Combinations of antisense agents, pharmaceutical compositions and methods of use

Abstract

Disclosed are, inter alia, combinations comprising a first antisense (e.g., first double stranded RNAi (dsRNAi)) agent for inhibiting expression of proprotein convertase subtilisin kexin 9 (PCSK9), for example, human PCSK9, and a second antisense agent (e.g., second dsRNAi agent) for inhibiting expression of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR); pharmaceutical compositions including the same, and methods of treatment using the same.

Description

PAT059887-PCT-SEC01COMBINATIONS OF ANTISENSE AGENTS, PHARMACEUTICAL COMPOSITIONS AND METHODS OF USECROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The present application claims priority and benefit to the U.S. Patent Application No. 63 / 737,052, filed December 20, 2024, the disclosure of which is incorporated herein by reference in its entirety.TECHNICAL FIELD

[0002] The present disclosure provides, inter alia, combinations comprising double stranded RNAi (dsRNAi) agents inhibiting expression of proprotein convertase subtilisin kexin 9 (PCSK9), for example, human PCSK9 and dsRNAi agents inhibiting expression of 3-hydroxy-3- methylglutaryl-CoA reductase (HMGCR), for example, human HMGCR, pharmaceutical compositions including the same, and methods of treatment using the same.BACKGROUND

[0003] Cumulative low-density lipoprotein cholesterol (LDL-C) exposure in the arterial wall is a major cause of atherosclerotic cardiovascular disease (ASCVD). The level of LDL-C in the arterial wall can be controlled (e.g., lowered) by modulating cholesterol homeostasis (e.g., cholesterol biosynthesis in liver cells) and upregulating LDL-C uptake from the blood.

[0004] PCSK9 is a member of the subtilisin serine protease family and is involved in cholesterol metabolism and homeostasis. A liver cell uptakes LDL-C via low-density lipoprotein receptor (LDLR) to directly remove such atherosclerotic lipoproteins from the plasma via uptake into a liver cell. If the level of LDLR decreases, LDL-C level increases in circulation, and the elevated circulating LDL-C level causes increased deposition in the arteries of LDL particles and the cholesterol they carry, which promotes the formation and progression of atherosclerotic plaques in the artery. PCSK9 binds to hepatic LDLR to induce endocytosis and lysosomal degradation of LDLR in the liver cell, thereby reducing LDL-C uptake by LDLR. PCSK9 inhibitors have been clinically proven to reduce LDLR degradation by inhibiting PCSK9 expression / function and lower LDL-C levels in the general population.

[0005] However, there is still an unmet need in the art for LDL-C lowering treatments that have increased potency and / or durability of action.PAT059887-PCT-SEC01

[0006] HMGCR is a key enzyme that converts 3- hydroxy-3 -methyl-glutaryl-CoA (HMGCoA) into mevalonate in the rate-limiting step in the cholesterol biosynthesis pathway. Due to its critical role in cholesterol biosynthesis, HMGCR has been a target for drug development for the treatment of high cholesterol and cardiovascular disease risk reduction (CVRR)s. For example, statins, small molecule inhibitors of HMGCR, are the current standard of care for lowering cholesterol. However, statins also have adverse side effects such as myalgia and rhabdomyolysis, a rare, but potentially fatal, breakdown of skeletal muscle. Real-world studies demonstrate that a staggering 80% of US patients on standard of care do not achieve their LDL-C goal. This is due, in large part, to poor adherence.

[0007] Therefore, there is an unmet need in the art for alternative treatments (e.g., lowering cholesterol or LDL-C) for subjects having lipid metabolism disorders.

[0008] There is also a need in the art for more convenient treatments for lowering cholesterol or LDL-C, particularly in view of the poor patient adherence often associated with such treatments.SUMMARY OF THE INVENTION

[0009] Provided herein are, inter alia, compounds that can inhibit expression of PCSK9 and / or HMGCR in a subject, for example, e.g., in liver cells of a subject.

[0010] In an aspect, the disclosure provides a combination comprising a first antisense agent and a second antisense agent, wherein:(a) the first antisense agent is a proprotein convertase subtilisin kexin 9 (PCSK9) inhibitor; and(b) the second antisense agent is a 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) inhibitor.

[0011] In some embodiments, the first antisense agent is a double stranded RNAi (dsRNAi) agent. In some embodiments, the second antisense agent is a dsRNAi agent. In some embodiments, the first antisense agent is a double stranded RNAi (dsRNAi) agent and the second antisense agent is a dsRNAi agent. In some embodiments, the first antisense agent is an antisense oligonucleotide (ASO) agent. In some embodiments, the second antisense agent is an ASO agent. In some embodiments, the first antisense agent is an ASO agent and the second antisense agent is an ASO agent. In some embodiments, the first antisense agent is a dsRNAi agent and the second antisensePAT059887-PCT-SEC01 agent is an ASO agent. In some embodiments, the first antisense agent is an ASO agent and the second antisense agent is a dsRNAi agent.

[0012] In an aspect, the disclosure provides a combination comprising a first double stranded RNAi (dsRNAi) agent and a second dsRNAi agent, wherein:(a) the first dsRNAi agent is a PCSK9 inhibitor; and(b) the second dsRNAi agent is an HMGCR inhibitor.

[0013] In some embodiments, one or more nucleotides in the sense strand and the antisense strand of the first dsRNAi agent are modified nucleotides.

[0014] In some embodiments, one or more nucleotides in the sense strand and the antisense strand of the second dsRNAi agent are modified nucleotides.

[0015] In some embodiments, each of the one or more modified nucleotides independently comprises one or more modifications selected from a 2’-deoxy modification, a 2’-O-alkyl modification, a 2'-halo modification, a threofuranosyl nucleotide (TNA) modification, a 2’-5’- linkage modification, a conformationally restricting modification, an abasic modification, a 2’- amino-modification, a 2’-O-allyl modification, 2’-C-alkyl modification, a 2’-O-alkoxyalkyl modification, a morpholino modification, a phosphoramidate modification, a non-natural nucleobase modification, a modification in a tetrahydropyran, a modification containing a 1,5- anhydrohexitol, a modification containing a cyclohexenyl, a modification containing a phosphor othioate group, a modification containing a 5’-vinyl-phosphonate, a modification containing a 5 ’-phosphate, a modification to form a thermally destabilizing nucleotide, a glycol nucleic acid (GNA) modification, and a 2-O-(N-methylacetamide) modification.

[0016] In some embodiments, each of the one or more modified nucleotides independently comprises one or more modifications selected from 2’ -deoxy modification, 2'-O-alkoxyalkyl modification, 2'-O-alkyl modification, 2'-O-allyl modification, 2'-C-alkyl modification, 2'-halo modification, modification containing a non-natural nucleobase, a GNA modification, and a TNA modification.

[0017] In some embodiments, the first and / or second dsRNAi agent comprises a 3’- phosphorothioate (PS) modification.

[0018] In some embodiments, each of the one or more modified nucleotides independently comprises one or more modifications selected from 2’-deoxy modification, 2’-O-methyl (2’-0Me) modification, 2’ -fluoro (2’-F) modification, 2’-O-methoxyethyl (2’ -MOE) modification, aPAT059887-PCT-SEC01 modification containing a non-natural nucleobase, TNA, GNA, 3 ’ -phosphorothioate (PS) modification, and 5’-vinyl-phosphonate (5 ’-VP) modification.

[0019] In some embodiments, the sense strand is 21 nucleotides in length and the antisense strand is 23 nucleotides in length.

[0020] In some embodiments, the first dsRNAi agent further comprises a ligand.

[0021] In some embodiments, the second dsRNAi agent further comprises a ligand.

[0022] In some embodiments, the ligand comprises a N-acetylgalactosamine (GalNAc) moiety.

[0023] In some embodiments, the ligand has a structure of:or a pharmaceutically acceptable salt thereof, wherein: each L1is independently a linker which may be same or different in each occurrence;L2is a linker; n is an integer from 1 to 3; and is an attachment point to the sense strand or the antisense strand, or to a conjugate linker conjugated to the sense strand or the antisense strand.

[0024] In some embodiments, the ligand comprises the following structure ofPAT059887-PCT-SEC01or a pharmaceutically acceptable salt thereof, wherein: each pl, p2, p3, ql, q2, rl, r2 and r3 is independently an integer from 0 to 12; each nl, n2, and n3 is independently an integer from 1 to 3; and is an attachment point to L2.

[0025] In some embodiments, the ligand has a structure of:or a pharmaceutically acceptable salt thereof, wherein: each L11, L12, L13, L14, and L15is an independently a linker;L2is a linker; is an attachment point to the sense strand or the antisense strand, or to a conjugate linker conjugated to the sense strand or the antisense strand.

[0026] In some embodiments, the ligand has a structure of:PAT059887-PCT-SEC01or a pharmaceutically acceptable salt thereof, wherein: each pl 1 and ql 1 is independently an integer from 0 to 12; each zl, z2, and z3 is independently an integer of 0 to 12; and is an attachment point to the sense strand or the antisense strand, or to a conjugate linker conjugated to the sense strand or the antisense strand.

[0027] In some embodiments, the ligand comprises the following structure:PAT059887-PCT-SEC01or a pharmaceutically acceptable salt thereof, wherein is an attachment point to the sense strand or the antisense strand or to a conjugate linker conjugated to the sense strand or the antisense strand.PAT059887-PCT-SEC01

[0028] In some embodiments, the ligand is conjugated to 3’ end of the sense strand to form the following structure:acceptable salt thereof, wherein W is -OH or -SH.

[0029] In some embodiments, the ligand is conjugated to 5’ end of the sense strand to form the following structure:PAT059887-PCT-SEC01 or a pharmaceutically acceptable salt thereof, wherein W is -OH or -SH.

[0030] In some embodiments, W is -OH.

[0031] In some embodiments, the first antisense agent (e.g., first dsRNAi agent) is in a pharmaceutically acceptable salt form.

[0032] In some embodiments, the second antisense agent (e.g., second dsRNAi agent) is in a pharmaceutically acceptable salt form.

[0033] In some embodiments, the pharmaceutically acceptable salt is a sodium salt.

[0034] In some embodiments, the first antisense agent (e.g., first dsRNAi agent) and the second antisense agent (e.g., second dsRNAi agent) are provided as a mixture.

[0035] In some embodiments, the first antisense agent (e.g., first dsRNAi agent) and the second antisense agent (e.g., second dsRNAi agent) are formulated separately.

[0036] In an aspect, the disclosure provides a pharmaceutical composition comprising a combination as described herein, and a pharmaceutically acceptable carrier.In some embodiments, the pharmaceutical composition is in an aqueous solution form.

[0037] In an aspect, the disclosure provides a method of inhibiting PCSK9 and / or HMGCR expression in a cell, the method comprising:(a) contacting the cell with a combination as described herein, or a pharmaceutical composition as described herein; and(b) maintaining the cell produced in step (a) for a time sufficient to obtain degradation of the mRNA transcript of a PCSK9 gene and / or an HMGCR gene, thereby inhibiting expression of the PCSK9 gene and / or the HMGCR gene in the cell.

[0038] In an aspect, the disclosure provides a method of lowering a level of low-density lipoprotein cholesterol (LDL-C) in a subject in need thereof, comprising administering to the subject a combination as described herein, or a pharmaceutical composition as described herein.

[0039] In an aspect, the disclosure provides a method of treating a disorder (e.g. lipidemia) mediated by PCSK9 and / or HMGCR expression in a subject in need thereof, comprising administering to the subject a combination as described herein, or a pharmaceutical composition as described herein.PAT059887-PCT-SEC01

[0040] In an aspect, the disclosure provides a method of treating or preventing atherosclerotic cardiovascular disease (ASCVD) in a subject in need thereof, comprising administering to the subject a combination as described herein, or a pharmaceutical composition as described herein.

[0041] In an aspect, the disclosure provides a method of reducing or preventing cardiovascular event in a subject in need thereof, comprising administering to the subject a combination as described herein, or a pharmaceutical composition as described herein.

[0042] In some embodiments, the cardiovascular event is cardiovascular death, non-fatal myocardial infarction (MI), non-fatal ischemic stroke, urgent coronary revascularization, coronary heart disease (CHD) death, or any combination thereof.

[0043] In an aspect, the disclosure provides a method of reducing or preventing a major limb adverse event (MALE) in a subject in need thereof, comprising administering to the subject a combination as described herein, or a pharmaceutical composition as described herein.

[0044] In some embodiments, the MALE is acute lower limb ischemia, lower limb amputation due to ischemia, urgent lower limb revascularization for ischemia, or any combination thereof.

[0045] In some embodiments, the first antisense agent (e.g., first dsRNAi agent) and the second antisense agent (e.g., second dsRNAi agent) are administered to the subject concurrently.

[0046] In some embodiments, the first antisense agent (e.g., first dsRNAi agent) and the second antisense agent (e.g., second dsRNAi agent) are administered to the subject sequentially.

[0047] In some embodiments, the first antisense agent (e.g., first dsRNAi agent) and the second antisense agent (e.g., second dsRNAi agent) are administered to the subject subcutaneously or intravenously.

[0048] In some embodiments, the subject is a human.

[0049] In some embodiments, the subject has or is diagnosed with hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, mixed hyperlipidemia, congestive heart disease (CHD) or atherosclerosis.

[0050] In an aspect, the disclosure provides a kit comprising a first antisense agent (e.g., first dsRNAi agent) and a second antisense agent (e.g. second dsRNAi agent) as described herein, or a pharmaceutical composition as described herein.

[0051] In some embodiments, the first antisense agent (e.g., first dsRNAi agent) and the second antisense agent (e.g., second dsRNAi agent) are contained in a single vial.PAT059887-PCT-SEC01

[0052] In some embodiments, the first antisense agent (e.g., first dsRNAi agent) and the second antisense agent (e.g., second dsRNAi agent) are contained in separate vials.

[0053] In some embodiments, the kit further comprises one or more applicators.

[0054] In some embodiments, the one or more applicators are syringes.

[0055] In some embodiments, the one or more applicators are pre-filled syringes.

[0056] Other aspects of the invention are disclosed infra.BRIEF DESCRIPTION OF DRAWINGS

[0057] Figure 1: Percent reduction in plasma LDL-C concentrations in cynomolgus monkeys administered a PCSK9 siRNA and an HMGCR siRNA compared to the plasma LDL-C concentration administered the PCSK9 siRNA alone (PCSK9 siRNA+PBS).DETAILED DESCRIPTIONDefinitions

[0058] Unless defined otherwise, all technical terms, scientific terms, abbreviations, chemical structures, and chemical formulae used herein have the same meaning as is commonly understood by one of ordinary skill in the art. The chemical structures and formulae set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts. All patents, applications, published applications, and other publications referenced herein are incorporated by reference in their entirety unless stated otherwise.

[0059] All patents, applications, published applications, and other publications referenced herein are incorporated by reference in their entirety unless stated otherwise. Unless otherwise indicated, conventional methods of mass spectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques, and pharmacology are employed.

[0060] Furthermore, use of the term “including” as well as other forms, such as “include”, “includes,” and “included,” is not limiting. As used in this specification, whether in a transitional phrase or in the body of the claim, the terms “comprise(s)” and “comprising” are to be interpreted as having an open-ended meaning. That is, the terms are to be interpreted synonymously with the phrases “having at least” or “including at least.” When used in the context of a process, the term “comprising” means that the process includes at least the recited steps, but may include additional steps. When used in the context of a combination, compound, pharmaceutical composition, orPAT059887-PCT-SEC01 device, the term “comprising” means that the combination, compound, pharmaceutical composition, or device includes at least the recited features or components, but may also include additional features or components. As used herein, the term "a,” "an,” "the” and similar terms used in the context of the present invention (especially in the context of the claims) are to be construed to cover both the singular and plural unless otherwise indicated herein or clearly contradicted by the context.

[0061] Unless otherwise indicated, all numbers, values, and / or expressions referring to nucleotide lengths, inhibition, activities, dosages, contents, and formulations used herein are to be understood as modified in all instances by the term “about” as such numbers are inherently approximations that are reflective of, among other things, the various uncertainties of measurement encountered in obtaining such values. Further, unless specifically stated or obvious from context, as used herein, the term “about” is understood as within a range of normal tolerance in the art, for example within 2 standard deviations of the “mean. “About” may be understood as within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01% of the stated value. Unless otherwise clear from the context, all numerical values provided herein are modified by the term “about.”

[0062] The term “nucleic acid” means a compound containing at least two nucleotide monomers covalently linked together. Nucleic acids include polynucleotides and oligonucleotides, including double-stranded oligonucleotides and single-stranded oligonucleotides, and modified versions thereof.

[0063] The term “nucleotide” means a compound including a nucleoside and a phosphate group (or phosphodiester linkage) that are covalently attached at 5' position or 3' position of the pentofuranosyl sugar (e.g., ribose or deoxyribose). In certain aspects, the nucleotide is a ribonucleotide (RNA) having the ribose as the pentofuranosyl sugar. In certain aspects, a nucleotide is a deoxyribonucleotide (DNA) having the deoxyribose (2'-deoxyribose) as the pentofuranosyl sugar. Unless otherwise specifically indicated, when referring a “nucleotide” in a chain of nucleotides (e.g., oligonucleotides), e.g., Xi to X21 and Xv to X23’, a nucleotide is meant by a nucleoside and a phosphate group (or phosphodiester linkage) that is covalently attached at 3' position of the pentofuranosyl sugar (e.g., ribose or deoxyribose).

[0064] The term “nucleoside” means a monomer consisting of a nucleobase and a pentofuranosyl sugar (e.g., ribose or deoxyribose). A nucleoside including a ribose sugar ring hasPAT059887-PCT-SEC01HCX Baseto a structure of OH OH or a pharmaceutically acceptable salt thereof, and a nucleotide HC Baseincluding a deoxyribose sugar ring has a structure of OH or a pharmaceutically acceptable salt, wherein in each structure, “Base” is a nucleobase.

[0065] The term “nucleobase” or “base,” as used herein, means the heterocyclic base moiety of a nucleoside or nucleotide. Non-limiting examples of nucleobases includes cytosine or a derivative thereof (e.g., cytosine analogue), guanine or a derivative thereof (e.g., guanine analogue), adenine or a derivative thereof (e.g., adenine analogue), thymine or a derivative thereof (e.g., thymine analogue), uracil or a derivative thereof (e.g., uracil analogue), hypoxanthine or a derivative thereof (e.g., hypoxanthine analogue), xanthine or a derivative thereof (e.g., xanthine analogue), 7-methylguanine or a derivative thereof (e.g., 7-methylguanine analogue), deazaadenine or a derivative thereof (e.g., deaza-adenine analogue), deaza- guanine or a derivative thereof (e.g., deaza-guanine), deaza-hypoxanthine or a derivative thereof, 5,6-dihydrouracil or a derivative thereof (e.g., 5,6-dihydrouracil analogue), 5-methylcytosine or a derivative thereof (e.g., 5-methylcytosine analogue), or 5 -hydroxymethylcytosine or a derivative thereof (e.g., 5- hydroxymethylcytosine analogue) moieties. In some embodiments, the nucleobase is adenine, guanine, hypoxanthine, xanthine, theobromine, caffeine, uric acid, or isoguanine, which may be optionally substituted or modified. In some embodiments, the nucleobase isPAT059887-PCT-SEC01adenine guanine thymine uracil or methylated uracilcytidine 4-methyl 5-methyl cytidine cytidine which may be optionally substituted or modified, wherein “” denotes the point of attachment to a pentofuranosyl sugar ring (e.g., 1' position).

