or optionally substituted NH; Y3 is CO, SO2, P(O)O, CH2-OC(O), CH2-NH-C(O), CH2-NH-SO2 or CH2; Y4 is CO, SO2, P(O)O, CH2-OC(O), CH2-NH-C(O), CH2-NH-SO2 or CH2; n2 is 0, 1, 2, 3, 4, 5 or 6; Each of n1, n3, n4, and n5 is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0224] In certain embodiments, the compound or oligonucleotide comprises one or more subunits of the following formula, or a salt, solvate or hydrate thereof: [ka] During the ceremony, 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 L1, L2, and L3 is independently absent, C(=O), or C(=O)NH; Each Y1 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, - OP(=O)2-O-, -OP(=O)(=S)-O-, -OP(=S)2-O-, -OP(=O)2-, -OP(=O)(=S)-, -OP(=S)2-, Each Y2 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)-O, P(=S)2-O, - OP(=O)2-O-, -OP(=O)(=S)-O-, -OP(=S)2-O-, -OP(=O)2-, -OP(=O)(=S)-, -OP(=S)2-, Each of Het1, Het2 and Het3 is independently optionally substituted heteroaryl or optionally substituted heterocyclyl; R 1 is an oligonucleotide sequence linked by bonds, phosphodiester bonds, phosphorothioate bonds, triazoles, tetrazoles, amides, reverse amides, carbamates, carbonates, ureas, alkyls or heteroalkyls; Each of R5, R6 and R7 is independently [ka] and R9 is optionally substituted heterocyclyl; Each R a are independently H, alkyl, halo, OR cor S.R. c and Each R b are independently H, alkyl, halo, OR c or S.R. c and Each R c is independently H or alkyl.

[0225] In certain embodiments, the subunits are selected from Formulae I-VIII, or salts, solvates, or hydrates thereof, where R is a 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 of formula IV and R' is S. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of formula V and R' is O. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of formula V and R' is S. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of formula VI and R' is O. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of formula VI and R' is S. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of formula VII and R' is O. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of formula VII and R' is S. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of formula VIII and R' is O. In certain embodiments, the 5' nucleoside of the modified oligonucleotide is of formula VIII and R' is S.

[0226] Target Nucleic Acids and Target Regions In certain embodiments, the compounds described herein comprise or consist of an oligonucleotide comprising a region 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 a non-coding nucleic acid. In certain such embodiments, the target nucleic acid is selected from an mRNA and a pre-mRNA comprising an intron region, an exon region, and an untranslated region. 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.

[0227] In certain embodiments, the compounds disclosed herein hybridize with PKK nucleic acid. The most common mechanism of hybridization involves hydrogen bonding between complementary nucleic acid bases of nucleic acid molecules. Hybridization can occur under various conditions. Hybridization conditions are sequence-dependent and depend on the nature and composition of the hybridizing nucleic acid molecule. Methods for determining whether a sequence specifically hybridizes to a target nucleic acid are well known in the art. In certain embodiments, the compounds provided herein specifically hybridize with PKK nucleic acid.

[0228] Nucleotide sequences encoding PKK include, but are not limited to, GENBANK Accession Nos. NM_000892.5 (incorporated herein as SEQ ID NO:1), NG_012095.2 truncated from positions 23529-54493 (incorporated herein as SEQ ID NO:2), XM_017008181.1 (incorporated herein as SEQ ID NO:3), NC_000004.12 truncated from positions 186215714-186258477 (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).

