Prokallikrein modulating compositions and methods of use thereof

Abstract

Some aspects of the present disclosure provide compounds, compositions, and methods for modulating the expression or activity of plasma kallikrein (PKK). In some aspects, the compounds, compositions, and methods of the present disclosure are useful for reducing the expression of PKK mRNA in a cell or animal. In some aspects, the compounds, compositions, and methods of the present disclosure are useful for reducing the expression of PKK protein in a cell or animal.

Description

[0001] Cross-references to related applications

[0002] This application claims the benefits of U.S. Provisional Application No. 63 / 251,571, filed October 1, 2021; U.S. Provisional Application No. 63 / 252,554, filed October 5, 2021; U.S. Provisional Application No. 63 / 270,504, filed October 21, 2021; U.S. Provisional Application No. 63 / 283,175, filed November 24, 2021; and U.S. Provisional Application No. 63 / 287,969, filed December 9, 2021. The disclosures of each of these prior applications are considered part of the disclosure of this application and are incorporated herein by reference in their entirety. Background Technology

[0003] Prekallikrein (PKK) is a surface-dependent glycoprotein involved in blood coagulation, fibrinolysis, kinin production, and inflammation. Encoded by the KLKB1 gene, PKK is a precursor to kallikrein (PK). PKK exists in plasma as a contact factor, forming a non-covalent complex with high molecular weight kininogen. PKK is converted from factor XIIa to PK by cleaving the internal Arg-Ile peptide bond. PK is a member of the kallikrein pathway, which consists of several proteins that play roles in inflammation, blood pressure control, coagulation, and pain. PK releases kinins from kininogen and also produces plasmin from plasminogen. For example, plasma kallikrein cleaves high molecular weight kininogen (HMWK) to produce bradykinin. Kinins, especially bradykinin, continue to induce downstream effects, including vasodilation and edema (see, for example, Schmaier. J. Thromb. Haemost 14:28-39, 2016).

[0004] Certain mutations in PKK cause PKK deficiency, also known as Fletcher factor deficiency, a rare coagulation disorder characterized by prolonged activated partial thromboplastin time (PTT). PKK deficiency is associated with inflammatory and thrombotic conditions.

[0005] Mutations in PKK prevent the release of plasmin and kinins (e.g., bradykinin), and / or reduce fibrinolysis. This leads to decreased vasodilation and increased blood clot formation, which in turn increases the likelihood of developing inflammatory or thrombotic diseases. Patients with PKK deficiency are often asymptomatic but still exhibit prolonged activated PTT and are at risk of developing such a disease.

[0006] Inflammatory disorders occur when the immune system mistakenly attacks the body's own cells or tissues. This causes abnormal inflammation, which can lead to chronic pain, redness, swelling, stiffness, and damage to other healthy body tissues. Inflammatory diseases encompass a wide range of disorders and conditions characterized by inflammation. Some examples include rheumatoid arthritis, allergic reactions, asthma, autoimmune diseases, celiac disease, glomerulonephritis, hepatitis, inflammatory bowel disease, pre-perfusion injury, and transplant rejection. It is estimated that in the United States, more than 1.36 million adults have rheumatoid arthritis and 3 million have inflammatory bowel disease.

[0007] Thrombosis is the formation of a blood clot within 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 blood clot to stop bleeding. Even when blood vessels are not damaged, blood clots can form in certain situations. In healthy individuals, a homeostatic balance exists between procoagulant (clotting) forces and anticoagulant and fibrinolytic forces. Many genetic, acquired, and environmental factors can tilt this balance towards clotting, leading to pathological formation of thrombi in veins (e.g., deep vein thrombosis), arteries (e.g., myocardial infarction, ischemic stroke), or heart chambers. A thrombus can block blood flow at its site of formation or detach and cause an embolism, 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, and about 100,000 of these people will die from blood clot-related complications.

[0008] Hereditary angioedema (HAE) is a rare inflammatory disease characterized by recurrent episodes of swelling around the head and extremities (Zuraw, BLNEngl. J. Med. 359:1027-36, 2008). Angioedema episodes occur with unpredictable frequency and are typically concentrated in the skin, as well as the gastric, oropharyngeal, and laryngeal mucosa. Asphyxiation due to laryngeal swelling can lead to death. 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 a major inhibitor of coagulation factors 12 and 11 (factor 11) in 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 leads to inactivation of the kallikrein pathway and decreased bradykinin (BK) levels. C1-INH deficiency or dysfunction results in excessive BK production, which is believed to be the mechanism underlying HAE attacks. Type III HAE is associated with mutations in the factor 12 gene, which encodes the clotting protein factor 12 (Cichon, S. et al. Am. J. Hum. Genet. 79:1098-1104, 2006).

[0009] Currently, there are no cures for certain inflammatory conditions such as HAE, or for thrombotic conditions associated with dysregulation of PKK or other members of the kallikrein pathway. Therefore, there is a need to find effective treatments for PKK-related diseases. Invention Overview

[0011] This disclosure provides compounds, compositions, and methods for regulating the expression or activity of PKK. In some embodiments, the compounds, compositions, and methods can be used to reduce the expression of PKK mRNA in cells or animals. In some embodiments, the compounds, compositions, and methods can be used to reduce the amount of PKK protein in cells or animals.

[0012] In some embodiments, the animal suffers from an inflammatory or thrombotic disease, disorder, or condition, or its symptoms. In some 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 relate to alleviating inflammatory or thrombotic diseases, disorders, or conditions, or their symptoms, in animals, 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 some embodiments, the compounds and compositions provided herein are potent and tolerable and inhibit PKK expression, and may be used to treat, prevent, improve, or slow the progression of inflammatory or thrombotic diseases, disorders or conditions or their symptoms, 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.

[0013] In some embodiments, the compounds and compositions comprise one or more features effective in enhancing potency. In some embodiments, the compounds and compositions comprise one or more features effective in enhancing tolerability. In some embodiments, the compounds and compositions comprise one or more features effective in targeting the compounds or compositions to cells or tissues. In some embodiments, the compounds and compositions are more potent or have greater therapeutic value compared to publicly disclosed compounds. Invention Details

[0015] It should be understood that the foregoing description of the invention and the following detailed description are merely exemplary and illustrative, and do not constitute a limitation on the claimed embodiments. Section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter.

[0016] All documents or portions thereof cited in this application, including but not limited to patents, patent applications, articles, books, papers, and GenBank, NCBI, and other sequence reference records, are expressly incorporated herein by reference in whole or in part as of the date of filing of this application.

[0017] It should be understood that the sequence shown in each SEQ ID NO contained herein is independent of any modification to the sugar moiety, internucleotide linkage, or nucleobase, even when shown in the context of a modified compound. Therefore, a compound defined by SEQ ID NO may independently contain one or more modifications to the sugar moiety, internucleotide linkage, or nucleobase. Oligomeric compounds referenced by compound number or Ref ID NO represent combinations of nucleobase sequences, chemical modifications, and motifs.

[0018] Herein, unless otherwise expressly stated, the use of the singular includes the plural. For example, a noun without a quantifier as used herein refers to one or more grammatical objects (i.e., at least one). For instance, “element” means one or more elements, such as multiple elements. Unless otherwise stated, the use of “or” herein means “and / or”. Furthermore, the use of the term “including / contains” and other forms (e.g., their variations) is not restrictive and may be used interchangeably with the phrase “including but not limited to”.

[0019] definition

[0020] Unless otherwise stated, the following terms have the following meanings:

[0021] The term "plasma prekallikrein" or "kallikrein B1," which can be used interchangeably with "PKK," refers to any nucleic acid or protein of PKK. Exemplary nucleotide and amino acid sequences of PKK can be found, for example, in GenBank accession No. NM_000892.5 (incorporated herein by SEQ ID NO: 1), NG_012095.2 truncated from 23529..54493 (incorporated herein by SEQ ID NO: 2), XM_0170081811 (incorporated herein by SEQ ID NO: 3), NC_000004.12 truncated from 186215714 to 186258477 (incorporated herein by SEQ ID NO: 4), NM_001318394.2 (incorporated herein by SEQ ID NO: 5), and NM_001318396.2 (incorporated herein by SEQ ID NO: 6). Other instances of PKK sequences are readily available from publicly accessible databases such as GenBank, UniProt, and OMIM. Further information about PKK can be found, for example, at ncbi.nlm.nih.gov / gene / ?term=PKK. As used herein, PKK also refers to variations of the PKK gene, including variants available in SNP databases. Numerous sequence variations within the PKK gene have been identified and are available, for example, in NCBI dbSNP and UniProt (see, for example, ncbi.nlm.nih.gov / snp / ?term=PKK). "PKK mRNA" refers to the mRNA encoding the PKK protein. PKK can be represented in uppercase or lowercase.

[0022] "PKK-specific inhibitors" refer to any agent that can specifically inhibit 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 that can inhibit the expression of PKK RNA and / or PKK protein.

[0023] "2'-O-methoxyethyl" or "2'-MOE" refers to 2'-O(CH2)2-OCH3 modification. Sugars modified with 2'-O-methoxyethyl are modified sugars that have 2'-O(CH2)2-OCH3 at the 2'-OH position of the ribosyl ring.

[0024] The “5’ start site” refers to the nucleotide in the target nucleic acid or region that is aligned with the 3’-nucleotide of the antisense oligonucleotide.

[0025] The “3’ termination site” refers to the nucleotide of the target nucleic acid or region that is aligned with the 5’-nucleotide of the antisense oligonucleotide.

[0026] "Approximately / about" means within ±10% of the value. For example, if the statement "the compound achieved approximately 70% PKK inhibition" means that the PKK level was inhibited in the range of 60% to 80%. When "about" appears before a series of numbers or ranges, it should be understood that "approximately / about" can modify each number in that series or range.

[0027] "Administration" and its variations refer to the means by which a compound or composition provided herein is introduced into an individual to achieve its intended function. For example, possible routes of administration include, but are not limited to, parenteral administration, such as subcutaneous, intravenous, or intramuscular injection or infusion.

[0028] "Improvement" means an improvement or reduction in at least one indicator, sign, or symptom of a related disease, disorder, or condition. In some embodiments, improvement includes delaying or slowing the progression or severity of one or more indicators of the condition or disease. The progression or severity of the indicator can be determined by subjective or objective measurements known to those skilled in the art.

[0029] "Animal" refers to human or non-human animals, including but not limited to mice, rats, rabbits, dogs, cats, pigs, and non-human primates, including but not limited to monkeys and chimpanzees.

[0030] "Antisense oligonucleotide" or "antisense strand" refers to an oligonucleotide that contains a region complementary to a target nucleic acid (e.g., PKK RNA or a region thereof).

[0031] The term "complementarity" for oligonucleotides means that when two nucleobase sequences are aligned in opposite directions, such an oligonucleotide, or one or more regions thereof, is complementary to the nucleobase sequence of another oligonucleotide or nucleic acid, or one or more regions thereof. Unless otherwise stated, complementary nucleobases as described herein are limited to the following pairings: adenine (A) and thymine (T), adenine (A) and uracil (U), and cytosine (C) and guanine (G). Complementary oligonucleotides and / or nucleic acids do not need to have nucleobase complementarity at every nucleoside and may contain one or more nucleobase mismatches. In contrast, the term "perfect complementarity" or "100% complementarity" for oligonucleotides means that such an oligonucleotide has nucleobase matches at every nucleoside without any nucleobase mismatches.

[0032] "Composition" or "pharmaceutical composition" means a mixture of substances suitable for administration to an individual. For example, a composition may contain one or more compounds or salts thereof, along with a sterile aqueous solution.

[0033] "Co-administration" means administering two or more compounds in any manner, where the pharmacological effects of both compounds are observed in the patient. Co-administration does not require the two compounds to be administered as a single drug composition, in the same dosage form, via the same route of administration, or simultaneously. The effects of the two compounds do not need to be simultaneous. The effects only need to overlap over a period of time and do not need to be co-prolonged. Co-administration includes parallel or sequential administration of one or more compounds.

[0034] A "conjugation group" refers to a group of atoms linked to an oligonucleotide. Conjugation groups can optionally be linked to oligonucleotides via conjugation linkers. For example, conjugation groups can alter the distribution, targeting, or half-life of the compound they are incorporated into. Conjugation groups include targeting moieties.

[0035] "Fuse linker" refers to a group of atoms that contains at least one bond that connects the linker portion to the oligonucleotide.

[0036] The term "identity" in oligonucleotides refers to the nucleotide sequence of an oligonucleotide, or one or more regions thereof, matching the nucleotide sequence of another oligonucleotide or nucleic acid, or one or more regions thereof. Identity between one oligonucleotide and another does not require a perfect match of every nucleobase, and may include one or more distinct nucleobases. In contrast, "identical" or "100% identical" oligonucleotides mean that such an oligonucleotide has the same nucleobases at every relative position along its length as other oligonucleotides or nucleic acids.

[0037] "Individual" refers to a human or non-human animal chosen for treatment or therapy.

[0038] "Inhibition of expression or activity" in relation to a target nucleic acid or protein means reducing or blocking the expression or activity of such a target relative to the expression or activity in untreated or control samples, and does not necessarily mean complete elimination of expression or activity.

[0039] As used herein, the term "nucleoside linkage" refers to a covalent bond between adjacent nucleosides in an oligonucleotide. As used herein, "modified nucleoside linkage" refers to any nucleoside linkage other than a phosphodiester nucleoside linkage. A "thiophosphate nucleoside linkage" is a modified nucleoside linkage in which a non-bridging oxygen atom in the phosphodiester nucleoside linkage is replaced by a sulfur atom.

[0040] Representative internucleotide linkages with chiral centers include, but are not limited to, alkylphosphonates and thiophosphates. Modified oligonucleotides containing internucleotide linkages with chiral centers can be prepared as modified oligonucleotide groups containing stereorandom internucleotide linkages, or as modified oligonucleotide groups containing thiophosphate linkages with specific stereochemical configurations, as further described below. Unless otherwise stated, the chiral internucleotide linkages of modified oligonucleotides described herein can be stereorandom or specific stereochemical configurations.

[0041] The compounds disclosed herein may also contain atomic isotopes in non-natural proportions at one or more atoms constituting such compounds. For example, the compounds may use radioactive isotopes (e.g., tritium). 3 H), Iodine-125 ( 125 I) or carbon-14 ( 14 C) Radioactive labeling. All isotopic variations of the compounds of this invention, whether or not radioactive, are covered within the scope of this disclosure.

[0042] The term "isotope variant" refers to a therapeutic agent (e.g., compounds and / or modified oligonucleotides disclosed herein) that contains an isotope in a non-natural proportion at one or more atoms constituting the therapeutic agent. In some embodiments, the "isotope variant" of the therapeutic agent contains one or more isotopes in a non-natural proportion, including but not limited to hydrogen (H), deuterium (H), and uranium (U). 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). In some embodiments, the "isotopic variant" of the therapeutic agent contains one or more isotopes in non-natural proportions, including but not limited to hydrogen (H), deuterium (H), and so on. 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).

[0043] It should be understood that in therapeutic agents (e.g., the compounds disclosed herein and / or modified oligonucleotides), where feasible, any hydrogen may be present, as determined by a person skilled in the art. 2 H, or any carbon, can be H. 13 C, or any nitrogen, can be C. 15 N, or any oxygen, can be N. 18 O. In some implementations, the "isotope variant" of the therapeutic agent contains a non-natural proportion of deuterium (D).

[0044] "Mismatch" or "non-complementary" means that when the first oligonucleotide / nucleic acid and the second oligonucleotide / nucleic acid are aligned in an antiparallel direction, the nucleobases of the first oligonucleotide or nucleic acid are non-complementary to the corresponding nucleobases of the second oligonucleotide or nucleic acid. For example, nucleobases, including but not limited to universal nucleobases, inosine, and hypoxanthine, can hybridize with at least one nucleobase but are still mismatched or non-complementary to the nucleobase they hybridize with. As another example, when the first oligonucleotide and the second oligonucleotide are aligned in an antiparallel direction, the nucleobases of the first oligonucleotide / nucleic acid that cannot hybridize with the corresponding nucleobases of the second oligonucleotide / nucleic acid are mismatched or non-complementary nucleobases.

[0045] "Modified oligonucleotides" refers to oligonucleotides in which at least one sugar, nucleobase, or nucleoside bond is modified.

[0046] "Regulation" refers to altering or modulating characteristics in cells, tissues, organs, or organisms. For example, regulating PKK RNA can mean increasing or decreasing the levels of PKK RNA and / or PKK protein in cells, tissues, organs, or organisms. "Regulators" affect changes in cells, tissues, organs, or organisms. For example, PKK compounds can be regulators that decrease the amount of PKK RNA and / or PKK protein in cells, tissues, organs, or organisms.

[0047] "Motif" refers to the pattern of linkages between unmodified and modified sugar portions, nucleobases, and / or nucleosides in an oligonucleotide.

[0048] Nucleic acids are molecules 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.

[0049] "Nucleobase" refers to a heterocyclic moiety that can pair with a base of another nucleic acid. In this article, "naturally occurring nucleobases" are adenine (A), thymine (T), cytosine (C), uracil (U), and guanine (G). "Modified nucleobases" are naturally occurring nucleobases that have undergone chemical modification. "Universal bases" or "universal nucleobases" are nucleobases other than naturally occurring and modified nucleobases, and can pair with any nucleobase.

[0050] "Nucleobase sequence" refers to the sequence of consecutive nucleobases in a nucleic acid or oligonucleotide that is independent of any bond between sugars or nucleosides.

[0051] "Nucleoside" refers to a compound that contains a nucleobase and a sugar moiety. The nucleobase and sugar moiety are either unmodified or modified independently. "Modified nucleoside" refers to a nucleoside that contains a modified nucleobase and / or a modified sugar moiety. Modified nucleosides include abase-free nucleosides lacking a nucleobase.

[0052] "Oligomeric compound" refers to a compound that contains one or more oligonucleotides and optionally one or more additional features (such as conjugation groups or terminal groups). Examples of oligoomeric compounds include single-stranded and double-stranded compounds, such as oligonucleotides, antisense oligonucleotides, interfering RNA compounds (RNAi compounds), microRNA-targeting oligonucleotides, and site-based compounds (e.g., mRNA processing or translation blocking compounds and splicing compounds). RNAi compounds include double-stranded compounds (e.g., short-interfering RNA (siRNA) and double-stranded RNA (dsRNA)) and single-stranded compounds (e.g., single-stranded siRNA (ssRNA), single-stranded RNAi (ssRNAi), short hairpin RNA (shRNA), and microRNA mimics) that function at least in part through the RNA-induced silencing complex (RISC) pathway, resulting in sequence-specific degradation and / or sequestration of target nucleic acids via a process called RNA interference (RNAi). The term "RNAi compound" is intended to be equivalent to 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. Additionally, the term "RNAi" is synonymous with other terms used to describe sequence-specific RNA interference.

[0053] "Oligonucleotide" refers to a polymer of independent linked nucleosides, each of which may be modified or unmodified.

[0054] The term "oligoduplex" refers to a duplex formed by two oligomeric compounds having complementary nucleobase sequences. Each oligomeric compound of an oligoduplex may be referred to as a "double-stranded oligomeric compound." The oligonucleotide of each oligomeric compound of an oligoduplex may include a non-complementary protruding nucleoside. In some embodiments, the terms "double-stranded oligomeric compound" and "modified oligonucleotide" are used interchangeably. In other embodiments, the terms "oligoduplex" and "compound" are used interchangeably.

[0055] "Parenteral administration" refers to administration via injection or infusion. Parenteral administration includes subcutaneous, intravenous, intramuscular, intra-arterial, intraperitoneal, or intracranial administration, such as intrathecal or intraventricular administration.

[0056] "Pharmaceutical-grade carrier or diluent" means any substance suitable for administration to an individual. In some embodiments, a pharmaceutical-grade carrier or diluent facilitates the administration and absorption of a compound to an individual and may be included in the compositions of this disclosure without causing significant adverse toxicological effects on the patient. Non-limiting examples of pharmaceutical-grade excipients include water, NaCl, normal saline solutions, etc. For example, a pharmaceutical-grade carrier may be a sterile aqueous solution, such as PBS or water for injection. Those skilled in the art will recognize that other pharmaceutical excipients may be used in this disclosure.

[0057] "Medicinal salts" refers to physiologically and pharmacologically acceptable salts of compounds (such as oligomers or oligonucleotides), that is, salts that retain the desired biological activity of the parent compound without producing undesirable toxicological effects on it.

[0058] As used herein, a pharmaceutically acceptable salt is any salt of the compounds provided herein that retains its biological properties and is non-toxic or otherwise desirable for medicinal use. Pharmaceutically acceptable salts of the therapeutic agents disclosed herein include salts prepared with relatively non-toxic acids or bases, depending on the specific substituents of the compounds or modified oligonucleotides described herein.

[0059] When the compounds of this disclosure contain relatively acidic functional groups, base addition salts can be obtained by contacting such compounds in their neutral form with a sufficient amount of the desired base (whether pure or in a suitable inert solvent).

[0060] When the compounds of this disclosure contain relatively basic functional groups, acid addition salts can be obtained by contacting such compounds in their neutral form with a sufficient amount of the desired acid (whether pure or in a suitable inert solvent).

[0061] Therefore, the compounds of this disclosure can exist as salts, for example, together with pharmaceutically acceptable acids. Such salts can be derived from a variety of organic and inorganic anti-charge ions known in the art. Such salts include, but are not limited to: (1) acid addition salts formed with organic or inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, aminosulfonic 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, and 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[2.2.2]-oct-2-en-1-carboxylic acid, glucoheponic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfate, gluconic acid, benzoic acid, glutamic acid, Acids such as hydroxynaphthyl acid, salicylic acid, stearic acid, cyclohexylsulfamic acid, quinic acid, and mucoconic acid; or (2) salts formed when the acidic protons present in the parent compound undergo the following (a) or (b): (a) replaced by a metal ion, such as an alkali metal ion, an alkaline earth metal ion, or an aluminum ion, or an alkali metal or alkaline earth metal hydroxide, such as sodium, potassium, calcium, magnesium, aluminum, lithium, zinc, and barium hydroxide, or ammonia; (b) coordinated with an organic base, such as an aliphatic, alicyclic, or aromatic organic amine, such as ammonia, methylamine, dimethylamine, diethylamine, methylpyridine, ethanolamine, diethanolamine, triethanolamine, ethylenediamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenylethylamine, N-methylglucosamine piperazine, tris(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide, etc. (see, for example, Berge et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 1977, 66, 1-19).