[0066] The term “phosphate,” or “phosphate group” as used herein a chemical species made of one phosphorus atom and four oxygen atomsr esters, salts, or acids thereof. In certain aspects, when the phosphate groups are positioned between adjacent nucleosides in RNA or DNA strand and form a “backbone” of the oligonucleotides, these terms “phosphate,” or “phosphate group” may be interchangeable used as “phosphate group,” “phosphate linkage,” “phosphodi ester linkage,” or “linkage.” For example, the phosphate or phosphodi ester linkage in the backbone of RNA or DNA may have the structuresesters, salts (e.g., pharmaceutically acceptable salts), or acidsthereof, wherein” denotesPAT059887-PCT-SEC01 the point of attachment to pentofuranosyl sugar rings (e.g., 5' and 3' positions) in adjacent nucleosides. In certain aspects, a variant of a phosphate or phosphodiester linkage, e.g., phosphorothioate (PS) linkage, can replace a phosphate group (or phosphodiester linkage) in the backbone and connect two adjacent nucleosides. In certain aspects, a variant of a phosphate or phosphodiester linkage, e.g., phosphorothioate (PS) linkage or vinyl phosphonate (VP) group, may be additionally attached at 3' end or 5' end of the oligonucleotides (e.g., RNA or DNA), e.g., 3'- OH or 5'-OH position of the terminal pentofuranosyl sugar (e.g., ribose or deoxyribose), so as to act as chemically or biologically functional group. In certain aspects, a variant of phosphate or phosphodiester linkage may also be referred as a phosphorus-derived internucleoside linkage that includes at least one phosphorus atom in the backbone.

[0067] Unless otherwise indicated herein, an unmodified RNA (or “ribonucleotide”) in a chain of nucleotides (e.g., mRNA, rRNA, or sense strand or antisense strand of siRNA) as disclosed refers to a structure ofpharmaceutically acceptable salt thereof. Likewise, an unmodified DNA(or “deoxyribonucleotides”) in a chain of nucleotides (e.g., genomic DNA or cDNA) as disclosed herein specifically refers to a structure ofpharmaceutically acceptable salt thereof. In each structure “Base” is a nucleobase and ® is an attachment point to the adjacent nucleotides.

[0068] Unless otherwise indicated herein, when an unmodified RNA is the first nucleotide from the 5' end of an RNA chain (e.g., mRNA, or sense strand or antisense strand of siRNA), thatPAT059887-PCT-SEC01 nucleotide has a structurepharmaceutically acceptable salt thereof.Likewise, when an unmodified DNA is the first nucleotide from the 5' end of a DNA chain (e.g., genomic DNA or cDNA), that nucleotide has a structureor a pharmaceutically acceptable salt thereof. In each structure “Base” is a nucleobase and is an attachment point (5' oxygen) to the adjacent nucleotides. Alternatively but equivalently, for example, the first nucleotide from the 5' end of an RNA chain (e.g., mRNA, or sense strand or antisense strand of siRNA), that nucleotide has a structurepharmaceutically acceptable salt thereof and the first nucleotide from the 5' end of a DNA chain(e.g., genomic DNA or cDNA), that nucleotide has a structurepharmaceutically acceptable salt thereof, when is an attachment point (5' oxygen) to the adjacent nucleotides.

[0069] Unless otherwise indicated herein, when an unmodified RNA is the first nucleotide from the 3' end of an RNA chain (e.g., mRNA, or sense strand or antisense strand of siRNA), thatPAT059887-PCT-SEC01XX Base nucleotide has a structure, or a pharmaceutically acceptable salt.Likewise, when an unmodified DNA is the first nucleotide from the 3' end of a DNA chain (e.g., ^,0^ Baseo I 0=P — OH I genomic DNA or cDNA), that nucleotide has a structure of OH , or a pharmaceutically acceptable salt thereof. In certain embodiments, when an unmodified RNA is the first nucleotide from the 3' end of an RNA chain (e.g., mRNA, or sense strand or antisense strand of siRNA) that nucleotide does not include 3' end phosphate group or phosphodi ester linkage, for example, which has been removed during hydrolysis or synthesis, has a structure ofXX BaseOH OH , or a pharmaceutically acceptable salt. Likewise, when an unmodified DNA is the first nucleotide from the 3' end of a DNA chain (e.g., genomic DNA or cDNA), that nucleotide does not include 3' end phosphate group, for example, which has been removed during c^CX Basehydrolysis or synthesis, has a structure of OH , or a pharmaceutically acceptable salt thereof. In each structure “Base” is a nucleobase andis an attachment point (e.g., phosphorus of the phosphate linkage) to the adjacent nucleotides.

[0070] A code “A”, “G”, “C”, or “U” presented in a sequence list as disclosed herein stand for a RNA nucleotide that contains adenine, guanine, cytosine, or uracil as a base, respectively. A code “dA”, “dG”, “dC” or “dT” presented in a sequence list as disclosed herein stand for a DNA nucleotide that contains adenine, guanine, cytosine, and thymine as a base, respectively. In somePAT059887-PCT-SEC01 embodiments, the code “T” may be present in a RNA sequence then it may refer to a nucleotide (e.g. modified nucleotide) that thymine as a base.

[0071] The term “oligonucleotide” means a shorter length nucleic acid, e.g. of less than 100 nucleotides in length. Oligonucleotides may be single-stranded or double-stranded. In some embodiments, an oligonucleotide may include naturally occurring ribonucleotides, naturally occurring deoxyribonucleotides, and / or nucleotides having one or more modifications to a naturally occurring terminus, sugar, nucleobase, and / or internucleoside linkage. Non-limiting examples of oligonucleotides include double-stranded oligonucleotides (e.g., dsRNA), singlestranded oligonucleotides (e.g., single stranded RNA or ssRNA), antisense oligonucleotides (“ASO”), small interfering RNA (siRNA), microRNA mimics, short hairpin RNAs (shRNA), single-strand small interfering RNA (ssRNAi), RNaseH oligonucleotides, anti-microRNA oligonucleotides, steric blocking oligonucleotides, exon-skipping oligonucleotides, CRISPR guide RNAs, and aptamers. In certain aspects, the oligonucleotide is a dsRNA and each strand has a length less than 100 nucleotides (“nt”), less than 90 nt, less than 80 nt, less than 70 nt, less than 60 nt, less than 50 nt, less than 40 nt, less than 35 nt, less than 30 nt, less than 28 nt, less than 26 nt, less than 25 nt, less than 24 nt, less than 23 nt, less than 22 nt, less than 21 nt, less than 20 nt, less than 19 nt, less than 18 nt, less than 17 nt, less than 16 nt, or 15 nt.

[0072] The terms “iRNA”, “RNAi agent,” “iRNA agent,”, “RNA interference agent” as used interchangeably herein, refer to an agent that contains RNA as that term is defined herein, and which mediates the targeted cleavage of an RNA transcript (mRNA) via an RNA-induced silencing complex (RISC) pathway. An RNAi agent directs the sequence-specific degradation of mRNA through a process and thereafter inhibits expression of the gene encoded by the mRNA in a cell in vivo, e.g., in a subject (e.g., any vertebrate, mammal, or human).

[0073] The term “small interfering RNA” or “siRNA” means a double-stranded oligonucleotide (dsRNA) formed with two anti-parallel, and partially, substantially or fully complementary nucleic acid strands (e.g., a first strand and a second strand; or a “sense” strand and an “antisense” strand), which interferes with the expression of genes in a sequence-specific manner by facilitating mRNA degradation before translation through the RNA interference pathway. In some embodiments, depending on the context, the first strand can be a “guide” or antisense strand, and the second strand can be a “passenger” or sense strand. In some embodiments, depending on the context, the “first” strand can be a passenger or sense strand, andPAT059887-PCT-SEC01 the “second” strand can be a guide or antisense. In certain aspects, an “RNAi agent” or “siRNA agent,” as used herein, refers a double-stranded RNA (dsRNA) with or without a ligand or other conjugate, and may be interchangeably used with a term “double stranded RNAi agent (dsRNAi agent),” or “dsRNA agent.” In certain aspects of the disclosure, the term “siRNA” can be used to describe a dsRNA with specific nucleotide sequences (unmodified or modified nucleotide sequences), without a ligand or other conjugate.

[0074] The term “antisense strand,” as used herein, refers an oligonucleotide (e.g., RNA) of an siRNA or a dsRNAi that is complementary (e.g., partially, substantially, or fully complementary) to the target mRNA and is incorporated into the RNA-induced silencing complex (RISC) to direct gene silencing in a sequence-specific manner through the RNA interference pathway. An antisense strand may also be referred to as the “guide strand.” In some embodiments, the antisense strand may have a length from 15-30 nt, 15-26 nt, 15-23 nt, 15-22 nt, 15-21 nt, 15- 20 nt, 15-19 nt, 15-18 nt, 15-17 nt, 18-30 nt, 18-26 nt, 18-23 nt, 18-22 nt, 18-21 nt, 18-20 nt, 19- 30 nt, 19-26 nt, 19-23 nt, 19-22 nt, 19-21 nt, 19-20 nt, 19 nt, 20-30 nt, 20-26 nt, 20-25 nt, 20-24 nt, 20-23 nt, 20-22 nt, 20-21 nt, 20 nt, 21-30 nt, 21-26 nt, 21-25 nt, 21-24 nt, 21-23 nt, 21-22 nt, 9 nt, 10 nt, 11 nt, 12 nt, 13 nt, 14 nt, 15 nt, 16 nt, 17 nt, 18 nt, 19 nt, 20 nt, 21 nt, 22 nt, 23 nt, 24 nt, 25 nt, 26 nt, 27 nt, 28 nt, 29 nt, 30 nt, 31 nt, 32 nt, 33 nt, 34 nt, 35 nt, or 36 nt.

[0075] The term “sense strand,” as used herein, refers an oligonucleotide that is complementary (e.g., partially, substantially, or fully complementary) to the antisense strand. The sense strand is typically degraded following incorporation of the antisense strand into RISC. The sense strand may also be referred to as the “passenger strand.” In some embodiments, the sense strand may have a length from 15-30 nt, 15-26 nt, 15-23 nt, 15-22 nt, 15-21 nt, 15-20 nt, 15-19 nt, 15-18 nt, 15-17 nt, 18-30 nt, 18-26 nt, 18-23 nt, 18-22 nt, 18-21 nt, 18-20 nt, 19-30 nt, 19-26 nt, 19-23 nt, 19-22 nt, 19-21 nt, 19-20 nt, 19 nt, 20-30 nt, 20-26 nt, 20-25 nt, 20-24 nt, 20-23 nt, 20- 22 nt, 20-21 nt, 20 nt, 21-30 nt, 21-26 nt, 21-25 nt, 21-24 nt, 21-23 nt, 21-22 nt, 9 nt, 10 nt, 11 nt, 12 nt, 13 nt, 14 nt, 15 nt, 16 nt, 17 nt, 18 nt, 19 nt, 20 nt, 21 nt, 22 nt, 23 nt, 24 nt, 25 nt, 26 nt, 27 nt, 28 nt, 29 nt, 30 nt, 31 nt, 32 nt, 33 nt, 34 nt, 35 nt, or 36 nt.

[0076] The term “complementary” means that a nucleotide (e.g., RNA or DNA) or a sequence of nucleotides are capable of base pairing non-covalently via hydrogen bonding with another nucleotide or sequence of nucleotides. As described herein and commonly known in the art the complementary (matching) nucleotide of adenosine is thymidine or uridine and the complementaryPAT059887-PCT-SEC01(matching) nucleotide of guanosine is cytidine. The complementarity of sequences may be partial, in which only some of the nucleic acids match according to base pairing, or complete, where all the nucleic acids match according to base pairing. For example, two sequences that are complementary to each other, may have a specified percentage of nucleotides that participate in nucleobase-pairing (i.e., about 50% complementarity, preferably 50%, 55%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or greater complementarity over a specified region). In some embodiments, two sequences are partially complementary when the percentage of nucleotides that participate in nucleobase-pairing is about 50%, about 55%, about 65%, about 70%, about 75%, or about 80%, or ranges from about 50% to about 80%. In some embodiments, two sequences are substantially complementary when the percentage of nucleotides that participate in nucleobase-pairing is about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 92%, about 93%, about 94%, or about 95%, or ranges from about 80% to about 95%.

[0077] Examples of complementary (e.g., partially, substantially, or fully complementary) sequences are sense and antisense sequences, wherein the sense sequence contains complementary (e.g., partially, substantially, or fully complementary) nucleotides to the antisense sequence and thus forms the complement of the antisense sequence. In certain aspects, a sense strand and an antisense strand of a double-stranded oligonucleotide (e.g., double stranded RNA) are substantially or fully complementary over their entire lengths. In some embodiments, a sense strand and an antisense strand of dsRNA are substantially or fully complementary over the entire length of the double-stranded region of the siRNA, and one or both termini of either strand comprises singlestranded nucleotides.

[0078] Other examples of complementary (e.g., partially, substantially, or fully complementary) sequences are an antisense strand and its target mRNA sequence. In certain aspects, an antisense strand is substantially or fully complementary to its target mRNA. For example, the complementary (e.g., partially, substantially, or fully complementary) sequences may be between an antisense strand and a coding region of the target mRNA, or a non-coding sequence of the target mRNA. In certain aspects, an antisense strand is substantially, or fully complementary to its target mRNA to reduce or eliminate off-target profile for and to improve down-regulation of the target gene (e.g., gene of the target mRNA sequence).PAT059887-PCT-SEC01

[0079] The terms “identical” or percent “identity,” in the context of two or more nucleic acids or polypeptide sequences, refer to two or more sequences or subsequences that are the same or have a specified percentage of amino acid residues or nucleotides that are the same (i.e., at least 60% identity, or at least 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or within a range defined by any of two of the preceding values, identity over a specified region when compared and aligned for maximum correspondence over a comparison window or designated region) as measured using a BLAST or BLAST 2.0 sequence comparison algorithms with default parameters described below, or by manual alignment and visual inspection (see, e.g., NCBI web site or the like). This definition also refers to, or may be applied to, the complement of a test sequence. The definition also includes sequences that have deletions and / or additions, as well as those that have substitutions. As described below, the preferred algorithms can account for gaps, insertions and the like. Alignment for purposes of determining percent sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN, ALIGN-2 or Megalign (DNASTAR) software. Appropriate parameters for measuring alignment, including any algorithms needed to achieve maximal alignment over the full-length of the sequences being compared can be determined by known methods.

[0080] As used herein, “target sequence” or “target gene” refer to a contiguous portion of the nucleotide sequence of an mRNA molecule formed during the transcription of a gene including mRNA that is a product of RNA processing of a primary transcription product. The target portion of the sequence will be at least long enough to serve as a substrate for RNAi-directed cleavage at or near that portion. For example, the target sequence will generally be from 9-36 nucleotides (“nt”) in length, e.g., 15-30 nt in length, including all sub-ranges therebetween. As non-limiting examples, the target sequence may have a length from 15-30 nt, 15-26 nt, 15-23 nt, 15-22 nt, 15- 21 nt, 15-20 nt, 15-19 nt, 15-18 nt, 15-17 nt, 18-30 nt, 18-26 nt, 18-23 nt, 18-22 nt, 18-21 nt, 18- 20 nt, 19-30 nt, 19-26 nt, 19-23 nt, 19-22 nt, 19-21 nt, 19-20 nt, 19 nt, 20-30 nt, 20-26 nt, 20-25 nt, 20-24 nt, 20-23 nt, 20-22 nt, 20-21 nt, 20 nt, 21-30 nt, 21-26 nt, 21-25 nt, 21-24 nt, 21-23 nt, 21-22 nt, 9 nt, 10 nt, 11 nt, 12 nt, 13 nt, 14 nt, 15 nt, 16 nt, 17 nt, 18 nt, 19 nt, 20 nt, 21 nt, 22 nt, 23 nt, 24 nt, 25 nt, 26 nt, 27 nt, 28 nt, 29 nt, 30 nt, 31 nt, 32 nt, 33 nt, 34 nt, 35 nt, or 36 nt.PAT059887-PCT-SEC01

[0081] The term “ligand,” as used herein, refers to a compound or moiety that can impose characteristics to provide additional properties, e.g., affinity or cell delivery efficiency, to an RNAi (e.g., dsRNAi) as described herein. The ligand may be coupled or conjugated directly to the RNAi (e.g., sense strand or antisense strand of dsRNA), or indirectly to the RNAi agent (e.g., sense strand or antisense strand of dsRNA) via an intervening linker (“linker”). When a ligand is conjugated or coupled indirectly to the RNAi (e.g., dsRNA) via a linker, the ligand may be formed of a core moiety (e.g., targeting moiety) that has specific function to provide affinity or efficacy and the linker that provides merely an optimal distance, e.g., between the core moiety and the RNAi agent (dsRNA). In certain aspects, the term “ligand” embraces the ligand in combination with the linker. Examples of ligands or targeting moieties thereof may include, but not be limited to, one or more selected from a synthetic or natural compound, a peptide, an antibody, a carbohydrate (e.g., sugar moiety), or an additional nucleic acid.

[0082] The term “modified nucleotide” means a nucleotide having one or more modifications relative to a naturally occurring nucleotide, e.g., RNA. The modified nucleotide may be selected over an unmodified form because of desirable properties such as, for example, enhanced cellular uptake, enhanced affinity for other oligonucleotides or nucleic acid targets, increased stability in the presence of nucleases, and / or reduced immune stimulation. In certain aspects, the modification may be present in at least one of (i) an internucleoside linkage (“linkage”), (ii) a nucleobase, and (iii) a sugar moiety of the nucleotide. In certain aspects, the modification is present in the internucleoside linkage, e.g., by chemically modifying a phosphate (or phosphodi ester) linkage or replacing a phosphate (or phosphodiester) linkage with other linking groups. In certain aspects, the modification is present in a sugar moiety, i.e., ribose ring, by substituting hydroxyl group on 2' position of the ribose ring with other chemical group or by replacing a ring structure with other heterocycloalkyl or cycloalkyl, glycol group having a structurebicyclic or bridged ring on the ribose such as locked nucleic acid (LNA) having a structurethe like. In certain aspects, the modification is present in a nucleobase (e.g., A, G, C, T, or U) by chemical modification in a nucleobase by replacing the nucleobase with other moiety, forPAT059887-PCT-SEC01 example, by replacing one naturally occurring nucleobase with another naturally occurring nucleobase. In certain aspects, a modified nucleotide may contain a modification in a sugar moiety and an unmodified phosphate (or phosphodiester) linkage. In certain aspects, a modified nucleotide may have a modification in a sugar moiety but with an unmodified nucleobase. In certain aspects, a modified nucleotide may have a modification in a sugar moiety and a nucleobase. In certain aspects, a modified nucleotide may have a modification in a sugar moiety and a phosphate (or phosphodiester) linkage. In certain aspects, a modified nucleotide may have a modification in a sugar moiety, a phosphate (or phosphodiester) linkage and a nucleobase. In certain aspects, a modified nucleotide may have an unmodified sugar moiety and an unmodified phosphate (or phosphodiester) linkage. In certain aspects, a modified nucleotide may have an unmodified sugar moiety and an unmodified nucleobase. In certain aspects, a modified nucleotide may have an unmodified sugar moiety and a modified nucleobase. In certain aspects, a modified nucleotide may have an unmodified sugar moiety and a modified phosphate (or phosphodiester) linkage. In certain aspects, a modified nucleotide may have a modified sugar moiety, a modified phosphate (or phosphodiester) linkage and a modified nucleobase.