[0229] Complementarity The oligonucleotides provided by the present invention may have a defined degree of complementarity to a particular nucleic acid, target region, oligonucleotide, or portion thereof. Non-complementary nucleobases may be permitted as long as the oligonucleotide can still specifically hybridize to the nucleic acid, oligonucleotide, or portion thereof. In certain embodiments, the oligonucleotides provided by the present invention, or a predetermined portion thereof, are at least or at most 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% complementary to the target nucleic acid, target region, oligonucleotide, or a predetermined portion thereof. In certain embodiments, the oligonucleotides provided by the present invention, or a predetermined portion thereof, are 70%-75%, 75%-80%, 80%-85%, 85%-90%, 90%-95%, 95%-100%, or any value between these ranges, to the target nucleic acid, target region, oligonucleotide, or a predetermined portion thereof. The complementarity of an oligonucleotide with a target nucleic acid, a target region, an oligonucleotide or a specified portion thereof can be determined by a conventional method. For example, an oligonucleotide in which 18 of the 20 nucleobases of the oligonucleotide are complementary to the target region, i.e., hybridize specifically, has a complementarity of 90%. In this example, the remaining non-complementary nucleobases can be clustered together or interspersed with complementary nucleobases, and do not have to be contiguous with each other or with complementary nucleobases. That is, an oligonucleotide that is 18 nucleobases long and has 4 non-complementary nucleobases flanked by two regions that are completely complementary to the target nucleic acid has an overall complementarity of 77.8% with the target nucleic acid. The complementarity of an oligonucleotide with a target nucleic acid, a target region, an oligonucleotide or a specified portion thereof can be determined by a conventional method using the BLAST program (basic local alignment search tool) known in the art.In certain embodiments, the oligonucleotides described herein or a given portion thereof are fully complementary (i.e., 100% complementary) to a target nucleic acid, target region, oligonucleotide, or a given portion thereof. For example, an oligonucleotide may be fully complementary to a target nucleic acid, target region, oligonucleotide, or a given portion thereof. As used herein, "fully complementary" means that each nucleobase of an oligonucleotide is complementary to a corresponding nucleobase of a target nucleic acid, target region, oligonucleotide, or a given portion thereof. For example, a 20 nucleobase oligonucleotide is fully complementary to its target sequence as long as a corresponding 20 nucleobase portion of a target nucleic acid that is 400 nucleobases long is fully complementary to the compound. "Fully complementary" can also be used in reference to a given portion of a first and / or 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. A 20 nucleobase portion of a 30 nucleobase compound is fully complementary to a target sequence if the target sequence has a corresponding 20 nucleobase portion to which 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.

[0230] In certain embodiments, the oligonucleotides described herein comprise one or more nucleobases that are mismatched with target nucleic acid, target region, oligonucleotide or a predetermined portion thereof.In certain embodiments, the oligonucleotides described herein comprise 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22 or 23 nucleobases in length or up to this nucleobase length, comprise 4 or less, 3 or less, 2 or less, or 1 or less nucleobases that are non-complementary with target nucleic acid or a predetermined 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 contain 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 nucleobase that is non-complementary to a target nucleic acid, target region, oligonucleotide, or a given portion thereof. In certain embodiments, the mismatch is at the 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th, or 14th position from the 5' end of the oligonucleotide. In certain embodiments, the mismatch is at the 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th or 14th position from the 3' end of the oligonucleotide. In certain embodiments, the mismatch forms a wobble base pair with the 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). Thus, in certain embodiments, the mismatched nucleobase on the oligonucleotide comprises hypoxanthine, guanine or uracil.