[0062] Pharmaceutical salts also include (by way of example only, not limitation) sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, etc., and when the compound contains a basic functional group, they also include salts of non-toxic organic or inorganic acids such as hydrohalides, such as hydrochlorides and hydrobroms, sulfates, phosphates, aminosulfonates, nitrates, acetates, trifluoroacetates, trichloroacetates, propionates, hexanoates, cyclopentylpropionates, glycolates, glutarates, pyruvates, lactates, malonates, succinates, sorbates, ascorbic acid salts, malates, maleates, fumarates, tartrates, citrates, benzoates, 3-(4-hydroxybenzoyl)benzoates, picrates, cinnamates, mandelates, phthalates, laurates, and methanesulfonic acid. Salts include methanesulfonate, mesylate, 1,2-ethane-disulfonate, 2-hydroxyethanesulfonate, benzenesulfonate, 4-chlorobenzenesulfonate, 2-naphthalenesulfonate, 4-toluenesulfonate, camphorate, camphor sulfonate, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylate, glucono-2-carboxylate, 3-phenylpropionate, trimethylacetate, tert-butylacetate, lauryl sulfate, gluconate, benzoate, glutamate, hydroxynaphthalate, salicylate, stearate, cyclohexylaminosulfonate, quinic acid salt, mucoconate, etc. In some embodiments, the pharmaceutically acceptable salts of the compounds and modified oligonucleotides disclosed herein are sodium or potassium salts. In some embodiments, the pharmaceutically acceptable salts of the compounds and modified oligonucleotides disclosed herein are sodium salts.

[0063] The neutral form of the compound is preferably regenerated by contacting the salt with a base or acid and separating the parent compound in a conventional manner. The parent form of the compound may differ from various salt forms in certain physical properties (e.g., solubility in polar solvents). In some embodiments, the compounds of this disclosure contain both basic and acidic functional groups that allow the compound to be converted into a base addition salt or an acid addition salt. The neutral form of the compound can be regenerated by contacting the salt with a base or acid and separating the parent compound in a conventional manner. The parent form of the compound may differ from various salt forms in certain physical properties (e.g., solubility in polar solvents); however, unless specifically indicated, the salts disclosed herein are equivalent to the parent forms of the compounds used for the purposes of this disclosure.

[0064] "Pharmaceutical" refers to a compound that provides therapeutic benefits when administered to an individual.

[0065] "Thiophosphate bonding" refers to modified phosphate bonding in which one of the non-bridging oxygen atoms is replaced by a sulfur atom.

[0066] "Partial" refers to a defined number of consecutive (i.e., linked) nucleobases of a nucleic acid. In some embodiments, the partial is a defined number of consecutive nucleobases of the target nucleic acid. In some embodiments, the partial is a defined number of consecutive nucleobases of an oligonucleotide.

[0067] "Prevention" refers to delaying or preventing the onset, occurrence, or progression of a disease, disorder, or ailment over a period of time.

[0068] "RNA interference compound" or "RNAi compound" means a compound that regulates a target nucleic acid and / or the protein encoded by the target nucleic acid by at least partly 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.

[0069] "Sense oligonucleotide" or "sense chain" refers to the chain of a double-stranded compound that contains a region substantially complementary to the region of the antisense chain of the compound.

[0070] "Specific inhibition" of target nucleic acids or proteins refers to reducing or blocking the expression or activity of target nucleic acids or proteins while minimizing or eliminating the effects on non-target nucleic acids or proteins.

[0071] The term "subunit" in oligonucleotides refers to nucleotides, nucleosides, nucleobases, or sugars as provided in this article, or modified nucleotides, nucleosides, nucleobases, or sugars.

[0072] "Target nucleic acid", "target RNA" and "nucleic acid target" all refer to nucleic acids that can be targeted by the compounds described in this article.

[0073] "Target region" refers to a portion of the target nucleic acid that is targeted by one or more compounds.

[0074] "Targeting moiety" refers to a conjugate group that provides enhanced affinity to a selected target (e.g., molecule, cell or cell type, compartment (e.g., cell or organ compartment), tissue, organ or body region) compared to a compound that does not contain such a moiety.

[0075] "Terminal group" refers to a chemical group or atomic group that is covalently linked to the end of an oligonucleotide.

[0076] "Therapeutic effective amount" or "effective amount" refers to the amount of a compound, agent, or composition that provides therapeutic benefit to an individual. "Therapeutic effective amount" or "effective amount" is an amount sufficient, relative to the absence of the compound, to enable the compound to achieve its stated purpose (e.g., to achieve the effect targeted by its administration, to treat, prevent, or improve a disease, or to alleviate one or more symptoms of a disease or condition). Examples of "therapeutic effective amount" or "effective amount" are amounts sufficient to help treat, prevent, improve, or alleviate one or more symptoms of a disease. "Amelioration" of one or more symptoms (and its grammatical equivalents) means a reduction in the severity or frequency of one or more symptoms, or the elimination of one or more symptoms. A "preventive effective amount" of a drug is an amount of drug that, when administered to a subject, will have the intended preventive effect, such as preventing or delaying the onset (or recurrence) of an injury, disease, pathological condition, or symptom, or reducing the likelihood of the onset (or recurrence) of an injury, disease, pathological condition, or symptom or its symptoms. As used herein, the term "therapeutic effective amount" refers to an amount of a therapeutic agent sufficient to provide therapeutic benefit to an individual, such as treating, preventing, or improving a disease or condition or its symptoms as described above. For example, for a given parameter, the effective therapeutic dose will show an increase or decrease of at least 5%, 10%, 15%, 20%, 25%, 40%, 50%, 60%, 75%, 80%, 90%, or at least 100%. The therapeutic effect can also be expressed as an increase or decrease in "times." For example, the effective therapeutic dose may have an effect of at least 1.2 times, 1.5 times, 2 times, 5 times, or more relative to the control.

[0077] The term "treatment" and its variations refer to any indication of successful treatment or improvement of an injury, disease, pathological condition, or symptom, including any objective or subjective parameter, such as relief; alleviation; reduction of symptoms or making the injury, pathological condition, or symptom more tolerable for the patient; slowing the rate of degeneration or decline; making the endpoint of degeneration less debilitating; or improving the patient's physical or mental health. Treatment or improvement of symptoms may be based on objective or subjective parameters, including the results of a physical examination. The term "treatment" and its variations may include prevention of an injury, pathological condition, symptom, or disease. In some implementations, treatment is prevention. In some implementations, treatment does not include prevention.

[0078] As used herein, “treatment” or variations thereof (and as well as is well understood in the art) also broadly includes any method used to obtain a beneficial or desired outcome (including clinical outcomes) in the subject’s condition. Beneficial or desired clinical outcomes may include, but are not limited to, relief or improvement of one or more symptoms or conditions, reduction of the severity of the disease, stabilization of the disease state (i.e., preventing its worsening), prevention of the spread or diffusion of the disease, delay or slowing the progression of the disease, improvement or relief of the disease state, reduction of disease recurrence, and remission, whether partial or complete, and whether detectable or undetectable. In other words, as used herein, “treatment” includes any cure, improvement, or prevention of disease. Treatment may prevent the onset of disease; inhibit the spread of disease; relieve symptoms of disease; completely or partially eliminate the underlying cause of disease; shorten the duration of disease; or perform a combination of these events.

[0079] As used herein, "treatment" and its variations include preventative treatment. Treatment methods include administering a therapeutically effective amount of the compound described herein to a subject. Administration may consist of a single administration or may include a series of administrations. The length of treatment depends on various factors, such as the severity of the condition, the patient's age, the concentration of the compound, the activity of the composition used in the treatment, or combinations thereof. It should also be understood that the effective dose of the agent used for treatment or prevention may be increased or decreased during a particular treatment or prevention regimen. In some cases, prolonged administration may be necessary. For example, administering the composition to a subject in an amount and for a duration sufficient to treat the patient.

[0080] "Treatment" refers to the administration of a compound or pharmaceutical composition to an animal to achieve a change or improvement in a disease, disorder, or symptom.

[0081] Certain compounds of this disclosure have asymmetric carbon atoms (optical or chiral centers) or double bonds; enantiomers, racemates, diastereomers, tautomers, geometric isomers, and stereoisomers that are definitively (R)- or (S)- or (D)- or (L)- (for amino acids) in absolute stereochemistry, and each individual isomer is covered within the scope of this disclosure. The compounds of this disclosure do not include compounds known in the art that are too unstable to be synthesized and / or isolated. This disclosure is intended to include compounds in both racemic and optically pure forms. Optically active (R)- and (S)- or (D)- and (L)- isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain an alkene bond or other geometrically asymmetric center, and unless otherwise stated, it is intended that the compounds include both E and Z geometric isomers.

[0082] As used in this article, the term "isomer" refers to a compound that has the same number and type of atoms and therefore the same molecular weight, but with different atomic arrangements or configurations.

[0083] As used herein, the term "tautomer" refers to one of two or more structural isomers that exist in equilibrium and are readily convertible from one isomer to another.

[0084] It will be apparent to those skilled in the art that some of the compounds disclosed herein may exist in tautomer form, and all such tautomer forms of compounds are within the scope of this disclosure.

[0085] Unless otherwise stated, the structures described herein are intended to include all stereochemical forms of the structure (i.e., R and S configurations for each asymmetric center). Therefore, single stereochemical isomers of the compounds of the present invention, as well as enantiomers and diastereomeric mixtures, are within the scope of this disclosure.

[0086] As used herein, a "chiral enrichment cluster" refers to a group of molecules with the same molecular formula, wherein the number or percentage of molecules in a group containing a specific stereochemical configuration at a specific chiral center is greater than the expected number or percentage of molecules in a group containing the same specific stereochemical configuration at the same specific chiral center if the specific chiral center is stereoironic. A chiral enrichment cluster with multiple chiral centers per molecule may contain one or more stereoironic chiral centers. In some embodiments, the molecule is a modified oligonucleotide. In some embodiments, the molecule is a compound comprising a modified oligonucleotide.

[0087] Unless otherwise stated, the structures described herein are also intended to include compounds distinguished only by the presence of one or more isotopically enriched atoms. For example, except that hydrogen is replaced by deuterium or tritium, or carbon is enriched... 13 C or 14 Compounds having the structure of this invention, except for carbon substitution of C, are all within the scope of this disclosure.

[0088] As used herein, "stereochiral center" refers to a chiral center with an atactic stereochemical configuration in the context of a group of molecules with the same molecular formula. For example, in a group of molecules containing a stereochiral center, the number of molecules with the (S) configuration may, but is not necessarily, the same as the number of molecules with the (R) configuration. A chiral center is considered atactic when its stereochemical configuration is the result of a synthetic method not intended to control the stereochemical configuration. In some embodiments, the stereochiral center is a stereochiral phosphate ester nucleoside linker.

[0089] Some implementation schemes

[0090] In some aspects, this disclosure relates to methods, compounds, and compositions for inhibiting PKK. In some embodiments, PKK is specifically inhibited. In some embodiments, PKK is specifically degraded. In some embodiments, PKK expression is inhibited. In some embodiments, PKK translation is inhibited. In some embodiments, PKK activity is inhibited. In some embodiments, PKK expression, translation, or activity is reduced by at least 10% relative to expression, translation, or activity in untreated or control samples. For example, in some embodiments, PKK expression, translation, or activity is reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, 10% to 50%, 25% to 50%, 25% to 75%, 50% to 75%, 50% to 99%, or 75% to 99% relative to expression, translation, or activity in untreated or control samples. In some implementations, PKK expression, translation, or activity is reduced, as measured by any suitable assay (including but not limited to immunoassays, hybridization-based assays, or sequencing-based assays (e.g., RNA-Seq)).

[0091] In some aspects, this disclosure relates to compounds targeting PKK nucleic acids. In some embodiments, the PKK nucleic acid has the sequences shown below: GENBANK registration No. NM_000892.5 (incorporated herein by SEQ ID NO: 1), NG_012095.2 truncated from 23529..54493 (incorporated herein by SEQ ID NO: 2), XM_017008181.1 (incorporated herein by SEQ ID NO: 3), NC_000004.12 truncated from 186215714 to 186258477 (incorporated herein by SEQ ID NO: 4), NM_001318394.2 (incorporated herein by SEQ ID NO: 5), and NM_0013183962 (incorporated herein by SEQ ID NO: 6).

[0092] In some embodiments, the compound is an oligomer. In some embodiments, the compound is single-chained. In some embodiments, the compound is double-chained.

[0093] Some embodiments provide compounds comprising modified oligonucleotides (e.g., modified oligonucleotides of length 14 to 30, such as 14 to 23 linked nucleosides) 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 of SEQ ID NO: 10 to 313, 626, 627, and 628.

[0094] Some embodiments provide compounds comprising modified oligonucleotides (e.g., modified oligonucleotides of length 14 to 30, such as 14 to 23 linked nucleosides) having a nucleobase sequence comprising any of SEQ ID NO: 10 to 313, 626, 627 and 628.

[0095] Some embodiments provide compounds comprising modified oligonucleotides having a nucleobase sequence selected from any of SEQ ID NO: 10 to 313, 626, 627 and 628.

[0096] In some 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 some embodiments, the modified oligonucleotide comprises at least one modification selected from modified nucleoside linkages, modified sugars, and modified nucleobases. In some embodiments, the compound is double-stranded.

[0097] Some embodiments provide a compound comprising: a first modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, such as 14 to 23 linked nucleosides) 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 nucleosides; and a second modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, such as 14 to 23 linked nucleosides) having a region complementary to the first modified oligonucleotide.

[0098] In some embodiments, the compound comprises: a first modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, such as a modified oligonucleotide of 14 to 23 linked nucleosides) 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 provided in Tables 2 to 4, 6, and 8; and a second modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, such as a modified oligonucleotide of 14 to 23 linked nucleosides) having a region complementary to the first modified oligonucleotide.

[0099] Some embodiments provide a compound comprising a first modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, such as 14 to 23 linked nucleosides) having a nucleobase sequence comprising any of SEQ ID NO: 10 to 631; and a second modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, such as 14 to 23 linked nucleosides) having a region complementary to the first modified oligonucleotide.

[0100] Some embodiments provide a compound comprising a first modified oligonucleotide having a nucleobase sequence selected from any of SEQ ID NO: 10 to 631; and a second modified oligonucleotide having a length of 19 to 23 linked nucleosides having a region complementary to the first modified oligonucleotide.

[0101] In some embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, such as 14 to 23 linked nucleosides) 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 of SEQ ID NO: 307, 312, or 626. In some embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, for example, 14 to 23 linked nucleosides) having a nucleobase sequence of 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 comprising the nucleobase sequence of SEQ ID NO:468, 611, 616, 619, or 629. In some embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence selected from SEQ ID NO:307, SEQ ID NO:312, and SEQ ID NO:626. In some embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence selected from SEQ ID NO:468, SEQ ID NO:611, SEQ ID NO:616, SEQ ID NO:619, and SEQ ID NO:629. In some embodiments, the compound comprises a first modified oligonucleotide having the nucleobase sequence of SEQ ID NO:312 and a second modified oligonucleotide having the nucleobase sequence of SEQ ID NO:619. In some 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.

[0102] In some embodiments, the modified oligonucleotide or the first modified oligonucleotide of any of the foregoing compounds has at least 80%, at least 85%, at least 90%, or at least 95% complementarity or identity in length with SEQ ID NO:1, 3, 5, or 6. In some embodiments, the modified oligonucleotide or the first modified oligonucleotide has at least one, at least two, or at least three mismatches with the region of SEQ ID NO:1, 3, 5, or 6. In some embodiments, the length of the complementary region between the first modified oligonucleotide or the first chain and the second modified oligonucleotide or the second chain is 14 to 30 links of nucleoside. In some embodiments, the length of the complementary region between the first modified oligonucleotide or the first chain and the second modified oligonucleotide or the second chain is 14 to 23 links of nucleoside. In some embodiments, the length of the complementary region between the first modified oligonucleotide or the first chain and the second modified oligonucleotide or the second chain is 19 to 23 links of nucleoside. In some embodiments, the length of the complementary region between the first modified oligonucleotide or the first chain and the second modified oligonucleotide or the second chain is 21 to 23 links of nucleoside. In some implementations, the first modified oligonucleotide is completely complementary to the second modified oligonucleotide.

[0103] In some embodiments, the modified oligonucleotide or first modified oligonucleotide of any of the foregoing compounds comprises at least one modification selected from modified nucleoside linkages, modified sugars, and modified nucleobases. In some embodiments, the second modified oligonucleotide of any of the foregoing compounds comprises at least one modification selected from modified nucleoside linkages, modified sugars, and modified nucleobases. In some embodiments, the modified nucleoside linkage is a phosphate thioester nucleoside linkage or a methylphosphonate nucleoside linkage. In some embodiments, the phosphate thioester nucleoside linkage or the methylphosphonate nucleoside linkage is at the 3' end of the first or second modified oligonucleotide or at the 5' end of the first modified oligonucleotide. In some embodiments, the modified sugar comprises a modification selected from halogens, alkoxy groups, and bicyclic sugars. In some embodiments, the modified sugar comprises a 2'-F modification. In some embodiments, the modified sugar comprises a 2'-OMe modification. In some embodiments, each nucleoside of the first modified oligonucleotide comprises a modified sugar. In some embodiments, each nucleoside of the second modified oligonucleotide comprises a modified sugar. In some embodiments, the modified sugar comprises a modification selected from halogens, alkoxy groups, and bicyclic sugars, or combinations thereof. In some embodiments, the modified sugar comprises a modification selected from 2'-MOE, 2'-F, and 2'-OMe, or combinations thereof. In some embodiments, the first modified oligonucleotide comprises no more than ten 2'-F sugar modifications. In some embodiments, the second modified oligonucleotide comprises no more than five 2'-F sugar modifications.

[0104] In some embodiments, any of the compounds described in the foregoing embodiments comprises a conjugating group. In some embodiments, the conjugating group is attached to the 5' end of the modified oligonucleotide. In some embodiments, the conjugating group is a targeting moiety. In some embodiments, the targeting moiety comprises one or more GalNAcs. In some embodiments, the modified oligonucleotide is a second modified oligonucleotide or a sense oligonucleotide. In some embodiments, one or more GalNAcs are attached to the 2' or 3' position of the ribosyl ring. In some embodiments, one or more GalNAcs are attached to the 5' nucleoside of the modified oligonucleotide. In some embodiments, the 5' nucleoside of the modified oligonucleotide is selected from the following formula or its salt, solvate, or hydrate, wherein R is the portion of the modified oligonucleotide other than the 5' nucleoside:

[0109] In some embodiments, R' is O. In some embodiments, R' is S. In some embodiments, the 5' nucleoside of the modified oligonucleotide is Formula I and R' is O. In some embodiments, the 5' nucleoside of the modified oligonucleotide is Formula I and R' is S. In some embodiments, the 5' nucleoside of the modified oligonucleotide is Formula II and R' is O. In some embodiments, the 5' nucleoside of the modified oligonucleotide is Formula II and R' is S. In some embodiments, the 5' nucleoside of the modified oligonucleotide is Formula III and R' is O. In some embodiments, the 5' nucleoside of the modified oligonucleotide is Formula III and R' is S. In some embodiments, the 5' nucleoside of the modified oligonucleotide is Formula IV and R' is O. In some embodiments, the 5' nucleoside of the modified oligonucleotide is Formula IV and R' is S. In some embodiments, the 5' nucleoside of the modified oligonucleotide is Formula V and R' is O. In some embodiments, the 5' nucleoside of the modified oligonucleotide is Formula V and R' is S. In some embodiments, the 5' nucleoside of the modified oligonucleotide is Formula VI and R' is O. In some embodiments, the 5' nucleoside of the modified oligonucleotide is Formula VI and R' is S. In some embodiments, the 5' nucleoside of the modified oligonucleotide is Formula VII and R' is O. In some embodiments, the 5' nucleoside of the modified oligonucleotide is Formula VII and R' is S. In some embodiments, the 5' nucleoside of the modified oligonucleotide is Formula VIII and R' is O. In some embodiments, the 5' nucleoside of the modified oligonucleotide is Formula VIII and R' is S.

[0110] Some embodiments provide a compound comprising a first modified oligonucleotide selected from any of Ref ID NO: IA0812 to 821; and a second modified oligonucleotide having a length of 14 to 21 linked nucleosides, which is completely complementary to the first modified oligonucleotide.

[0111] Some embodiments provide compounds comprising a first modified oligonucleotide consisting of IA0813 and a second modified oligonucleotide consisting of IS1002.

[0112] Some embodiments provide compounds comprising a first modified oligonucleotide consisting of IA0818 and a second modified oligonucleotide consisting of IS1007.

[0113] Some embodiments provide compounds comprising a first modified oligonucleotide consisting of IA0818 and a second modified oligonucleotide consisting of IS1068.

[0114] Some embodiments provide a compound comprising a first modified oligonucleotide selected from any of Ref ID NO: IA0864 to 866; and a second modified oligonucleotide having a length of 14 to 21 linked nucleosides, which is completely complementary to the first modified oligonucleotide.

[0115] Some embodiments provide compounds comprising a first modified oligonucleotide selected from Ref ID NO: IA0818 and IA0864; and a second modified oligonucleotide selected from Ref ID NO: IS1058 and IS1059.

[0116] Some embodiments provide compounds comprising a first modified oligonucleotide consisting of IA0864 and a second modified oligonucleotide consisting of IS1059. Some embodiments provide compounds comprising a first modified oligonucleotide consisting of IA0818 and a second modified oligonucleotide consisting of IS1058.

[0117] In some embodiments, the compound comprises a first modified oligonucleotide consisting of IA0864 and a second modified oligonucleotide consisting of IS1059. In some embodiments, the compound comprises a first modified oligonucleotide consisting of IA0818 and a second modified oligonucleotide consisting of IS1058.

[0118] In some embodiments, any of the compounds described in the foregoing embodiments are in the form of a pharmaceutically acceptable salt. In some embodiments, the pharmaceutically acceptable salt is a sodium salt. In some embodiments, the pharmaceutically acceptable salt is a potassium salt.

[0119] One aspect presented herein is a modified oligonucleotide based on the following chemical structure:

[0121] Or its pharmaceutically acceptable salt or stereoisomer. In some embodiments, Ref ID NO: IA0818 is a modified oligonucleotide or its pharmaceutically acceptable salt or stereoisomer based on the aforementioned chemical structure.

[0122] One aspect presented herein is a modified oligonucleotide based on the following chemical structure:

[0124] Or its pharmaceutically acceptable salt or stereoisomer. In some embodiments, Ref ID NO: IS1058 is a modified oligonucleotide or its pharmaceutically acceptable salt or stereoisomer based on the aforementioned chemical structure.

[0125] One aspect presented herein is a modified oligonucleotide based on the following chemical structure:

[0127] Or its pharmaceutically acceptable salt or stereoisomer. In some embodiments, Ref ID NO: IA0864 is a modified oligonucleotide or its pharmaceutically acceptable salt or stereoisomer based on the aforementioned chemical structure.

[0128] One aspect presented herein is a modified oligonucleotide based on the following chemical structure:

[0130] Or its pharmaceutically acceptable salt or stereoisomer. In some embodiments, Ref ID NO: IS1059 is a modified oligonucleotide or its pharmaceutically acceptable salt or stereoisomer based on the aforementioned chemical structure.

[0131] In some embodiments, the pharmaceutically acceptable salts of the modified oligonucleotides provided herein are sodium or potassium salts.