[0083] The term “modified phosphate group,” or “modified phosphodiester linkage” as used herein refers to a chemical group in place of a phosphate group (or phosphodiester linkage) in a nucleotide as being attached to the 3' end (3' carbon) of the pentofuranosyl group.

[0084] The terms “identical” or percent “identity,” in the context of two or more nucleic acids or polypeptide sequences, refer to two or more sequences or subsequences that are the same or have a specified percentage of amino acid residues or nucleotides that are the same (i.e., at least 60% identity, or at least 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or within a range defined by any of two of the preceding values, identity over a specified region when compared and aligned for maximum correspondence over a comparison window or designated region) as measured using a BLAST or BLAST 2.0 sequence comparison algorithms with default parameters described below, or by manual alignment and visual inspection (see, e.g., NCBI web site or the like). This definition also refers to, or may be applied to, the complement of a test sequence. The definition also includes sequences that have deletions and / or additions, as well as those that have substitutions. As described below, the preferred algorithms can account for gaps, insertions and the like. AlignmentPAT059887-PCT-SEC01 for purposes of determining percent sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN, ALIGN-2 or Megalign (DNASTAR) software. Appropriate parameters for measuring alignment, including any algorithms needed to achieve maximal alignment over the full-length of the sequences being compared can be determined by known methods.

[0085] Throughout the disclosure, nucleotide positions or coordinates are relative to the beginning (5' end) of the reference transcript.

[0086] The term “overhang” or “nucleotide overhang” herein refers to at least one unpaired nucleotide that protrudes from the end of at least one of the two strands of the duplex structure of an RNAi agent. In some embodiments, when a 3'-end of one strand extends beyond the 5'-end of the other strand, or vice versa, this forms a nucleotide overhang, e.g., the unpaired nucleotide(s) form the overhang.

[0087] ‘Blunt” or “blunt end” means that there are no unpaired nucleotides at that end of the double stranded RNAi agent, i.e., no nucleotide overhang. A “blunt ended” dsRNAi agent is a dsRNA that is double-stranded over its entire length, i.e., no nucleotide overhang at either end of the molecule.

[0088] A “mismatch” is defined herein as a difference between the base sequence (e.g., A instead of G) or length when two sequences are maximally aligned and compared. In certain aspects, the term “mismatch” means a nucleobase of a first oligonucleotide (e.g., a first strand) that is not capable of pairing with a nucleobase at a corresponding position of a second oligonucleotide (e.g., a second strand).

[0089] The term “non-end” herein refers to a position between the 3' end and the 5' end of the sense or antisense strand.

[0090] The term “PCSK9,” refers to a proprotein convertase subtilisin kexin 9 gene or a protein encoded by that gene. PCSK9 is also known as FH3, PC9, FHCL3, NARC1, LDLCQ1, NARC-1, or HCHOLA3. The PCSK9 gene as used herein includes human PCSK9 (e.g., Gene ID: 255738; GenBank Accession No. NM_174936.3 or NM_174936.4), mouse PCSK9 gene (e.g., Gene ID: 100102; GenBank Accession No. NM_153565.2), and dog PCSK9 gene (e.g., Gene ID: 102152231; GenBank Accession No. XM_038667514.1). Additional examples ofPCSK9 mRNA sequences from different species and variants are readily available using, e.g., GenBank.PAT059887-PCT-SEC01

[0091] Homo sapiens PCSK9, transcript variant 1, mRNA : GenBank: NM 174936.3 (SEQ ID NO: 1)1 gtccgatggg gctctggtgg cgtgatctgc gcgccccagg cgtcaagcac ccacacccta61 gaaggtttcc gcagcgacgt cgaggcgctc atggttgcag gcgggcgccg ccgttcagtt121 cagggtctga gcctggagga gtgagccagg cagtgagact ggctcgggcg ggccgggacg181 cgtcgttgca gcagcggctc ccagctccca gccaggattc cgcgcgcccc ttcacgcgcc241 ctgctcctga acttcagctc ctgcacagtc ctccccaccg caaggctcaa ggcgccgccg301 gcgtggaccg cgcacggcct ctaggtctcc tcgccaggac agcaacctct cccctggccc361 tcatgggcac cgtcagctcc aggcggtcct ggtggccgct gccactgctg ctgctgctgc421 tgctgctcct gggtcccgcg ggcgcccgtg cgcaggagga cgaggacggc gactacgagg481 agctggtgct agccttgcgt tccgaggagg acggcctggc cgaagcaccc gagcacggaa541 ccacagccac cttccaccgc tgcgccaagg atccgtggag gttgcctggc acctacgtgg601 tggtgctgaa ggaggagacc cacctctcgc agtcagagcg cactgcccgc cgcctgcagg661 cccaggctgc ccgccgggga tacctcacca agatcctgca tgtcttccat ggccttcttc721 ctggcttcct ggtgaagatg agtggcgacc tgctggagct ggccttgaag ttgccccatg781 tcgactacat cgaggaggac tcctctgtct ttgcccagag catcccgtgg aacctggagc841 ggattacccc tccacggtac cgggcggatg aataccagcc ccccgacgga ggcagcctgg901 tggaggtgta tctcctagac accagcatac agagtgacca ccgggaaatc gagggcaggg961 tcatggtcac cgacttcgag aatgtgcccg aggaggacgg gacccgcttc cacagacagg1021 ccagcaagtg tgacagtcat ggcacccacc tggcaggggt ggtcagcggc cgggatgccg1081 gcgtggccaa gggtgccagc atgcgcagcc tgcgcgtgct caactgccaa gggaagggca1141 cggttagcgg caccctcata ggcctggagt ttattcggaa aagccagctg gtccagcctg1201 tggggccact ggtggtgctg ctgcccctgg cgggtgggta cagccgcgtc ctcaacgccg1261 cctgccagcg cctggcgagg gctggggtcg tgctggtcac cgctgccggc aacttccggg1321 acgatgcctg cctctactcc ccagcctcag ctcccgaggt catcacagtt ggggccacca1381 atgcccaaga ccagccggtg accctgggga ctttggggac caactttggc cgctgtgtgg1441 acctctttgc cccaggggag gacatcattg gtgcctccag cgactgcagc acctgctttg1501 tgtcacagag tgggacatca caggctgctg cccacgtggc tggcattgca gccatgatgc1561 tgtctgccga gccggagctc accctggccg agttgaggca gagactgatc cacttctctg1621 ccaaagatgt catcaatgag gcctggttcc ctgaggacca gcgggtactg acccccaacc1681 tggtggccgc cctgcccccc agcacccatg gggcaggttg gcagctgttt tgcaggactgPAT059887-PCT-SEC011741 tatggtcagc acactcgggg cctacacgga tggccacagc cgtcgcccgc tgcgccccag1801 atgaggagct gctgagctgc tccagtttct ccaggagtgg gaagcggcgg ggcgagcgca1861 tggaggccca agggggcaag ctggtctgcc gggcccacaa cgcttttggg ggtgagggtg1921 tctacgccat tgccaggtgc tgcctgctac cccaggccaa ctgcagcgtc cacacagctc1981 caccagctga ggccagcatg gggacccgtg tccactgcca ccaacagggc cacgtcctca2041 caggctgcag ctcccactgg gaggtggagg accttggcac ccacaagccg cctgtgctga2101 ggccacgagg tcagcccaac cagtgcgtgg gccacaggga ggccagcatc cacgcttcct2161 gctgccatgc cccaggtctg gaatgcaaag tcaaggagca tggaatcccg gcccctcagg2221 agcaggtgac cgtggcctgc gaggagggct ggaccctgac tggctgcagt gccctccctg2281 ggacctccca cgtcctgggg gcctacgccg tagacaacac gtgtgtagtc aggagccggg2341 acgtcagcac tacaggcagc accagcgaag gggccgtgac agccgttgcc atctgctgcc2401 ggagccggca cctggcgcag gcctcccagg agctccagtg acagccccat cccaggatgg2461 gtgtctgggg agggtcaagg gctggggctg agctttaaaa tggttccgac ttgtccctct2521 ctcagccctc catggcctgg cacgagggga tggggatgct tccgcctttc cggggctgct2581 ggcctggccc ttgagtgggg cagcctcctt gcctggaact cactcactct gggtgcctcc2641 tccccaggtg gaggtgccag gaagctccct ccctcactgt ggggcatttc accattcaaa2701 caggtcgagc tgtgctcggg tgctgccagc tgctcccaat gtgccgatgt ccgtgggcag2761 aatgactttt attgagctct tgttccgtgc caggcattca atcctcaggt ctccaccaag2821 gaggcaggat tcttcccatg gataggggag ggggcggtag gggctgcagg gacaaacatc2881 gttggggggt gagtgtgaaa ggtgctgatg gccctcatct ccagctaact gtggagaagc2941 ccctgggggc tccctgatta atggaggctt agctttctgg atggcatcta gccagaggct3001 ggagacaggt gcgcccctgg tggtcacagg ctgtgccttg gtttcctgag ccacctttac3061 tctgctctat gccaggctgt gctagcaaca cccaaaggtg gcctgcgggg agccatcacc3121 taggactgac tcggcagtgt gcagtggtgc atgcactgtc tcagccaacc cgctccacta3181 cccggcaggg tacacattcg cacccctact tcacagagga agaaacctgg aaccagaggg3241 ggcgtgcctg ccaagctcac acagcaggaa ctgagccaga aacgcagatt gggctggctc3301 tgaagccaag cctcttctta cttcacccgg ctgggctcct catttttacg ggtaacagtg3361 aggctgggaa ggggaacaca gaccaggaag ctcggtgagt gatggcagaa cgatgcctgc3421 aggcatggaa ctttttccgt tatcacccag gcctgattca ctggcctggc ggagatgctt3481 ctaaggcatg gtcgggggag agggccaaca actgtccctc cttgagcacc agccccaccc3541 aagcaagcag acatttatct tttgggtctg tcctctctgt tgccttttta cagccaacttPAT059887-PCT-SEC013601 ttctagacct gttttgcttt tgtaacttga agatatttat tctgggtttt gtagcatttt3661 tattaatatg gtgacttttt aaaataaaaa caaacaaacg ttgtcctaac aaaaaaaaaa3721 aaaaaaaaaa a

[0092] Homo sapiens PCSK9, transcript variant 1, mRNA : GenBank: NM_174936.4 (SEQ ID NO: 2)1 agcgacgtcg aggcgctcat ggttgcaggc gggcgccgcc gttcagttca gggtctgagc61 ctggaggagt gagccaggca gtgagactgg ctcgggcggg ccgggacgcg tcgttgcagc121 agcggctccc agctcccagc caggattccg cgcgcccctt cacgcgccct gctcctgaac181 ttcagctcct gcacagtcct ccccaccgca aggctcaagg cgccgccggc gtggaccgcg241 cacggcctct aggtctcctc gccaggacag caacctctcc cctggccctc atgggcaccg301 tcagctccag gcggtcctgg tggccgctgc cactgctgct gctgctgctg ctgctcctgg361 gtcccgcggg cgcccgtgcg caggaggacg aggacggcga ctacgaggag ctggtgctag421 ccttgcgttc cgaggaggac ggcctggccg aagcacccga gcacggaacc acagccacct481 tccaccgctg cgccaaggat ccgtggaggt tgcctggcac ctacgtggtg gtgctgaagg541 aggagaccca cctctcgcag tcagagcgca ctgcccgccg cctgcaggcc caggctgccc601 gccggggata cctcaccaag atcctgcatg tcttccatgg ccttcttcct ggcttcctgg661 tgaagatgag tggcgacctg ctggagctgg ccttgaagtt gccccatgtc gactacatcg721 aggaggactc ctctgtcttt gcccagagca tcccgtggaa cctggagcgg attacccctc781 cacggtaccg ggcggatgaa taccagcccc ccgacggagg cagcctggtg gaggtgtatc841 tcctagacac cagcatacag agtgaccacc gggaaatcga gggcagggtc atggtcaccg901 acttcgagaa tgtgcccgag gaggacggga cccgcttcca cagacaggcc agcaagtgtg961 acagtcatgg cacccacctg gcaggggtgg tcagcggccg ggatgccggc gtggccaagg1021 gtgccagcat gcgcagcctg cgcgtgctca actgccaagg gaagggcacg gttagcggca1081 ccctcatagg cctggagttt attcggaaaa gccagctggt ccagcctgtg gggccactgg1141 tggtgctgct gcccctggcg ggtgggtaca gccgcgtcct caacgccgcc tgccagcgcc1201 tggcgagggc tggggtcgtg ctggtcaccg ctgccggcaa cttccgggac gatgcctgcc1261 tctactcccc agcctcagct cccgaggtca tcacagttgg ggccaccaat gcccaagacc1321 agccggtgac cctggggact ttggggacca actttggccg ctgtgtggac ctctttgccc1381 caggggagga catcattggt gcctccagcg actgcagcac ctgctttgtg tcacagagtg1441 ggacatcaca ggctgctgcc cacgtggctg gcattgcagc catgatgctg tctgccgagc1501 cggagctcac cctggccgag ttgaggcaga gactgatcca cttctctgcc aaagatgtcaPAT059887-PCT-SEC011561 tcaatgaggc ctggttccct gaggaccagc gggtactgac ccccaacctg gtggccgccc1621 tgccccccag cacccatggg gcaggttggc agctgttttg caggactgta tggtcagcac1681 actcggggcc tacacggatg gccacagccg tcgcccgctg cgccccagat gaggagctgc1741 tgagctgctc cagtttctcc aggagtggga agcggcgggg cgagcgcatg gaggcccaag1801 ggggcaagct ggtctgccgg gcccacaacg cttttggggg tgagggtgtc tacgccattg1861 ccaggtgctg cctgctaccc caggccaact gcagcgtcca cacagctcca ccagctgagg1921 ccagcatggg gacccgtgtc cactgccacc aacagggcca cgtcctcaca ggctgcagct1981 cccactggga ggtggaggac cttggcaccc acaagccgcc tgtgctgagg ccacgaggtc2041 agcccaacca gtgcgtgggc cacagggagg ccagcatcca cgcttcctgc tgccatgccc2101 caggtctgga atgcaaagtc aaggagcatg gaatcccggc ccctcaggag caggtgaccg2161 tggcctgcga ggagggctgg accctgactg gctgcagtgc cctccctggg acctcccacg2221 tcctgggggc ctacgccgta gacaacacgt gtgtagtcag gagccgggac gtcagcacta2281 caggcagcac cagcgaaggg gccgtgacag ccgttgccat ctgctgccgg agccggcacc2341 tggcgcaggc ctcccaggag ctccagtgac agccccatcc caggatgggt gtctggggag2401 ggtcaagggc tggggctgag ctttaaaatg gttccgactt gtccctctct cagccctcca2461 tggcctggca cgaggggatg gggatgcttc cgcctttccg gggctgctgg cctggccctt2521 gagtggggca gcctccttgc ctggaactca ctcactctgg gtgcctcctc cccaggtgga2581 ggtgccagga agctccctcc ctcactgtgg ggcatttcac cattcaaaca ggtcgagctg2641 tgctcgggtg ctgccagctg ctcccaatgt gccgatgtcc gtgggcagaa tgacttttat2701 tgagctcttg ttccgtgcca ggcattcaat cctcaggtct ccaccaagga ggcaggattc2761 ttcccatgga taggggaggg ggcggtaggg gctgcaggga caaacatcgt tggggggtga2821 gtgtgaaagg tgctgatggc cctcatctcc agctaactgt ggagaagccc ctgggggctc2881 cctgattaat ggaggcttag ctttctggat ggcatctagc cagaggctgg agacaggtgc2941 gcccctggtg gtcacaggct gtgccttggt ttcctgagcc acctttactc tgctctatgc3001 caggctgtgc tagcaacacc caaaggtggc ctgcggggag ccatcaccta ggactgactc3061 ggcagtgtgc agtggtgcat gcactgtctc agccaacccg ctccactacc cggcagggta3121 cacattcgca cccctacttc acagaggaag aaacctggaa ccagaggggg cgtgcctgcc3181 aagctcacac agcaggaact gagccagaaa cgcagattgg gctggctctg aagccaagcc3241 tcttcttact tcacccggct gggctcctca tttttacggg taacagtgag gctgggaagg3301 ggaacacaga ccaggaagct cggtgagtga tggcagaacg atgcctgcag gcatggaact3361 ttttccgtta tcacccaggc ctgattcact ggcctggcgg agatgcttct aaggcatggtPAT059887-PCT-SEC013421 cgggggagag ggccaacaac tgtccctcct tgagcaccag ccccacccaa gcaagcagac3481 atttatcttt tgggtctgtc ctctctgttg cctttttaca gccaactttt ctagacctgt3541 tttgcttttg taacttgaag atatttattc tgggttttgt agcattttta ttaatatggt3601 gactttttaa aataaaaaca aacaaacgtt gtcctaa

[0093] In certain aspects, PCSK9 may include a fragment, variant, or mutant of the protein that may have the same or similar amino acid sequences (e.g., having about 80%, 85%, 90%, 95%, or 99% or greater of similarity or identity of amino acid sequences) with any one of the above listed PCSK9 gene (mRNA) or protein sequences. In certain aspects, PCSK9 may include a fragment, variant, or mutant of the protein having the same or in similar in vivo or in vitro enzymatic (e.g., reductase) activity, for example, having about 80%, 85%, 90%, 95%, or 99% or the native protein activity, to bind to LDLR on the surface of a liver cell.

[0094] The term “3-hydroxy-3-methylglutaryl-CoA reductase,” as used herein and also interchangeably used with the term “HMGCR,” refers to a gene or protein (e.g., enzyme or reductase) thereof that converts 3-hydroxy-3-methylglutaryl coenzyme A (“HMG-CoA”) to mevalonate in cholesterol or isoprenoid synthesis. The term “HMGCR” also includes isoforms of proteins encoded by HMGCR mRNA sequences expressed in any vertebrate or mammals (e.g., human, mouse, rat, monkey, dog, cat, horse, pig, or cow). In certain aspect, HMGCR may be identified with NCBI Gene ID, for example, human HMGCR Gene ID: 3156, mouse HMGCR Gene ID: 15357, rat HMGCR Gene ID: 25675, Rhesus monkey HMGCR Gene ID: 705479, dog HMGCR Gene ID: 479182, or cat HMGCR Gene ID: 101098922.