[0231] In certain embodiments, the oligonucleotides described herein may be complementary to a portion of a nucleic acid. As used herein, a "portion" refers to a predetermined number of consecutive nucleobases within a region of a nucleic acid. A "portion" can also refer to a predetermined number of consecutive nucleobases of an oligonucleotide. In certain embodiments, the oligonucleotide is complementary to at least an 8 nucleobase portion of a nucleic acid. In certain embodiments, the oligonucleotide is complementary to at least an 9 nucleobase portion of a nucleic acid. In certain embodiments, the oligonucleotide is complementary to at least an 10 nucleobase portion of a nucleic acid. In certain embodiments, the oligonucleotide is complementary to at least an 11 nucleobase portion of a nucleic acid. In certain embodiments, the oligonucleotide is complementary to at least an 12 nucleobase portion of a nucleic acid. In certain embodiments, the oligonucleotide is complementary to at least an 13 nucleobase portion of a nucleic acid. In certain embodiments, the oligonucleotide is complementary to at least an 14 nucleobase portion of a nucleic acid. In certain embodiments, the oligonucleotide is complementary to at least an 15 nucleobase portion of a nucleic acid. In certain embodiments, the oligonucleotide is complementary to at least an 16 nucleobase portion of a nucleic acid. Also contemplated is an oligonucleotide that is complementary to at least 9 nucleobases, 10 nucleobases, 17 nucleobases, 18 nucleobases, 19 nucleobases, 20 nucleobases, 21 nucleobases, 22 nucleobases or 23 nucleobases or more of 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 with an equal length portion of target nucleic acid.In certain embodiments, a portion of 8 nucleobases, 9 nucleobases, 10 nucleobases, 11 nucleobases, 12 nucleobases, 13 nucleobases, 14 nucleobases, 15 nucleobases, 16 nucleobases, 17 nucleobases, 18 nucleobases, 19 nucleobases, 20 nucleobases, 21 nucleobases, 22 nucleobases, 23 nucleobases, 24 nucleobases or 25 nucleobases is compared with an equal length portion of target nucleic acid.In certain embodiments, the oligonucleotide is a sense oligonucleotide.In certain embodiments, a portion of the sense oligonucleotide is compared with the same length portion of antisense oligonucleotide.In certain embodiments, 8 nucleobases, 9 nucleobases, 10 nucleobases, 11 nucleobases, 12 nucleobases, 13 nucleobases, 14 nucleobases, 15 nucleobases, 16 nucleobases, 17 nucleobases, 18 nucleobases, 19 nucleobases, 20 nucleobases, 21 nucleobases, 22 nucleobases, 23 nucleobases, 24 nucleobases or 25 nucleobases of the sense oligonucleotide are compared with the same length portion of antisense oligonucleotide.

[0232] identity The oligonucleotides provided herein may also be specified with a percent identity with a particular nucleic acid, target region, oligonucleotide or a given portion thereof.As used herein, an oligonucleotide is identical to a sequence disclosed herein if it has the same nucleic acid base pairing ability.For example, since both uracil and thymidine pair with adenine, a DNA containing thymidine instead of uracil in a disclosed RNA sequence will be considered identical to the RNA sequence.Shortened and extended forms of the compounds described herein are also contemplated, as well as compounds with non-identical bases to the compounds provided herein.The non-identical bases may be adjacent to each other or distributed throughout the compound.The percent identity of an oligonucleotide is calculated according to the number of bases that are identical base pairing compared to the sequence to which it is compared. In certain embodiments, the oligonucleotides or portions thereof described herein are 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, or at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or at least 100% identical to one or more of the nucleic acids, oligonucleotides or portions thereof disclosed herein. In certain embodiments, the oligonucleotides described herein are about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98% or about 99% identical to a particular nucleic acid or oligonucleotide or portion thereof, or any percentage between such values.

[0233] In certain embodiments, oligonucleotide may have one or more mismatched nucleobases.In certain such embodiments, the mismatch is at the 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th or 14th position from the 5' end of the oligonucleotide.In certain such embodiments, the mismatch is at the 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th or 14th position from the 3' end of the oligonucleotide.In certain embodiments, a portion of the oligonucleotide is compared with a portion of the target nucleic acid of equal length. In certain embodiments, 8 nucleobases, 9 nucleobases, 10 nucleobases, 11 nucleobases, 12 nucleobases, 13 nucleobases, 14 nucleobases, 15 nucleobases, 16 nucleobases, 17 nucleobases, 18 nucleobases, 19 nucleobases, 20 nucleobases, 21 nucleobases, 22 nucleobases, 23 nucleobases, 24 nucleobases or 25 nucleobases are compared with the part of the target nucleic acid of equal length.In certain embodiments, the oligonucleotide is a sense oligonucleotide.In certain embodiments, the part of the sense oligonucleotide is compared with the part of the target nucleic acid of equal length.In certain embodiments, 8 nucleobases, 9 nucleobases, 10 nucleobases, 11 nucleobases, 12 nucleobases, 13 nucleobases, 14 nucleobases, 15 nucleobases, 16 nucleobases, 17 nucleobases, 18 nucleobases, 19 nucleobases, 20 nucleobases, 21 nucleobases, 22 nucleobases, 23 nucleobases, 24 nucleobases or 25 nucleobases are compared with the part of the target nucleic acid of equal length.