[0132] In one aspect presented herein, there is a sodium salt of a modified oligonucleotide based on the following chemical structure:

[0134] Or its stereoisomers. In some embodiments, Ref ID NO: IA0818 is a modified oligonucleotide or its stereoisomers according to the aforementioned chemical structure.

[0135] In one aspect presented herein, there is a sodium salt of a modified oligonucleotide based on the following chemical structure:

[0137] Or its stereoisomers. In some embodiments, Ref ID NO: IS1058 is a modified oligonucleotide or its stereoisomers according to the aforementioned chemical structure.

[0138] In one aspect presented herein, there is a sodium salt of a modified oligonucleotide based on the following chemical structure:

[0140] Or its stereoisomers. In some embodiments, Ref ID NO: IA0864 is a modified oligonucleotide or its stereoisomers according to the aforementioned chemical structure.

[0141] In one aspect presented herein, there is a sodium salt of a modified oligonucleotide based on the following chemical structure:

[0143] Or its stereoisomers. In some embodiments, Ref ID NO: IS1059 is a modified oligonucleotide or its stereoisomers according to the aforementioned chemical structure.

[0144] One aspect presented herein is a compound based on the following chemical structure:

[0146] Or its pharmaceutically acceptable salts or stereoisomers. In some embodiments, compound number RD2423 is a compound with the aforementioned chemical structure or its pharmaceutically acceptable salts or stereoisomers.

[0147] One aspect presented herein is a compound based on the following chemical structure:

[0149] Or its pharmaceutically acceptable salts or stereoisomers. In some embodiments, compound number RD2424 is a compound with the aforementioned chemical structure or its pharmaceutically acceptable salts or stereoisomers.

[0150] In some embodiments, the pharmaceutically acceptable salts of the compounds provided herein are sodium or potassium salts.

[0151] One aspect presented herein is a sodium salt of a compound with the following chemical structure:

[0153] Or its stereoisomers. In some embodiments, compound number RD2423 is a compound or its stereoisomers according to the aforementioned chemical structure.

[0154] One aspect presented herein is a sodium salt of a compound with the following chemical structure:

[0156] Or its stereoisomers. In some embodiments, compound number RD2424 is a compound or its stereoisomers according to the aforementioned chemical structure.

[0157] In some embodiments, a group of modified oligonucleotides is provided herein, wherein all phosphate thioester nucleoside linkages of the modified oligonucleotides are stereoatactic. In some embodiments, a group of compounds is provided herein, wherein all phosphate thioester nucleoside linkages of the modified oligonucleotides are stereoatactic.

[0158] Some embodiments provide compositions comprising the compound described in any one of the foregoing embodiments and a pharmaceutically acceptable carrier.

[0159] Some embodiments provide compositions comprising any of the compounds described in the foregoing embodiments for therapeutic purposes.

[0160] Certain embodiments provide methods for treating, preventing, or improving diseases, disorders, or conditions associated with PKK and / or dysregulated kallikrein pathways in an individual, comprising administering to the individual a compound that targets PKK, thereby treating, preventing, or improving the disease, disorder, or condition. In certain embodiments, any of the compounds or compositions described in the foregoing embodiments are 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, the compound is administered to inhibit or reduce or improve inflammatory or thrombotic diseases, disorders, or conditions, or their symptoms. In some implementations, the compound is administered to inhibit or reduce or improve 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 their symptoms.

[0161] In some embodiments, any of the compounds described in the foregoing embodiments, or compositions containing such compounds, are administered to an individual in a therapeutically effective amount. In some embodiments, compositions containing any of the compounds described in the foregoing embodiments are administered to an individual at a dose level sufficient to deliver about 1 to 100 mg / kg of individual body weight. In some embodiments, any of the compounds described in the foregoing embodiments, or compositions containing such compounds, are administered to an individual at a fixed dose of about 25 mg to about 1,000 mg. In some embodiments, the compound or composition is administered to an individual once or more times a day at up to the stated dose level or at a fixed dose.

[0162] In some embodiments, the composition comprising any of the compounds described in the preceding embodiments is administered to an individual daily, weekly, monthly, quarterly, or annually. In some embodiments, any of the compounds described in the preceding embodiments or the composition comprising such compounds is administered to an individual about once per quarter (i.e., every three months) to about once per year. In some embodiments, any of the compounds described in the preceding embodiments or the composition comprising such compounds is administered to an individual about once per quarter, about once every six months, or about once per year.

[0163] Some implementations provide a method for inhibiting PKK expression in cells, which includes contacting cells with a compound that targets PKK, thereby inhibiting PKK expression in the cells. In some implementations, the cells are in the liver of an individual. In some implementations, the individual has or is at risk of having: inflammatory or thrombotic diseases, disorders or conditions, or their symptoms. In some implementations, 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.

[0164] Some embodiments provide methods for alleviating or suppressing inflammatory or thrombotic diseases, disorders, or conditions or their symptoms in an individual, comprising administering a PKK-targeting compound to the individual, thereby alleviating or suppressing the inflammatory or thrombotic disease, disorder, or condition or its symptoms in the individual. In some 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 some embodiments, the compound is a PKK-targeting compound. In some embodiments, the compound is any of the aforementioned compounds. In some embodiments, the compound or composition is administered parenterally.

[0165] Some embodiments provide for the use of PKK-targeting compounds for the treatment, prevention, or improvement of PKK-related diseases, disorders, or conditions. In some embodiments, the disease, disorder, or condition is an 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 some embodiments, the compound is a PKK-targeting compound. In some embodiments, the compound is any of the aforementioned compounds.

[0166] Certain embodiments provide for the use of PKK-targeting compounds in the preparation of medicaments for treating, preventing, or improving PKK-related diseases, disorders, or conditions. In certain embodiments, the disease, disorder, or condition is an 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 PKK-targeting compound. In certain embodiments, the compound is any of the aforementioned compounds.

[0167] certain indications

[0168] In some aspects, this disclosure relates to methods for inhibiting PKK expression, which can be used to treat, prevent, or improve PKK-related diseases, disorders, or conditions in an individual by administering a compound that targets PKK. In some embodiments, the compound may be a PKK-specific inhibitor. In some embodiments, the compound may be an antisense oligonucleotide, oligomer, or oligonucleotide that targets PKK.

[0169] In some aspects, this disclosure relates to the treatment, prevention, or improvement of PKK-related diseases, disorders, or conditions. In some embodiments, the methods provided herein can be used to treat, prevent, and / or improve PKK-related diseases, disorders, or conditions including 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. Certain compounds provided herein relate to compounds and compositions that alleviate 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 animals.

[0170] In some embodiments, methods of treating, preventing, or improving a PKK-related disease, disorder, or condition in an individual include administering a compound containing a PKK-specific inhibitor to the individual, thereby treating, preventing, or improving the disease, disorder, or condition. In some embodiments, the individual is identified as having or at risk of having a PKK-related disease, disorder, or condition. In some embodiments, the disease, disorder, or condition is an inflammatory disease or a thrombotic disease. In some embodiments, the compound contains an antisense oligonucleotide targeting PKK. In some embodiments, the compound contains an oligonucleotide targeting PKK. In some embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, such as a modified oligonucleotide of 14 to 23 linked nucleosides) having a nucleobase sequence of 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 nucleosides comprising any one of SEQ ID NO: 10 to 313, 626, 627, and 628. In some embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, such as a modified oligonucleotide of 14 to 23 linked nucleosides) having a nucleobase sequence comprising any one of SEQ ID NO: 10 to 313, 626, 627, and 628. In some embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence selected from any of SEQ ID NO: 10 to 313, 626, 627, and 628. In some embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, such as 14 to 23 linked nucleosides) having a nucleobase sequence comprising any of SEQ ID NO: 307, 312, and 626. In some embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence consisting of any of SEQ ID NO: 307, 312, and 626.

[0171] In any of the foregoing embodiments, the compound may be single-stranded or double-stranded. In some embodiments, the single-stranded compound may be 14 to 30, 14 to 23, 14 to 20, 16 to 20, or 14 to 16 linked nucleosides. In some embodiments, the single-stranded compound may be 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 linked nucleosides. In some embodiments, the double-stranded compound may comprise two oligonucleotides of the same or different lengths, as described elsewhere herein. In some embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, such as 14 to 23 linked nucleosides) having a nucleobase sequence of 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 comprising the nucleobase sequence of SEQ ID NO: 307, 312, or 626. In some embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, for example, 14 to 23 linked nucleosides) having a nucleobase sequence of 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 comprising the nucleobase sequence of SEQ ID NO:468, 611, 616, 619, or 629. In some embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence selected from SEQ ID NO:307, SEQ ID NO:312, and SEQ ID NO:626. In some embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence selected from SEQ ID NO:468, SEQ ID NO:611, SEQ ID NO:616, SEQ ID NO:619, and SEQ ID NO:629. In some embodiments, the compound comprises a first modified oligonucleotide having the nucleobase sequence of SEQ ID NO:312 and a second modified oligonucleotide having the nucleobase sequence of SEQ ID NO:619. In some 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.

[0172] In any of the foregoing embodiments, the compound may be an antisense oligonucleotide or an oligomeric compound. In some embodiments, the compound comprises a first modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, such as a modified oligonucleotide of 14 to 23 linked nucleosides) 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 nucleosides from any of the nucleobase sequences of SEQ ID NO: 10 to 631; and a second modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, such as a modified oligonucleotide of 14 to 23 linked nucleosides) having a region complementary to the first modified oligonucleotide. In some embodiments, the compound comprises a first modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, such as 14 to 23 linked nucleosides) having a nucleobase sequence comprising any one of SEQ ID NO: 10 to 313, 626, 627, and 628; and a second modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, such as 14 to 23 linked nucleosides) having a region complementary to the first modified oligonucleotide. In some embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence selected from any one of SEQ ID NO: 10 to 631; and a second modified oligonucleotide of 19 to 23 linked nucleosides having a region complementary to the first modified oligonucleotide. In some embodiments, the compound is administered parenterally to an individual. In some embodiments, administration of the compound in animals improves, 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.

[0173] In some embodiments, methods of treating, preventing, or improving 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 animals include administering to an individual a compound comprising a PKK-specific inhibitor, thereby treating, preventing, or improving 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 some embodiments, the compound comprises an antisense oligonucleotide targeting PKK. In some embodiments, the compound comprises an oligonucleotide targeting PKK. In some embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, such as a modified oligonucleotide of 14 to 23 linked nucleosides) having a nucleobase sequence of 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 nucleosides comprising any one of SEQ ID NO: 10 to 313, 626, 627, and 628. In some embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, such as a modified oligonucleotide of 14 to 23 linked nucleosides) having a nucleobase sequence comprising any one of SEQ ID NO: 10 to 313, 626, 627, and 628. In some embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence selected from any of SEQ ID NO: 10 to 313, 626, 627, and 628. In some embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, such as 14 to 23 linked nucleosides) having a nucleobase sequence comprising any of SEQ ID NO: 307, 312, and 626. In some embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence selected from any of SEQ ID NO: 307, 312, and 626. In some embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, such as 14 to 23 linked nucleosides) having a nucleobase sequence of 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 comprising the nucleobase sequence of SEQ ID NO: 307, 312, or 626.In some embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, for example, 14 to 23 linked nucleosides) having a nucleobase sequence of 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 comprising the nucleobase sequence of SEQ ID NO:468, 611, 616, 619, or 629. In some embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence selected from SEQ ID NO:307, SEQ ID NO:312, and SEQ ID NO:626. In some embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence selected from SEQ ID NO:468, SEQ ID NO:611, SEQ ID NO:616, SEQ ID NO:619, and SEQ ID NO:629. In some embodiments, the compound comprises a first modified oligonucleotide having the nucleobase sequence of SEQ ID NO:312 and a second modified oligonucleotide having the nucleobase sequence of SEQ ID NO:619. In some 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 foregoing embodiments, the compound may be single-stranded or double-stranded. In any of the foregoing embodiments, the compound may be an antisense oligonucleotide or an oligomeric compound. In some embodiments, the compound comprises a first modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, such as a modified oligonucleotide of 14 to 23 linked nucleosides) 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 nucleosides from any of the nucleobase sequences in SEQ ID NO: 10 to 631; and a second modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, such as a modified oligonucleotide of 14 to 23 linked nucleosides) having a region complementary to the first modified oligonucleotide. In some embodiments, the compound comprises a first modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, such as 14 to 23 linked nucleosides) having a nucleobase sequence comprising any one of SEQ ID NO: 10 to 631; and a second modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, such as 14 to 23 linked nucleosides) having a region complementary to the first modified oligonucleotide.In some embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence selected from any of SEQ ID NO: 10 to 631; and a second modified oligonucleotide having a length of 19 to 23 linked nucleosides having a region complementary to the first modified oligonucleotide. In some embodiments, administration of the compound in animals improves, 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. In some embodiments, the individual is identified as having a PKK-related disease or at risk of having a PKK-related disease.

[0174] In some embodiments, a method of inhibiting PKK expression in an individual suffering from or at risk of suffering from a PKK-related disease, disorder, or condition includes administering a compound containing a PKK-specific inhibitor to the individual, thereby inhibiting PKK expression in that individual. In some embodiments, the compound is administered to inhibit PKK expression in the liver. In some embodiments, the disease, disorder, or condition is an inflammatory disease or a thrombotic disease. In some embodiments, the individual suffers from or is at risk of suffering from: 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 some embodiments, the compound contains an antisense oligonucleotide targeting PKK. In some embodiments, the compound contains an oligonucleotide targeting PKK. In some embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, such as a modified oligonucleotide of 14 to 23 linked nucleosides) having a nucleobase sequence of 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 nucleosides comprising any one of SEQ ID NO: 10 to 313, 626, 627, and 628. In some embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, such as a modified oligonucleotide of 14 to 23 linked nucleosides) having a nucleobase sequence comprising any one of SEQ ID NO: 10 to 313, 626, 627, and 628. In some embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence selected from any of SEQ ID NO: 10 to 313, 626, 627, and 628. In some embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, such as 14 to 23 linked nucleosides) having a nucleobase sequence selected from any of SEQ ID NO: 307, 312, and 626. In some embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence selected from any of SEQ ID NO: 307, 312, and 626.In some embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, such as 14 to 23 linked nucleosides) having a nucleobase sequence of 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 comprising the nucleobase sequence of SEQ ID NO: 307, 312, or 626. In some embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, for example, 14 to 23 linked nucleosides) having a nucleobase sequence of 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 comprising the nucleobase sequence of SEQ ID NO:468, 611, 616, 619, or 629. In some embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence selected from SEQ ID NO:307, SEQ ID NO:312, and SEQ ID NO:626. In some embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence selected from SEQ ID NO:468, SEQ ID NO:611, SEQ ID NO:616, SEQ ID NO:619, and SEQ ID NO:629. In some embodiments, the compound comprises a first modified oligonucleotide having the nucleobase sequence of SEQ ID NO:312 and a second modified oligonucleotide having the nucleobase sequence of SEQ ID NO:619. In some 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 foregoing embodiments, the compound may be single-stranded or double-stranded. In any of the foregoing embodiments, the compound may be an antisense oligonucleotide or an oligomeric compound. In some embodiments, the compound comprises a first modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, such as a modified oligonucleotide of 14 to 23 linked nucleosides) 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 nucleosides from any of the nucleobase sequences in SEQ ID NO: 10 to 631; and a second modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, such as a modified oligonucleotide of 14 to 23 linked nucleosides) having a region complementary to the first modified oligonucleotide.In some embodiments, the compound comprises a first modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, such as 14 to 23 linked nucleosides) having a nucleobase sequence comprising any one of SEQ ID NO: 10 to 631; and a second modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, such as 14 to 23 linked nucleosides) having a region complementary to the first modified oligonucleotide. In some embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence selected from any one of SEQ ID NO: 10 to 631; and a second modified oligonucleotide of 19 to 23 linked nucleosides having a region complementary to the first modified oligonucleotide. In some embodiments, the compound is administered parenterally to an individual. In some implementations, the application of the compound improves, 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.

[0175] In some embodiments, the method of inhibiting PKK expression in cells includes contacting the cells with a compound containing a PKK-specific inhibitor, thereby inhibiting PKK expression in the cells. In some embodiments, the cells are hepatocytes. In some embodiments, the cells are in the liver. In some embodiments, the cells are in the liver of an individual suffering from or at risk of suffering from: 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 some embodiments, the compound contains an antisense oligonucleotide targeting PKK. In some embodiments, the compound contains an oligonucleotide targeting PKK. In some embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, such as a modified oligonucleotide of 14 to 23 linked nucleosides) having a nucleobase sequence of 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 nucleosides comprising any one of SEQ ID NO: 10 to 313, 626, 627, and 628. In some embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, such as a modified oligonucleotide of 14 to 23 linked nucleosides) having a nucleobase sequence comprising any one of SEQ ID NO: 10 to 313, 626, 627, and 628. In some embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence selected from any of SEQ ID NO: 10 to 313, 626, 627, and 628. In some embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, such as 14 to 23 linked nucleosides) having a nucleobase sequence comprising any of SEQ ID NO: 307, 312, and 626. In some embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence selected from any of SEQ ID NO: 307, 312, and 626. In some embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, such as 14 to 23 linked nucleosides) having a nucleobase sequence of 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 comprising the nucleobase sequence of SEQ ID NO: 307, 312, or 626.In some embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, for example, 14 to 23 linked nucleosides) having a nucleobase sequence of 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 comprising the nucleobase sequence of SEQ ID NO:468, 611, 616, 619, or 629. In some embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence selected from SEQ ID NO:307, SEQ ID NO:312, and SEQ ID NO:626. In some embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence selected from SEQ ID NO:468, SEQ ID NO:611, SEQ ID NO:616, SEQ ID NO:619, and SEQ ID NO:629. In some embodiments, the compound comprises a first modified oligonucleotide having the nucleobase sequence of SEQ ID NO:312 and a second modified oligonucleotide having the nucleobase sequence of SEQ ID NO:619. In some 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.

[0176] In any of the foregoing embodiments, the compound may be single-stranded or double-stranded. In any of the foregoing embodiments, the compound may be an antisense oligonucleotide or an oligomeric compound. In some embodiments, the compound comprises a first modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, such as a modified oligonucleotide of 14 to 23 linked nucleosides) 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 of SEQ ID NO: 10 to 631; and a second modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, such as a modified oligonucleotide of 14 to 23 linked nucleosides) having a region complementary to the first modified oligonucleotide. In some embodiments, the compound comprises a first modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, such as 14 to 23 linked nucleosides) having a nucleobase sequence comprising any one of SEQ ID NO: 10 to 631; and a second modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, such as 14 to 23 linked nucleosides) having a region complementary to the first modified oligonucleotide. In some embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence selected from any one of SEQ ID NO: 10 to 631; and a second modified oligonucleotide of 19 to 23 linked nucleosides having a region complementary to the first modified oligonucleotide.

[0177] In some implementations, methods for reducing or inhibiting 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 individuals who have PKK-related diseases or are at risk of having PKK-related diseases include administering a compound containing a PKK-specific inhibitor to the individual, thereby reducing or inhibiting 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 the individual. In some embodiments, an individual has or is at risk of having: 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 some embodiments, the compound comprises an antisense oligonucleotide targeting PKK. In some embodiments, the compound comprises an oligonucleotide targeting PKK. In some embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, such as a modified oligonucleotide of 14 to 23 linked nucleosides) having a nucleobase sequence of 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 nucleosides comprising any one of SEQ ID NO: 10 to 313, 626, 627, and 628. In some embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, such as a modified oligonucleotide of 14 to 23 linked nucleosides) having a nucleobase sequence comprising any one of SEQ ID NO: 10 to 313, 626, 627, and 628. In some embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence selected from any of SEQ ID NO: 10 to 313, 626, 627, and 628. In some embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, such as 14 to 23 linked nucleosides) having a nucleobase sequence comprising any of SEQ ID NO: 307, 312, and 626. In some embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence selected from any of SEQ ID NO: 307, 312, and 626.In some embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, such as 14 to 23 linked nucleosides) having a nucleobase sequence of 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 comprising the nucleobase sequence of SEQ ID NO: 307, 312, or 626. In some embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, for example, 14 to 23 linked nucleosides) having a nucleobase sequence of 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 comprising the nucleobase sequence of SEQ ID NO:468, 611, 616, 619, or 629. In some embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence selected from SEQ ID NO:307, SEQ ID NO:312, and SEQ ID NO:626. In some embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence selected from SEQ ID NO:468, SEQ ID NO:611, SEQ ID NO:616, SEQ ID NO:619, and SEQ ID NO:629. In some embodiments, the compound comprises a first modified oligonucleotide having the nucleobase sequence of SEQ ID NO:312 and a second modified oligonucleotide having the nucleobase sequence of SEQ ID NO:619. In some 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 foregoing embodiments, the compound may be single-stranded or double-stranded. In any of the foregoing embodiments, the compound may be an antisense oligonucleotide or an oligomeric compound. In some embodiments, the compound comprises a first modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, such as a modified oligonucleotide of 14 to 23 linked nucleosides) 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 nucleosides from any of the nucleobase sequences in SEQ ID NO: 10 to 631; and a second modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, such as a modified oligonucleotide of 14 to 23 linked nucleosides) having a region complementary to the first modified oligonucleotide.In some embodiments, the compound comprises a first modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, such as 14 to 23 linked nucleosides) having a nucleobase sequence comprising any one of SEQ ID NO: 10 to 631; and a second modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, such as 14 to 23 linked nucleosides) having a region complementary to the first modified oligonucleotide. In some embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence selected from any one of SEQ ID NO: 10 to 631; and a second modified oligonucleotide of 19 to 23 linked nucleosides having a region complementary to the first modified oligonucleotide. In some embodiments, the compound is administered parenterally to an individual. In some embodiments, the individual is identified as having or at risk of having a PKK-related disease, disorder, or condition.