[0095] In certain aspect, HMGCR may be identified with mRNA transcript, for example, human HMGCR mRNA transcript (e.g., NM_000859.3; NM_001130996.2; and NM_001364187.1), mouse HMGCR mRNA transcript (e.g., NM_008255.2; NM_001360165.1; and NM_001360166.1), rat HMGCR mRNA transcript (e.g., NM_013134.2), Cynomolgus monkey HMGCR mRNA (e.g., XM_005557178.1), Rhesus monkey HMGCR mRNA (e.g., XM_001104607.4; and XM_002804417.3), dog HMGCR mRNA (e.g., XM_038471609.1; XM_038471611.1; and XM_038471610.1) and cat HMGCR mRNA (e.g., XM_003981075.6; and XM 019835641.3). In certain aspect, HMGCR may be identified with amino acid sequences, such as such as human HMGCR protein (e.g., NP_000850.1; NP_001124468.1; and NP_001351116.1), mouse HMGCR protein (e.g., NP_032281.2; NP_001347094.1; and NP_001347095.1), rat HMGCR protein (e.g., NP_037266.2), Rhesus monkey protein (e.g.,PAT059887-PCT-SEC01XP_OO 1104607.3; and XP_002804463.3), dog HMGCR protein (e.g., XP 038327537.1; XP_038327539.1; and XP_038327538.1), or cat HMGCR protein (e.g., XP_003981124.1 and XP_019691200.1). Examples of HMGCR gene, mRNA and proteins are not limited to the above list and may further include examples publicly available information from web database, for example, in GenBank, UniProt, Ensembl, Alliance and the like.

[0096] In certain aspect, HMGCR may include a fragment, variant, or mutant of the protein that may have the same or similar amino acid sequences (e.g., having about 80%, 85%, 90%, 95%, or 99% or greater of similarity or identity of amino acid sequences) with any one of the above listed HMGCR gene (mRNA) or protein sequences. In certain aspect, HMGCR may include a fragment, variant, or mutant of the protein having the same or in similar in vivo or in vitro enzymatic (e.g., reductase) activity, for example, having about 80%, 85%, 90%, 95%, or 99% or the native enzyme activity, to produce mevalonate from HMG-CoA.

[0097] As defined herein, the term “inhibition”, “inhibit”, “inhibiting” and the like mean negatively affecting (e.g. decreasing) activity, expression or function relative to the activity, expression or function in the absence of an inhibitor. In certain aspects, inhibition can mean negatively affecting (e.g. decreasing) the concentration or levels of a biomolecule, such as a protein or mRNA, relative to the concentration or level of the biomolecule in the absence of an inhibitor. In certain aspects, inhibition includes, partially or totally, blocking stimulation, decreasing, preventing, or delaying activation; inactivating, desensitizing, or down-regulating signal transduction or enzymatic activity; or decreasing the amount of a biomolecule target (e.g., protein target or mRNA target). In certain aspects, inhibition refers to a reduction in the expression of a particular biomolecule target, such as a protein target (e.g., PCSK9 protein and / or HMGCR protein) or an mRNA target (e.g., PCSK9 mRNA and / or HMGCR mRNA). In certain aspects, inhibition refers to a reduction of amount of a target biomolecule (e.g., PCSK9 protein or mRNA and / or HMGCR protein or mRNA) resulting from a down-regulating protein expression (e.g. directly inhibiting translation or transcription). In certain aspects, inhibition refers to a reduction of activity of a target biomolecule (e.g., PCSK9 protein or mRNA and / or HMGCR protein or mRNA) from an indirect interaction (e.g., inhibiting or regulating other transcriptional or translational factors).

[0098] The term “inhibitor” also refers to antisense agent(s) (e.g., dsRNAi agent(s)), compounds, pharmaceutical compositions, or substances capable of detectably negativelyPAT059887-PCT-SEC01 affecting (e.g. decreasing) activity, expression or function of a given protein or gene. For example, an inhibitor may decrease activity, expression or function by about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or greater in comparison to a control in the absence of the inhibitor. Inhibitors include, for example, synthetic or biological molecules, such as oligonucleotides. In some embodiments, the inhibitors include an RNAi agent, e.g., siRNA agent, dsRNAi agent, or dsRNA agent. In some embodiments, the inhibitors include an antisense oligonucleotide (ASO).