[0234] Pharmaceutical Compositions and Formulations The compounds described herein may be mixed with pharma- ceutically acceptable active or inactive substances for the preparation of pharmaceutical compositions or formulations. The compositions and methods for preparing pharmaceutical compositions depend on many criteria, including but not limited to the route of administration, the extent of the disease, or the dosage administered. Certain embodiments provide pharmaceutical compositions comprising one or more compounds or salts 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 compositions comprise one or more compounds and a suitable pharma- ceutically acceptable diluent or carrier. In certain embodiments, the pharmaceutical compositions comprise one or more compounds and sterile saline. In certain embodiments, such pharmaceutical compositions consist of a compound and sterile saline. In certain embodiments, the sterile saline is pharmaceutical grade saline. In certain embodiments, the pharmaceutical compositions comprise one or more compounds and sterile water. In certain embodiments, the pharmaceutical compositions consist of a compound and sterile water. In certain embodiments, the sterile water is pharmaceutical grade water. In certain embodiments, the pharmaceutical composition comprises one or more compounds and phosphate buffered saline (PBS). In certain embodiments, the pharmaceutical composition consists of a compound and sterile PBS. In certain embodiments, the sterile PBS is pharmaceutical grade PBS.

[0235] The compound described herein that targets PKK can be used in pharmaceutical compositions by combining the compound with a suitable pharmaceutically acceptable diluent or carrier.In certain embodiments, the pharmaceutically acceptable diluent is water, for example, sterile water suitable for injection.Thus, in one embodiment, the method described herein uses a pharmaceutical composition that includes the compound that targets 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 oligonucleotides provided by the present invention.

[0236] Pharmaceutical compositions containing the compounds provided herein include any pharma- ceutically acceptable salts, esters, salts of such esters, or any other oligonucleotides that, when administered to an animal, including a human, can result (directly or indirectly) in a biologically active metabolite or residue thereof. In certain embodiments, the compound is an antisense oligonucleotide. In certain embodiments, the compound is an oligomeric compound. In certain embodiments, the compound comprises or consists of one or more modified oligonucleotides. Thus, for example, the disclosure is also directed to pharma- ceutically acceptable salts of the compounds, prodrugs, pharma- ceutically acceptable salts of such prodrugs, and other bioequivalents. Suitable pharma- ceutically acceptable salts include, but are not limited to, sodium and potassium salts. Prodrugs can include those that incorporate additional nucleosides at one or both ends of the compound, which are cleaved by endogenous nucleases in the body to form the active compound. In certain embodiments, the compound or composition further comprises a pharma- ceutically acceptable carrier or diluent. EXAMPLES

[0237] The Examples below describe the process of identifying lead compounds that target PKK. Certain compounds stand out as being highly potent and well tolerated.

[0238] The following examples merely serve to illustrate the compounds described herein and are not intended to limit the compounds. The following examples and the associated sequence listing attached to this application may define sequences as either "RNA" or "DNA", however, as disclosed herein, these sequences may be modified with any combination of chemical modifications. Those skilled in the art will readily recognize that the definition of a sequence as "RNA" or "DNA" is optional in certain cases. For example, an oligonucleotide containing a nucleoside containing a 2'-OH sugar moiety and a thymine base may be described as a DNA with a modified sugar (2'-OH instead of the natural 2'-H of DNA) or an RNA with a modified base (methylated uracil instead of the natural uracil of RNA). Thus, the nucleic acid sequences provided herein, including but not limited to those in the sequence listing, are intended to include nucleic acids that contain any combination of natural or modified RNA and / or DNA, including but not limited to those nucleic acids with modified nucleobases.

[0239] Each of the references cited in this application is incorporated herein by reference in its entirety.