[0178] Some embodiments involve compounds comprising PKK-specific inhibitors for the treatment of PKK-related diseases, disorders, or conditions. In some embodiments, the disease, disorder, or condition is 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 some embodiments, the compound comprises an antisense oligonucleotide targeting PKK. In some embodiments, the compound comprises an oligonucleotide targeting PKK. In some embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, such as a modified oligonucleotide of 14 to 23 linked nucleosides) having a nucleobase sequence of 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 nucleosides comprising any one of SEQ ID NO: 10 to 313, 626, 627, and 628. In some embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, such as a modified oligonucleotide of 14 to 23 linked nucleosides) having a nucleobase sequence comprising any one of SEQ ID NO: 10 to 313, 626, 627, and 628. In some embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence selected from any of SEQ ID NO: 10 to 313, 626, 627, and 628. In some embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, such as 14 to 23 linked nucleosides) having a nucleobase sequence comprising any of SEQ ID NO: 307, 312, and 626. In some embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence selected from any of SEQ ID NO: 307, 312, and 626. In some embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, such as 14 to 23 linked nucleosides) having a nucleobase sequence of 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 comprising the nucleobase sequence of SEQ ID NO: 307, 312, or 626.In some embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, for example, 14 to 23 linked nucleosides) having a nucleobase sequence of 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 comprising the nucleobase sequence of SEQ ID NO:468, 611, 616, 619, or 629. In some embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence selected from SEQ ID NO:307, SEQ ID NO:312, and SEQ ID NO:626. In some embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence selected from SEQ ID NO:468, SEQ ID NO:611, SEQ ID NO:616, SEQ ID NO:619, and SEQ ID NO:629. In some embodiments, the compound comprises a first modified oligonucleotide having the nucleobase sequence of SEQ ID NO:312 and a second modified oligonucleotide having the nucleobase sequence of SEQ ID NO:619. In some 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 foregoing embodiments, the compound may be single-stranded or double-stranded. In any of the foregoing embodiments, the compound may be an antisense oligonucleotide or an oligomeric compound. In some embodiments, the compound comprises a first modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, such as a modified oligonucleotide of 14 to 23 linked nucleosides) 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 nucleosides from any of the nucleobase sequences in SEQ ID NO: 10 to 631; and a second modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, such as a modified oligonucleotide of 14 to 23 linked nucleosides) having a region complementary to the first modified oligonucleotide. In some embodiments, the compound comprises a first modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, such as 14 to 23 linked nucleosides) having a nucleobase sequence comprising any one of SEQ ID NO: 10 to 631; and a second modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, such as 14 to 23 linked nucleosides) having a region complementary to the first modified oligonucleotide.In some embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence selected from any of SEQ ID NO: 10 to 631; and a second modified oligonucleotide having a length of 19 to 23 linked nucleosides and having a region complementary to the first modified oligonucleotide. In some embodiments, the compound is administered parenterally to an individual.

[0179] Some embodiments involve compounds comprising PKK-specific inhibitors for the purpose of alleviating or inhibiting 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 some embodiments, the compound comprises an antisense oligonucleotide targeting PKK. In some embodiments, the compound comprises an oligonucleotide targeting PKK. In some embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, such as a modified oligonucleotide of 14 to 23 linked nucleosides) having a nucleobase sequence of 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 nucleosides comprising any one of SEQ ID NO: 10 to 313, 626, 627, and 628. In some embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, such as a modified oligonucleotide of 14 to 23 linked nucleosides) having a nucleobase sequence comprising any one of SEQ ID NO: 10 to 313, 626, 627, and 628. In some embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence selected from any of SEQ ID NO: 10 to 313, 626, 627, and 628. In some embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, such as 14 to 23 linked nucleosides) having a nucleobase sequence comprising any of SEQ ID NO: 307, 312, and 626. In some embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence selected from any of SEQ ID NO: 307, 312, and 626. In some embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, such as 14 to 23 linked nucleosides) having a nucleobase sequence of 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 comprising the nucleobase sequence of SEQ ID NO: 307, 312, or 626.In some embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, for example, 14 to 23 linked nucleosides) having a nucleobase sequence of 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 comprising the nucleobase sequence of SEQ ID NO:468, 611, 616, 619, or 629. In some embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence selected from SEQ ID NO:307, SEQ ID NO:312, and SEQ ID NO:626. In some embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence selected from SEQ ID NO:468, SEQ ID NO:611, SEQ ID NO:616, SEQ ID NO:619, and SEQ ID NO:629. In some embodiments, the compound comprises a first modified oligonucleotide having the nucleobase sequence of SEQ ID NO:312 and a second modified oligonucleotide having the nucleobase sequence of SEQ ID NO:619. In some 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 foregoing embodiments, the compound may be single-stranded or double-stranded. In any of the foregoing embodiments, the compound may be an antisense oligonucleotide or an oligomeric compound. In some embodiments, the compound comprises a first modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, such as a modified oligonucleotide of 14 to 23 linked nucleosides) 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 nucleosides from any of the nucleobase sequences in SEQ ID NO: 10 to 631; and a second modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, such as a modified oligonucleotide of 14 to 23 linked nucleosides) having a region complementary to the first modified oligonucleotide. In some embodiments, the compound comprises a first modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, such as 14 to 23 linked nucleosides) having a nucleobase sequence comprising any one of SEQ ID NO: 10 to 631; and a second modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, such as 14 to 23 linked nucleosides) having a region complementary to the first modified oligonucleotide.In some embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence selected from any of SEQ ID NO: 10 to 631; and a second modified oligonucleotide having a length of 19 to 23 linked nucleosides having a region complementary to the first modified oligonucleotide.

[0180] Some embodiments relate to the use of compounds containing PKK-specific inhibitors for the manufacture or preparation of medicaments for treating PKK-related diseases, disorders, or conditions. In some embodiments, the disease is an inflammatory or thrombotic disease. In some 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 some embodiments, the compound contains an antisense oligonucleotide targeting PKK. In some embodiments, the compound contains an oligonucleotide targeting PKK. In some embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, such as a modified oligonucleotide of 14 to 23 linked nucleosides) having a nucleobase sequence of 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 nucleosides comprising any one of SEQ ID NO: 10 to 313, 626, 627, and 628. In some embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, such as a modified oligonucleotide of 14 to 23 linked nucleosides) having a nucleobase sequence comprising any one of SEQ ID NO: 10 to 313, 626, 627, and 628. In some embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence selected from any of SEQ ID NO: 10 to 313, 626, 627, and 628. In some embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, such as 14 to 23 linked nucleosides) having a nucleobase sequence comprising any of SEQ ID NO: 307, 312, and 626. In some embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence selected from any of SEQ ID NO: 307, 312, and 626. In some embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, such as 14 to 23 linked nucleosides) having a nucleobase sequence of 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 comprising the nucleobase sequence of SEQ ID NO: 307, 312, or 626.In some embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, for example, 14 to 23 linked nucleosides) having a nucleobase sequence of 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 comprising the nucleobase sequence of SEQ ID NO:468, 611, 616, 619, or 629. In some embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence selected from SEQ ID NO:307, SEQ ID NO:312, and SEQ ID NO:626. In some embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence selected from SEQ ID NO:468, SEQ ID NO:611, SEQ ID NO:616, SEQ ID NO:619, and SEQ ID NO:629. In some embodiments, the compound comprises a first modified oligonucleotide having the nucleobase sequence of SEQ ID NO:312 and a second modified oligonucleotide having the nucleobase sequence of SEQ ID NO:619. In some 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 foregoing embodiments, the compound may be single-stranded or double-stranded. In any of the foregoing embodiments, the compound may be an antisense oligonucleotide or an oligomeric compound. In some embodiments, the compound comprises a first modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, such as a modified oligonucleotide of 14 to 23 linked nucleosides) 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 nucleosides from any of the nucleobase sequences in SEQ ID NO: 10 to 631; and a second modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, such as a modified oligonucleotide of 14 to 23 linked nucleosides) having a region complementary to the first modified oligonucleotide. In some embodiments, the compound comprises a first modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, such as 14 to 23 linked nucleosides) having a nucleobase sequence comprising any one of SEQ ID NO: 10 to 631; and a second modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, such as 14 to 23 linked nucleosides) having a region complementary to the first modified oligonucleotide.In some embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence selected from any of SEQ ID NO: 10 to 631; and a second modified oligonucleotide having a length of 19 to 23 linked nucleosides having a region complementary to the first modified oligonucleotide.

[0181] Some embodiments involve the use of compounds comprising PKK-specific inhibitors for the manufacture or preparation of medicaments for the relief or inhibition of inflammatory or thrombotic diseases in individuals suffering from or at risk of suffering from PKK-related inflammatory or thrombotic diseases. In some embodiments, the inflammatory 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. Some embodiments involve the use of compounds comprising PKK-specific inhibitors for the preparation of medicaments for the treatment of PKK-related diseases. In some embodiments, the disease is 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 some embodiments, the compound comprises an antisense oligonucleotide targeting PKK. In some embodiments, the compound comprises an oligonucleotide targeting PKK. In some embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, such as a modified oligonucleotide of 14 to 23 linked nucleosides) having a nucleobase sequence of 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 nucleosides comprising any one of SEQ ID NO: 10 to 313, 626, 627, and 628. In some embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, such as a modified oligonucleotide of 14 to 23 linked nucleosides) having a nucleobase sequence comprising any one of SEQ ID NO: 10 to 313, 626, 627, and 628. In some embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence selected from any of SEQ ID NO: 10 to 313, 626, 627, and 628. In some embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, such as 14 to 23 linked nucleosides) having a nucleobase sequence comprising any of SEQ ID NO: 307, 312, and 626. In some embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence selected from any of SEQ ID NO: 307, 312, and 626.In some embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, such as 14 to 23 linked nucleosides) having a nucleobase sequence of 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 comprising the nucleobase sequence of SEQ ID NO: 307, 312, or 626. In some embodiments, the compound comprises a modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, for example, 14 to 23 linked nucleosides) having a nucleobase sequence of 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 comprising the nucleobase sequence of SEQ ID NO:468, 611, 616, 619, or 629. In some embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence selected from SEQ ID NO:307, SEQ ID NO:312, and SEQ ID NO:626. In some embodiments, the compound comprises a modified oligonucleotide having a nucleobase sequence selected from SEQ ID NO:468, SEQ ID NO:611, SEQ ID NO:616, SEQ ID NO:619, and SEQ ID NO:629. In some embodiments, the compound comprises a first modified oligonucleotide having the nucleobase sequence of SEQ ID NO:312 and a second modified oligonucleotide having the nucleobase sequence of SEQ ID NO:619. In some 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 foregoing embodiments, the compound may be single-stranded or double-stranded. In any of the foregoing embodiments, the compound may be an antisense oligonucleotide or an oligomeric compound. In some embodiments, the compound comprises a first modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, such as a modified oligonucleotide of 14 to 23 linked nucleosides) 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 nucleosides from any of the nucleobase sequences in SEQ ID NO: 10 to 631; and a second modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, such as a modified oligonucleotide of 14 to 23 linked nucleosides) having a region complementary to the first modified oligonucleotide.In some embodiments, the compound comprises a first modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, such as 14 to 23 linked nucleosides) having a nucleobase sequence comprising any one of SEQ ID NO: 10 to 631; and a second modified oligonucleotide (e.g., a modified oligonucleotide of 14 to 30, such as 14 to 23 linked nucleosides) having a region complementary to the first modified oligonucleotide. In some embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence selected from any one of SEQ ID NO: 10 to 631; and a second modified oligonucleotide of 19 to 23 linked nucleosides having a region complementary to the first modified oligonucleotide.

[0182] In any of the foregoing methods or uses, the compound may be an oligomeric compound. In any of the foregoing methods or uses, the compound may be single-stranded or double-stranded. In any of the foregoing methods or uses, the compound may target PKK. In some embodiments, the compound comprises or is composed of a modified oligonucleotide. In some embodiments, the compound comprises one or more modified oligonucleotides. In some embodiments, the compound comprises a first modified oligonucleotide and a second modified oligonucleotide. In some embodiments, the modified oligonucleotide has a length of 8 to 80 linked nucleosides, a length of 10 to 30 linked nucleosides, a length of 14 to 30 linked nucleosides, a length of 14 to 23 linked nucleosides, or a length of 19 to 23 linked nucleosides. In some embodiments, the modified oligonucleotide is at least 80%, at least 85%, at least 90%, at least 95%, or 100% complementary in length to any of the nucleobase sequences described in SEQ ID NO: 1, 3, 5, or 6. In some embodiments, the modified oligonucleotide comprises at least one modified nucleoside linker, at least one modified sugar, and / or at least one modified nucleobase. In some embodiments, the modified nucleoside linker is a phosphate thioester nucleoside linker. In some embodiments, the modified sugar is a bicyclic sugar, 2'-MOE, 2'-F, or 2'-OMe. In some embodiments, the modified nucleobase is 5-methylcytosine. In any of the foregoing embodiments, the length of each modified oligonucleotide is independently 12 to 30, 14 to 30, 14 to 25, 14 to 24, 14 to 23, 16 to 23, 17 to 23, 18 to 23, 19 to 23, 19 to 22, or 19 to 20 linked nucleosides. In some embodiments, the modified oligonucleotide has at least one, at least two, or at least three mismatches with the region of SEQ ID NO: 1, 3, 5, or 6.

[0183] In any of the foregoing methods or uses, the compound comprises first and second modified oligonucleotides, wherein a complementary region exists between the first and second modified oligonucleotides. In some embodiments, the length of the complementary region between the first and second oligonucleotides is 14 to 23, 19 to 23, or 21 to 23 linked nucleosides. In some embodiments, the first and second modified oligonucleotides are completely complementary. In some embodiments, the first modified oligonucleotide comprises at least one modification selected from modified nucleoside linkages, modified sugars, and modified nucleobases. In some embodiments, the second modified oligonucleotide comprises at least one modification selected from modified nucleoside linkages, modified sugars, and modified nucleobases. In some embodiments, the modified nucleoside linkage is a phosphate thioate nucleoside linkage or a methylphosphonate nucleoside linkage. In some embodiments, the modified nucleoside linkage is at the 3' end or the 5' end of the first or second modified oligonucleotide. In some embodiments, the first or second modified oligonucleotide comprises one or more modified sugars. In some embodiments, each nucleoside of the first or second modified oligonucleotide comprises a modified sugar. In some embodiments, the modified sugar comprises a modification selected from halogens, alkoxy groups, and bicyclic sugars. In some embodiments, the modified sugar comprises a modification selected from 2'-MOE, 2'-F, and 2'-OMe, or combinations thereof. In some embodiments, the first or second modified oligonucleotide comprises no more than ten 2'-F sugar modifications. In some embodiments, the first or second modified oligonucleotide comprises no more than five 2'-F sugar modifications.

[0184] In any of the foregoing methods or uses, the compound comprises a conjugating group. In some embodiments, the conjugating group is attached to the 5' end of the modified oligonucleotide. In some embodiments, the conjugating group is a targeting moiety. In some embodiments, the targeting moiety comprises one or more GalNAcs. In some embodiments, one or more GalNAcs are attached to the 2' or 3' position of the ribosyl ring. In some embodiments, one or more GalNAcs are attached to the 5' nucleoside of the modified oligonucleotide. In some embodiments, the 5' nucleoside of the modified oligonucleotide is selected from Formulas I to VIII, or their salts, solvates, or hydrates, wherein R is a modified oligonucleotide other than the 5' nucleoside. In some embodiments, the 5' nucleoside of the modified oligonucleotide is Formula I and R' is O. In some embodiments, the 5' nucleoside of the modified oligonucleotide is Formula I and R' is S. In some embodiments, the 5' nucleoside of the modified oligonucleotide is Formula II and R' is O. In some embodiments, the 5' nucleoside of the modified oligonucleotide is Formula II and R' is S. In some embodiments, the 5' nucleoside of the modified oligonucleotide is Formula III and R' is O. In some embodiments, the 5' nucleoside of the modified oligonucleotide is Formula III and R' is S. In some embodiments, the 5' nucleoside of the modified oligonucleotide is Formula IV and R' is O. In some embodiments, the 5' nucleoside of the modified oligonucleotide is Formula IV and R' is S. In some embodiments, the 5' nucleoside of the modified oligonucleotide is Formula V and R' is O. In some embodiments, the 5' nucleoside of the modified oligonucleotide is Formula V and R' is S. In some embodiments, the 5' nucleoside of the modified oligonucleotide is Formula VI and R' is O. In some embodiments, the 5' nucleoside of the modified oligonucleotide is Formula VI and R' is S. In some embodiments, the 5' nucleoside of the modified oligonucleotide is Formula VII and R' is O. In some embodiments, the 5' nucleoside of the modified oligonucleotide is Formula VII and R' is S. In some embodiments, the 5' nucleoside of the modified oligonucleotide is Formula VIII and R' is O. In some embodiments, the 5' nucleotide of the modified oligonucleotide is of formula VIII and R' is S.

[0185] In any of the foregoing methods or uses, the compound comprises a first modified oligonucleotide selected from any of Ref ID NO: IA0812 to 821, and a second modified oligonucleotide of 14 to 21 linked nucleosides, which is completely complementary to the first modified oligonucleotide. In some embodiments, the compound comprises a first modified oligonucleotide composed of IA0813 and a second modified oligonucleotide composed of IS1002. In some embodiments, the compound comprises a first modified oligonucleotide composed of IA0818 and a second modified oligonucleotide composed of IS1007. In some embodiments, the compound comprises a first modified oligonucleotide composed of IA0818 and a second modified oligonucleotide composed of IS1068.

[0186] In any of the foregoing methods or uses, the compound comprises a first modified oligonucleotide selected from any of Ref ID NO: IA0864 to 866; and a second modified oligonucleotide of 14 to 21 linked nucleosides, which is completely complementary to the first modified oligonucleotide. In some embodiments, the compound comprises a first modified oligonucleotide composed of IA0864 and a second modified oligonucleotide composed of IS1059. Some embodiments provide a compound comprising a first modified oligonucleotide selected from Ref ID NO: IA0818 and IA0864 and a second modified oligonucleotide selected from Ref ID NO: IS1058 and IS1059. Some embodiments provide a compound comprising a first modified oligonucleotide composed of IA0864 and a second modified oligonucleotide composed of IS1059. Some embodiments provide a compound comprising a first modified oligonucleotide composed of IA0818 and a second modified oligonucleotide composed of IS1058.

[0187] In some embodiments, the compound comprises a first modified oligonucleotide selected from Ref ID NO: IA0818 and IA0864 and a second modified oligonucleotide selected from Ref ID NO: IS1058 and IS1059. In some embodiments, the compound comprises a first modified oligonucleotide composed of IA0864 and a second modified oligonucleotide composed of IS1059. In some embodiments, the compound comprises a first modified oligonucleotide composed of IA0818 and a second modified oligonucleotide composed of IS1058.

[0188] In some embodiments, the compound is in the form of a pharmaceutically acceptable salt. In some embodiments, the pharmaceutically acceptable salt is a sodium salt. In some embodiments, the pharmaceutically acceptable salt is a potassium salt. In some embodiments, the composition comprises the compound of any one of the foregoing embodiments and a pharmaceutically acceptable carrier.

[0189] In any of the foregoing methods or uses, the compound or composition comprising the compound described in any of the foregoing embodiments is administered to an individual in a therapeutically effective amount. In some embodiments, the compound or composition comprising the compound described in any of the foregoing embodiments is administered to an individual at a dose level sufficient to deliver about 1 to 100 mg / kg of individual body weight. In some embodiments, the compound or composition comprising the compound described in any of the foregoing embodiments is administered to an individual at a fixed dose of about 25 mg to about 1,000 mg. In some embodiments, the composition is administered to an individual once or more times a day at up to the dose level or at a fixed dose.

[0190] In any of the foregoing methods or uses, the compound or composition comprising the compound described in any of the foregoing embodiments is applied to an individual daily, weekly, monthly, quarterly, or annually. In some embodiments, the compound or composition comprising the compound described in any of the foregoing embodiments is applied to an individual about once per quarter (i.e., every three months) to about once per year. In some embodiments, the compound or composition comprising the compound described in any of the foregoing embodiments is applied to an individual about once per quarter, about once every six months, or about once per year.

[0191] Some compounds

[0192] In some aspects, this disclosure relates to compounds comprising or composed of oligomers. In some embodiments, the oligomer contains a nucleobase sequence complementary to the nucleobase sequence of a target nucleic acid.

[0193] In some aspects, this disclosure relates to compounds comprising or composed of modified oligonucleotides. In some embodiments, the modified oligonucleotides have a nucleobase sequence complementary to the nucleobase sequence of the target nucleic acid.

[0194] In some aspects, this disclosure relates to compounds comprising or composed of antisense oligonucleotides. In some embodiments, the antisense oligonucleotide has a nucleobase sequence complementary to the nucleobase sequence of the target nucleic acid.

[0195] In some aspects, this disclosure relates to compounds that are single-chain compounds. In some embodiments, the single-chain compound comprises or is composed of an oligomeric compound. In some embodiments, such an oligomeric compound comprises or is composed of an oligonucleotide and optionally a conjugating group. In some embodiments, the oligonucleotide is a modified oligonucleotide. In some embodiments, the oligonucleotide is an antisense oligonucleotide. In some embodiments, the oligonucleotide or modified oligonucleotide of the single-chain compound comprises a self-complementary nucleobase sequence.

[0196] In some aspects, this disclosure relates to compounds that are double-stranded compounds. In some embodiments, the double-stranded compound comprises or is composed of an oligomeric compound. In some embodiments, the double-stranded compound comprises a first oligonucleotide and a second oligonucleotide. In some 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 some embodiments, the double-stranded compound comprises a modified oligonucleotide. In some embodiments, the modified oligonucleotide has a region complementary to the target nucleic acid. In some embodiments, the double-stranded compound comprises a first modified oligonucleotide and a second modified oligonucleotide. In some 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 some embodiments, the oligonucleotide or modified oligonucleotide of the double-stranded compound is an RNA oligonucleotide. In such embodiments, the thymine nucleotide in the modified oligonucleotide is replaced by a uracil nucleotide.

[0197] In some embodiments, the compounds described herein contain a conjugating group. In some embodiments, the first oligonucleotide or first modified oligonucleotide of the double-stranded compound contains a conjugating group. In some embodiments, the second oligonucleotide or second modified oligonucleotide of the double-stranded compound contains a conjugating group. In some embodiments, both the first oligonucleotide or first modified oligonucleotide and the second oligonucleotide or second modified oligonucleotide of the double-stranded compound contain a conjugating group.

[0198] In some embodiments, the compound has a length of 14 to 30 linked nucleosides. In some embodiments, the first oligonucleotide or first modified oligonucleotide of the double-stranded compound has a length of 14 to 30 linked nucleosides. In some embodiments, the second oligonucleotide or second modified oligonucleotide has a length of 14 to 30 linked nucleosides. In some embodiments, the oligonucleotide or modified oligonucleotide of the double-stranded compound has blunt ends at one or both ends of the compound. In some embodiments, the oligonucleotide or modified oligonucleotide of the double-stranded compound contains non-complementary protruding nucleosides at one or both ends of the compound.

[0199] In some embodiments, the compound has a nucleobase sequence comprising at least 14 consecutive nucleobases including any one of SEQ ID NO: 10 to 313, 626, 627, and 628. In some embodiments, one of the oligonucleotides or modified oligonucleotides of the double-stranded compound has a nucleobase sequence comprising at least 14 consecutive nucleobases including any one of SEQ ID NO: 10 to 313, 626, 627, and 628.

[0200] Some examples of single-stranded and double-stranded compounds include, but are not limited to, oligonucleotides, antisense oligonucleotides, siRNA, microRNA-targeting oligonucleotides, site-based compounds (e.g., mRNA processing or translation blocking compounds and splicing compounds), and single-stranded RNAi compounds (e.g., small hairpin RNA (shRNA), single-stranded siRNA (ssRNA), and microRNA mimics).