[0099] As used herein, the “level or degree of inhibiting or decreasing expression” of a given gene refers to the at least partial suppression of the expression of a target gene (e.g., PCSK9 and / or HMGCR), as manifested by a reduction of the amount of the target gene mRNA (e.g., PCSK9 mRNA and / or HMGCR mRNA) or protein (e.g., PCSK9 and / or HMGCR) encoded by the target gene, which may be isolated from or detected in a group of cells (“a first cell”) in which a target gene is transcribed and which has or have been treated such that the expression of a target gene is inhibited, as compared to group of cells substantially identical to the first cell but without treated (“control cells” or “a second cell”).[000100] In some embodiments, the level or expression of the target gene (e.g., PCSK9 and / or HMGCR) can be measured by evaluation of mRNA (e.g., via Northern blots or PCR). The effect of the antisense agent(s) (e.g., dsRNAi(s) agent) on the target gene (e.g., PCSK9 and / or HMGCR) expression can be determined by measuring the gene transcription rates (e.g., via Northern blots; or reverse transcriptase polymerase chain reaction or real-time polymerase chain reaction). In some embodiments, the degree of inhibition can be calculated as the following equation:(mRNA in control cells) - (mRNA in treated cells) - • 100 %(mRNA in control cells)[000101] Alternatively, the degree of inhibition may be given in terms of a reduction of a parameter that is functionally linked to target gene (e.g., PCSK9 and / or HMGCR) expression, e.g., the amount of protein encoded by a target gene (e.g., PCSK9 and / or HMGCR), alteration in expression of the protein whose expression is dependent on the target gene (e.g., PCSK9 and / or HMGCR), alteration in an activity of the enzyme (e.g., PCSK9 and / or HMGCR) encoded by the target gene (e.g., PCSK9 and / or HMGCR). In some embodiments, the level or expression of the protein (e.g., PCSK9 and / or HMGCR) from the target gene can be evaluated by measuring the expressed protein amount (e.g., Western blots). In some embodiments, the level or expression ofPAT059887-PCT-SEC01 the protein from the target gene can be measured by the enzymatic assay (e.g., kinetic assay) of the protein.[000102] As used herein, the term “down-regulate” or “down-regulating” refers to any decrease (e.g., statistically significant) in a biological activity and / or expression of the target protein (e.g., PCSK9 and / or HMGCR), including full blocking of the activity (i.e., complete inhibition) and / or expression. For example, “down-regulation” can refer to a decrease of at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100% in target protein (e.g., PCSK9 and / or HMGCR) level, activity and / or expression.[000103] As used herein, the terms “salt” or “salts” refers to an acid addition or base addition salt of an antisense agent or antisense agents (e.g., dsRNAi agent or dsRNAi agents) of the present invention. “Salts” include in particular “pharmaceutical acceptable salts”. The term “pharmaceutically acceptable salts” refers to salts that retain the biological effectiveness and properties of the antisense agent(s) (e.g., dsRNAi agent(s)) of this invention and, which typically are not biologically or otherwise undesirable. In many cases, the antisense agent(s) (e.g., dsRNAi agent(s)) of the present invention are capable of forming acid and / or base salts by virtue of the presence of amino and / or carboxyl groups or groups similar thereto. When both a basic group and an acid group are present in the same molecule, the antisense agent(s) (e.g., dsRNAi agent(s)) of the present invention may also form internal salts, e.g., zwitterionic molecules. In certain aspects, pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Examples of the inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Examples of the organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, and the like. In certain aspects, the pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Examples of the inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I to XII of the periodic table, such as sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium and magnesium salts. Examples of the organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted aminesPAT059887-PCT-SEC01 including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, such as organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine and tromethamine.[000104] In certain aspects, the term “pharmaceutically acceptable salt” as used herein may include the salts forms in acetate, ascorbate, adipate, aspartate, benzoate, besylate, bromide / hydrobromide, bicarbonate / carbonate, bisulfate / sulfate, camphorsulf onate, caprate, chloride / hydrochloride, chlortheophyllonate, citrate, ethandisulfonate, fumarate, gluceptate, gluconate, glucuronate, glutamate, glutarate, glycolate, hippurate, hydroiodide / iodide, isethionate, lactate, lactobionate, laurylsulfate, malate, maleate, malonate, mandelate, mesylate, methylsulphate, mucate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, polygalacturonate, propionate, sebacate, stearate, succinate, sulfosalicylate, sulfate, tartrate, tosylate trifenatate, trifluoroacetate or xinafoate.[000105] As used herein, the term "pharmaceutically acceptable carrier" refers to a substance useful in the preparation or use of a pharmaceutical composition and includes, for example, suitable diluents, solvents, dispersion media, surfactants, antioxidants, preservatives, isotonic agents, buffering agents, emulsifiers, absorption delaying agents, salts, drug stabilizers, binders, excipients, disintegration agents, lubricants, wetting agents, sweetening agents, flavoring agents, dyes, and combinations thereof, as would be known to those skilled in the art (see, for example, Remington The Science and Practice of Pharmacy, 22nd Ed. Pharmaceutical Press, 2013, pp. 1049-1070).[000106] As used herein, the term “treat,” “treating,” or “treatment” of any disease or disorder refers to alleviating or ameliorating the disease or disorder (i.e., slowing or arresting the development of the disease or at least one of the clinical symptoms thereof); or alleviating or ameliorating at least one physical parameter or biomarker associated with the disease or disorder, including those which may not be discernible to the patient. In some embodiments, treating does not include preventing.[000107] As used herein, the term “prevent”, “preventing" or “prevention” of any disease or disorder refers to the prophylactic treatment of the disease or disorder; or delaying the onset or progression of the disease or disorder. It also refers to a reduction in the likelihood that a subject will develop a symptom associated with such a disease, disorder, or condition, e.g., a symptom ofPAT059887-PCT-SEC01 a PCSK9-associated disorder and / or an HMGCR-associated disorder, e.g., a disorder of lipid metabolism, e.g., hyperlipidemia. The failure to develop a disease, disorder or condition, or the reduction in the development of a symptom associated with such a disease, disorder or condition (e.g., by at least about 10% on a clinically accepted scale for that disease or disorder), or the exhibition of delayed symptoms that are delayed, e.g., by days, weeks, months or years, which is considered an effective prevention.[000108] The term “therapy,” as used herein refers to an application of one or more specific procedures used for the amelioration of at least one indicator or a disease or condition. In certain aspects, the specific procedure is the administration of one or more pharmaceutical or therapeutic agents.[000109] The term “associated” or “associated with” in the context of a substance or substance activity or function associated with a disease (e.g. a protein associated disease, or PCSK9 associated disease and / or HMGCR associated disease) means that the disease is caused by (in whole or in part), or a symptom of the disease is caused by (in whole or in part) the substance or substance activity or function (e.g., PCSK9 activity or function and / or HMGCR activity or function). Thus, as used herein, what is described as “being associated” with a disease, if a causative agent, could be a target for treatment of the disease.[000110] As used herein, the term “hyperlipidemia” refers to any disorder, disease or condition characterized by abnormal elevation of levels of any or all lipids, such as cholesterol and triglycerides, and / or lipoproteins in the blood or a condition that can lead to abnormal elevation of levels of any or all lipids and / or lipoproteins in the blood. In some embodiments, the hyperlipidemia is hypertriglyceridemia. As used herein, the term “hypertriglyceridemia” refers to a condition in which triglyceride levels are elevated, often caused or exacerbated by uncontrolled hyperlipidemia mellitus, obesity, and sedentary habits. In some embodiments, hypertriglyceridemia means triglycerides in blood are greater than 1000-2000 mg / dL. In some embodiments, the hyperlipidemia is hypercholesterolemia. As used herein the term “hypercholesterolemia” refers to a form of hyperlipidemia (elevated levels of lipids in the blood) in which there are high levels of cholesterol in the serum of a subject. In some embodiments, hypercholesterolemia means at least about 240 mg / dL of total cholesterol.[000111] As used herein, the term “administering” means oral administration, administration as a suppository, topical contact, intravenous, intraperitoneal, intramuscular, intralesional,PAT059887-PCT-SEC01 intrathecal, intranasal or subcutaneous administration, or the implantation of a slow-release device, e.g., a mini-osmotic pump, to a subject. Administration is by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal) compatible with the preparation. Parenteral administration includes, e.g., intravenous, intramuscular, intra-arteriole, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, etc.[000112] As used herein, the term “antisense agent” refers to an oligonucleotide that can provide a therapeutic effect, e.g. by interacting with a biomolecule and / or by regulating gene expression. Antisense agents include, but are not limited to, RNA interference (RNAi) agents (e.g. dsRNAi agents) and antisense oligonucleotides (ASO). RNAi is a post-transcriptional, targeted genesilencing technique that uses RNAi agents to degrade messenger RNA (mRNA) from a gene of interest. ASOs are single-stranded nucleic acids that can be used to target mRNA derived from a gene of interest. ASOs can alter gene expression via a number of mechanisms including direct steric blockage of mRNA and ribonuclease H (RNase H) mediated degradation of mRNA.[000113] The term “combination,” embraces mixtures of first and second antisense agents, e.g., dsRNAi agents. The term “combination,” also embraces first and second antisense agents, e.g., dsRNAi agents, which are formulated separately. In some embodiments, the first antisense agent (e.g., a first dsRNAi agent) and / or the second antisense agent (e.g., a second dsRNAi agent) are administered together with one or more additional therapeutic agents. In certain embodiments, the first antisense agent (e.g., a first dsRNAi agent) is administered at the same time, prior to, or after the administration of the second antisense agent (e.g., a second dsRNAi agent). In certain embodiments, the first antisense agent (e.g., a first dsRNAi agent) and the second antisense agent (e.g., a second dsRNAi agent) are administered together. In some embodiments, the first antisense agent (e.g., a first dsRNAi agent) is formulated with one or more additional therapeutic agents, optionally in the same pharmaceutical composition as the first antisense agent (e.g., the first dsRNAi agent). In some embodiments, the second antisense agent (e.g., a second dsRNAi agent) is formulated with one or more additional therapeutic agents, optionally in the same pharmaceutical composition as the second antisense agent (e.g., a second dsRNAi agent). In some embodiments, the first antisense agent (e.g., a first dsRNAi agent) and the second antisense agent (e.g., a second dsRNAi agent) are formulated with one or more additional therapeutic agents,PAT059887-PCT-SEC01 optionally in the same pharmaceutical composition as the first antisense agent (e.g., the first dsRNAi agent) and the second antisense agent (e.g., the second dsRNAi agent).[000114] Additional therapeutic agents include, for example, other active drugs known to be useful in treating a disease (e.g., hyperlipidemia, hypercholesterolemia or ASCVD) or with adjunctive agents that may not be effective alone or may be known to be useful in treating a disease (e.g., hyperlipidemia, hypercholesterolemia or ASCVD). In some embodiments, the one or more additional therapeutic agents are administered alone (or separately) or can be co-administered to a patient with the first and / or second dsRNAi agent.[000115] In some embodiments, the first antisense agent (e.g., first dsRNAi agent) and the second antisense agent (e.g., second dsRNAi agent) are co-administered. Co-administration includes administering the first antisense agent (e.g., first dsRNAi agent) within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours of the second antisense agent (e.g., second dsRNAi agent). Coadministration includes administering the first antisense agent (e.g., first dsRNAi agent) and the second antisense agent (e.g. second dsRNAi agent) simultaneously, approximately simultaneously (e.g., within about 1, 5, 10, 15, 20, or 30 minutes of each other), or sequentially in any order. In some embodiments, co-administration can be accomplished by co-formulation, i.e., preparing a single pharmaceutical composition including the first antisense agent (e.g., first dsRNAi agent) and the second antisense agent (e.g., second dsRNAi agent). In some embodiments, the first antisense agent (e.g., first dsRNAi agent) and the second antisense agent (e.g., second dsRNAi agent) are formulated separately.[000116] The terms "subject" and “patient” as used herein are used interchangeably. The term subject includes a human or non-human animal, preferably a vertebrate, and more preferably a mammal. In certain aspects, the subject is a human. In certain aspects, the subject is a human patient.[000117] As used herein, a subject is “in need of’ a treatment if such subject would benefit biologically, medically or in quality of life from such treatment.[000118] The term "a therapeutically effective amount" of an antisense agent or antisense agents, e.g., dsRNAi agent or dsRNAi agent(s) (e.g., siRNA(s)) as disclosed herein refers to an amount of the antisense agent or antisense agents (e.g., dsRNAi agent or dsRNAi agent(s)) that will elicit the biological or medical response of a subject, for example, reduction or inhibition of an enzyme or a protein activity, or ameliorate symptoms, alleviate conditions, slow or delay diseasePAT059887-PCT-SEC01 progression, or prevent a disease, etc. In certain aspects, the term “a therapeutically effective amount” refers to the amount of the antisense agent or antisense agents, e.g., dsRNAi agent or dsRNAi agent(s) (e.g., siRNA(s)) of the disclosure that, when administered to a subject, is effective to (1) at least partially alleviate, prevent and / or ameliorate a condition, or a disorder or a disease (i) mediated by the target gene (e.g., PCSK9 and / or HMGCR), or (ii) associated with its activity, or (iii) characterized by activity (normal or abnormal) of the protein encoded by the target gene (e.g., PCSK9 and / or HMGCR); or (2) reduce or inhibit the activity of the protein encoded by the target gene (e.g., PCSK9 and / or HMGCR); or (3) reduce or inhibit the expression of the target gene (e.g., PCSK9 and / or HMGCR). In certain aspects, the term “a therapeutically effective amount” refers to the amount of the antisense agent(s) (e.g., dsRNAi agent(s)) that, when administered to a cell, or a tissue, or a non-cellular biological material, or a medium, is effective to at least partially reducing or inhibiting the activity of the protein encoded by the target gene (e.g., PCSK9 and / or HMGCR); or at least partially reducing or inhibiting the expression of the protein (e.g., PCSK9 and / or HMGCR) encoded by the target gene. The meaning of the term “a therapeutically effective amount” as illustrated in the above embodiment for the target gene expression also applies by the same means to any other relevant proteins / peptides / enzymes (e.g., PCSK9, HMGCR or other proteins relevant to cholesterol uptake or biosynthesis).[000119] For any antisense agent(s) (e.g., dsRNAi agent(s)) described herein, the therapeutically effective amount can be initially determined from cell culture assays. Target concentrations will be those concentrations of active antisense agent(s) (e.g., dsRNAi agent(s)) or compound(s) that are capable of achieving the methods described herein, as measured using the methods described herein or known in the art. Therapeutically effective amounts for use in humans can also be determined from animal models. For example, a dose for humans can be formulated to achieve a concentration that has been found to be effective in animals. The dosage in humans can be adjusted by monitoring effectiveness and adjusting the dosage upwards or downwards, as described above. An example of an “therapeutically effective amount” is an amount sufficient to contribute to the treatment, prevention, or reduction of a symptom or symptoms of a disease. For example, for the given parameter (e.g., biomarker), a therapeutically effective amount will show an increase or decrease of at least about 5%, about 10%, about 15%, about 20%, about 25%, about 40%, about 50%, about 60%, about 75%, about 80%, about 90%, or about 95%. Therapeutic efficacy can alsoPAT059887-PCT-SEC01 be expressed as “-fold” increase or decrease. For example, a therapeutically effective amount can have at least a 1.2-fold, 1.5-fold, 2-fold, 5-fold, or more effect over a control.[000120] The term “control” or “control experiment” is used in accordance with its plain ordinary meaning and refers to an experiment in which the subjects or reagents of the experiment are treated as in a parallel experiment except for omission of a procedure, reagent, or variable of the experiment. Typically, a control is used as a standard of comparison in evaluating experimental effects. In some embodiments, a control is the measurement of the expression of a protein or mRNA (e.g., PCSK9 and / or HMGCR) in the absence of antisense agent(s) (e.g., RNAi agent(s)) as described herein.[000121] Unless defined otherwise, the chemical structures and formulae set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts.[000122] The term “alkyl,” by itself or as part of another substituent, means, unless otherwise stated, a straight (i.e., unbranched) or branched carbon chain (or carbon), or combination thereof, which is fully saturated (i.e., molecule by only single bonds) and include mono-, di- and multivalent radicals. As used herein, the alkyl is an uncyclized chain. The alkyl may include a designated number of carbons (e.g., Ci-Cio means one to ten carbons). Examples of alkyl include, but are not limited to, groups such as C1-30 alkyl, C1-25 alkyl, C1-20 alkyl, C1-15 alkyl, C1-12 alkyl, Ci- 10 alkyl, C1-8 alkyl, C1-6 alkyl, Ci-4 alkyl, or C1-3 alkyl. For example, C1-6 alkyl include, but are not limited to, methyl, ethyl, n-propyl, 1 -methylethyl (iso-propyl), n-butyl, n-pentyl and 1,1- dimethylethyl (t-butyl), and their isomers.[000123] A term “alkylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkyl, as exemplified, but not limited by, - CH2CH2CH2CH2-.[000124] As used herein, the term "alkenyl," by itself or as part of another substituent, means, unless otherwise stated, a straight (i.e., unbranched) or branched carbon chain (or carbon), or combination thereof, which is mono- or polyunsaturated (i.e., molecule including at least one double bond) and include mono-, di- and multivalent radicals. As used herein, the alkenyl is an uncyclized chain. Like the alkyl, the alkenyl may include a designated number of carbons (e.g., C1-C10 means one to ten carbons). Examples of alkenyl include, but are not limited to, groups such as Ci-30 alkenyl, C1-25 alkenyl, C1-20 alkenyl, C1-15 alkenyl, C1-12 alkenyl, C1-10 alkenyl, C1-8 alkenyl, C1-6 alkenyl, Ci-4 alkenyl, or C1-3 alkenyl. For example, C2-6 alkenyl include, but are not limited to,PAT059887-PCT-SEC01 ethenyl (vinyl), prop-l-enyl, but-l-enyl, pent-l-enyl, pent-4-enyl and penta- 1,4-dienyl, and their isomers. A term “alkenylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkenyl, as exemplified, but not limited by, - CH=CHCH2CH2-.[000125] As used herein, the term " alkynyl," by itself or as part of another substituent, means, unless otherwise stated, a straight (i.e., unbranched) or branched carbon chain (or carbon), or combination thereof, which is mono- or polyunsaturated (i.e., molecule including at least one triple bond) and include mono-, di- and multivalent radicals. As used herein, the alkynyl is an uncyclized chain. Like the alkyl, the alkynyl may include a designated number of carbons (e.g., C1-C10 means one to ten carbons). Examples of alkynyl include, but are not limited to, groups such as C1-30 alkynyl, Ci-25 alkynyl, C1-20 alkynyl, C1-15 alkynyl, C1-12 alkynyl, C1-10 alkynyl, C1-8 alkynyl, C1-6 alkynyl, Ci-4 alkynyl, or C1-3 alkynyl. For example, C2-6 alkynyl include, but are not limited to, alkynyl, and their isomers. A term “alkynyl,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkenyl, as exemplified, but not limited by, -CCH2CH2-.[000126] As used herein, the term “alkoxy” refers to a radical of the formula -ORawhere Rais an alkyl (e.g., C1-30 alkyl, Ci-25 alkyl, C1-20 alkyl, C1-15 alkyl, C1-12 alkyl, C1-10 alkyl, C1-8 alkyl, C1-6 alkyl, C1-4 alkyl, or C1-3 alkyl) radical as generally defined above. For example, C1-6 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentoxy, and hexoxy.[000127] As used herein, the term " alkoxyalkyl " refers to a radical of the formula -Ra-0-Rbwhere each Raand Rbis independently an alkyl (e.g., C1-30 alkyl, Ci-25 alkyl, C1-20 alkyl, C1-15 alkyl, Ci-i2alkyl, Ci-10 alkyl, C1-8 alkyl, C1-6 alkyl, C1-4 alkyl, or C1-3 alkyl) radical as defined above and oxygen atom may be bonded to any carbon atom in either alkyl radical. For example, Ci-ealkoxy Ci-ealkyl include, but are not limited to, methoxy-methyl, methoxy-ethyl, ethoxy-ethyl, 1 -ethoxy- propyl and 2-methoxy-butyl.[000128] As used herein, the term “alkylcarbonyl” refers to a radical of the formula -C(=O)-Ra where Rais an alkyl (e.g., C1-30 alkyl, Ci-25 alkyl, C1-20 alkyl, C1-15 alkyl, C1-12 alkyl, C1-10 alkyl, Ci- 8 alkyl, C1-6 alkyl, Ci-4 alkyl, or C1-3 alkyl) radical as defined above.[000129] As used herein, the term "alkyl-carbonyl alkyl” refers to a radical of the formula, e.g., -Ra-C(=O)-Rbwhere each Raand Rbis independently an alkyl (e.g., C1-30 alkyl, Ci-25 alkyl, C1-20PAT059887-PCT-SEC01 alkyl, Ci-15 alkyl, C1-12 alkyl, C1-10 alkyl, C1-8 alkyl, C1-6 alkyl, C1-4 alkyl, or C1-3 alkyl) radical as defined above. The carbon atom of the carbonyl group may be bonded to any carbon atom in either alkyl radical.[000130] As used herein, the term "alkylaminocarbonyl" refers to a radical of the formula - C(=O)-NH-Rawhere Rais an alkyl (e.g., C1-30 alkyl, C1-25 alkyl, C1-20 alkyl, C1-15 alkyl, C1-12 alkyl, Ci-10 alkyl, Ci-8 alkyl, C1-6 alkyl, Ci-4 alkyl, or C1-3 alkyl) as defined above.[000131] As used herein, the term "alkoxy carbonyl” refers to a radical of the formula -C(=O)- O-Rawhere Rais an alkyl (e.g., C1-30 alkyl, C1-25 alkyl, C1-20 alkyl, C 1-15 alkyl, C1-12 alkyl, C1-10 alkyl, Ci-8 alkyl, C1-6 alkyl, Ci-4 alkyl, or C1-3 alkyl) radical as defined above.[000132] As used herein, the term “alkoxy carbonyl alkyl” refers to a radical of the formula -Ra- C(=O)-O-Rbwhere each Raand Rbis independently an alkyl (e.g., C1-30 alkyl, C1-25 alkyl, C1-20 alkyl, Ci-15 alkyl, C1-12 alkyl, C1-10 alkyl, C1-8 alkyl, C1-6 alkyl, C1-4 alkyl, or C1-3 alkyl) radical as defined above.[000133] As used herein, the term "haloalkyl" refers to an alkyl (e.g., C1-30 alkyl, C1-25 alkyl, Ci- 20 alkyl, Ci -15 alkyl, Ci -12 alkyl, Ci-10 alkyl, C1-8 alkyl, C1-6 alkyl, C1-4 alkyl, or C1-3 alkyl) radical, as defined above, substituted by one or more halo radicals, as defined above. Examples of halogenCi- ealkyl include, but are not limited to, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, l,3-dibromopropan-2-yl, 3-bromo-2-fluoropropyl and 1,4,4- trifluorobutan-2-yl.[000134] As used herein, the term "hydroxyalkyl” refers to an alkyl (e.g., C1-30 alkyl, C1-25 alkyl, C1-20 alkyl, Ci-15 alkyl, C1-12 alkyl, C1-10 alkyl, C1-8 alkyl, C1-6 alkyl, C1-4 alkyl, or C1-3 alkyl) radical as defined above, wherein one of the hydrogen atoms of the alkyl radical is replaced by OH. Examples of hydroxyCi-6 alkyl include, but are not limited to, hydroxy-methyl, 2-hydroxy-ethyl, 2-hydroxy-propyl, 3-hydroxy-propyl and 5-hydroxy-pentyl.