[0240] The compounds are unmodified unless otherwise indicated in a separate table below regarding the chemical data of the compounds. Abbreviations for the chemical modifications are shown in Table 1 below. In the reference ID numbers, IA defines the antisense strand of the compound and IS defines the sense strand of the compound. [Table 1]

[0241] Example 1 - Inhibition of PKK in HEK-293T cells HEK-293T cells were seeded at 20,000 cells / well in antibiotic-free medium in white-walled 96-well plates. The next day, cells were co-transfected with 50 ng of PKK-siCHECK-2 and 10 nM of PKK compound using Lipofectamine 2000 (each transfection was performed in triplicate). Cells were then incubated at 37°C / 5% CO2 for 48 hours.

[0242] The Dual-Luciferase Reporter 1000 Assay (Promega Cat. No. E1980) was used to assess the expression of firefly luciferase and Renilla luciferase according to the kit instructions. The expression of firefly luciferase and Renilla luciferase was measured using a luminometer. Renilla luciferase was the readout for PKK gene expression, whereas firefly luciferase served as an internal control. All Renilla luciferase readouts from each well were normalized to their corresponding firefly luciferase readouts to obtain Renilla:firefly ratios. The ratios obtained from each well transfected with compound were then further normalized to the ratios obtained from cells not transfected with compound. These non-transfected cells served as 100% controls. Inhibition of PKK was determined by comparing the expression of PKK to non-transfected cells and was recorded as % PKK inhibition (Tables 2-4). [Table 2] [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 4-1] [Table 4-2] [Table 4-3]

[0243] Example 2 - Dose-dependent inhibition of human PKK in HEK-293T cells Among the compounds obtained from the above test, those that showed significant in vitro PKK mRNA inhibition were selected and tested in HEK-293T cells at various doses as described above. Compounds were tested at concentrations of 0.01 nM, 0.1 nM, 1 nM and 10 nM, and IC50 values ​​were calculated (Table 5). [Table 5]

[0244] Example 3: Effects of compounds targeting human PKK in cynomolgus monkeys Compounds of interest identified from the in vitro gene expression screen were evaluated in cynomolgus monkeys (Table 7). Prior to testing, the monkeys were kept in an isolated facility during which their general health was monitored daily. On study day 1, 10 groups of one cynomolgus monkey each were injected with a single subcutaneous dose of 6 mg / kg of oligonucleotide. The monkeys were observed daily for signs of disease or psychological distress throughout the study. Monkeys were bled on days -6 and 1 (pre-dose), 4, 8, 15, 22, 29, 36, 43, 50, 57, and 64 for serum collection and analysis. The protocol described was approved by the Institutional Animal Care and Use Committee (IACUC). Circulating PKK levels were quantified using an ELISA specific for human angiotensinogen (with cross-reactivity to cynomolgus monkeys) according to the manufacturer's protocol (IBL America #27412). PKK inhibition data are expressed as a percentage of baseline values ​​(pre-dose, day 1) (Table 8). [Table 6] [Table 7] [Table 8]

[0245] Example 4: Effects of compounds targeting human PKK in cynomolgus monkeys Compounds of interest identified from the in vitro gene expression screen were evaluated in cynomolgus monkeys (Table 10). Prior to testing, the monkeys were kept in an isolated facility during which their general health was monitored daily. On study day 1, eight groups of two cynomolgus monkeys each were injected with a single 4 mg / kg subcutaneous dose of oligonucleotide. The monkeys were observed daily for signs of illness or distress during the study. Monkeys were bled on days -6 and 1 (pre-dose), 4, 8, and 15 for serum collection and analysis. Subsequent collections were on days 22, 29, 36, 43, 50, 57, 64, 71, 78, and 85. In a second set of experiments, monkeys were bled on days -6 and 1 (pre-dose), 4, 8, 15, and 22 for serum collection and analysis. Subsequent collections were on days 29, 36, 43, 50, 57, 64, 71, 78, and 85 in the second set of experiments. In the third set of experiments, monkeys were bled for serum collection and analysis on days -6 and 1 (pre-dose), 4, 8, 15, 22, 29, and 36. Subsequent collections were on days 43, 50, 57, 64, 71, 78, and 85 in the third set of experiments. In the fourth set of experiments, monkeys were bled for serum collection and analysis on days -6 and 1 (pre-dose), 4, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78, and 85. The protocol described was approved by the Institutional Animal Care and Use Committee (IACUC). Circulating PKK levels were quantified using an ELISA specific for human angiotensinogen (with cross-reactivity to cynomolgus monkeys) according to the manufacturer's protocol (IBL America#27412). PKK inhibition data were expressed as a percentage of baseline values ​​(day 1, pre-dose) for each compound and as group averages. The results of these four sets of experiments are shown in Tables 11, 12, 13, and 14.Clinical chemistry data reviews were performed on days -1 or -6, and on days 63 or 64 and 92. There were no test article-related effects on body weight (Table 15) and all serum chemistry values ​​were within the reference range (Tables 16 and 17). [Table 9] [Table 10] [Table 11] [Table 12] [Table 13] [Table 14] [Table 15] [Table 16] [Table 17]