[0201] In some embodiments, the compounds described herein have a nucleobase sequence that, when written in the 5' to 3' orientation, contains the reverse complementary sequence of the target region of the target nucleic acid to which it is targeted.

[0202] In some embodiments, the compounds described herein comprise oligonucleotides with 12 to 30 linked subunits. In some embodiments, the compounds described herein comprise oligonucleotides with 12 to 23 linked subunits. In some embodiments, the compounds described herein comprise oligonucleotides with 14 to 30 linked subunits. In some embodiments, the compounds described herein comprise oligonucleotides with 14 to 23 linked subunits. In some embodiments, the compounds described herein comprise oligonucleotides with 15 to 30 linked subunits. In some embodiments, the compounds described herein comprise oligonucleotides with 15 to 23 linked subunits. In some embodiments, the compounds described herein comprise oligonucleotides with 15 to 23 linked subunits. In some embodiments, the compounds described herein comprise oligonucleotides with 16 to 30 linked subunits. In some embodiments, the compounds described herein comprise oligonucleotides with 16 to 23 linked subunits. In some embodiments, the compounds described herein comprise oligonucleotides with 17 to 30 linked subunits. In some embodiments, the compounds described herein comprise oligonucleotides with 17 to 23 linked subunits. In some embodiments, the compounds described herein comprise oligonucleotides with 18 to 30 linked subunits. In some embodiments, the compounds described herein comprise oligonucleotides with 18 to 23 linked subunits. In some embodiments, the compounds described herein comprise oligonucleotides with 19 to 30 linked subunits. In some embodiments, the compounds described herein comprise oligonucleotides with 19 to 23 linked subunits. In other words, such oligonucleotides are 12 to 30 linked subunits, 12 to 23 linked subunits, 14 to 30 linked subunits, 14 to 23 linked subunits, 15 to 30 linked subunits, 15 to 23 linked subunits, 16 to 30 linked subunits, 16 to 23 linked subunits, 17 to 30 linked subunits, 17 to 23 linked subunits, 18 to 30 linked subunits, 18 to 23 linked subunits, 19 to 30 linked subunits, or 19 to 23 linked subunits. In some embodiments, the compounds described herein comprise oligonucleotides with 14 linked subunits. In some embodiments, the compounds described herein comprise oligonucleotides with 16 linked subunits. In some embodiments, the compounds described herein comprise oligonucleotides with 17 linked subunits. In some embodiments, the compounds described herein comprise oligonucleotides with 18 linked subunits. In some embodiments, the compounds described herein comprise oligonucleotides with 19 linked subunits. In some embodiments, the compounds described herein comprise oligonucleotides with 20 linked subunits. In some embodiments, the compounds described herein comprise oligonucleotides with 21 linked subunits.In some embodiments, the compounds described herein comprise oligonucleotides with 22 linked subunits. In some embodiments, the compounds described herein comprise oligonucleotides with 23 linked subunits. In other embodiments, the compounds described herein comprise oligonucleotides with 8 to 80, 12 to 50, 13 to 30, 13 to 50, 14 to 30, 14 to 50, 15 to 30, 15 to 50, 16 to 30, 16 to 50, 17 to 30, 17 to 50, 18 to 23, 18 to 24, 18 to 25, 18 to 50, 19 to 23, 19 to 30, 19 to 50, 20 to 23, or 20 to 30 linked subunits. In some such embodiments, the compounds described herein comprise oligonucleotides having a length of 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, or a range defined by any two of the above values.

[0203] In some embodiments, the compound may further comprise additional portions, such as conjugation groups or delivery portions. In some embodiments, such compounds are oligomers, and the additional portions are linked to oligonucleotides. In some embodiments, the conjugation groups are linked to the nucleosides of the oligonucleotides.

[0204] In some 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' truncated) or alternatively from the 3' end (3' truncated).

[0205] In some embodiments, the compound can be elongated. For example, one or more subunits can be linked to the 3' or 5' end of the oligonucleotide. In some embodiments, at least one subunit (e.g.,

[0206] 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

[0207] (or more subunits) are attached to the 5' end of the oligonucleotide. In some embodiments, at least one subunit (e.g.,

[0208] 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

[0209] One or more subunits are attached to the 3' end of the oligonucleotide. In some embodiments, at least one or more subunits may be attached to the 3' or 5' end of the oligonucleotide of the double-stranded compound, creating 3' and / or 5' end overhangs. In some embodiments, at least one subunit (e.g.,

[0210] 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

[0211] (or more subunits) are linked to the 5' ends of two oligonucleotides of the double-stranded compound. In some embodiments, at least one subunit (e.g.,

[0212] 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

[0213] (One or more subunits) are attached to the 3' end of two oligonucleotides of the double-stranded compound. In some embodiments, the subunits are attached to two oligonucleotides of the 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 some embodiments, when the subunits are attached to two oligonucleotides of the double-stranded compound at the same end, the number of subunits attached to each oligonucleotide may be the same or may be different. In some embodiments, when the subunits are attached to two oligonucleotides of the double-stranded compound at the same end, the number of subunits attached to each oligonucleotide is the same. In some embodiments, when the subunits are attached to two oligonucleotides of the double-stranded compound at the same end, the number of subunits attached to each oligonucleotide is different. The case where the subunits are attached to two oligonucleotides of the double-stranded compound at the same end can occur at one end or both ends of the double-stranded compound. In some embodiments, the subunits attached to the 3' and / or 5' ends are modified.

[0214] In some embodiments, the compounds described herein are oligonucleotides. In some embodiments, the compounds described herein are modified oligonucleotides. In some embodiments, the compounds described herein are antisense oligonucleotides. In some embodiments, the compounds described herein are oligomeric compounds. In some embodiments, the compounds described herein are RNAi compounds. In some embodiments, the compounds described herein are siRNA compounds.

[0215] In some embodiments, the compounds described herein may comprise any of the PKK-targeting oligonucleotide sequences described herein. In some embodiments, the compounds may be double-stranded.

[0216] In some embodiments, the compound comprises an oligonucleotide comprising a portion of at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23 consecutive nucleotides of any one of SEQ ID NO: 10 to 313, 626, 627, and 628. In some embodiments, the compound comprises an oligonucleotide comprising a portion of at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23 consecutive nucleotides of SEQ ID NO: 307, 312, or 626. In some embodiments, the compound comprises a second oligonucleotide. In some embodiments, the compound comprises an oligonucleotide comprising a portion of at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23 consecutive nucleotides of SEQ ID NO: 468, 611, 616, 619, or 629. In some embodiments, the compound comprises a first oligonucleotide and a second oligonucleotide, the first oligonucleotide comprising a portion of at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23 consecutive nucleotides of SEQ ID NO: 312, and the second oligonucleotide comprising a portion of at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23 consecutive nucleotides of SEQ ID NO: 619. In some embodiments, the compound comprises a first oligonucleotide and a second oligonucleotide, the first oligonucleotide comprising a portion of at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22 or 23 consecutive nucleobases of SEQ ID NO:626, and the second oligonucleotide comprising a portion of at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22 or 23 consecutive nucleobases of SEQ ID NO:629.

[0217] In some embodiments, the compound comprises a ribonucleotide, wherein for any sequence provided herein, the oligonucleotide has uracil (U) instead of thymine (T). In some embodiments, the compound comprises a deoxyribonucleotide, wherein for any sequence provided herein, the oligonucleotide has thymine (T) instead of uracil (U).

[0218] certain mechanisms

[0219] In some embodiments, the compounds described herein comprise or consist of modified oligonucleotides. In some embodiments, the compounds described herein comprise or consist of antisense oligonucleotides. In some embodiments, the compounds comprise or consist of oligomeric compounds. In some embodiments, the compounds described herein are capable of hybridizing with target nucleic acids. In some embodiments, the compounds described herein selectively affect one or more target nucleic acids. Such compounds comprise a nucleobase sequence that hybridizes with one or more target nucleic acids to produce one or more desired activities, and does not hybridize with one or more non-target nucleic acids, or does not hybridize with one or more non-target nucleic acids in a manner that results in significant undesirable activities.

[0220] In some embodiments, hybridization of the compounds described herein with the target nucleic acid results in the recruitment of one or more proteins that cause cleavage of the target nucleic acid. For example, loading certain compounds or portions of compounds described herein into an RNA-induced silencing complex (RISC) ultimately leads to cleavage of the target nucleic acid. For example, certain compounds described herein cause the target nucleic acid to be cleaved by Argonaute. The compounds loaded into the RISC are RNAi compounds. RNAi compounds can be double-stranded (siRNA) or single-stranded (ssRNA).

[0221] In some embodiments, hybridization of the compounds described herein with the target nucleic acid does not result in the recruitment of proteins that cleave the target nucleic acid. In some such embodiments, hybridization of the compounds with the target nucleic acid leads to alterations in target nucleic acid splicing. In some embodiments, hybridization of the compounds with the target nucleic acid leads to inhibition of binding interactions between the target nucleic acid and proteins or other nucleic acids. In some such embodiments, hybridization of the compounds with the target nucleic acid leads to alterations in RNA processing. In some such embodiments, hybridization of the compounds with the target nucleic acid leads to alterations in target nucleic acid translation.

[0222] The activity resulting from hybridization of a compound with a target nucleic acid can be observed directly or indirectly. In some embodiments, the observation or detection of activity involves observing or detecting changes in the amount of the target nucleic acid or the protein encoded by such a target nucleic acid, changes in the proportion of splice variants of the nucleic acid or protein, and / or phenotypic changes in cells or animals.

[0223] certain modifications

[0224] In some aspects, this disclosure relates to compounds comprising or composed of oligonucleotides. Oligonucleotides consist of linked nucleosides. In some embodiments, the oligonucleotide may be unmodified RNA or DNA, or it may be modified. In some embodiments, the oligonucleotide is a modified oligonucleotide. In some embodiments, the modified oligonucleotide comprises at least one modified sugar, modified nucleobase, or modified nucleoside linker relative to unmodified RNA or DNA. In some embodiments, the oligonucleotide has a modified nucleoside. The modified nucleoside may comprise a modified sugar, a modified nucleobase, or both. The modified oligonucleotide may also include terminal modifications, such as 5'-terminal and 3'-terminal modifications.

[0225] Sugar modification and motif

[0226] In some embodiments, the modified sugar is a substituted furanyl sugar or a non-bicyclic modified sugar. In some embodiments, the modified sugar is a bicyclic or tricyclic modified sugar. In some embodiments, the modified sugar is a sugar substitute. The sugar substitute may comprise one or more of the substitutes described herein.

[0227] In some embodiments, the modified sugar is a substituted furanyl or non-bicyclic modified sugar. In some embodiments, the furanyl sugar is a ribosyl sugar. In some embodiments, the furanyl sugar contains one or more substituents, including but not limited to substituents at the 2', 3', 4', and 5' positions.

[0228] In some embodiments, the substituents at the 2' position include, but are not limited to, F and OCH3 (“OMe”, “O-methyl”, or “methoxy”). In some embodiments, suitable substituents at the 2' position for non-bicyclic modified sugars include, but are not limited to, halogens, allyl groups, amino groups, azides, SH, CN, OCN, CF3, OCF3, F, Cl, Br, SCH3, SOCH3, SO2CH3, ONO2, N3, and NH2. In some embodiments, the substituents at the 2' position include, but are not limited to, O-(C1-C2) 10 Alkoxy, alkoxyalkyl, O-alkyl, S-alkyl, N-alkyl, O-alkenyl, S-alkenyl, N-alkenyl, O-ynyl, S-ynyl, N-ynyl, O-alkyl-O-alkyl, ynyl, wherein the alkyl, alkenyl, and ynyl groups can be substituted or unsubstituted C1 to C2 groups. 10 Alkyl or C2 to C 10Alkenyl and alkynyl groups. In some embodiments, the substituents at the 2' position include, but are not limited to, alkylaryl, aralkyl, O-alkylaryl, and O-aralkyl. In some embodiments, these 2' substituents may be further substituted by one or more substituents independently selected from: hydroxyl, alkoxy, carboxyl, benzyl, phenyl, nitro(NO2), thiol, thioalkoxy, thioalkyl, halogen, alkyl, aryl, alkenyl, and alkynyl. In some 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, wherein n and m are independently 1 to about 10. In some embodiments, the substituents at the 2' position include, but are 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”).

[0229] In some embodiments, suitable substituents at the 4' position for non-bicyclic modified sugars include, but are not limited to, alkoxy (e.g., methoxy), alkyl, and those described in Manoharan et al., WO 2015 / 106128. In some embodiments, suitable substituents at the 5' position for non-bicyclic modified sugars include, but are not limited to, methyl (“Me”) (R or S), vinyl, and methoxy. In some embodiments, the substituents described herein at the 2', 4', and 5' positions may be added to other specific positions on the sugar. In some embodiments, such substituents may be added to the 3' position of a sugar on a 3'-terminal nucleotide or the 5' position of a 5'-terminal nucleotide. In some embodiments, the non-bicyclic modified sugar may contain more than one non-bridging sugar substituent. In some such embodiments, non-bicyclic modified sugar substituents include, but are not limited to, 5'-Me-2'-F and 5'-Me-2'-OMe (including both R and S isomers). In some embodiments, the modified sugar substituents include those described in Migawa et al., WO 2008 / 101157 and Rajeev et al., US2013 / 0203836.

[0230] In some embodiments, the modified sugar is a bicyclic sugar. A bicyclic sugar is a modified sugar comprising two rings, wherein the second ring is formed by a bridge connecting two atoms in the first ring, thereby forming a bicyclic structure. In some embodiments, the bicyclic sugar contains a bridging substituent that bridges the two atoms of the furanyl ring to form the second ring. In some embodiments, the bicyclic sugar does not contain a furanyl moiety. A “bicyclic nucleoside” (“BNA”) is a nucleoside having a bicyclic sugar. In some embodiments, the bicyclic sugar contains a bridge between the 4' and 2' furanyl ring atoms. In some embodiments, the bicyclic sugar contains a bridge between the 5' and 3' furanyl ring atoms. In some such embodiments, the furanyl ring is a ribose ring. In some embodiments, the 4' to 2' bridging substituents include, but are not limited to, 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' (“restricted ethyl” or “cEt” when in the S configuration), 4'-CH2-O-CH2-2', 4'-CH2-N(R)-2', 4'-CH(CH2OCH3)-O-2' (…). “Constrained MOE” or “cMOE” and its analogues (e.g., U.S. Patent No. 7,399,845), 4'-C(CH3)(CH3)-O-2' and its analogues (e.g., U.S. Patent No. 8,278,283), 4'-CH2-N(OCH3)-2' and its analogues (e.g., U.S. Patent No. 8,278,425), 4'-CH2-ON(CH3)-2' (e.g., U.S. Patent Publication No. 2004 / 0171570), 4'-CH2-N(R)-O-2', wherein R is H, C1-C 12 Alkyl or protecting groups (e.g., U.S. Patent No. 7,427,672), 4'-CH2-C(H)(CH3)-2' (e.g., Chattopadhyaya et al., J. Org. Chem., 2009, 74, 118-134), and 4'-CH2-C(=CH2)-2' and their analogues (e.g., U.S. Patent No. 8,278,426). The entire contents of each of the foregoing are incorporated herein by reference. Other representative U.S. patents and U.S. patent publications teaching the preparation of bicyclic nucleic acid nucleotides include, but are not limited to, the following:

[0231] U.S. Patent Nos. 6,268,490; 6,525,191; 6,670,461; 6,770,748; 6,794,499; 6,998,484; 7,053,207; 7,034,133; 7,084,125; 7,399,845; 7,427,672; 7,569,686; 7,741,457; 8,022,193; 8,030,467; 8,278,425; 8,278,426; 8,278,283; US 2008 / 0039618; and US 2009 / 0012281, US 2013 / 0190383; and WO 2013 / 036868,

[0232] The entire contents of each of these documents are incorporated herein by reference. Any of the aforementioned bicyclic nucleotides having one or more stereochemical sugar configurations can be prepared, including, for example, α-L-ribofranose and β-D-ribofranose (see, for example, WO 99 / 14226). Unless otherwise specified, the bicyclic nucleotides specified herein are of the β-D configuration.

[0233] In some embodiments, the modified sugar is a sugar substitute. In some embodiments, the sugar substitute has an oxygen atom replaced by, for example, a sulfur, carbon, or nitrogen atom. In some such embodiments, the sugar substitute may also contain bridging and / or non-bridging substituents as described herein. In some embodiments, the sugar substitute comprises a ring having more than five atoms. In some such embodiments, the sugar substitute comprises a cyclobutyl moiety replacing the pentofuranose sugar. In some embodiments, the sugar substitute comprises a six-membered ring replacing the pentofuranose sugar. In some embodiments, the sugar substitute comprises a tetrahydropyran (“THP”) replacing the pentofuranose sugar. In some embodiments, the sugar substitute comprises a morpholino replacing the pentofuranose sugar. Representative U.S. patents teaching the preparation of such modified sugar structures include, but are not limited to, those...

[0234] U.S. Patent Nos. 4,981,957; 5,118,800; 5,166,315; 5,185,444; 5,319,080; 5,359,044; 5,393,878; 5,446,137; 5,466,786; 5,514,785; 5,519,134; 5,567,811; 5,576,427; 5, 591,722; 5,597,909; 5,610,300; 5,627,053; 5,639,873; 5,646,265; 5,658,873; 5,670,633; 5,700,920; 7,875,733; 7,939,677; 8,088,904; 8,440,803; and 9,005,906,

[0235] All of the aforementioned content is incorporated herein by reference.

[0236] In some embodiments, the sugar substitute comprises an acyclic moiety. In some embodiments, the sugar substitute is an unlocked nucleic acid (“UNA”). An UNA is an unlocked acyclic nucleic acid in which any bond of the sugar has been removed, forming an unlocked “sugar” residue. In one instance, UNA also encompasses monomers in which the bond between C1' and C4' (i.e., the covalent carbon-oxygen-carbon bond between C1' and C4' carbons) has been removed. In another instance, the C2'-C3' bond of the sugar (i.e., the covalent carbon-carbon bond between C2' and C3' carbons) has been removed. Representative U.S. publications teaching the preparation of UNA include, but are not limited to, U.S. Patent No. 8,314,227; and U.S. Patent Publications Nos. 2013 / 0096289, 2013 / 0011922, and 2011 / 0313020, the entire contents of which are incorporated herein by reference. In some embodiments, the sugar substitute comprises peptide nucleic acid (“PNA”), acyclic butyl nucleic acid (see, for example, Kumar et al., Org. Biomol. Chem., 2013, 11, 5853-5865), and nucleosides and oligonucleotides described in Manoharan et al., US2013 / 130378, the entire contents of which are incorporated herein by reference. Many other bicyclic and tricyclic sugar and sugar-substituted ring systems known in the art can be used for modified nucleosides.

[0237] In some aspects, this disclosure relates to compounds comprising at least one oligonucleotide, wherein the nucleoside of such oligonucleotide comprises one or more types of modified and / or unmodified sugars arranged in a defined pattern or “glycomolecular motif” along the oligonucleotide or a region thereof. In some cases, such glycomolecular motifs include, but are not limited to, any sugar modification patterns described herein.

[0238] In some embodiments, the oligonucleotide comprises a spacer polymeric glycoside motif. The spacer polymeric oligonucleotide comprises or consists of a region having two outer “wing” regions and a central or inner “spacer” region. The spacer and wing regions form a continuous sequence of nucleosides, wherein the majority of the nucleotide sugar in each wing differs from the majority of the nucleotide sugar in the spacer. In some embodiments, the wing regions comprise the majority of modified sugars, and the spacer comprises the majority of unmodified sugars. In some embodiments, the nucleoside of the spacer is a deoxynucleoside. Compounds having spacer polymeric glycoside motifs are described, for example, in U.S. Patent 8,790,919, the entire contents of which are incorporated herein by reference.

[0239] In some embodiments, one or two oligonucleotides of the double-stranded compound contain a triplet glycosidic motif. The oligonucleotide having a triplet glycosidic motif contains three identical sugar modifications on three consecutive nucleosides. In some embodiments, the triplet is located at or near the cleavage site of the oligonucleotide. In some embodiments, the oligonucleotide of the double-stranded compound may contain more than one triplet glycosidic motif. In some embodiments, the identical sugar modification of the triplet glycosidic motif is a 2'-F modification. For example, compounds having triplet glycosidic motifs are disclosed in, for example, in U.S. Patent 10,668,170, the entire contents of which are incorporated herein by reference.

[0240] In some embodiments, one or two oligonucleotides of the double-stranded compound contain a tetrad glycosidic motif. The oligonucleotide with the tetrad glycosidic motif contains four identical sugar modifications on four consecutive nucleotides. In some embodiments, the tetrad is located at or near the cleavage site. In some embodiments, the oligonucleotide of the double-stranded compound may contain more than one tetrad glycosidic motif. In some embodiments, the identical sugar modification of the tetrad glycosidic motif is a 2'-F modification. For double-stranded compounds having a double-stranded region of 19 to 23 nucleotides in length, the cleavage site of the antisense oligonucleotide is typically located approximately at positions 10, 11, and 12 from the 5' end. In some embodiments, counting begins with the first nucleotide at the 5' end of the sense oligonucleotide, or with the first paired nucleotide in the double-stranded region at the 5' end of the sense oligonucleotide, with the tetrameric glycosequence at positions 8, 9, 10, 11; 9, 10, 11, 12; 10, 11, 12, 13; 11, 12, 13, 14; or 12, 13, 14, 15 of the sense oligonucleotide. In some embodiments, counting begins with the first nucleotide at the 5' end of the antisense oligonucleotide, or with the first paired nucleotide in the double-stranded region at the 5' end of the antisense oligonucleotide, with the tetrameric glycosequence at positions 8, 9, 10, 11; 9, 10, 11, 12; 10, 11, 12, 13; 11, 12, 13, 14; or 12, 13, 14, 15 of the antisense oligonucleotide. The cleavage site can vary depending on the length of the double-stranded region of the double-stranded compound, and the position of the tetrad can be changed accordingly.

[0241] In some embodiments, the oligonucleotide comprises alternating glycoside motifs. In some embodiments, one or both oligonucleotides of the double-stranded compound comprise alternating glycoside motifs. Oligonucleotides having alternating glycoside motifs comprise at least two different sugar modifications, wherein one or more consecutive nucleotides comprising a first sugar modification alternate with one or more consecutive nucleotides comprising a second sugar modification and one or more consecutive nucleotides comprising a third sugar modification. For example, if A, B, and C each represent a type of nucleotide modification, the alternating motif could be…

[0242] "ABABABABABAB...," "AABBAABBAABB..." "AABAABAABAAB...," "AAABAAABAAAB...," "AAABBBAAABBB...," or "ABCABCABCABC..." etc.