[000135] As used herein, the term “aminoalkyl” refers to an alkyl (e.g., C1-30 alkyl, C1-25 alkyl, C1-20 alkyl, Ci-15 alkyl, C1-12 alkyl, C1-10 alkyl, C1-8 alkyl, C1-6 alkyl, C1-4 alkyl, or C1-3 alkyl) radical as defined above, wherein one of the hydrogen atoms of the Ci -ealkyl group is replaced by a primary amino group. Examples of amino C1-6 alkyl include, but are not limited to, amino-methyl, 2-amino-ethyl, 2-amino-propyl, 3 -amino-propyl, 3 -amino-pentyl and 5-amino-pentyl.PAT059887-PCT-SEC01[000136] As used herein, the term “alkylamino” refers to a radical of the formula -NH-Rawhere Rais an alkyl (e.g., C1-30 alkyl, C1-25 alkyl, C1-20 alkyl, C1-15 alkyl, C1-12 alkyl, C1-10 alkyl, C1-8 alkyl, C1-6 alkyl, C1-4 alkyl, or C1-3 alkyl) radical as defined above.[000137] The term “heteroalkyl,” by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or combination thereof, which is fully saturated (i.e., molecule by only single bonds) and include mono-, di- and multivalent radicals, including at least one carbon atom and at least one heteroatom (e.g., O, N, S, Si, or P), and wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. The heteroatom(s) (e.g., O, N, S, Si, or P) may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. Heteroalkyl is an uncyclized chain. The heteroalkyl may include a designated number of carbons and heteroatoms (e.g., “2 to 10 membered heteroalkyl” means two to 10 atoms including carbons and heteroatoms).[000138] Similarly, the term “heteroalkylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from heteroalkyl, as exemplified, but not limited by, -CH2-CH2-S-CH2-CH2- and -CH2-S-CH2-CH2-NH-CH2-. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like).[000139] As used herein, the term "heteroalkenyl," by itself or as part of another substituent, means, unless otherwise stated, a straight (i.e., unbranched) or branched carbon chain (or carbon), or combination thereof, which is mono- or polyunsaturated (i.e., molecule including at least one double bond between carbon and carbon) and include mono-, di- and multivalent radicals. As used herein, the alkenyl is an uncyclized chain. Like the alkenyl, the heteroalkenyl may include a designated number of carbons and heteroatoms (e.g., “2 to 10 membered heteroalkenyl” means two to 10 atoms including carbons and heteroatoms).[000140] As used herein, the term " heteroalkynyl," by itself or as part of another substituent, means, unless otherwise stated, a straight (i.e., unbranched) or branched carbon chain (or carbon), or combination thereof, which is mono- or polyunsaturated (i.e., molecule including at least one triple bond between carbon and carbon) and include mono-, di- and multivalent radicals. As used herein, the alkynyl is an uncyclized chain. The heteroalkynyl may include a designated numberPAT059887-PCT-SEC01 of carbons and heteroatoms (e.g., “2 to 10 membered heteroalkynyl” means two to 10 atoms including carbons and heteroatoms).[000141] For alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula -C(O)2R'- represents both -C(O)2R'- and -R'C(O)2-.[000142] A “cycloalkylene” and a “heterocycloalkylene,” alone or as part of another substituent, means a divalent radical derived from a cycloalkyl and heterocycloalkyl, respectively. The terms “cycloalkyl” and “heterocycloalkyl,” by themselves or in combination with other terms, mean, unless otherwise stated, cyclic versions of “alkyl” and “heteroalkyl,” respectively. Cycloalkyl and heterocycloalkyl are not aromatic. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1- cyclohexenyl, 3 -cyclohexenyl, cycloheptyl, and the like. Examples of heterocycloalkyl include, but are not limited to, l-(l,2,5,6-tetrahydropyridyl), 1 -piperidinyl, 2-piperidinyl, 3-piperidinyl, 4- morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1 -piperazinyl, 2-piperazinyl, and the like. A “cycloalkylene” and a “heterocycloalkylene,” alone or as part of another substituent, means a divalent radical derived from a cycloalkyl and heterocycloalkyl, respectively.[000143] The term “aryl” means, unless otherwise stated, a polyunsaturated, aromatic, hydrocarbon substituent, which can be a single ring or multiple rings (preferably from 1 to 3 rings) that are fused together (i.e., a fused ring aryl) or linked covalently. A fused ring aryl refers to multiple rings fused together wherein at least one of the fused rings is an aryl ring. The term “heteroaryl” refers to aryl groups (or rings) that contain at least one heteroatom such as N, O, or S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized. Thus, the term “heteroaryl” includes fused ring heteroaryl groups (i.e., multiple rings fused together wherein at least one of the fused rings is a heteroaromatic ring). A5.6-fused ring heteroarylene refers to two rings fused together, wherein one ring has 5 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring. Likewise, a6.6-fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring. And a 6,5- fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members andPAT059887-PCT-SEC01 the other ring has 5 members, and wherein at least one ring is a heteroaryl ring. A heteroaryl group can be attached to the remainder of the molecule through a carbon or heteroatom. Non-limiting examples of aryl and heteroaryl groups include phenyl, naphthyl, pyrrolyl, pyrazolyl, pyridazinyl, triazinyl, pyrimidinyl, imidazolyl, pyrazinyl, purinyl, oxazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidyl, benzothiazolyl, benzooxazoyl benzimidazolyl, benzofuran, isobenzofuranyl, indolyl, isoindolyl, benzothiophenyl, isoquinolyl, quinoxalinyl, quinolyl, 1 -naphthyl, 2-naphthyl, 4-biphenyl, 1 -pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3 -furyl, 2-thienyl, 3 -thienyl, 2-pyridyl, 3 -pyridyl, 4- pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1- isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-quinolyl. Substituents for each of the above noted aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below. An “arylene” and a “heteroarylene,” alone or as part of another substituent, mean a divalent radical derived from an aryl and heteroaryl, respectively.[000144] The terms “halo” or “halogen,” by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as “haloalky 1” are meant to include monohaloalkyl and polyhaloalkyl. For example, the term “halo(Ci-C4)alkyl” includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3 -bromopropyl, and the like.[000145] The symbol “” denotes the point of attachment of a chemical moiety to the remainder of a molecule or chemical formula.[000146] The term “oxo,” as used herein, means an oxygen that is double-bonded to a carbon atom.[000147] Each of the above terms (e.g., “alkyl,” “heteroalkyl,” “cycloalkyl,” “heterocycloalkyl,” “aryl,” and “heteroaryl”) includes both substituted and unsubstituted forms of the indicated radical. Substituents for the alkyl and heteroalkyl radicals (including those groups often referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) can be one or more of a variety of groups selected from, but not limited to, —OR', =0, =NR', =N— OR', — NR'R", —SR', -halogen, — SiR'R''R'", — OC(O)R', — C(O)R', — CO2R', — CONR'R", — OC(O)NR'R", — NR''C(O)R', — NR'—PAT059887-PCT-SEC01C(O)NR"R'", — NR"C(O)2R', — NR— C(NR'R"R'")=NR"", — NR— C(NR'R")=NR'", — S(O)R', — S(O)2R', — S(O)2NR'R", — NRSO2R', — NR'NR"R'", — ONR'R", — NR'C(O)NR"NR'"R"", — CN, — NO2, — NR'SChR", — NR'C(O)R", — NR'C(O)— OR", — NR'OR", in a number ranging from zero to (2m'+l), where m' is the total number of carbon atoms in such radical. R, R', R", R'", and R"" each preferably independently refer to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl (e.g., aryl substituted with 1-3 halogens), substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl, alkoxy, or thioalkoxy groups, or arylalkyl groups. When a dsRNAi agent described herein includes more than one R group, for example, each of the R groups is independently selected as are each R', R", R'", and R"" group when more than one of these groups is present. When R' and R" are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 4-, 5-, 6-, or 7-membered ring. For example, — NR'R" includes, but is not limited to, 1 -pyrrolidinyl and 4-morpholinyl. From the above discussion of substituents, one of skill in the art will understand that the term “alkyl” is meant to include groups including carbon atoms bound to groups other than hydrogen groups, such as haloalky 1 (e.g., - CF3and -CH2CF3) and acyl (e.g., -C(O)CH3, — C(O)CF3, — C(O)CH2OCH3, and the like).[000148] Certain dsRNAi agent(s) provided herein possess asymmetric carbon atoms (optical or chiral centers) or double bonds; the enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)- or, as (D)- or (L)- for amino acids, and individual isomers are encompassed within the scope of the present disclosure. The dsRNAi agent(s) provided herein do not include those that are known in art to be too unstable to synthesize and / or isolate. dsRNAi agent(s) provided herein include those in racemic and optically pure forms. Optically active (R)- and (S)-, or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When the dsRNAi agent(s) described herein contain olefinic bonds (vinyl group) and unless specified otherwise, it is intended that the compounds include both (E) and (Z) geometric isomers.[000149] As used herein, the term “isomers” refers to antisense agent(s) (e.g., dsRNAi agent(s)) having the same number and kind of atoms, and hence the same molecular weight, but differing in respect to the structural arrangement or configuration of the atoms.PAT059887-PCT-SEC01Antisense Agents[000150] The antisense agent may be an RNAi agent. In an aspect, the disclosure provides RNAi agents including a double stranded RNA (dsRNA). In an aspect, also provided are dsRNA interference (dsRNAi) agents that include a dsRNA comprising (i) a sense strand and (ii) an antisense strand. In an aspect, also provided are dsRNA interference (dsRNAi) agents that include a dsRNA comprising (i) a sense strand and (ii) an antisense strand, and a ligand attached to at least one of the sense strand and the antisense strand.[000151] A dsRNA is a complex of ribonucleic acid (RNA) molecules formed in a duplex structure. In certain aspects, the dsRNA may be a small interfering RNA (siRNA) that has 10 to 30, or particularly 15-25 nucleotides in each RNA molecule, respectively, “passenger strand” and “guide strand”, and can be incorporated into an RNA-induced silencing complex (RISC). The siRNA is dissociated or unwounded in the RISC, and the passenger strand is degraded while the guide strand remains in the RISC pathway. The guide strand can subsequently bind to an mRNA molecule that includes a complementary sequence to the guide strand and induce or initiate cleavage or degradation of the mRNA molecule. In certain aspects, the mRNA encodes a target gene (e.g., mRNA transcript of a target gene) such that expression of the target gene is suppressed or inhibited through a post-transcriptional gene-silencing (“RNA silencing”). A guide RNA molecule has a complementary sequence to a target mRNA sequence and has anti-parallel orientation to the target gene, so it is interchangeably referred to as an antisense strand. A passenger RNA molecule forming a duplex with the guide RNA and having a complementary sequence to the guide strand (antisense strand) has the same orientation with the target mRNA sequence, so it is interchangeably referred to as a sense strand.The first antisense agent[000152] In an aspect, the first antisense agent is a PCSK9 inhibitor.[000153] In some embodiments, the first antisense agent is a dsRNAi agent. In some embodiments, the first antisense agent is an ASO or an ASO agent.[000154] The disclosure provides a dsRNA interference (dsRNAi) agent that is capable of interacting or recruiting a target mRNA sequence, e.g., PCSK9 mRNA sequence, in the RISC thereby cleaving the target mRNA. The first dsRNAi agent can silence PCSK9 gene, e.g., by inhibiting, downregulating, or suppressing the expression of PCSK9 gene. Gene-silencing (e.g., inhibiting, downregulating, or suppressing of the gene) may be assessed by a decrease in anPAT059887-PCT-SEC01 absolute or relative level of one or more variables that are associated with PCSK9 expression compared with a control level. The control level may be any type obtained from, e.g., a pre-dose baseline level, or a level determined from a similar subject, cell, or untreated or treated subject with inactive agents (e.g., PBS buffer). In some embodiments, the level of silencing the PCSK9 may be demonstrated by a reduction of the amount of a total PCSK9 mRNA in a cell. In some embodiments, the level of silencing the PCSK9 may be demonstrated by a reduction of the amount of a total PCSK9 protein in a cell.[000155] In some embodiments, expression of the PCSK9 gene (e.g., human PCSK9) is inhibited by at least about 10%, about 15%, about 20%, about 25%, about 30 %, about 40%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95% based on the expression level of the PCSK9 gene in untreated cell or subject. In some embodiments, expression of the PCSK9 gene (e.g., human PCSK9) is inhibited by at least about 20% based on the expression level of the PCSK9 gene in untreated cell or subject. In some embodiments, expression of the PCSK9 gene (e.g., human PCSK9) is inhibited by at least about 30% based on the expression level of the PCSK9 gene in untreated cell or subject. In some embodiments, expression of the PCSK9 gene (e.g., human PCSK9) is inhibited by at least about 40% based on the expression level of the PCSK9 gene in untreated cell or subject. In some embodiments, expression of the PCSK9 gene (e.g., human PCSK9) is inhibited by at least about 50% based on the expression level of the PCSK9 gene in untreated cell or subject. In some embodiments, expression of the PCSK9 gene (e.g., human PCSK9) is inhibited by at least about 60% based on the expression level of the PCSK9 gene in untreated cell or subject. In some embodiments, expression of the PCSK9 gene (e.g., human PCSK9) is inhibited by at least about 70% based on the expression level of the PCSK9 gene in untreated cell or subject.[000156] In some embodiments, inhibition of the expression of the PCSK9 gene may be manifested by a reduction of the amount of mRNA expressed in a first cell or a first group of cells obtained from a subject that has been treated, e.g., by contacting the cell or by administering the first antisense agent (e.g., first dsRNAi agent) as described herein, as compared to a second cell or a second group of cells obtained from a subject that has not been treated but is identical to the first cell or the first group of cells. For example, the level of gene-silencing (e.g., inhibiting, downregulating, or suppressing of the gene) of the PCSK9 (e.g., human PCSK9) may be presentedPAT059887-PCT-SEC01 as a percentage of remaining mRNA in the treated cells (first cell or group of cells) compared to the mRNA amount in the control (untreated) cells, as shown in the following equation:(mRNA in control cells) - (mRNA in treated cells) - • 100 % (mRNA in control cells)[000157] In some embodiments, the level of gene-silencing (e.g., inhibiting, downregulating, or suppressing of the gene) of the PCSK9 (e.g., human PCSK9) may be assessed by measuring a parameter or biomarker, e.g., human PCSK9 protein level, in a biological sample (e.g., e.g., a blood, serum or liver tissue obtained from a subject), which may be treated or untreated. Conventional analytical methods as known in the art such as electrophoresis (e.g., SDS or capillary electrophoresis), chromatography (e.g., high performance liquid chromatography (HPLC)), spectroscopy, western blotting, enzyme- linked immunosorbent assays (ELISAs), immunofluorescent assays, electrochemiluminescence assays, and the like can be used without limitation, but examples are not limited thereto. In some embodiments, reduced level of genesilencing (e.g., inhibiting, downregulating, or suppressing of the gene) of the PCSK9 (e.g., human PCSK9) may be observed or assessed by in a liver (tissue) biopsy of the treated subject.[000158] In certain aspects, the first antisense agent (e.g., first dsRNAi agent) is a free acid. In certain aspects, the first antisense agent (e.g. first dsRNAi agent) is in a salt form (e.g., a pharmaceutically acceptable salt form). It will be understood that references to first antisense agent (e.g., first dsRNAi agent) are meant to also include the pharmaceutically acceptable salts of the first antisense agent (e.g., first dsRNAi agent). If the first antisense agent (e.g., first dsRNAi agent) has, for example, at least one basic center, they can form acid addition salts. Corresponding acid addition salts can also be formed having, if desired, an additionally present basic center. Active substances having an acid group, e.g., COOH, can form salts with bases. The first antisense agent (e.g. first dsRNAi agent) or pharmaceutically acceptable salts thereof may also be used in form of a hydrate or include other solvents used for crystallization. In some embodiments, the first antisense agent (e.g., dsRNAi agent) is a sodium salt. In some embodiments, the first antisense agent (e.g., first dsRNAi agent) is in a salt form (e.g., a pharmaceutically acceptable salt form), where the salt is sodium (Na+), ammonium (NH-T), calcium (Ca2+), iron (Fe2+or Fe3+), magnesium (Mg2+), potassium (K+), pyridinium (CsFENEE), quaternary ammonium (NRC, R being an alkyl group or an aryl group as described herein), or copper (Cu2+).PAT059887-PCT-SEC01[000159] In an aspect, the disclosure provides a first dsRNA agent having sequences (e.g., antisense strand sequence) that can recognize a specific region of a PCSK9 mRNA (e.g., human PCSK9 mRNA) and lead cleavage of the PCSK9 mRNA and silencing of the gene. The first dsRNA agent includes a sense strand and an antisense strand and each strand may range from 12 to 30 nucleotides in length. In some embodiments, each strand may have 15 to 30 nucleotides in length. In some embodiments, each strand may have 15 to 25 nucleotides in length. In some embodiments, the antisense strand may have 15 to 25 nucleotides in length. In some embodiments, the sense strand may have 15 to 25 nucleotides in length. In some embodiments, the antisense strand may have 15 to 23 nucleotides in length. In some embodiments, the sense strand may have 15 to 23 nucleotides in length. In some embodiments, the antisense strand may have 18 to 25 nucleotides in length. In some embodiments, the sense strand may have 18 to 25 nucleotides in length.[000160] In some embodiments, the sense strand may have 19 to 23 nucleotides in length. In some embodiments, the sense strand may have 21 to 23 nucleotides in length. In some embodiments, the sense strand may have 19 nucleotides in length. In some embodiments, the sense strand may have 20 nucleotides in length. In some embodiments, the sense strand may have 21 nucleotides in length. In some embodiments, the sense strand may have 22 nucleotides in length. In some embodiments, the sense strand may have 23 nucleotides in length.[000161] In some embodiments, the antisense strand may have 19 to 25 nucleotides in length. In some embodiments, the antisense strand may have 19 to 23 nucleotides in length. In some embodiments, the antisense strand may have 21 to 23 nucleotides in length. In some embodiments, the antisense strand may have 23 to 25 nucleotides in length. In some embodiments, the antisense strand may have 19 nucleotides in length. In some embodiments, the antisense strand may have 20 nucleotides in length. In some embodiments, the antisense strand may have 21 nucleotides in length. In some embodiments, the antisense strand may have 22 nucleotides in length. In some embodiments, the antisense strand may have 23 nucleotides in length. In some embodiments, the antisense strand may have 24 nucleotides in length. In some embodiments, the antisense strand may have 25 nucleotides in length.[000162] In some embodiments, the sense strand is 21 to 23 nucleotides in length and the antisense strand is 23 to 25 nucleotides in length. In some embodiments, the sense strand is 21 nucleotides in length and the antisense strand is 23 nucleotides in length. In some embodiments,PAT059887-PCT-SEC01 the sense strand is 22 nucleotides in length and the antisense strand is 24 nucleotides in length. In some embodiments, the sense strand is 23 nucleotides in length and the antisense strand is 25 nucleotides in length.[000163] In an aspect, a first dsRNAi agent as described herein forms a double-stranded (or“duplex”) region made between a sense strand and an antisense strand and having 10 to 25 nucleotide pairs in length. The double stranded or duplex region are loaded into the RISC and subsequent specific degradation of the sense strand occurs during the RISC pathway. In some embodiments, the double stranded region has 10 nucleotide base pairs in length. In some embodiments, the double stranded region has 11 nucleotide base pairs in length. In some embodiments, the double stranded region has 12 nucleotide base pairs in length. In some embodiments, the double stranded region has 13 nucleotide base pairs in length. In some embodiments, the double stranded region has 14 nucleotide base pairs in length. In some embodiments, the double stranded region has 15 nucleotide base pairs in length. In some embodiments, the double stranded region has 16 nucleotide base pairs in length. In some embodiments, the double stranded region has 17 nucleotide base pairs in length. In some embodiments, the double stranded region has 18 nucleotide base pairs in length. In some embodiments, the double stranded region has 19 nucleotide base pairs in length. In some embodiments, the double stranded region has 20 nucleotide base pairs in length. In some embodiments, the double stranded region has 21 nucleotide base pairs in length. In some embodiments, the double stranded region has 22 nucleotide base pairs in length. In some embodiments, the double stranded region has 23 nucleotide base pairs in length.[000164] In an aspect, a first dsRNAi agent as described herein may include at least one singlestranded nucleotide overhang, for example, for increasing in vivo effectiveness of the first dsRNAi agent and having substantially improved inhibition of the target genes. In certain aspects, the first dsRNAi agent may contain one or more extra nucleotides constituting overhang regions that locate other than the double stranded region at the 3 '-end, 5 '-end, or both ends of either stand or both strands (sense and antisense strands). In some embodiments, the overhang region may exist at the3 '-end, 5 '-end, or both ends of the sense strand. In some embodiments, the overhang region may exist at the 3'-end, 5'-end, or both ends of the antisense strand. In some embodiments, the antisense strand may have a greater length than a length in the sense strand. In some embodiments, the antisense strand may have a shorter length than a length in the sense strand.PAT059887-PCT-SEC01[000165] In some embodiments, the first dsRNA agent may contain one or more extra nucleotides constituting overhang regions at the 3'-end, 5'-end, or both ends of the antisense strand. In some embodiments, the overhang region in the antisense strand may consist of 1-6 nucleotides in length, for example, 1 nucleotide, 2 nucleotides, 3 nucleotides, 4 nucleotides, 5 nucleotides, or 6 nucleotides in length. In some embodiments, the first dsRNA agent may contain one or more extra nucleotides constituting overhang regions at the 3'-end, 5'-end, or both ends of the sense strand. In some embodiments, the overhang region may consist of 1 to 6 nucleotides in length, for example, 1 nucleotide, 2 nucleotides, 3 nucleotides, 4 nucleotides, 5 nucleotides, or 6 nucleotides in length.[000166] In some embodiments, the antisense strand may include one-nucleotide overhang at the 5' end. In some embodiments, the antisense strand may include one-nucleotide overhang at the 3' end. In some embodiments, the antisense strand may include two-nucleotides overhang. In some embodiments, the antisense contains two-nucleotides overhang at the 5' end. In some embodiments, the antisense contains two-nucleotides overhang at the 3' end. In some embodiments, the antisense contains one-nucleotide overhang at the 5' end and one-nucleotide overhang at the 3' end. In some embodiments, the antisense strand may include three-nucleotide overhang. In some embodiments, the antisense contains three-nucleotides overhang at the 5' end. In some embodiments, the antisense contains three-nucleotides overhang at the 3' end. In some embodiments, the antisense contains two-nucleotides overhang at the 5' end and one-nucleotide overhang at the 3' end. In some embodiments, the antisense contains two nucleotides overhang at the 3' end and one-nucleotide overhang at the 5' end.