[0246] Example 5: Effects of compounds targeting human PKK in cynomolgus monkeys The compounds of interest were evaluated in cynomolgus monkeys (Table 19). Prior to testing, the monkeys were kept in an isolation facility during which their general health was monitored daily. On day 1 of the study, eight groups of two cynomolgus monkeys each were injected with a single subcutaneous dose of 4 mg / kg of oligonucleotide. The monkeys were observed daily for signs of illness or distress during the study. For serum collection and analysis, the monkeys were bled on days -6 and 1 (pre-dose), 8, 15, and 22. Subsequent collections were on days 29, 36, 43, 50, 57, 64, and 71. In a second set of experiments, the monkeys were bled on days -6 and 1 (pre-dose), 8, 15, 22, 29, 36, 43, 50, 57, 64, and 71. The protocol described was approved by the Institutional Animal Care and Use Committee (IACUC). Circulating PKK levels were quantified using an ELISA specific for human angiotensinogen (cross-reactive with cynomolgus monkeys) according to the manufacturer's protocol (IBL America #27412). PKK inhibition data were expressed as a percentage of baseline values ​​(day 1, pre-dose) and as group means for each compound. The results of these two sets of experiments are shown in Tables 20 and 21. Clinical chemistry data were examined on days -1 or -6, and on days 64 and 92. No test article-related effects were observed on body weight (Table 22), and all serum chemistry values ​​were within the reference range (Tables 23 and 24). [Table 18] [Table 19] [Table 20] [Table 21] [Table 22] [Table 23] [Table 24]

[0247] Example 6: Effects of compounds targeting human PKK in Lewis rats On day 1, female Lewis rats (5 females / group, 8 weeks old) were injected subcutaneously (SC) once with 0 mg / kg (vehicle control (phosphate buffered saline (PBS)), 200 mg / kg RD2423 or 200 mg / kg RD2438 in a dose volume in mL / kg in groups 1-3, respectively. Observations included viability, clinical signs and body weight (days 1 and 10). Blood samples were taken for clinical chemistry data (days 0 (pre-dose), 3 and 10), hematology data (day 10) and coagulation data (day 10). On day 10, the heart, liver and both kidneys were removed from each rat, weighed and fixed in 10% neutral buffered formalin.

[0248] Results: No drug-related effects were observed on viability, clinical observations, body or organ weights (heart, liver and kidney), clinical chemistry parameters, hematology parameters or coagulation parameters (prothrombin clotting time).A single subcutaneous dose of 200 mg / kg of compounds RD2423 or RD2438 to female Lewis rats was well tolerated.

[0249] SEQ ID NO:1

Claims

1. 1. A compound comprising: a first modified oligonucleotide of 14 to 23 linked nucleosides in length, said first modified oligonucleotide comprising a nucleobase sequence comprising at least 14 contiguous nucleobases of the nucleobase sequence of SEQ ID NO: 619; and a second modified oligonucleotide of 14 to 23 linked nucleosides in length, said second modified oligonucleotide comprising a region complementary to said first modified oligonucleotide.