[0243] In some embodiments, the alternating glycomotif is repeated along the oligonucleotide for at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23 consecutive nucleotide bases. In some embodiments, the alternating glycomotif is composed of two different sugar modifications. In some embodiments, the alternating glycomotif comprises 2'-OMe and 2'-F sugar modifications.

[0244] In some embodiments, each nucleotide of the oligonucleotide is independently modified by one or more sugar modifications provided herein. In some embodiments, each oligonucleotide of the double-stranded compound independently has one or more glycomolecular motifs provided herein. In some embodiments, the oligonucleotide containing the glycomolecular motif is fully modified because each nucleotide other than the nucleotide containing the glycomolecular motif contains a sugar modification.

[0245] Nucleobase modification and motif

[0246] In some embodiments, the compounds described herein comprise modified oligonucleotides. In some embodiments, the modified oligonucleotides comprise one or more nucleosides containing modified nucleobases. In some embodiments, the modified oligonucleotides comprise one or more nucleosides without nucleobases, referred to as base-free nucleosides.

[0247] In some 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 some embodiments, the modified nucleobase is selected from: 2-aminopropyladenine, 5-hydroxymethylcytosine, 5-methylcytosine, xanthine, hypoxanthine, 2-aminoadenine, 6-N-methylguanine, 6-N-methyladenine, 2-propyladenine, 2-thiouracil, 2-thiothymidine and 2-thiocytosine, 5-propynyl(C≡C-CH3)uracil, 5-propynylcytosine, 6-azouracil, 6-azocytosine, 6-azothymidine, 5-ribosyluracil (pseudouracil), 4-thiouracil, 8-halogenated, 8-amino, 8-thiol, 8-thioalkyl, 8-hydroxy, 8-nitrogen Hybrids and other 8-substituted purines, 5-halogenated purines, especially 5-bromo, 5-trifluoromethyl, 5-halogenated uracil and 5-halogenated cytosine, 7-methylguanine, 7-methyladenine, 2-F-adenine, 2-aminoadenine, 7-deazoguanine, 7-deazoadenine, 3-deazoguanine, 3-deazoadenine, 6-N-benzoyladenine, 2-N-isobutyrylguanine, 4-N-benzoylcytosine, 4-N-benzoyluracil, 5-methyl4-N-benzoylcytosine, 5-methyl4-N-benzoyluracil, universal bases, hydrophobic bases, promiscuous bases, size-expanded bases, and fluorinated bases. Further modified nucleobases include tricyclic pyrimidines, such as 1,3-diazaphene.

[0248] Other nucleobases include those disclosed below:

[0249] U.S. Patent 3,687,808; Modified Nucleosides in Biochemistry, Biotechnology and Medicine, Herdewijn, P.ed. Wiley-VCH, 2008; The Concise Encyclopedia Of Polymer Science And Engineering, pp. 858-859; Kroschwitz, JL, Ed., John Wiley & Sons, 1990, 858-859; Englisch et al. 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, pp. 163-166 and 442-443 (Chapters 6 and 15),

[0250] Each of them is incorporated herein by reference.

[0251] Publications teaching the preparation of certain of the above-mentioned modified nucleosides and other modified nucleosides include, but are not limited to, U.S. applications 2003 / 0158403 and 2003 / 0175906;

[0252] U.S. Patents 4,845,205; 5,130,302; 5,134,066; 5,175,273; 5,367,066; 5,432,272; 5,434,257; 5,457,187; 5,459,255; 5,484,908; 5,502,177; 5,525,711; 5,552,540; 5,587,469; 5,594,121; 5,596,091; 5,614,617; 5,645,985; 5,681,941; 5,811,534; 5,7 50,692; 5,948,903; 5,587,470; 5,457,191; 5,763,588; 5,830,653; 5,808,027; 6,005,096; 6,015,886; 6,147,200; 6,166,197; 6,166,199; 6,222,025; 6,235,887; 6,380,368; 6,528,640; 6,639,062; 6,617,438; 7,045,610; 7,427,672; and 7,495,088,

[0253] Its entire content is incorporated herein by reference.

[0254] In some embodiments, the compounds described herein comprise oligonucleotides. In some embodiments, the oligonucleotide comprises modified and / or unmodified nucleobases arranged in a defined pattern or motif along the oligonucleotide or a region thereof. In some embodiments, each nucleobase is modified. In some embodiments, no nucleobase is modified. In some embodiments, each purine or each pyrimidine is modified. In some embodiments, each adenine is modified. In some embodiments, each guanine is modified. In some embodiments, each thymine is modified. In some embodiments, each uracil is modified. In some embodiments, each cytosine is modified. In some embodiments, some or all of the cytosine nucleobases in the modified oligonucleotide are 5-methylcytosine.

[0255] In some embodiments, the modified oligonucleotide comprises a block of modified nucleosides. In some such embodiments, the block is located at the 3' end of the oligonucleotide. In some embodiments, the block is located within three nucleosides at the 3' end of the oligonucleotide. In some embodiments, the block is located at the 5' end of the oligonucleotide. In some embodiments, the block is located within three nucleosides at the 5' end of the oligonucleotide.

[0256] Nucleoside inter-linking modifications and motifs

[0257] 3' to 5' phosphodiester bonds are naturally occurring nucleoside-to-nucleotide bonds in RNA and DNA. In some embodiments, the compounds described herein have one or more modified, i.e., non-naturally occurring nucleoside-to-nucleotide bonds. Certain non-naturally occurring nucleoside-to-nucleotide bonds can confer desired properties, such as enhanced cellular uptake, enhanced affinity for target nucleic acids, and improved stability in the presence of nucleases. Representative phosphorus-containing modified nucleoside-to-nucleotide bonds include, but are not limited to, phosphodiester, alkylphosphonates (e.g., methylphosphonates), hypophosphite, and thiophosphates (“P=S”) and dithiophosphates (“HS-P=S”). Representative phosphorus-free nucleoside interlinking groups include, but are not limited to, methylene methylimino (-CH2-N(CH3)-O-CH2), thiodiester, thiocarbamate (-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 nucleoside interlinking groups are well known to those skilled in the art. Neutral nucleoside interlinking groups include, but are not limited to, triphosphates, methylphosphonates, and MMI (3'- The bonds between neutral nucleosides include CH2-N(CH3)-O-5', amide-3 (3'-CH2-C(=O)-N(H)-5'), amide-4 (3'-CH2-N(H)-C(=O)-5'), methyl acetal (3'-O-CH2-O-5'), methoxypropyl, and thiomethyl acetal (3'-S-CH2-O-5'). Other neutral nucleoside bonds include nonionic bonds containing the following: siloxanes (dialkylsiloxanes), carboxylic esters, formamides, sulfides, sulfonates, and amides (see, for example: Carbohydrate Modifications in Antisense Research; YSSanghvi and PDCook, Eds., ACS Symposium Series 580; Chapters 3 and 4, 40-65). Still other neutral nucleoside bonds include nonionic bonds containing a mixture of N, O, S, and CH2 components.

[0258] In some embodiments, the compounds provided herein comprise at least one modified nucleoside link. The modified nucleoside link can be placed at any position on the oligonucleotide. For double-stranded compounds, the modified nucleoside link can be placed within a sense oligonucleotide, an antisense oligonucleotide, or both oligonucleotides of the double-stranded compound.

[0259] In some embodiments, internucleotide linking modification may occur on each nucleoside of the oligonucleotide. In some embodiments, internucleotide linking modification may occur along the oligonucleotide in an alternating pattern. In some embodiments, substantially each internucleotide linking group is a phosphate linking (P=O). In some embodiments, each internucleotide linking group of the modified oligonucleotide is a phosphate thioester (P=S). In some embodiments, each internucleotide linking group of the modified oligonucleotide is independently selected from phosphate thioester and phosphate ester internucleotide links. In some embodiments, the pattern of internucleotide linking modification on each oligonucleotide of the double-stranded compound is the same. In some embodiments, the pattern of internucleotide linking modification on each oligonucleotide of the double-stranded compound is different. In some embodiments, the double-stranded compound contains 6 to 8 modified internucleotide links. In some embodiments, the 6 to 8 modified internucleotide links are phosphate thioester internucleotide links or alkylphosphonate internucleotide links. In some embodiments, the sense oligonucleotide contains at least two modified nucleoside links at one or both of the 5' and 3' ends. In some such embodiments, the modified nucleoside links are phosphate thioester nucleoside links or alkylphosphonate nucleoside links. In some embodiments, the antisense oligonucleotide contains at least two modified nucleoside links at one or both of the 5' and 3' ends. In some such embodiments, the modified nucleoside links are phosphate thioester nucleoside links or alkylphosphonate nucleoside links.

[0260] In some embodiments, the double-stranded compound includes a salient region. In some embodiments, the double-stranded compound includes an internucleotide linker of phosphate thioester or alkylphosphonate in the salient region. In some embodiments, the double-stranded compound includes an internucleotide linker of phosphate thioester or alkylphosphonate, said linker connecting the salient nucleotide to a paired nucleotide adjacent to the salient nucleotide. For example, at least two phosphate thioester internucleotide links may be present between the three terminal nucleotides, wherein two of the three nucleotides are salient nucleotides, and the third is a paired nucleotide adjacent to the salient nucleotide. These three terminal nucleotides may be located at the 3' end of an antisense oligonucleotide, the 3' end of a sense oligonucleotide, the 5' end of an antisense oligonucleotide, or the 5' end of an antisense oligonucleotide.

[0261] In some embodiments, the modified oligonucleotide comprises one or more internucleotide links having a chiral center. Representative chiral internucleotide links include, but are not limited to, alkylphosphonates and thiophosphates. Modified oligonucleotides comprising internucleotide links having a chiral center can be prepared as modified oligonucleotide groups comprising stereorandom internucleotide links, or as modified oligonucleotide groups comprising thiophosphate links in a specific stereochemical configuration. In some embodiments, the modified oligonucleotide group comprises thiophosphate internucleotide links, wherein all thiophosphate internucleotide links are stereorandom. Such modified oligonucleotides can be produced using synthetic methods that result in the random selection of the stereochemical configuration of each thiophosphate link. As is known to those skilled in the art, each individual thiophosphate in each individual oligonucleotide molecule has a defined stereochemical configuration. In some embodiments, the modified oligonucleotide group is enriched in modified oligonucleotides comprising one or more specific thiophosphate internucleotide links in a specific, independently selected stereochemical configuration. In some embodiments, a specific configuration with a specific thiophosphate bond is present in at least 65% of the molecules in the group. In some embodiments, a specific configuration with a specific thiophosphate bond is present in at least 70% of the molecules in the group. In some embodiments, a specific configuration with a specific thiophosphate bond is present in at least 80% of the molecules in the group. In some embodiments, a specific configuration with a specific thiophosphate bond is present in at least 90% of the molecules in the group. In some embodiments, a specific configuration with a specific thiophosphate bond is present in at least 99% of the molecules in the group. Such enriched modified oligonucleotide groups can be produced using synthetic methods known in the art, for example, those described in Oka et al., JACS125, 8307 (2003), Wan et al., Nuc. Acid. Res. 42, 13456 (2014), and WO 2017 / 015555. In some embodiments, the modified oligonucleotide group is enriched in modified oligonucleotides having at least one indicated thiophosphate in the (Sp) configuration. In some embodiments, the modified oligonucleotide group is enriched in the modified oligonucleotide having at least one thiophosphate ester in the (Rp) configuration.

[0262] Conjugated groups

[0263] In some embodiments, the compounds described herein comprise or consist of one or more oligonucleotides and optionally one or more conjugating groups. The conjugating groups may be attached to one or both ends of the oligonucleotide and / or at any internal position. In some embodiments, the conjugating group is attached to the 3' end of the oligonucleotide. In some embodiments, the conjugating group is attached to the 5' end of the oligonucleotide. In some embodiments, the oligonucleotide is covalently linked to one or more conjugating groups.

[0264] In some embodiments, the conjugating group is a terminal group attached to one or both ends of the oligonucleotide. In some such embodiments, the terminal group is attached to the 3' end of the oligonucleotide. In some such embodiments, the terminal group is attached to the 5' end of the oligonucleotide. In some 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 independently modified or unmodified nucleosides, such as overhangs.

[0265] In some embodiments, the conjugating group modifies one or more properties of the linked oligonucleotide, including but not limited to pharmacodynamics, pharmacokinetics, stability, activity, half-life, binding, absorption, tissue distribution, cellular distribution, cellular uptake, charge, and clearance. In some embodiments, the conjugating group enhances the affinity of the compound for a selected target, such as a molecule, cell or cell type, compartment (e.g., a cell or organ compartment), tissue, organ, or body region, compared to a compound without such a conjugating group. In some embodiments, the conjugating group imparts novel properties to the linked oligonucleotide, such as enabling the detection of a fluorophore or reporter group of the oligonucleotide.

[0266] In some embodiments, the conjugation groups include, but are not limited to, intercalating agents, reporter molecules, polyamines, polyamides, peptides, carbohydrates, vitamin fractions, polyethylene glycols, thioethers, polyethers, cholesterol, thiocholesterol, bile acid fractions, folic acid, lipids, phospholipids, biotin, phenazine, phenanthridine, anthraquinones, adamantane, acridine, fluorescein, rhodamine, coumarin, fluorophores, and dyes.

[0267] In some embodiments, the conjugation group includes active pharmaceutical substances such as aspirin, warfarin, phenylbutazone, ibuprofen, suprafen, fen-bufen, ketoprofen, (S)-(+)-pranoprofen, carprofen, dansyl sarcosinate, 2,3,5-triiodobenzoic acid, fingolimod, flufenamic acid, leucovorin, benzothiazide, chlorothiazide, and diazoxide.

[0268] In some embodiments, the conjugation group is the targeting moiety. In some embodiments, the targeting moiety includes, but is not limited to, lectins, glycoproteins, lipids, proteins, peptides, peptide mimics, receptor ligands, antibodies, thyroid-stimulating hormone, melanocyte-stimulating hormone, surfactant protein A, carbohydrates, carbohydrate derivatives, modified carbohydrates, carbohydrate clusters, polysaccharides, modified polysaccharides or polysaccharide derivatives, mucinous carbohydrates, polyvalent lactose, polyvalent galactose, N-acetyl-galactosamine (GalNAc), N-acetylglucosamine polymannose, polyvalent fucose, glycosylated polyamino acids, polyvalent galactose, transferrin, bisphosphonates, polyglutamic acid, polyaspartic acid, lipids, cholesterol, steroids, bile acids, folic acid, vitamin B12, vitamin A, biotin, or RGD peptides or RGD peptide mimics.

[0269] In some embodiments, the conjugating group may include, but is not limited to, the conjugating groups described in the following references: for example, cholesterol (e.g., Letsinger et al., Proc. Natl. Acid. Sci. USA, 1989, 86: 6553-6556); bile acids (e.g., Manoharan et al., Biorg. Med. Chem. Let., 1994, 4: 1053-1060); thioethers, for example, hexyl-S-triphenylmethylthiol (e.g., Manoharan et al., Ann. NY. Acad. Sci., 1992, 660: 306-309; Manoharan et al., Biorg. Med. Chem. Let., 1993, 3: 2765-2770); thiocholesterol (e.g., Oberhauser et al., Nucl. Acids Res., 1992, 20:533-538); aliphatic chains, 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 triethylammonium 1,2-di-O-hexadecyl-rac-glycerol-3-H-phosphate (e.g., Manoharan et al., Tetrahedron Lett., 1995, 36:3651-3654; Shea et al., Nucl. Acids Res., 1990, 18:3777-3783); polyamines 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 groups (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); tocopherols (e.g., Nishina et al.).,Molecular Therapy Nucleic Acids, 2015, 4, e220 and Nishina et al.,Molecular Therapy, 2008, 16:734-740); GalNAc and other carbohydrates (e.g., Maier et al., Bioconjugate Chemistry, 2003, 14, 18-29; Rensen et al., J. Med. Chem. 2004, 47, 5798-5808; WO2009 / 073809 and U.S. Patents 8,106,022, 8,450,467 and 8,828,957; and WO2014 / 179445; WO2014 / 179620 and U.S. Patents 9,127,276, 9,181,549 and 10,844,379), each incorporated herein by reference in its entirety. .

[0270] The conjugating group can be linked to an oligonucleotide via a conjugating linker. In some embodiments, the conjugating linker comprises an oligomer of a chain structure (e.g., a hydrocarbon chain) or repeating units, or a combination of such repeating units. In some embodiments, the conjugating linker comprises one or more groups selected from alkyl, amino, oxo, amide, disulfide, polyethylene glycol, ether, thioether, and hydroxyamino groups. In some embodiments, the conjugating linker comprises at least one phosphorus group. In some embodiments, the conjugating linker comprises at least one phosphate group. In some embodiments, the conjugating linker comprises at least one neutral linking group. In some embodiments, the conjugating linker includes, but is not limited to, pyrrolidine, 8-amino-3,6-dioxanoic acid (ADO), succinimide-4-(N-maleimide-methyl)cyclohexane-1-carboxylic acid ester (SMCC), and 6-aminohexanoic acid (AHEX or AHA). Other conjugating linkers include, but are not limited to, substituted or unsubstituted C1-C... 10 Alkyl, substituted or unsubstituted C2-C 10 Alkenyl or substituted or unsubstituted C2-C 10The alkynyl group, wherein a non-limiting list of preferred substituents includes hydroxyl, amino, alkoxy, carboxyl, benzyl, phenyl, nitro, thiol, thioalkoxy, halogen, alkyl, aryl, alkenyl, and alkynyl. In some embodiments, the conjugation linker comprises 1 to 10 linker-nucleosides. In some embodiments, such linker-nucleosides may be modified or unmodified nucleosides. It is generally desirable to cleave the linker-nucleosides from the compound after it reaches the target tissue. Therefore, the linker-nucleosides herein may be interconnected by cleavable bonds and linked to the remainder of the compound. In this document, linker-nucleosides are not considered part of an oligonucleotide. Therefore, in embodiments in which the compound comprises an oligonucleotide consisting of a specific number or range of linker-nucleosides and / or having a specific percentage of complementarity with a reference nucleic acid, and the compound further comprises a conjugation group containing a linker-nucleoside-containing conjugation linker, these linker-nucleosides are not included in the length of the oligonucleotide and are not used to determine the percentage of complementarity of the oligonucleotide to the reference nucleic acid.

[0271] In some embodiments, the conjugating groups and conjugating links, as well as other modifications, include, but are not limited to, those described in the following references:

[0272] US 5,994,517; US 6,300,319; US 6,660,720; US 6,906,182; US 7,262,177; US 7,491,805; US 8,106,022; US 7,723,509; US 9,127,276; US 2006 / 0148740; US 2011 / 0123520;

[0273] WO2013 / 033230;W02012 / 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.,J.Med.Chem.1999,42,609-618;Valentijn et al.,Tetrahedron,1997,53,759-770;Lee,Carhohydr Res,1978,67,509-514;Connolly et al.,J Biol Chem,1982,257,939-945;Pavia et al.,Int J Pep Protein Res,1983,22,539-548;Lee et al.,Biochem,1984,23,4255-4261;Lee et al.,Glycoconjugate J,1987,4,317-328;Toyokuni et al.,Tetrahedron Lett,1990,31,2673-2676;Biessen et al.,J Med Chem,1995,38,1538-1546;Valentijn et al.,Tetrahedron,1997,53,759-770;Kim et al.,Tetrahedron Lett,1997,38,3487-3490;Lee et al.,Bioconjug Chem,1997,8,762-765,Kato et al.,Glycohiol,2001,11,821-829;Rensen et al.,J Biol Chem,2001,276,37577-37584;Lee et al.,Methods Enzymol,2003,362,38-43,Westerlind et al.,Glycoconj J,2004,21,227-241,Lee et al.,Bioorg Med Chem Lett,2006,16(19),5132-5135;Maierhofer et al.,Bioorg Med Chem,2007,15,7661-7676;Khorev et al.,Bioorg Med Chem,2008,16,5216-5231;Lee et al.,Bioorg Med Chem,2011,19,2494-2500;Komilova et al.,Analyt Biochem,2012,425,43-46;Pujol et al.,Angew Chemie Int Ed Engl,2012,51,7445-7448;Biessen et a1.,J Med Chem,1995,38,1846-1852;Sliedregt et al.,J Med Chem,1999,429-668;Rensen et al. al.,J Med Chem,2004,47,5798-5808;Rensen et al.,Arterioscler Thromh Vase Biol,2006,26,169-175;van Rossenberg et al.,Gene Ther,2004,11,457-464;Sato et al.,JAm Chem Soc,2004,126,14013-14022;Lee et al.,J Org Chem,2012,757-751;Biessen et al. al.,FASEB J,2000,14,1784-1792;Rajur et al.,Bioconjug Chem,1997,8,935-940;Duffet al.,Methods Enzymol,2000,313,297-321;Maier et a1.,Bioconjug Chem,2003,14,18-29;Jayaprakash et a1,Org Lett,2010,12,5410-5413;Manoharan,Antisense Nucleic Acid Drug Dev,2002,12,103-128;Merwin et al,Bioconjug Chem,1994,Tomiya et al.2016-266 al.,Bioorg Med Chem,2013,21,5275-5281;.

[0274] International Applications: WO1998 / 013381; WO2011 / 038356; WO1997 / 046098; W02008 / 098788; W02004 / 101619; WO2012 / 037254; WO2011 / 120053; WO2011 / 100131; WO2011 / 163121; WO2012 / 177947; WO2013 / 033230; WO2013 / 075035; WO2012 / 0831 85; WO2012 / 083046; W02009 / 082607; WO2009 / 134487; W02010 / 144740; W02010 / 148013; WO1997 / 020563; WO201 0 / 088537; WO2002 / 043771; WO2010 / 129709; WO2012 / 068187; WO2009 / 126933; WO2004 / 024757; WO2010 / 054406 WO2012 / 089352; WO2012 / 089602; WO2013 / 166121; WO2013 / 165816; US Patents 4,751,219; 7,582,744; 8,552,163; 8,137,695; 6,908,903; 6,383,812; 7,262,177; 6,525,031; 5,994,517; 6,660,720; 6,300,319; 7,723,509; 8, 106,022; 7,491,805; 7,491,805; 8,541,548; 8,344,125; 8,313,772; 8,349,308; 8,450,467; 8,501,930; 8,158,601; 7,262,177; 6,906,182; 6,620,916; 8,435,491; 8,404,862; 7,851,615; Publication of U.S. Patent Application Publication US2011 / 0097264;

[0275] US2011 / 0097265; US2013 / 0004427; US2003 / 0119724; US2011 / 0207799;

[0276] US2012 / 0035115; US2012 / 0230938; US2005 / 0164235; US2006 / 0183886;

[0277] US2012 / 0136042; US2012 / 0095075; US2013 / 0109817; US2006 / 0148740;

[0278] US2008 / 0206869; US2012 / 0165393; US2012 / 0101148; US2013 / 0121954;

[0279] US2011 / 0123520; US2003 / 0077829; US2008 / 0108801; and US2009 / 0203132;

[0280] Each of them is incorporated into this article through citation.