[000167] In certain aspects, a first dsRNAi agent as described herein may include at least one blunt end, e.g., for increasing in vivo stability with resistance to degradation in physiological surroundings. In some embodiments, the first dsRNAi agent may have a blunt end at the 3 '-end, 5'-end, or both ends of the duplex. In some embodiments, the first dsRNAi agent includes one overhang (e.g., at 3' end of antisense strand) and one blunt end (e.g., at 5' end of antisense strand). In some embodiments, the first dsRNAi agent includes a blunt end at the 5 '-end of the sense strand (and at 3' end of the antisense strand) and contain overhang nucleotide(s) at the other end. In some embodiments, the first dsRNAi agent may have a blunt end at the 3 '-end of the sense strand (and at 5' end of the antisense strand) and contain overhang nucleotide(s) at the other end.PAT059887-PCT-SEC01[000168] In certain aspects, the target PCSK9 mRNA sequence may range from 12 to 30 nucleotides, from 15 to 30 nucleotides, from 18 to 30 nucleotides, from 18 to 25 nucleotides, from 18 to 23 nucleotides. In certain aspects, the target PCSK9 mRNA sequence may range from 19 to 25 nucleotides, from 19 to 23 nucleotides, or from 19 to 21 nucleotides. In some embodiments, the target PCSK9 mRNA sequence may have 15 nucleotides in length. In some embodiments, the target PCSK9 mRNA sequence may have 16 nucleotides in length. In some embodiments, the target PCSK9 mRNA sequence may have 17 nucleotides in length. In some embodiments, the target PCSK9 mRNA sequence may have 18 nucleotides in length. In some embodiments, the target PCSK9 mRNA sequence may have 19 nucleotides in length. In some embodiments, the target PCSK9 mRNA sequence may have 20 nucleotides in length. In some embodiments, the target PCSK9 mRNA sequence may have 21 nucleotides in length. In some embodiments, the target PCSK9 mRNA sequence may have 22 nucleotides in length. In some embodiments, the target PCSK9 mRNA sequence may have 23 nucleotides in length.[000169] In certain aspects, exemplary first dsRNAi agent sequences including sense strands and antisense strands targeting human PCSK9 mRNAs of SEQ ID NO: 2 (GenBank: NM_174936.4) are in Table 1.Table 1: Examples of unmodified nucleotide sequences of first dsRNAi agents (e.g.,PCSK9 siRNA)PAT059887-PCT-SEC01PAT059887-PCT-SEC01PAT059887-PCT-SEC01PAT059887-PCT-SEC01PAT059887-PCT-SEC01PAT059887-PCT-SEC01PAT059887-PCT-SEC01PAT059887-PCT-SEC01PAT059887-PCT-SEC01PAT059887-PCT-SEC01* site of mRNA target is located in human PCSK9 mRNA sequence in SEQ ID NO: 2.[000170] In Table 1, each code (letter, e.g., A, G, C, and U) represents a single ribonucleotide in the first dsRNAi agent. In some embodiments, the sequence list may be inclusive of any possible modifications, for example, a modification in a nucleobase, a ribose sugar ring, and / or a phosphate group (i.e., phosphodiester internucleoside linkage). In some embodiments, the last nucleotide from the 5' end (or the first nucleotide from 3' end) in each strand (sense strand and antisense strand) may have not include a phosphate group as being hydrolyzed or processed, e.g., during the synthesis of the oligonucleotides, but may contain 3 '-terminal -OH group. In some embodiments, a phosphate group in the last nucleotide from the 5' end (or the first nucleotide from 3' end) in the sense strand may be added as a functional group for conjugation with a ligand.[000171] In some embodiments, the first dsRNA agent includes a sense strand having 10 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 3 to 381. In some embodiments, the first dsRNAi agent includes an antisense strand having 10 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of SEQ ID NOs: 382 to 760. In some embodiments, the first dsRNAi agent includes a sense strand having 11 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 3 to 381. In some embodiments, the first dsRNAi agent includes an antisense strand having 11 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 382 to 760. In some embodiments, the first dsRNAi agent includes a sense strand having 12 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 3 to 381. In some embodiments, the first dsRNAi agent includes an antisense strand having 12 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 382 to 760. In some embodiments, the first dsRNAi agent includes a sense strand having 13 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 3 to 381. In some embodiments, the first dsRNAi agent includes an antisense strand having 13 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 382 to 760. In some embodiments, the first dsRNAi agent includes aPAT059887-PCT-SEC01 sense strand having 14 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 3 to 381. In some embodiments, the first dsRNAi agent includes an antisense strand having 14 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 382 to 760. In some embodiments, the first dsRNAi agent includes a sense strand having 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 3 to 381. In some embodiments, the first dsRNAi agent includes an antisense strand having 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 382 to 760. In some embodiments, the first dsRNAi agent includes a sense strand having 16 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 3 to 381. In some embodiments, the first dsRNAi agent includes an antisense strand having 16 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 382 to 760. In some embodiments, the first dsRNAi agent includes a sense strand having 17 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 3 to 381. In some embodiments, the first dsRNAi agent includes an antisense strand having 17 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 382 to 760. In some embodiments, the first dsRNAi agent includes a sense strand having 18 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 3 to 381. In some embodiments, the first dsRNAi agent includes an antisense strand having 18 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 382 to 760. In some embodiments, the first dsRNAi agent includes a sense strand having 19 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 3 to 381. In some embodiments, the first dsRNAi agent includes an antisense strand having 19 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 382 to 760. In some embodiments, the first dsRNAi agent includes a sense strand having 20 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 3 to 381. In some embodiments, the first dsRNAi agent includes an antisense strand having 20 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 382 to 760. In somePAT059887-PCT-SEC01 embodiments, the first dsRNAi agent includes a sense strand having 21 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 3 to 381. In some embodiments, the first dsRNAi agent includes an antisense strand having 21 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 382 to 760. In some embodiments, the first dsRNAi agent includes an antisense strand having 22 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 382 to 760. In some embodiments, the first dsRNAi agent includes an antisense strand having 23 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 382 to 760.[000172] In some embodiments, the first dsRNAi agent includes a sense strand having 10 contiguous nucleotides differing by no more than 2 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 3 to 381. In some embodiments, the first dsRNAi agent includes an antisense strand having 10 contiguous nucleotides differing by no more than 2 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 382 to 760. In some embodiments, the first dsRNAi agent includes a sense strand having 11 contiguous nucleotides differing by no more than 2 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 3 to 381. In some embodiments, the first dsRNAi includes an antisense strand having 11 contiguous nucleotides differing by no more than 2 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 382 to 760. In some embodiments, the first dsRNAi agent includes a sense strand having 12 contiguous nucleotides differing by no more than 2 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 3 to 381. In some embodiments, the first dsRNAi agent includes an antisense strand having 12 contiguous nucleotides differing by no more than 2 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 382 to 760. In some embodiments, the first dsRNAi agent includes a sense strand having 13 contiguous nucleotides differing by no more than 2 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 3 to 381. In some embodiments, the first dsRNAi agent includes an antisense strand having 13 contiguous nucleotides differing by no more than 2 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 382 to 760. In some embodiments, the first dsRNAi agent includes a sense strand having 14 contiguous nucleotides differing by no more than 2 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 3 to 381. In some embodiments, the first dsRNAi agent includes an antisense strand having 14 contiguous nucleotides differing by no more than 2PAT059887-PCT-SEC01 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 382 to 760. In some embodiments, the first dsRNAi agent includes a sense strand having 15 contiguous nucleotides differing by no more than 2 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 3 to 381. In some embodiments, the first dsRNAi agent includes an antisense strand having 15 contiguous nucleotides differing by no more than 2 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 382 to 760. In some embodiments, the first dsRNAi agent includes a sense strand having 16 contiguous nucleotides differing by no more than 2 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 3 to 381. In some embodiments, the first dsRNAi agent includes an antisense strand having 16 contiguous nucleotides differing by no more than 2 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 382 to 760. In some embodiments, the first dsRNAi agent includes a sense strand having 17 contiguous nucleotides differing by no more than 2 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 3 to 381. In some embodiments, the first dsRNAi agent includes an antisense strand having 17 contiguous nucleotides differing by no more than 2 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 382 to 760. In some embodiments, the first dsRNAi agent includes a sense strand having 18 contiguous nucleotides differing by no more than 2 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 3 to 381. In some embodiments, the first dsRNAi agent includes an antisense strand having 18 contiguous nucleotides differing by no more than 2 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 382 to 760. In some embodiments, the first dsRNAi agent includes a sense strand having 19 contiguous nucleotides differing by no more than 2 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 3 to 381. In some embodiments, the first dsRNAi agent includes an antisense strand having 19 contiguous nucleotides differing by no more than 2 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 382 to 760. In some embodiments, the first dsRNAi agent includes a sense strand having 20 contiguous nucleotides differing by no more than 2 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 3 to 381. In some embodiments, the first dsRNAi agent includes an antisense strand having 20 contiguous nucleotides differing by no more than 2 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 382 to 760. In some embodiments, the first dsRNAi agent includes a sense strand having 21 contiguous nucleotides differing by no more than 2 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 3 to 381. In some embodiments, the first dsRNAi agent includes an antisense strand having 21PAT059887-PCT-SEC01 contiguous nucleotides differing by no more than 2 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 382 to 760. In some embodiments, the first dsRNAi agent includes an antisense strand having 22 contiguous nucleotides differing by no more than 2 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 382 to 760. In some embodiments, the first dsRNAi agent includes an antisense strand having 23 contiguous nucleotides differing by no more than 2 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 382 to 760.[000173] In some embodiments, the first dsRNAi agent includes a sense strand having 10 contiguous nucleotides differing by no more than 1 nucleotide from the nucleotide sequence selected from SEQ ID NOs: 3 to 381. In some embodiments, the first dsRNAi agent includes an antisense strand having 10 contiguous nucleotides differing by no more than 1 nucleotide from the nucleotide sequence selected from SEQ ID NOs: 382 to 760. In some embodiments, the first dsRNAi agent includes a sense strand having 11 contiguous nucleotides differing by no more than 1 nucleotide from the nucleotide sequence selected from SEQ ID NOs: 3 to 381. In some embodiments, the first dsRNAi agent includes an antisense strand having 11 contiguous nucleotides differing by no more than 1 nucleotide from the nucleotide sequence selected from SEQ ID NOs: 382 to 760. In some embodiments, the first dsRNAi agent includes a sense strand having 12 contiguous nucleotides differing by no more than 1 nucleotide from the nucleotide sequence selected from SEQ ID NOs: 3 to 381. In some embodiments, the first dsRNAi agent includes an antisense strand having 12 contiguous nucleotides differing by no more than 1 nucleotide from the nucleotide sequence selected from SEQ ID NOs: 382 to 760. In some embodiments, the first dsRNAi agent includes a sense strand having 13 contiguous nucleotides differing by no more than 1 nucleotide from the nucleotide sequence selected from SEQ ID NOs: 3 to 381. In some embodiments, the first dsRNAi agent includes an antisense strand having 13 contiguous nucleotides differing by no more than 1 nucleotide from the nucleotide sequence selected from SEQ ID NOs: 382 to 760. In some embodiments, the first dsRNAi agent includes a sense strand having 14 contiguous nucleotides differing by no more than 1 nucleotide from the nucleotide sequence selected from SEQ ID NOs: 3 to 381. In some embodiments, the first dsRNAi agent includes an antisense strand having 14 contiguous nucleotides differing by no more than 1 nucleotide from the nucleotide sequence selected from SEQ ID NOs: 382 to 760. In some embodiments, the first dsRNAi agent includes a sense strand having 15 contiguous nucleotides differing by no more than 1 nucleotide from the nucleotide sequence selected from SEQ ID NOs:PAT059887-PCT-SEC013 to 381. In some embodiments, the first dsRNAi agent includes an antisense strand having 15 contiguous nucleotides differing by no more than 1 nucleotide from the nucleotide sequence selected from SEQ ID NOs: 382 to 760. In some embodiments, the first dsRNAi agent includes a sense strand having 16 contiguous nucleotides differing by no more than 1 nucleotide from the nucleotide sequence selected from SEQ ID NOs: 3 to 381. In some embodiments, the first dsRNAi agent includes an antisense strand having 16 contiguous nucleotides differing by no more than 1 nucleotide from the nucleotide sequence selected from SEQ ID NOs: 382 to 760. In some embodiments, the first dsRNAi agent includes a sense strand having 17 contiguous nucleotides differing by no more than 1 nucleotide from the nucleotide sequence selected from SEQ ID NOs: 3 to 381. In some embodiments, the first dsRNAi agent includes an antisense strand having 17 contiguous nucleotides differing by no more than 1 nucleotide from the nucleotide sequence selected from SEQ ID NOs: 382 to 760. In some embodiments, the first dsRNAi agent includes a sense strand having 18 contiguous nucleotides differing by no more than 1 nucleotide from the nucleotide sequence selected from SEQ ID NOs: 3 to 381. In some embodiments, the first dsRNAi agent includes an antisense strand having 18 contiguous nucleotides differing by no more than 1 nucleotide from the nucleotide sequence selected from SEQ ID NOs: 382 to 760. In some embodiments, the first dsRNAi agent includes a sense strand having 19 contiguous nucleotides differing by no more than 1 nucleotide from the nucleotide sequence selected from SEQ ID NOs: 3 to 381. In some embodiments, the first dsRNAi agent includes an antisense strand having 19 contiguous nucleotides differing by no more than 1 nucleotide from the nucleotide sequence selected from SEQ ID NOs: 382 to 760. In some embodiments, the first dsRNAi agent includes a sense strand having 20 contiguous nucleotides differing by no more than 1 nucleotide from the nucleotide sequence selected from SEQ ID NOs: 3 to 381. In some embodiments, the first dsRNAi agent includes an antisense strand having 20 contiguous nucleotides differing by no more than 1 nucleotide from the nucleotide sequence selected from SEQ ID NOs: 382 to 760. In some embodiments, the first dsRNAi agent includes a sense strand having 21 contiguous nucleotides differing by no more than 1 nucleotide from the nucleotide sequence selected from SEQ ID NOs: 3 to 381. In some embodiments, the first dsRNAi agent includes an antisense strand having 21 contiguous nucleotides differing by no more than 1 nucleotide from the nucleotide sequence selected from SEQ ID NOs: 382 to 760. In some embodiments, the first dsRNAi agent includes an antisense strand having 22 contiguous nucleotides differing by no more than 1 nucleotide fromPAT059887-PCT-SEC01 the nucleotide sequence selected from SEQ ID NOs: 382 to 760. In some embodiments, the first dsRNAi agent includes an antisense strand having 23 contiguous nucleotides differing by no more than 1 nucleotide from the nucleotide sequence selected from SEQ ID NOs: 382 to 760.[000174] In some embodiments, the first dsRNAi agent includes (i) a sense strand having 15 contiguous nucleotides differing by no more than one, two or three nucleotides from the nucleotide sequence selected from SEQ ID NOs: 3 to 381 and (ii) an antisense strand forming a duplex with the sense strand of (i) and having 15 contiguous nucleotides differing by no more than one, two or three nucleotides from the nucleotide sequence selected from SEQ ID NOs: 382 to 760. In some embodiments, the first dsRNAi agent includes (i) a sense strand having 16 contiguous nucleotides differing by no more than one, two or three from the nucleotide sequence selected from SEQ ID NOs: 3 to 381 and (ii) an antisense strand forming a duplex with the sense strand of (i) and having 16 contiguous nucleotides differing by no more than one, two or three nucleotides from the nucleotide sequence selected from SEQ ID NOs: 382 to 760. In some embodiments, the first dsRNAi agent includes (i) a sense strand having 17 contiguous nucleotides differing by no more than one, two or three nucleotides from the nucleotide sequence selected from SEQ ID NOs: 3 to 381 and (ii) an antisense strand forming a duplex with the sense strand of (i) and having 17 contiguous nucleotides differing by no more than one, two or three nucleotides from the nucleotide sequence selected from SEQ ID NOs: 382 to 760. In some embodiments, the first dsRNAi agent includes (i) a sense strand having 18 contiguous nucleotides differing by no more than one, two or three nucleotides from the nucleotide sequence selected from SEQ ID NOs: 3 to 381 and (ii) an antisense strand forming a duplex with the sense strand of (i) and having 18 contiguous nucleotides differing by no more than one, two or three nucleotides from the nucleotide sequence selected from SEQ ID NOs: 382 to 760. In some embodiments, the first dsRNAi agent includes (i) a sense strand having 19 contiguous nucleotides differing by no more than one, two or three nucleotides from the nucleotide sequence selected from SEQ ID NOs: 3 to 381 and (ii) an antisense strand forming a duplex with the sense strand of (i) and having 19 contiguous nucleotides differing by no more than one, two or three nucleotides from the nucleotide sequence selected from SEQ ID NOs: 382 to 760. In some embodiments, the first dsRNAi agent includes (i) a sense strand having 20 contiguous nucleotides differing by no more than one, two or three nucleotides from the nucleotide sequence selected from SEQ ID NOs: 3 to 381 and (ii) an antisense strand forming a duplex with the sense strand of (i) and having 20 contiguous nucleotides differing by no more than one, two orPAT059887-PCT-SEC01 three nucleotides from the nucleotide sequence selected from SEQ ID NOs: 382 to 760. In some embodiments, the first dsRNAi agent includes (i) a sense strand having 21 contiguous nucleotides differing by no more than one, two or three nucleotides from the nucleotide sequence selected from SEQ ID NOs: 3 to 381 and (ii) an antisense strand forming a duplex with the sense strand of (i) and having 21 contiguous nucleotides differing by no more than one, two or three nucleotides from the nucleotide sequence selected from SEQ ID NOs: 382 to 760. In some embodiments, the first dsRNAi agent includes (i) a sense strand having 21 contiguous nucleotides differing by no more than one, two or three nucleotides from the nucleotide sequence selected from SEQ ID NOs: 3 to 381 and (ii) an antisense strand forming a duplex with the sense strand of (i) and having 22 contiguous nucleotides differing by no more than one, two or three nucleotides from the nucleotide sequence selected from SEQ ID NOs: 382 to 760. In some embodiments, the first dsRNAi agent includes (i) a sense strand having 21 contiguous nucleotides differing by no more than one, two or three nucleotides from the nucleotide sequence selected from SEQ ID NOs: 3 to 381 and (ii) an antisense strand forming a duplex with the sense strand of (i) and having 23 contiguous nucleotides differing by no more than one, two or three nucleotides from the nucleotide sequence selected from SEQ ID NOs: 382 to 760.[000175] In certain aspects, the sequences of the single strands (i.e., sense strand and antisense strand) of the first dsRNAi agent can be selected by selecting a target region and a length in the PCSK9 mRNA. In certain aspects, a first dsRNAi agent as described herein may target a nucleotide region selected from regions of (i) 600-800; (ii) 800 to 1000; (iii) 1000-1200; (iv) 3100- 3300; or (v) 3400-3600 of a human PCSK9 mRNA sequence that has at least about 85% (e.g., about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99% or 100%) identity to SEQ ID NO: 2 (human PCSK9 isoform, transcript variant 1, mRNA (GenBank: NM_174936.4)). In some embodiments, the target region is selected from regions of (i) 650-750; (ii) 850-950; (hi) 1050-1150; (iv) 3200-3300; (v) 3400-3500; or (vi) 3500-3600 of a human PCSK9 mRNA sequence that has at least about 85% (e.g., about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99% or 100%) identity to SEQ ID NO: 2 (human PCSK9 isoform, transcript variant 1, mRNA (GenBank: NM_174936.4)).PAT059887-PCT-SEC01[000176] In some embodiments, the antisense strand of the first dsRNAi agent targets a region of (i) 600-800; (h) 800-1000; (hi) 1000-1200; (iv) 3100-3300; or (v) 3400-3600 nucleotides in a human PCSK9 mRNA sequence that has at least about 85% (e.g., about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99% or 100%) identity to SEQ ID NO: 2 (human PCSK9 isoform, transcript variant 1, mRNA (GenBank: NM_174936.4)). In some embodiments, the antisense strand of the first dsRNAi agent targets a region of (i) 650-750; (ii) 850-950; (iii) 1050-1150; (iv) 3200-3300; (v) 3400-3500; or (vi) 3500-3600 nucleotides in a human PCSK9 mRNA sequence that has at least about 85% (e.g., about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99% or 100%) identity to SEQ ID NO: 2 (human PCSK9 isoform, transcript variant 1, mRNA (GenBank: NM_174936.4)). In some embodiments, the antisense strand of the first dsRNAi agent targets a region of 3500th to 3600th nucleotides in a human PCSK9 mRNA sequence that has at least about 85% (e.g., about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99% or 100%) identity to SEQ ID NO: 2 (human PCSK9 isoform, transcript variant 1, mRNA (GenBank: NM_174936.4)).