2. The compound of claim 1 , wherein the nucleobase sequence of the first modified oligonucleotide has at least 80% complementarity with the second modified oligonucleotide.

3. 2. The compound of claim 1, wherein the first modified oligonucleotide has at least one mismatch with a region of the second modified oligonucleotide that is the same length as the first modified oligonucleotide.

4. The compound of claim 1, wherein the complementary region between the first modified oligonucleotide and the second modified oligonucleotide is 14 to 23 nucleosides in length.

5. The compound of claim 1 , wherein the first modified oligonucleotide is perfectly complementary to the second modified oligonucleotide.

6. The compound described in claim 1, wherein the second modified oligonucleotide comprises a nucleic acid base sequence comprising at least 14 consecutive nucleic acid bases of SEQ ID NO:

312.

7. 2. The compound of claim 1, wherein the first modified oligonucleotide comprises at least one modification selected from a modified internucleoside linkage, a modified sugar, and a modified nucleobase.

8. 2. The compound of claim 1, wherein 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.

9. 9. The compound of claim 7 or 8, wherein the modified internucleoside linkage is a phosphorothioate internucleoside linkage or a methylphosphonate internucleoside linkage.

10. 10. The compound of claim 9, wherein the phosphorothioate internucleoside linkage or methylphosphonate internucleoside linkage is at the 3' end of the first or second modified oligonucleotide or at the 5' end of the first or second modified oligonucleotide.

11. 9. The compound of claim 7 or 8, wherein the modified sugar comprises a 2'-F modification or a 2'-OMe modification.

12. The compound described in claim 1, wherein the first modified oligonucleotide comprises a conjugate group.

13. The compound of claim 12 , wherein the conjugate group is attached to the 5′ end of the first modified oligonucleotide.

14. The compound of claim 12, wherein the conjugate group comprises one or more N-acetyl-galactosamine (GalNAc).

15. 15. The compound of claim 14, wherein the one or more GalNAc is attached to the 2' or 3' position of the ribosyl ring of the 5' nucleoside of the first modified oligonucleotide.

16. the 5' nucleoside is of the formula: 【Chemistry 18】 During the ceremony, R ９ is H, adenine, guanine, thymine, cytosine or uracil, or adenine, guanine, thymine, cytosine or uracil, respectively, containing a protecting group, modified nucleobase, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, or nucleobase analog; L is a bond, a phosphodiester bond, a phosphorothioate bond, a triazole, a tetrazole, an amide, a reverse amide, a carbamate, a carbonate, a urea, an alkyl, or a heteroalkyl; R ２ is the remainder of the first modified oligonucleotide, Y １ But O, CH ２ , C.H. ２ O or substituted or unsubstituted NH, Y ２ But O, CH ２ , C.H. ２ O or substituted or unsubstituted NH, Y ３ But CO, SO ２ , P(O)O, CH ２ -O-C(O), CH ２ -NH-C(O), CH ２ -NH-SO ２ or CH ２ and Y ４ But CO, SO ２ , P(O)O, CH ２ -O-C(O), CH ２ -NH-C(O), CH ２ -NH-SO ２ or CH ２ and n ２ is 0, 1, 2, 3, 4, 5 or 6, Each n １ , n ３ , n ４ and n ５ is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

17. The compound described in claim 1, wherein the second modified oligonucleotide consists of reference ID number IA0818 and the first modified oligonucleotide consists of reference ID number IS1058.

18. 10. A composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

19. A pharmaceutical composition for the treatment of a disease, disorder or condition associated with PKK, comprising a compound of claim 1 or a composition of claim 18.

20. 20. The pharmaceutical composition of claim 19, wherein the PKK-associated disease, disorder, or condition is an inflammatory or thrombotic disease, disorder, or condition, or symptom thereof, hereditary angioedema (HAE), edema, angioedema, swelling, eyelid angioedema, ocular edema, macular edema, cerebral edema, thrombosis, embolism, thromboembolism, deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke, or infarction.

21. 19. A composition for use in a method for inhibiting expression of a PKK in a cell, comprising contacting the cell with a composition comprising a compound of claim 1 or a composition of claim 18.

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