[0281] certain target parts

[0282] In some embodiments, the compounds provided herein comprise a conjugating group. In some embodiments, the oligonucleotides provided herein comprise a conjugating group. In some embodiments, the conjugating group is a targeting moiety. In some embodiments, the targeting moiety comprises one or more GalNAcs. In some embodiments, one or more GalNAcs are linked to one or more positions on the furanose ring. In some embodiments, one or more GalNAcs are linked to the 2' or 3' position on the furanose ring. In some embodiments, the furanose ring is a subunit of the oligonucleotide. In some embodiments, the furanose ring is the 5' nucleotide sugar of the oligonucleotide. In some embodiments, the furanose ring is the 5' nucleotide sugar of a meaningful oligonucleotide. In some embodiments, the compound or oligonucleotide comprises one or more subunits having the following formula or its salt, solvate, or hydrate:

[0284] in:

[0285] R 1 It is an isostere of H, adenine, guanine, thymine, cytosine, uracil, carbocyclic group, heterocyclic group, aryl, heteroaryl or nucleobase electrons;

[0286] R 2 It is the oligonucleotide sequence;

[0287] L 1 It is an alkyl group or an alkyl-C(=O)-NH-alkyl group;

[0288] L 2 It is an alkyl group or an alkyl-C(=O)-NH-alkyl group;

[0289] L 3 The following are the bonds: phosphate diester bond, thiophosphate bond, triazole, tetraazole, amide, transamide, carbamate, carbonate, urea, O, S, S(=O), S(=O)2, NH, substituted N group, alkyl, alkenyl, dienyl, alkynyl, heteroalkyl, phosphate ester;

[0290] R 3 It is H, -C=(O)-NH-(CH2CH2O) j -GalNAc or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc;

[0291] R 4 It is H, -C=(O)-NH-(CH2CH2O) k -GalNAc or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc;

[0292] R 5 It is -C=(O)-NH-(CH2CH2O) m -GalNAc or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc;

[0293] R 6 It is -C=(O)-NH-(CH2CH2O) n -GalNAc or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc;

[0294] W and Q are each independently O, NH, CH2 or CH2O;

[0295] S 1 and S 2 Each is independently C(R) 7 ) or N, where R 7 Each instance is independently H, alkyl, heteroalkyl, or halogen;

[0296] j is an integer from 1 to 10, including the end value;

[0297] k is an integer from 1 to 10, including the end value;

[0298] m is an integer from 1 to 10, inclusive; and

[0299] n is an integer from 1 to 10, inclusive.

[0300] In some implementations, R 3 R 4 R 5 and R 6 They are the same. In some implementations, R 3 R 5 and R 6 They are the same. In some implementations, R 3 Or R 4 It is H.

[0301] In some implementations, L 1 and L 2 They are the same.

[0302] In some implementations, L 1 and L 2 Each is an alkyl group independently; R 3 It is H, -C=(O)-NH-(CH2CH2O) j -GalNAc or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc; R 4 It is H, -C=(O)-NH-(CH2CH2O) k -GalNAc or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc; R 5 It is -C=(O)-NH-(CH2CH2O) m -GalNAc or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc; and R 6 It is -C=(O)-NH-(CH2CH2O) n -GalNAc or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc.

[0303] In some implementations, L 1 and L 2 Each is independently an alkyl-C(=O)-NH-alkyl; R 3 It is H, -C=(O)-NH-(CH2CH2O) j -GalNAc or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc; R 4 It is H, -C=(O)-NH-(CH2CH2O) k -GalNAc or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc; R 5 It is -C=(O)-NH-(CH2CH2O) m -GalNAc or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc; and R 6 It is -C=(O)-NH-(CH2CH2O) n -GalNAc or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc.

[0304] In some implementations, R 4 It is H.

[0305] In some implementations, L 1 and L 2 Each is an alkyl group independently; R 3 It is -C=(O)-NH-(CH2CH2O) j -GalNAc or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc; R 4 It is H; R 5 It is -C=(O)-NH-(CH2CH2O) m -GalNAc or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc; and R 6 It is -C=(O)-NH-(CH2CH2O) n -GalNAc or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc.

[0306] In some implementations, L 1 and L 2 Each is independently an alkyl-C(=O)-NH-alkyl; R 3 It is -C=(O)-NH-(CH2CH2O) j -GalNAc or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc; R 4 It is H; R 5 It is -C=(O)-NH-(CH2CH2O) m -GalNAc or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc; and R 6 It is -C=(O)-NH-(CH2CH2O) n -GalNAc or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc.

[0307] In some implementations, R 3 It is -C=(O)-NH-(CH2CH2O) j -GalNAc;R 4 It is H; R 5 It is -C=(O)-NH-(CH2CH2O) m -GalNAc; and R 6 It is -C=(O)-NH-(CH2CH2O) n -GalNAc.

[0308] In some implementations, R 3It is -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc; R 4 It is H; R 5 It is -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc; and R 6 It is -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc.

[0309] In some embodiments, the compound or oligonucleotide comprises one or more subunits having the following formula or a salt, solvate, or hydrate thereof:

[0311] in:

[0312] R 9 It is H, adenine, guanine, thymine, cytosine, or uracil, or adenine, guanine, thymine, cytosine, or uracil, each containing a protecting group (PG), modified nucleobase, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclic, optionally substituted heterocyclic, or nucleobase isosteric.

[0313] L represents a bond, phosphodiester bond, thiophosphate bond, triazole, tetraazole, amide, transamide, carbamate, carbonate, urea, alkyl or heteroalkyl;

[0314] R 2 It is the oligonucleotide sequence;

[0315] Y1 is O, CH2, CH2O or optionally substituted NH;

[0316] Y2 is O, CH2, CH2O, or optionally substituted NH;

[0317] Y3 is CO, SO2, P(O)O, CH2-OC(O), CH2-NH-C(O), CH2-NH-SO2 or CH2;

[0318] Y4 is CO, SO2, P(O)O, CH2-OC(O), CH2-NH-C(O), CH2-NH-SO2 or CH2;

[0319] n² is 0, 1, 2, 3, 4, 5, or 6; and

[0320] n1, n3, n4 and n5 are each independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

[0321] In some embodiments, the compound or oligonucleotide comprises one or more subunits having the following formula or a salt, solvate, or hydrate thereof:

[0323] in:

[0324] Each n is independently 1, 2, 3, 4 or 5;

[0325] Each m is independently 0, 1, 2, 3, 4, 5, or 6;

[0326] Each 'o' is independently 0, 1, 2, 3, 4, 5, or 6;

[0327] L1, L2, and L3 are each independently nonexistent, C(=O), or C(=O)NH;

[0328] 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-;

[0329] 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-;

[0330] Het1, Het2, and Het3 are each independently a optionally substituted heteroaryl group or an optionally substituted heterocyclic group;

[0331] R 1 It is an oligonucleotide sequence linked by bonds, phosphodiester bonds, thiophosphate bonds, triazoles, tetraazoles, amides, transamides, carbamates, carbonates, ureas, alkyl groups, or heteroalkyl groups;

[0332] R5, R6, and R7 are each independent.

[0333] R9 is an optionally substituted heterocyclic group;

[0334] Each R a Independently, it is H, alkyl, halogen, OR c or SR c ;

[0335] Each R b Independently, it is H, alkyl, halogen, OR c or SR c ;and

[0336] Each R c It is H or alkyl independently.

[0337] In some embodiments, the subunit is selected from formulas I to VIII or their salts, solvates, or hydrates, wherein R is a modified oligonucleotide other than a 5' nucleoside. In some embodiments, the 5' nucleoside of the modified oligonucleotide is formula I and R' is O. In some embodiments, the 5' nucleoside of the modified oligonucleotide is formula I and R' is S. In some embodiments, the 5' nucleoside of the modified oligonucleotide is formula II and R' is O. In some embodiments, the 5' nucleoside of the modified oligonucleotide is formula II and R' is S. In some embodiments, the 5' nucleoside of the modified oligonucleotide is formula III and R' is O. In some embodiments, the 5' nucleoside of the modified oligonucleotide is formula III and R' is S. In some embodiments, the 5' nucleoside of the modified oligonucleotide is formula IV and R' is O. In some embodiments, the 5' nucleoside of the modified oligonucleotide is formula IV and R' is S. In some embodiments, the 5' nucleoside of the modified oligonucleotide is formula V and R' is O. In some embodiments, the 5' nucleoside of the modified oligonucleotide is formula V and R' is S. In some embodiments, the 5' nucleoside of the modified oligonucleotide is formula VI and R' is O. In some embodiments, the 5' nucleoside of the modified oligonucleotide is formula VI and R' is S. In some embodiments, the 5' nucleoside of the modified oligonucleotide is formula VII and R' is O. In some embodiments, the 5' nucleoside of the modified oligonucleotide is formula VII and R' is S. In some embodiments, the 5' nucleoside of the modified oligonucleotide is formula VIII and R' is O. In some embodiments, the 5' nucleoside of the modified oligonucleotide is formula VIII and R' is S.

[0338] Target nucleic acid and target region

[0339] In some embodiments, the compounds described herein comprise or consist of oligonucleotides containing a region complementary to the target nucleic acid. In some embodiments, the target nucleic acid is an endogenous RNA molecule. In some embodiments, the target nucleic acid encodes a protein. In some embodiments, the target nucleic acid is non-coding. In some such embodiments, the target nucleic acid is selected from mRNA and premRNA, including intron regions, exon regions, and untranslated regions. In some embodiments, the target RNA is mRNA. In some embodiments, the target nucleic acid is premRNA. In some such embodiments, the target region is entirely within an exon. In some such embodiments, the target region is entirely within an intron. In some embodiments, the target region spans an intron / exon junction. In some embodiments, at least 50% of the target region is within an intron.

[0340] In some embodiments, the compounds disclosed herein hybridize with PKK nucleic acids. The most common hybridization mechanism involves hydrogen bonds between complementary nucleobases of nucleic acid molecules. Hybridization can occur under different conditions. Hybridization conditions are sequence-dependent and determined by the properties and composition of the nucleic acid molecule to be hybridized. Methods for determining whether a sequence specifically hybridizes with a target nucleic acid are well known in the art. In some embodiments, the compounds provided herein specifically hybridize with PKK nucleic acids.

[0341] Nucleotide sequences encoding PKK include, but are not limited to, the following: GENBANK Login No. NM_000892 .5 (Included in this article with SEQ ID NO: 1), NG_012095.2 (included in this article with SEQ ID NO: 2), XM_017008181.1 (included in this article with SEQ ID NO: 3), NC_000004.12 (included in this article with SEQ ID NO: 4), NM_0013183942 (included in this article with SEQ ID NO: 5), and NM_001318396.2 (included in this article with SEQ ID NO: 6), which are truncated from 23529..54493.

[0342] Complementarity

[0343] The oligonucleotides provided herein may have a defined percentage of complementarity with a specific nucleic acid, target region, oligonucleotide, or portion thereof. Non-complementary nucleobases are permissible, provided that the oligonucleotide remains capable of specifically hybridizing with the nucleic acid, oligonucleotide, or portion thereof. In some embodiments, the oligonucleotides or specific portions thereof provided herein 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 specific portion thereof. In some embodiments, the oligonucleotides or specific portions thereof provided herein are complementary to the target nucleic acid, target region, oligonucleotide, or specific portion thereof by 70% to 75%, 75% to 80%, 80% to 85%, 85% to 90%, 90% to 95%, 95% to 100%, or any value between these ranges. The percentage of complementarity of an oligonucleotide with a target nucleic acid, target region, oligonucleotide, or a specific portion thereof can be determined using conventional methods. For example, an oligonucleotide in which 18 of its 20 nucleotide bases are complementary to the target region and thus specifically hybridize will represent 90% complementarity. In this example, the remaining non-complementary nucleotide bases may cluster or disperse with complementary nucleotide bases and do not need to be linked to each other or to complementary nucleotide bases. Thus, an oligonucleotide of 18 nucleotides in length has four non-complementary nucleotide bases flanked by two regions that are perfectly complementary to the target nucleic acid, resulting in a total complementarity of 77.8% with the target nucleic acid. The percentage of complementarity of an oligonucleotide with a region of the target nucleic acid, target region, oligonucleotide, or a specific portion thereof can be conventionally determined using BLAST (basic local alignment search tool) procedures known in the art. In some embodiments, the oligonucleotide or a specific portion thereof described herein is perfectly complementary (i.e., 100% complementary) to the target nucleic acid, target region, oligonucleotide, or a specific portion thereof. For example, the oligonucleotide may be perfectly complementary to the target nucleic acid, target region, oligonucleotide, or a specific portion thereof. As used in this article, "complete complementarity" means that each nucleobase of the oligonucleotide is complementary to the corresponding nucleobase of the target nucleic acid, target region, oligonucleotide, or a specific portion thereof. For example, a 20-nucleobase oligonucleotide is completely complementary to a 400-nucleobase-long target sequence, provided that the target nucleic acid contains a corresponding 20-nucleobase motif that is completely complementary to the compound. "Complete complementarity" can also be used to refer to a specific portion of the first and / or second nucleic acid. For example, a 20-nucleobase motif in a 30-nucleobase oligonucleotide can be "completely complementary" to a 20-nucleobase region in a 400-nucleobase-long target sequence. If the target sequence has a corresponding 20-nucleobase motif where each nucleobase is complementary to a 20-nucleobase motif in the compound, then the 20-nucleobase motif in a 30-nucleobase compound is completely complementary to the target sequence.Meanwhile, the entire 30 nucleobase compound may or may not be completely complementary to the target sequence, depending on whether the remaining 10 nucleobases of the compound are also complementary to the target sequence.

[0344] In some embodiments, the oligonucleotides described herein contain one or more mismatched nucleotides relative to the target nucleic acid, target region, oligonucleotide, or a specific portion thereof. In some embodiments, oligonucleotides described herein with a length of up to 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23 nucleotides contain no more than 4, 3, 2, or 1 non-complementary nucleotides relative to the target nucleic acid or a specific portion thereof. In some embodiments, oligonucleotides described herein with a length of up to 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides contain no more than 6, 5, 4, 3, 2, or 1 non-complementary nucleotides relative to the target nucleic acid, target region, oligonucleotide, or a specific portion thereof. In some embodiments, the mismatch occurs at positions 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 at the 5' end of the oligonucleotide. In some embodiments, the mismatch occurs at positions 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 at the 3' end of the oligonucleotide. In some embodiments, the mismatch forms a wobble base pair with the corresponding nucleotide on the target nucleic acid. For example, in some embodiments, the mismatch forms a wobble base pair selected from: hypoxanthine (the nucleotide 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). Therefore, in some embodiments, the mismatched nucleotide on the oligonucleotide comprises hypoxanthine, guanine, or uracil.

[0345] In some embodiments, the oligonucleotides described herein may be partially complementary to nucleic acids. As used herein, "partial" refers to a defined number of consecutive nucleotide bases within a nucleic acid region. "Partial" may also refer to a defined number of consecutive nucleotide bases of an oligonucleotide. In some embodiments, the oligonucleotide is complementary to at least 8 nucleotide bases of a nucleic acid. In some embodiments, the oligonucleotide is complementary to at least 9 nucleotide bases of a nucleic acid. In some embodiments, the oligonucleotide is complementary to at least 10 nucleotide bases of a nucleic acid. In some embodiments, the oligonucleotide is complementary to at least 11 nucleotide bases of a nucleic acid. In some embodiments, the oligonucleotide is complementary to at least 12 nucleotide bases of a nucleic acid. In some embodiments, the oligonucleotide is complementary to at least 13 nucleotide bases of a nucleic acid. In some embodiments, the oligonucleotide is complementary to at least 14 nucleotide bases of a nucleic acid. In some embodiments, the oligonucleotide is complementary to at least 15 nucleotide bases of a nucleic acid. In some embodiments, the oligonucleotide is complementary to at least 16 nucleotide bases of a nucleic acid. Oligonucleotides complementary to at least 9, 10, 17, 18, 19, 20, 21, 22, 23 or more nucleotide moieties in a nucleic acid, or a range defined by any two of these values, are also considered. In some embodiments, the oligonucleotide is an antisense oligonucleotide. In some embodiments, a portion of the antisense oligonucleotide is compared to an equivalent portion of the target nucleic acid. In some embodiments, a portion of 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 or 25 nucleotide moieties is compared to an equivalent portion of the target nucleic acid. In some embodiments, the oligonucleotide is a sense oligonucleotide. In some embodiments, a portion of the sense oligonucleotide is compared to an equivalent portion of the antisense oligonucleotide. In some implementations, the 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 nucleobase portions of a sense oligonucleotide are compared with an equal-length portion of an antisense oligonucleotide.

[0346] identity

[0347] The oligonucleotides provided herein may also have a defined percentage identity with specific nucleic acids, target regions, oligonucleotides, or specific portions thereof. As used herein, if an oligonucleotide has the same nucleobase pairing ability, it is considered identical to the sequence disclosed herein. For example, DNA containing thymidine instead of uracil in a disclosed RNA sequence would be considered identical to the RNA sequence because both uracil and thymidine pair with adenine. Shortened and extended forms of the compounds described herein, as well as compounds with different bases relative to those provided herein, are also considered. Different bases may be adjacent to each other or dispersed throughout the compound. The percentage of identity of an oligonucleotide is calculated based on the number of bases with the same nucleobase pairing ability relative to the sequence with which it is compared. In some embodiments, the oligonucleotides or portions thereof described herein have or have at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with one or more of the nucleic acids, oligonucleotides or portions thereof disclosed herein. In some embodiments, the oligonucleotides described herein have about 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with a specific nucleic acid or oligonucleotide or portion thereof, or any percentage between such values.

[0348] In some embodiments, the oligonucleotide may have one or more mismatched nucleotides. In some such embodiments, the mismatch is at positions 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 at the 5' end of the oligonucleotide. In some such embodiments, the mismatch is at positions 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, 13, or 14 at the 3' end of the oligonucleotide. In some embodiments, a portion of the oligonucleotide is compared to an equivalent portion of the target nucleic acid. In some embodiments, a portion of 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 nucleotides is compared to an equivalent portion of the target nucleic acid. In some embodiments, the oligonucleotide is a sense oligonucleotide. In some embodiments, a portion of the sense oligonucleotide is compared to an equivalent portion of the target nucleic acid. In some implementations, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 nucleobase portions are compared with an equal-length portion of the target nucleic acid.

[0349] Pharmaceutical compositions and formulations

[0350] The compounds described herein can be mixed with pharmaceutically acceptable active or inert substances to prepare pharmaceutical compositions or formulations. The compositions and methods used to formulate pharmaceutical compositions depend on many criteria, including but not limited to route of administration, disease severity, or dosage to be administered. Some embodiments provide pharmaceutical compositions comprising one or more compounds or salts thereof. In some embodiments, the compound is an antisense oligonucleotide. In some embodiments, the compound is an oligomeric compound. In some embodiments, the compound comprises one or more modified oligonucleotides or consists of one or more modified oligonucleotides. In some such embodiments, the pharmaceutical composition comprises one or more compounds and a suitable pharmaceutically acceptable diluent or carrier. In some embodiments, the pharmaceutical composition comprises one or more compounds and a sterile aqueous saline solution. In some embodiments, such a pharmaceutical composition consists of one compound and a sterile aqueous saline solution. In some embodiments, the sterile saline solution is pharmaceutical grade saline. In some embodiments, the pharmaceutical composition comprises one or more compounds and sterile water. In some embodiments, the pharmaceutical composition consists of one compound and sterile water. In some embodiments, the sterile water is pharmaceutical grade water. In some embodiments, the pharmaceutical composition comprises one or more compounds and phosphate-buffered saline (PBS). In some embodiments, the pharmaceutical composition consists of one compound and sterile PBS. In some embodiments, the sterile PBS is pharmaceutical grade PBS.

[0351] The compounds described herein that target PKK can be used in pharmaceutical compositions by combining them with a suitable pharmaceutically acceptable diluent or carrier. In some embodiments, the pharmaceutically acceptable diluent is water, such as sterile water suitable for injection. Thus, in one embodiment, the methods described herein employ a pharmaceutical composition comprising a PKK-targeting compound and a pharmaceutically acceptable diluent. In some embodiments, the pharmaceutically acceptable diluent is water. In some embodiments, the compound comprises or consists of one or more modified oligonucleotides provided herein.

[0352] Pharmaceutical compositions comprising the compounds provided herein encompass any pharmaceutically acceptable salt, ester, or salt of such ester, or any other oligonucleotide that, upon administration to an animal (including a human), provides (directly or indirectly) its biologically active metabolite or residues. In some embodiments, the compound is an antisense oligonucleotide. In some embodiments, the compound is an oligomeric compound. In some embodiments, the compound comprises or consists of one or more modified oligonucleotides. Thus, for example, this disclosure also relates to pharmaceutically acceptable salts of compounds, prodrugs, pharmaceutically acceptable salts of such prodrugs, and other bioequivalents. Suitable pharmaceutically acceptable salts include, but are not limited to, sodium and potassium salts. Prodrugs may comprise additional nucleosides incorporated at one or both ends of the compound, which are cleaved in vivo by endogenous nucleases to form the active compound. In some embodiments, the compound or composition also comprises a pharmaceutically acceptable carrier or diluent. Example

[0353] The following examples describe methods for identifying lead compounds targeting PKK. Some compounds are considered to possess high potency and tolerance.

[0354] The following examples are for illustrative purposes only and are not intended to limit the compounds described herein. The sequences described below and the associated sequence listings accompanying this document may be identified as “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 understand that, in certain circumstances, designating a sequence as “RNA” or “DNA” is arbitrary. For example, an oligonucleotide comprising a nucleoside containing a 2'-OH sugar moiety and a thymine base may be described as DNA having a modified sugar (2'-OH for the native 2'-H of DNA) or RNA having a modified base (methylated uracil for the native uracil of RNA). Therefore, the nucleic acid sequences provided herein, including but not limited to those in the sequence listings, are intended to cover nucleic acids containing any combination of native or modified RNA and / or DNA, including but not limited to such nucleic acids having modified nucleobases.

[0355] Each reference cited in this application is incorporated herein by reference in its entirety.

[0356] Unless otherwise specified in the separate compound chemical tables below, the compounds are unmodified. Abbreviations for chemical modifications are provided in Table 1 below. IA and IS in Ref ID NO: identify the antisense and sense strands of the compound, respectively.

[0357] Table 1 Chemical Nomenclature

[0358] abbreviation structure ‘m’ 2'-O-methyl sugar modification (e.g., mA, mG, mC, mU) ‘f’ 2'-F sugar modifications (e.g., fA, fG, fC, fU) ‘*’ Nucleoside-thiophosphate linkages ‘. Phosphoester nucleoside linkage 'dQ' Inverted abasic deoxyribose ‘H1’ Formula I ‘H2’ Formula II ‘H4” Formula III ‘H6” Formula IV ‘H7’ Formula V ‘H9’ Style VI 'Hd' Equation VII Hl Formula VIII

[0359] Example 1 – Inhibition of PKK in HEK-293T cells

[0360] HEK-293T cells were seeded at 20,000 cells / well in antibiotic-free medium in 96-well white-walled plates. The next day, cells were co-transfected using Lipofectamine 2000 with 50 ng of PKK-siCHECK-2 and 10 nM PKK compound (each transfection was performed in triplicate). The cells were then incubated at 37°C / 5% CO2 for 48 hours.

[0361] The expression of firefly and *Rhizophora spp.* luciferase was evaluated using the Dual-Luciferase Reporter 1000 Assay (Promega Cat#E1980) according to the kit instructions. Luciferase expression in both firefly and *Rhizophora spp.* was measured using a luminimeter. *Rhizophora spp.* luciferase was used as a readout of PKK gene expression, while firefly was used as an internal control. All *Rhizophora spp.* readouts from each well were normalized relative to their corresponding firefly readouts to obtain the *Rhizophora spp.*:firefly ratio. The ratio obtained for each well with the transfected compound was then further normalized relative to the ratio obtained for untransfected cells. These untransfected cells served as a 100% control. PKK inhibition was determined by comparing PKK expression to that of untransfected cells and reported as PKK inhibition % (Tables 2 to 4).

[0362] Table 2

[0363] Inhibition of PKK mRNA by the double-stranded compound targeting SEQ ID NO:1

[0365] Table 3

[0366] Inhibition of PKK mRNA by the double-stranded compound targeting SEQ ID NO:1

[0371] Table 4

[0372] Inhibition of PKK mRNA by the double-stranded compound targeting SEQ ID NO:1

[0376] Example 2 – Dose-dependent inhibition of human PKK in HEK-293T cells

[0377] Compounds exhibiting significant in vitro inhibition of PKK mRNA from the aforementioned studies were selected and tested in HEK-293T cells at different doses, as described above. The compounds were tested at concentrations of 0.01, 0.1, 1, and 10 nM, and IC50 values ​​were calculated (Table 5).

[0378] Table 5

[0380] Example 3: The role of compounds targeting human PKK in cynomolgus monkeys

[0381] The target compounds identified by in vitro gene expression screening were evaluated in cynomolgus monkeys (Table 7). Monkeys were isolated prior to the study, and their general health was monitored daily. On day 1 of the study, each of the ten cynomolgus monkey groups received a single subcutaneous dose of oligonucleotide at 6 mg / kg. Monkeys were monitored daily for signs of illness or distress during the study. Blood samples were collected from animals on days -6 and 1 (before administration), and on days 4, 8, 15, 22, 29, 36, 43, 50, 57, and 64 for serum collection and analysis. The protocol was approved by the Institutional Animal Care and Use Committee (IACUC). Circulating PKK levels were quantified using an ELISA specific for human angiotensinogen (and cross-reactive with cynomolgus monkeys) according to the manufacturer's protocol (IBLAmerica#27412). PKK inhibition data are expressed as a percentage of baseline values ​​(day 1 before administration) (Table 8).

[0382] Table 6

[0383] compound sequence

[0385] Table 7

[0386] Compound Chemistry

[0388] Table 8

[0389] Average PKK suppression

[0391] Example 4: The role of compounds targeting human PKK in cynomolgus monkeys

[0392] The target compounds identified by in vitro gene expression screening were evaluated in cynomolgus monkeys (Table 10). Monkeys were isolated prior to the study, and their general health was monitored daily. On day 1 of the study, each of the eight groups of two cynomolgus monkeys was injected subcutaneously with a single dose of oligonucleotide at 4 mg / kg. During the study, monkeys were observed daily for signs of illness or distress. Blood samples were collected from animals on days -6 and 1 (before administration), and on days 4, 8, and 15 for serum collection and analysis. Future collections will be conducted on days 22, 29, 36, 43, 50, 57, 64, 71, 78, and 85. In the second group of experiments, blood samples were collected from animals on days -6 and 1 (before administration), and on days 4, 8, 15, and 22 for serum collection and analysis. Future collections will be conducted on days 29, 36, 43, 50, 57, 64, 71, 78, and 85. In the third group of experiments, blood samples were collected from animals on days -6 and 1 (before administration), and on days 4, 8, 15, 22, 29, and 36 for serum collection and analysis. Future collections for the third group of experiments will be conducted on days 43, 50, 57, 64, 71, 78, and 85. In the fourth group of experiments, blood samples were collected from animals on days -6 and 1 (before administration), and on days 4, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78, and 85 for serum collection and analysis. The protocol was approved by the Institutional Animal Care and Use Committee (IACUC). Circulating PKK levels were quantified using an ELISA specific for human angiotensinogen (and cross-reactive with cynomolgus monkeys) according to the manufacturer's protocol (IBL America #27412). PKK inhibition data are expressed as a percentage of baseline values ​​(on day 1 before administration) and the mean for that group for each compound. The results of the four groups of experiments are shown in Tables 11, 12, 13, and 14. Clinical chemistry was performed on day -1 or day -6, day 63 or 64, and day 92. There were no effects on body weight related to the test product (Table 15), and all serum chemistry values ​​were within the reference range (Tables 16 and 17).

[0393] Table 9

[0394] compound sequence

[0395] Table 10

[0396] Compound Chemistry

[0397] Table 11

[0398] Average PKK suppression

[0400] Table 12

[0401] Average PKK suppression

[0403] Table 13

[0404] Average PKK suppression

[0406] Table 14

[0407] Average PKK suppression

[0409] Table 15

[0410] Weight(kg)

[0411] compound Day -1 Day 63 Day 91 RD2423 Crab-eating macaque #1 2.4 2.4 2.4 RD2423 Crab-eating Monkey #2 2.6 2.6 2.7 RD2436 Crab-eating macaque #1 2.9 3.1 3.2 RD2436 Crab-eating Monkey #2 2.5 2.6 2.7 RD2437 Crab-eating Monkey #1 3.1 3.2 3.2 RD2437 Crab-eating Monkey #2 2.6 2.7 2.9 RD2438 Crab-eating Monkey #1 3.2 3.2 3.4 RD2438 Crab-eating Monkey #2 2.5 2.6 2.6 RD2439 Crab-eating macaque #1 3.6 4.1 N / A RD2439 Crab-eating Monkey #2 2.7 2.8 N / A RD2440 Crab-eating Monkey #1 3.9 4.3 N / A RD2440 Crab-eating Monkey #2 2.3 2.4 N / A RD2442 Crab-eating macaque #1 4.4 4.5 4.6 RD2442 Crab-eating macaque #2 2.3 2.4 2.5 RD2492 Crab-eating macaque #1 4 4 N / A RD2492 Crab-eating Monkey #2 2.3 2.3 N / A

[0412] Table 16

[0413] Liver function markers

[0415] Table 17

[0416] Kidney function markers

[0419] Example 5: The role of compounds targeting human PKK in cynomolgus monkeys

[0420] The target compound was evaluated in cynomolgus monkeys (Table 19). Prior to the study, the monkeys were isolated, and their general health was observed daily. On day 1 of the study, each of the eight groups of two cynomolgus monkeys was injected subcutaneously with a single dose of the oligonucleotide at 4 mg / kg. During the study, the monkeys were observed daily for signs of illness or distress. Blood samples were collected from the animals on days -6 and 1 (before administration), and on days 8, 15, and 22 for serum collection and analysis. Future collections will be conducted on days 29, 36, 43, 50, 57, 64, and 71. In the second group of experiments, blood samples were collected from the animals on days -6 and 1 (before administration), and on days 8, 15, 22, 29, 36, 43, 50, 57, 64, and 71. The protocol was approved by the Institutional Animal Care and Use Committee (IACUC). Circulating PKK levels were quantified using an ELISA specific for human angiotensinogen (and cross-reactive with cynomolgus monkeys) according to the manufacturer's protocol (IBLAmerica#27412). PKK inhibition data are presented as a percentage of baseline values ​​(on day 1 prior to administration) and the mean for that group for each compound. Results from both groups are shown in Tables 20 and 21. Clinical chemistry was performed on day -1 or day -6, and on day 64 and day 92. There were no effects on body weight associated with the test product (Table 22), and all serum chemistry values ​​were within the reference range (Tables 23 and 24).

[0421] Table 18

[0422] compound sequence

[0424] Table 19

[0425] Compound Chemistry

[0427] Table 20

[0428] Average PKK suppression

[0430] Table 21

[0431] Average PKK suppression

[0433] Table 22

[0434] Weight(kg)

[0435] compound Day -1 Day 64 Day 92 RD2424 Crab-eating macaque #1 3.1 3.1 3.1 RI)2424 Crab-eating Monkey #2 3.2 3.6 3.7 RD2425 Crab-eating Mammal #1 2.9 3.3 N / A RI)2425 Crab-eating macaque #2 3.1 3.5 N / A RD2426 Crab-eating macaque #1 3.5 3.9 N / A RD2426 Crab-eating Monkey #2 2.8 3.2 N / A

[0436] Table 23

[0437] Liver function markers

[0439] Table 24

[0440] Kidney function markers

[0442] Example 6: Effects of compounds targeting human PKK in Lewis rats

[0443] On day 1, female Lewis rats (n=5 females / group, 8 weeks old) were administered a single subcutaneous (SC) injection of 0 (loador control (phosphate-buffered saline (PBS)), 200 mg / kg RD2423, or 200 mg / kg RD2438 at a dose volume of mL / kg in groups 1–3. Observations included viability, clinical signs, and body weight (days 1 and 10). Blood samples were collected for clinical chemistry (day 0 (before administration), days 3 and 10), hematology (day 10), and coagulation (day 10). On day 10, the heart, liver, and two kidneys were obtained from each rat and fixed in 10% neutral buffered formalin after weighing.

[0444] Results: No drug-related effects were observed on viability, clinical outcomes, body weight or organ weight (heart, liver, and kidney), clinical chemistry, hematology, or coagulation (prothrombin clotting time) parameters. A single subcutaneous administration of 200 mg / kg of compounds RD2423 or RD2438 to female Lewis rats was well tolerated.

[0445] SEQ ID NO:1

Claims

1. A compound comprising a modified oligonucleotide of 14 to 23 linked nucleosides, having a nucleobase sequence of 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 comprising any one of the nucleobase sequences of SEQ ID NO: 10 to 313, 626, 627, and 628.

2. A compound comprising a modified oligonucleotide of 14 to 23 linked nucleosides, having a nucleobase sequence comprising any one of SEQ ID NO: 10 to 313, 626, 627 and 628.

3. A compound comprising a modified oligonucleotide having a nucleobase sequence selected from any one of SEQ ID NO:10 to 313, 626, 627 and 628.

4. The compound of any one of claims 1 to 3, wherein the nucleobase sequence of the modified oligonucleotide is at least 80%, at least 85%, at least 90%, or at least 95% complementary to SEQ ID NO: 1, 3, 5, or 6.

5. The compound of any one of claims 1 to 4, wherein the modified oligonucleotide comprises at least one modification selected from modified nucleoside linkages, modified sugars, and modified nucleobases.

6. The compound of any one of claims 1 to 5, wherein the compound is double-stranded.

7. A compound comprising: a first modified oligonucleotide having 14 to 23 linked nucleosides, 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 nucleosides comprising any of the nucleobase sequences in SEQ ID NO: 10 to 631; and a second modified oligonucleotide having 14 to 23 linked nucleosides, having a region complementary to the first modified oligonucleotide.

8. A compound comprising: a first modified oligonucleotide having 14 to 23 linked nucleosides, having a nucleobase sequence comprising any one of SEQ ID NO: 10 to 631; and a second modified oligonucleotide having 14 to 23 linked nucleosides, having a region complementary to the first modified oligonucleotide.

9. A compound comprising: a first modified oligonucleotide having a nucleobase sequence selected from any of SEQ ID NO: 10 to 631; and a second modified oligonucleotide having a length of 19 to 23 linked nucleosides having a region complementary to the first modified oligonucleotide.

10. The compound of any one of claims 7 to 9, wherein the nucleobase sequence of the first modified oligonucleotide has at least 80%, at least 85%, at least 90%, or at least 95% complementarity or identity in length with SEQ ID NO: 1, 3, 5, or 6.

11. The compound of any one of claims 7 to 10, wherein the nucleobase sequence of the first modified oligonucleotide has at least one, at least two, or at least three mismatches with the region of SEQ ID NO: 1, 3, 5, or 6, and the region is of the same length as the first modified oligonucleotide.

12. The compound of any one of claims 7 to 11, wherein the length of the complementary region between the first modified oligonucleotide and the second modified oligonucleotide is 14 to 23 linked nucleosides.

13. The compound of any one of claims 7 to 11, wherein the length of the complementary region between the first modified oligonucleotide and the second modified oligonucleotide is 19 to 23 linked nucleosides.

14. The compound of any one of claims 7 to 11, wherein the length of the complementary region between the first modified oligonucleotide and the second modified oligonucleotide is 21 to 23 linked nucleosides.

15. The compound of any one of claims 7 to 11, wherein the first modified oligonucleotide is completely complementary to the second modified oligonucleotide.

16. The compound of any one of claims 7 to 15, wherein the first modified oligonucleotide comprises at least one modification selected from modified nucleoside linkages, modified sugars, and modified nucleobases.

17. The compound of any one of claims 7 to 16, wherein the second modified oligonucleotide comprises at least one modification selected from modified nucleoside linkages, modified sugars, and modified nucleobases.

18. The compound of any one of claims 5, 16 and 17, wherein the modified nucleoside linkage is a thiophosphate nucleoside linkage or a methylphosphonate nucleoside linkage.

19. The compound of claim 18, wherein the thiophosphate nucleoside linker or the methylphosphonate nucleoside linker is located at the 3' end of the first modified oligonucleotide or the second modified oligonucleotide, or at the 5' end of the first modified oligonucleotide.

20. The compound of any one of claims 5, 16 and 17, wherein the modified sugar comprises a modification selected from halogens, alkoxy groups and bicyclic sugars.

21. The compound of claim 20, wherein the modified sugar comprises 2'-F modification.

22. The compound of claim 20, wherein the modified sugar comprises 2'-OMe modification.

23. The compound of any one of claims 7 to 15, wherein each nucleoside of the first modified oligonucleotide comprises a modified sugar.

24. The compound of any one of claims 7 to 15, wherein each nucleoside of the second modified oligonucleotide comprises a modified sugar.

25. The compound of claim 23 or 24, wherein the modified sugar comprises a modification selected from halogens, alkoxy groups, and bicyclic sugars, or combinations thereof.

26. The compound of claim 25, wherein the modified sugar comprises a modification selected from LNA, cEt, 2'-MOE, 2'-F, 2'-OMe and 2'-deoxy, or a combination thereof.

27. The compound of claim 23, wherein the first modified oligonucleotide comprises no more than ten 2'-F sugar modifications.

28. The compound of claim 24, wherein the second modified oligonucleotide comprises no more than five 2'-F sugar modifications.

29. The compound of any one of the preceding claims, comprising a conjugated group.

30. The compound of claim 29, wherein the conjugating group is attached to the 5' end of the modified oligonucleotide.

31. The compound of claim 29 or 30, wherein the conjugated group comprises a targeting portion.

32. The compound of claim 31, wherein the targeting portion comprises one or more GalNAc.

33. The compound of claim 32, wherein the modified oligonucleotide is the second modified oligonucleotide.

34. The compound of claim 32 or 33, wherein one or more GalNAc molecules are linked to the 2' or 3' position of the ribosyl ring of the 5' nucleoside of the modified oligonucleotide.

35. The compound of claim 34, wherein the 5' nucleoside has the following formula: in: R 9 It is H, adenine, guanine, thymine, cytosine, or uracil, or adenine, guanine, thymine, cytosine, or uracil, each containing a protecting group (PG), a modified nucleobase, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclic, optionally substituted heterocyclic, or isosteric nucleobase; L represents a bond, phosphodiester bond, thiophosphate bond, triazole, tetraazole, amide, transamide, carbamate, carbonate, urea, alkyl or heteroalkyl; R 2 It is the oligonucleotide sequence; 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; and n1, n3, n4 and n5 are each independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

36. The compound of claim 34, wherein the 5' nucleoside is selected from any one of formulas I to VIII, and wherein R' is S and R is the portion of the modified oligonucleotide other than the 5' nucleoside.

37. The compound of claim 34, wherein the 5' nucleoside is selected from any one of formulas I to VIII, and wherein R' is O and R is the portion of the modified oligonucleotide other than the 5' nucleoside.

38. A compound comprising: a first modified oligonucleotide selected from any one of RefID NO: IA0812 to 821; and a second modified oligonucleotide having a length of 14 to 21 linked nucleosides, which is completely complementary to the first modified oligonucleotide.

39. A compound comprising a first modified oligonucleotide selected from Ref ID NO: IA0813 and IA0818, and a second modified oligonucleotide selected from Ref ID NO: IS1002, IS1007 and IS1068.

40. A compound comprising: a first modified oligonucleotide selected from any one of RefID NO: IA0864 to 866; and a second modified oligonucleotide having a length of 14 to 21 linked nucleosides, which is completely complementary to the first modified oligonucleotide.

41. A compound comprising a first modified oligonucleotide selected from Ref ID NO: IA0818 and IA0864, ​​and a second modified oligonucleotide selected from Ref ID NO: IS1058 and IS1059.

42. A compound comprising a first modified oligonucleotide consisting of Ref ID NO: IA0864 and a second modified oligonucleotide consisting of Ref ID NO: IS1059.

43. A compound comprising a first modified oligonucleotide consisting of Ref ID NO: IA0818 and a second modified oligonucleotide consisting of Ref ID NO: IS1058.

44. The compound of any one of claims 1 to 41, wherein the compound is in a pharmaceutically acceptable salt form.

45. The compound of claim 42, wherein the pharmaceutically acceptable salt is a sodium salt.

46. ​​The compound of claim 42, wherein the pharmaceutically acceptable salt is a potassium salt.

47. Modified oligonucleotides based on the following chemical structures: Alternatively, it may be a medicinal salt or stereoisomer.

48. The modified oligonucleotide of claim 47, wherein the pharmaceutically acceptable salt is a sodium or potassium salt.

49. The modified oligonucleotide of claim 48, wherein it is a sodium salt according to the following chemical structure: Or its stereoisomers.

50. Modified oligonucleotides based on the following chemical structures: Alternatively, it may be a medicinal salt or stereoisomer.

51. The modified oligonucleotide of claim 50, wherein the pharmaceutically acceptable salt is a sodium or potassium salt.

52. The modified oligonucleotide of claim 51, wherein it is a sodium salt according to the following chemical structure: Or its stereoisomers.

53. Modified oligonucleotides based on the following chemical structures: Alternatively, it may be a medicinal salt or stereoisomer.

54. The modified oligonucleotide of claim 53, wherein the pharmaceutically acceptable salt is a sodium or potassium salt.

55. The modified oligonucleotide of claim 54, wherein it is a sodium salt according to the following chemical structure: Or its stereoisomers.

56. Modified oligonucleotides based on the following chemical structures: Alternatively, it may be a medicinal salt or stereoisomer.

57. The modified oligonucleotide of claim 56, wherein the pharmaceutically acceptable salt is a sodium or potassium salt.

58. The modified oligonucleotide of claim 57, wherein it is a sodium salt according to the following chemical structure: Or its stereoisomers.

59. Compounds with the following chemical structures: Alternatively, it may be a medicinal salt or stereoisomer.

60. The compound of claim 59, wherein the pharmaceutically acceptable salt is a sodium or potassium salt.

61. The compound of claim 60, wherein it is a sodium salt according to the following chemical structure: Or its stereoisomers.

62. Compounds with the following chemical structures: Alternatively, it may be a medicinal salt or stereoisomer.

63. The compound of claim 62, wherein the pharmaceutically acceptable salt is a sodium or potassium salt.

64. The compound of claim 63, wherein it is a sodium salt according to the following chemical structure: Or its stereoisomers.

65. A composition comprising the compound or modified oligonucleotide of any one of claims 1 to 64 and a pharmaceutically acceptable carrier.

66. A composition comprising any one of the compounds of the preceding claims, for use in treatment.

67. A method for treating, preventing, or improving a PKK-related disease, disorder, or condition in an individual, comprising administering a PKK-targeting compound to the individual to treat, prevent, or improve the disease, disorder, or condition.

68. A method of administering to an individual the compound or modified oligonucleotide of any one of claims 1 to 64 or the composition of claim 65 or 66.

69. The method of claim 67 or 68, wherein the disease, disorder, or symptom is an inflammatory or thrombotic disease, disorder, or symptom or its symptoms, 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.

70. The method of any one of claims 67 to 69, wherein the application of said compound inhibits or alleviates or improves inflammatory or thrombotic diseases, disorders or conditions or their symptoms, 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.

71. A method for inhibiting PKK expression in cells, comprising contacting the cells with a compound that targets PKK, thereby inhibiting PKK expression in the cells.

72. The method of claim 71, wherein the cells are in the liver of an individual.

73. The method of claim 72, wherein the individual suffers from or is at risk of suffering from: inflammatory or thrombotic diseases, disorders or conditions or their symptoms, 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.

74. A method for reducing or inhibiting in an individual an inflammatory or thrombotic disease, disorder or condition or its symptoms, 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, comprising administering to said individual a compound targeting PKK, thereby reducing or inhibiting in said individual an inflammatory or thrombotic disease, disorder or condition or its symptoms, 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.

75. The method of claim 74, wherein the individual suffers from or is at risk of suffering from: inflammatory or thrombotic diseases, disorders or conditions or their symptoms, 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.

76. The method of any one of claims 67 to 75, wherein the compound is a PKK-targeting compound.

77. The method of any one of claims 67 to 76, wherein the compound is the compound of any one of claims 1 to 64 or the composition of claim 65 or 66.

78. The method of claim 77, wherein the compound or composition is administered parenterally.

79. The use of compounds targeting PKK for the treatment, prevention or improvement of diseases, disorders or conditions related to PKK.

80. The use as claimed in claim 79, wherein the disease, disorder, or symptom is an inflammatory or thrombotic disease, disorder, or symptom or its symptoms, 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.

81. The use as described in claim 79 or 80, wherein the compound is a PKK-targeting compound.

82. The use according to any one of claims 79 to 81, wherein the compound is the compound of any one of claims 1 to 64 or the composition of claim 65 or 66.

83. Use of PKK-targeting compounds in the preparation of medicaments for the treatment, prevention or improvement of PKK-related diseases, disorders or conditions.

84. The use as claimed in claim 83, wherein the disease is an inflammatory or thrombotic disease, disorder or condition or its symptoms, 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.

85. The use as described in claim 83 or 84, wherein the compound is a PKK-targeting compound.

86. The use according to any one of claims 83 to 85, wherein the compound is the compound of any one of claims 1 to 64 or the composition of claim 65 or 66.

87. The method or use of any of the preceding claims, wherein the compound or composition is applied to an individual about once every three months to about once a year.

88. The method or use of any of the preceding claims, wherein the compound or composition is applied to an individual about once every three months, about once every six months, or about once a year.

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