[000177] Exemplary selected first dsRNAi agent sequences targeting the regions described herein (e.g., target region of (i) 600-800; (ii) 800 to 1000; (iii) 1000-1200; (iv) 3100-3300; or (v) 3400-3600) are shown in Table 2.Table 2: Selected sequences of first dsRNAi agents (e.g., PCSK9 siRNA)(unmodified nucleotide sequences)PAT059887-PCT-SEC01* site of mRNA target is located in human PCSK9 mRNA sequence in SEQ ID NO: 2.Table 2A, Additional first dsRNAi agents (unmodified nucleotide sequences)PAT059887-PCT-SEC01[000178] In some embodiments, the first dsRNAi agent includes a sense strand having 10 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 761-776 or 2348-2389. In some embodiments, the first dsRNAi agent includes an antisense strand having 10 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of SEQ ID NOs: 777-792 or 2390-2431. In some embodiments, the first dsRNAi agent includes a sense strand having 11 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 761-776 or 2348-2389. In some embodiments, the first dsRNAi agent includes an antisense strand having 11 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 777-792 or 2390-2431. In some embodiments, the first dsRNAi agent includes a sense strand having 12 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 761-776 or 2348-2389. In some embodiments, the first dsRNAi agent includes an antisense strand having 12 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 777-792 or 2390-2431. In some embodiments, the first dsRNAi agent includes a sense strand having 13 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 761-776 or 2348-2389. In some embodiments, the first dsRNAi agent includes an antisense strand having 13 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 777-792 or 2390-2431. In some embodiments, the first dsRNAi agent includes a sense strand having 14 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 761-776 or 2348-2389. In some embodiments, the first dsRNAi agent includes an antisense strand having 14 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 777-792 or 2390-2431. In some embodiments, the first dsRNAi agent includes a sense strand having 15 contiguousPAT059887-PCT-SEC01 nucleotides differing by no more than 3 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 761-776 or 2348-2389. In some embodiments, the first dsRNAi agent includes an antisense strand having 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 777-792 or 2390-2431. In some embodiments, the first dsRNAi agent includes a sense strand having 16 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 761-776 or 2348-2389. In some embodiments, the first dsRNAi agent includes an antisense strand having 16 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 777-792 or 2390-2431. In some embodiments, the first dsRNAi agent includes a sense strand having 17 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 761-776 or 2348-2389. In some embodiments, the first dsRNAi agent includes an antisense strand having 17 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 777-792 or 2390-2431. In some embodiments, the first dsRNAi agent includes a sense strand having 18 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 761-776 or 2348-2389. In some embodiments, the first dsRNAi agent includes an antisense strand having 18 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 777-792 or 2390-2431. In some embodiments, the first dsRNAi agent includes a sense strand having 19 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 761-776 or 2348-2389. In some embodiments, the first dsRNAi agent includes an antisense strand having 19 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 777-792 or 2390-2431. In some embodiments, the first dsRNAi agent includes a sense strand having 20 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 761-776 or 2348-2389. In some embodiments, the first dsRNAi agent includes an antisense strand having 20 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 777-792 or 2390-2431. In some embodiments, the first dsRNAi agent includes a sense strand having 21 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 761-776 or 2348-2389. In some embodiments, the first dsRNAi agent includes an antisense strandPAT059887-PCT-SEC01 having 21 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 777-792 or 2390-2431. In some embodiments, the first dsRNAi agent includes an antisense strand having 22 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 777-792 or 2390- 2431. In some embodiments, the first dsRNAi agent includes an antisense strand having 23 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 777-792 or 2390-2431. In some embodiments, the first dsRNAi agent includes an antisense strand having 24 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 2390-2431.[000179] In some embodiments, the first dsRNAi agent includes a sense strand having 10 contiguous nucleotides differing by no more than 2 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 761-776 or 2348-2389. In some embodiments, the first dsRNAi agent includes an antisense strand having 10 contiguous nucleotides differing by no more than 2 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 777-792 or 2390-2431. In some embodiments, the first dsRNAi agent includes a sense strand having 11 contiguous nucleotides differing by no more than 2 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 761-776 or 2348-2389. In some embodiments, the first dsRNAi agent includes an antisense strand having 11 contiguous nucleotides differing by no more than 2 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 777-792 or 2390-2431. In some embodiments, the first dsRNAi agent includes a sense strand having 12 contiguous nucleotides differing by no more than 2 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 761-776 or 2348-2389. In some embodiments, the first dsRNAi agent includes an antisense strand having 12 contiguous nucleotides differing by no more than 2 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 777-792 or 2390-2431. In some embodiments, the first dsRNAi agent includes a sense strand having 13 contiguous nucleotides differing by no more than 2 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 761-776 or 2348-2389. In some embodiments, the first dsRNAi agent includes an antisense strand having 13 contiguous nucleotides differing by no more than 2 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 777-792 or 2390-2431. In some embodiments, the first dsRNAi agent includes a sense strand having 14 contiguous nucleotides differing by no more than 2 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 761-776 or 2348-2389. In some embodiments,PAT059887-PCT-SEC01 the first dsRNAi agent includes an antisense strand having 14 contiguous nucleotides differing by no more than 2 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 777-792 or 2390-2431. In some embodiments, the first dsRNAi agent includes a sense strand having 15 contiguous nucleotides differing by no more than 2 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 761-776 or 2348-2389. In some embodiments, the first dsRNAi agent includes an antisense strand having 15 contiguous nucleotides differing by no more than 2 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 777-792 or 2390-2431. In some embodiments, the first dsRNAi agent includes a sense strand having 16 contiguous nucleotides differing by no more than 2 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 761-776 or 2348-2389. In some embodiments, the first dsRNAi agent includes an antisense strand having 16 contiguous nucleotides differing by no more than 2 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 777-792 or 2390-2431. In some embodiments, the first dsRNAi agent includes a sense strand having 17 contiguous nucleotides differing by no more than 2 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 761-776 or 2348-2389. In some embodiments, the first dsRNAi agent includes an antisense strand having 17 contiguous nucleotides differing by no more than 2 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 777-792 or 2390-2431. In some embodiments, the first dsRNAi agent includes a sense strand having 18 contiguous nucleotides differing by no more than 2 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 761-776 or 2348-2389. In some embodiments, the first dsRNAi agent includes an antisense strand having 18 contiguous nucleotides differing by no more than 2 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 777-792 or 2390-2431. In some embodiments, the first dsRNAi agent includes a sense strand having 19 contiguous nucleotides differing by no more than 2 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 761-776 or 2348-2389. In some embodiments, the first dsRNAi agent includes an antisense strand having 19 contiguous nucleotides differing by no more than 2 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 777-792 or 2390-2431. In some embodiments, the first dsRNAi agent includes a sense strand having 20 contiguous nucleotides differing by no more than 2 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 761-776 or 2348-2389. In some embodiments, the first dsRNAi agent includes an antisense strand having 20 contiguous nucleotides differing by no more than 2 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 777-792 or 2390-2431. InPAT059887-PCT-SEC01 some embodiments, the first dsRNAi agent includes a sense strand having 21 contiguous nucleotides differing by no more than 2 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 761-776 or 2348-2389. In some embodiments, the first dsRNAi agent includes an antisense strand having 21 contiguous nucleotides differing by no more than 2 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 777-792 or 2390-2431. In some embodiments, the first dsRNAi agent includes an antisense strand having 22 contiguous nucleotides differing by no more than 2 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 777-792 or 2390-2431. In some embodiments, the first dsRNAi agent includes an antisense strand having 23 contiguous nucleotides differing by no more than 2 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 777-792 or 2390-2431. In some embodiments, the first dsRNAi agent includes an antisense strand having 24 contiguous nucleotides differing by no more than 2 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 2390-2431.[000180] In some embodiments, the first dsRNAi agent includes a sense strand having 10 contiguous nucleotides differing by no more than 1 nucleotide from the nucleotide sequence selected from SEQ ID NOs: 761-776 or 2348-2389. In some embodiments, the first dsRNAi agent includes an antisense strand having 10 contiguous nucleotides differing by no more than 1 nucleotide from the nucleotide sequence selected from SEQ ID NOs: 777-792 or 2390-2431. In some embodiments, the first dsRNAi agent includes a sense strand having 11 contiguous nucleotides differing by no more than 1 nucleotide from the nucleotide sequence selected from SEQ ID NOs: 761-776 or 2348-2389. In some embodiments, the first dsRNAi agent includes an antisense strand having 11 contiguous nucleotides differing by no more than 1 nucleotide from the nucleotide sequence selected from SEQ ID NOs: 777-792 or 2390-2431. In some embodiments, the first dsRNAi agent includes a sense strand having 12 contiguous nucleotides differing by no more than 1 nucleotide from the nucleotide sequence selected from SEQ ID NOs: 761-776 or 2348-2389. In some embodiments, the first dsRNAi agent includes an antisense strand having 12 contiguous nucleotides differing by no more than 1 nucleotide from the nucleotide sequence selected from SEQ ID NOs: 777-792 or 2390-2431. In some embodiments, the first dsRNAi agent includes a sense strand having 13 contiguous nucleotides differing by no more than 1 nucleotide from the nucleotide sequence selected from SEQ ID NOs: 761-776 or 2348-2389. In some embodiments, the first dsRNAi agent includes an antisense strand having 13 contiguousPAT059887-PCT-SEC01 nucleotides differing by no more than 1 nucleotide from the nucleotide sequence selected from SEQ ID NOs: 777-792 or 2390-2431. In some embodiments, the first dsRNAi agent includes a sense strand having 14 contiguous nucleotides differing by no more than 1 nucleotide from the nucleotide sequence selected from SEQ ID NOs: 761-776 or 2348-2389. In some embodiments, the first dsRNAi agent includes an antisense strand having 14 contiguous nucleotides differing by no more than 1 nucleotide from the nucleotide sequence selected from SEQ ID NOs: 777-792 or 2390-2431. In some embodiments, the first dsRNAi agent includes a sense strand having 15 contiguous nucleotides differing by no more than 1 nucleotide from the nucleotide sequence selected from SEQ ID NOs: 761-776 or 2348-2389. In some embodiments, the first dsRNAi agent includes an antisense strand having 15 contiguous nucleotides differing by no more than 1 nucleotide from the nucleotide sequence selected from SEQ ID NOs: 777-792 or 2390-2431. In some embodiments, the first dsRNAi agent includes a sense strand having 16 contiguous nucleotides differing by no more than 1 nucleotide from the nucleotide sequence selected from SEQ ID NOs: 761-776 or 2348-2389. In some embodiments, the first dsRNAi agent includes an antisense strand having 16 contiguous nucleotides differing by no more than 1 nucleotide from the nucleotide sequence selected from SEQ ID NOs: 777-792 or 2390-2431. In some embodiments, the first dsRNAi agent includes a sense strand having 17 contiguous nucleotides differing by no more than 1 nucleotide from the nucleotide sequence selected from SEQ ID NOs: 761-776 or 2348-2389. In some embodiments, the first dsRNAi agent includes an antisense strand having 17 contiguous nucleotides differing by no more than 1 nucleotide from the nucleotide sequence selected from SEQ ID NOs: 777-792 or 2390-2431. In some embodiments, the first dsRNAi agent includes a sense strand having 18 contiguous nucleotides differing by no more than 1 nucleotide from the nucleotide sequence selected from SEQ ID NOs: 761-776 or 2348-2389. In some embodiments, the first dsRNAi agent includes an antisense strand having 18 contiguous nucleotides differing by no more than 1 nucleotide from the nucleotide sequence selected from SEQ ID NOs: 777-792 or 2390-2431. In some embodiments, the first dsRNAi agent includes a sense strand having 19 contiguous nucleotides differing by no more than 1 nucleotide from the nucleotide sequence selected from SEQ ID NOs: 761-776 or 2348-2389. In some embodiments, the first dsRNAi agent includes an antisense strand having 19 contiguous nucleotides differing by no more than 1 nucleotide from the nucleotide sequence selected from SEQ ID NOs: 777-792 or 2390-2431. In some embodiments, the first dsRNAi agent includes a sense strand having 20PAT059887-PCT-SEC01 contiguous nucleotides differing by no more than 1 nucleotide from the nucleotide sequence selected from SEQ ID NOs: 761-776 or 2348-2389. In some embodiments, the first dsRNAi agent includes an antisense strand having 20 contiguous nucleotides differing by no more than 1 nucleotide from the nucleotide sequence selected from SEQ ID NOs: 777-792 or 2390-2431. In some embodiments, the first dsRNAi agent includes a sense strand having 21 contiguous nucleotides differing by no more than 1 nucleotide from the nucleotide sequence selected from SEQ ID NOs: 761-776 or 2348-2389. In some embodiments, the first dsRNAi agent includes an antisense strand having 21 contiguous nucleotides differing by no more than 1 nucleotide from the nucleotide sequence selected from SEQ ID NOs: 777-792 or 2390-2431. In some embodiments, the first dsRNAi agent includes an antisense strand having 22 contiguous nucleotides differing by no more than 1 nucleotide from the nucleotide sequence selected from SEQ ID NOs: 777-792 or 2390-2431. In some embodiments, the first dsRNAi agent includes an antisense strand having 23 contiguous nucleotides differing by no more than 1 nucleotide from the nucleotide sequence selected from SEQ ID NOs: 777-792 or 2390-2431. In some embodiments, the first dsRNAi agent includes an antisense strand having 24 contiguous nucleotides differing by no more than 1 nucleotide from the nucleotide sequence selected from SEQ ID NOs: 2390-2431.[000181] In some embodiments, the first dsRNAi agent includes (i) a sense strand having 15 contiguous nucleotides differing by no more than one, two or three nucleotides from the nucleotide sequence selected from SEQ ID NOs: 761-776 or 2348-2389 and (ii) an antisense strand forming a duplex with the sense strand of (i) and having 15 contiguous nucleotides differing by no more than one, two or three nucleotides from the nucleotide sequence selected from SEQ ID NOs: 777- 792 or 2390-2431. In some embodiments, the first dsRNAi agent includes (i) a sense strand having16 contiguous nucleotides differing by no more than one, two or three from the nucleotide sequence selected from SEQ ID NOs: 761-776 or 2348-2389 and (ii) an antisense strand forming a duplex with the sense strand of (i) and having 16 contiguous nucleotides differing by no more than one, two or three nucleotides from the nucleotide sequence selected from SEQ ID NOs: 777- 792 or 2390-2431. In some embodiments, the first dsRNAi agent includes (i) a sense strand having17 contiguous nucleotides differing by no more than one, two or three nucleotides from the nucleotide sequence selected from SEQ ID NOs: 761-776 or 2348-2389 and (ii) an antisense strand forming a duplex with the sense strand of (i) and having 17 contiguous nucleotides differing by no more than one, two or three nucleotides from the nucleotide sequence selected from SEQ ID NOs:PAT059887-PCT-SEC01777-792 or 2390-2431. In some embodiments, the first dsRNAi agent includes (i) a sense strand having 18 contiguous nucleotides differing by no more than one, two or three nucleotides from the nucleotide sequence selected from SEQ ID NOs: 761-776 or 2348-2389 and (ii) an antisense strand forming a duplex with the sense strand of (i) and having 18 contiguous nucleotides differing by no more than one, two or three nucleotides from the nucleotide sequence selected from SEQ ID NOs: 777-792 or 2390-2431. In some embodiments, the first dsRNAi agent includes (i) a sense strand having 19 contiguous nucleotides differing by no more than one, two or three nucleotides from the nucleotide sequence selected from SEQ ID NOs: 761-776 or 2348-2389 and (ii) an antisense strand forming a duplex with the sense strand of (i) and having 19 contiguous nucleotides differing by no more than one, two or three nucleotides from the nucleotide sequence selected from SEQ ID NOs: 777-792 or 2390-2431. In some embodiments, the first dsRNAi agent includes (i) a sense strand having 20 contiguous nucleotides differing by no more than one, two or three nucleotides from the nucleotide sequence selected from SEQ ID NOs: 761-776 or 2348-2389 and (ii) an antisense strand forming a duplex with the sense strand of (i) and having 20 contiguous nucleotides differing by no more than one, two or three nucleotides from the nucleotide sequence selected from SEQ ID NOs: 777-792 or 2390-2431. In some embodiments, the first dsRNAi agent includes (i) a sense strand having 21 contiguous nucleotides differing by no more than one, two or three nucleotides from the nucleotide sequence selected from SEQ ID NOs: 761-776 or 2348-2389 and (ii) an antisense strand forming a duplex with the sense strand of (i) and having 21 contiguous nucleotides differing by no more than one, two or three nucleotides from the nucleotide sequence selected from SEQ ID NOs: 777-792 or 2390-2431. In some embodiments, the first dsRNAi agent includes (i) a sense strand having 21 contiguous nucleotides differing by no more than one, two or three nucleotides from the nucleotide sequence selected from SEQ ID NOs: 761-776 or 2348-2389 and (ii) an antisense strand forming a duplex with the sense strand of (i) and having 22 contiguous nucleotides differing by no more than one, two or three nucleotides from the nucleotide sequence selected from SEQ ID NOs: 777-792 or 2390-2431. In some embodiments, the first dsRNAi agent includes (i) a sense strand having 21 contiguous nucleotides differing by no more than one, two or three nucleotides from the nucleotide sequence selected from SEQ ID NOs: 761-776 or 2348-2389 and (ii) an antisense strand forming a duplex with the sense strand of (i) and having 23 contiguous nucleotides differing by no more than one, two or three nucleotides from the nucleotide sequence selected from SEQ ID NOs: 777-792 or 2390-2431. In some embodiments, the first dsRNAi agent includes (i) a sense strandPAT059887-PCT-SEC01 having 21 contiguous nucleotides differing by no more than one, two or three nucleotides from the nucleotide sequence selected from SEQ ID NOs: 761-776 or 2348-2389 and (ii) an antisense strand forming a duplex with the sense strand of (i) and having 24 contiguous nucleotides differing by no more than one, two or three nucleotides from the nucleotide sequence selected from SEQ ID NOs: 777-792 or 2390-2431.[000182] In certain aspects, when a sense strand or an antisense strand of a first dsRNAi agent in above paragraphs is differing by a certain number of nucleotides (e.g., one, two or three nucleotides) from a specific sequence (e.g., SEQ ID NOs: 3-792 or 2348-2431), it is meant by that the sense strand or the antisense strand of the first dsRNAi agent includes one, two or three nucleotides having different nucleobases compared to the nucleobases of the nucleotides at the corresponding positions of the specific sequence (e.g., SEQ ID NOs: 3-792 or 2348-2431).[000183] Additional suitable first dsRNAi agents are described in CN120265777, WO2025077949, WO2025097633, CN118955591, CN120769912, WO2024188174, WO 2024 / 228030, GB2635479, WO2024163497, CN120501756, CN120505340, WO2025171649, WO2025171650, WO2025171684, CN120775842, US 2025 / 0313844, US 2024 / 0376476, CN118109463, CN119528986, CN119040325, W02025060884, WO2024263915, CN119662645, WO 2025 / 096355, WO2025 / 124364, WO 2025 / 184301, WO2025038418, W02025 / 021034, WO2014089313, W02022150508, W02019204021, WO2018039364, WO2018175839, WO2014207232, WO2022125913, CN109957565, and CN115572726, the entire contents of which are incorporated herein by reference.The second antisense agent[000184] In an aspect, the second antisense agent is an HMGCR inhibitor.[000185] In some embodiments, the second antisense agent is a dsRNAi agent. In some embodiments, the second antisense agent is an ASO or an ASO agent.[000186] The disclosure provides a second dsRNA interference (dsRNAi) agent that is capable of interacting or recruiting a target mRNA sequence, e.g., HMGCR target mRNA sequence, in the RISC thereby cleaving the target mRNA. The second dsRNAi agent can silence HMGCR gene, e.g., by inhibiting, downregulating, or suppressing the expression of HMGCR gene. Genesilencing (e.g., inhibiting, downregulating, or suppressing of the gene) may be assessed by a decrease in an absolute or relative level of one or more variables that are associated with HMGCRPAT059887-PCT-SEC01 expression compared with a control level. The control level may be any type obtained from, e.g., a pre-dose baseline level, or a level determined from a similar subject, cell, or untreated or treated subject with inactive agents (e.g., PBS buffer). In some embodiments, the level of silencing the HMGCR may be demonstrated by a reduction of the amount of a total HMGCR mRNA in a cell. In some embodiments, the level of silencing the HMGCR may be demonstrated by a reduction of the amount of a total HMGCR protein in a cell.[000187] In some embodiments, expression of the HMGCR gene (e.g., human HMGCR) is inhibited by at least about 10%, about 15%, about 20%, about 25%, about 30 %, about 40%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95% based on the expression level of the HMGCR gene in untreated cell or subject. In some embodiments, expression of the HMGCR gene (e.g., human HMGCR) is inhibited by at least about 20% based on the expression level of the HMGCR gene in untreated cell or subject. In some embodiments, expression of the HMGCR gene (e.g., human HMGCR) is inhibited by at least about 30% based on the expression level of the HMGCR gene in untreated cell or subject. In some embodiments, expression of the HMGCR gene (e.g., human HMGCR) is inhibited by at least about 40% based on the expression level of the HMGCR gene in untreated cell or subject. In some embodiments, expression of the HMGCR gene (e.g., human HMGCR) is inhibited by at least about 50% based on the expression level of the HMGCR gene in untreated cell or subject. In some embodiments, expression of the HMGCR gene (e.g., human HMGCR) is inhibited by at least about 60% based on the expression level of the HMGCR gene in untreated cell or subject. In some embodiments, expression of the HMGCR gene (e.g., human HMGCR) is inhibited by at least about 70% based on the expression level of the HMGCR gene in untreated cell or subject.[000188] In some embodiments, inhibition of the expression of the HMGCR gene may be manifested by a reduction of the amount of mRNA expressed in a first cell or a first group of cells obtained from a subject that has been treated, e.g., by contacting the cell or by administering the second antisense agent (e.g., second dsRNAi agent) as described herein, as compared to a second cell or a second group of cells obtained from a subject that has not been treated but is identical to the first cell or the first group of cells. For example, the level of gene-silencing (e.g., inhibiting, downregulating, or suppressing of the gene) of the HMGCR (e.g., human HMGCR) may be presented as a percentage of remaining mRNA in the treated cells (first cell or group of cells) compared to the mRNA amount in the control (untreated) cells, as shown in the following equation:PAT059887-PCT-SEC01(mRNA in control cells) - (mRNA in treated cells) - • 100 % (mRNA in control cells)[000189] In some embodiments, the level of gene-silencing (e.g., inhibiting, downregulating, or suppressing of the gene) of the HMGCR (e.g., human HMGCR) may be assessed by measuring a parameter or biomarker, e.g., human HMGCR protein level, in a biological sample (e.g., e.g., a blood, serum or liver tissue obtained from a subject), which may be treated or untreated. Conventional analytical methods as known in the art such as electrophoresis (e.g., SDS or capillary electrophoresis), chromatography (e.g., high performance liquid chromatography (HPLC)), spectroscopy, western blotting, enzyme- linked immunosorbent assays (ELISAs), immunofluorescent assays, electrochemiluminescence assays, and the like can be used without limitation, but examples are not limited thereto. In some embodiments, reduced level of genesilencing (e.g., inhibiting, downregulating, or suppressing of the gene) of the HMGCR (e.g., human HMGCR) may be observed or assessed by in a liver (tissue) biopsy of the treated subject. [000190] In certain aspect, the second antisense agent (e.g., second dsRNAi agent) is a free acid. In certain aspect, the second antisense agent (e.g., second dsRNAi agent) is in a salt form (e.g., a pharmaceutically acceptable salt form. It will be understood that references to second antisense agent (e.g., second dsRNAi agent) are meant to also include the pharmaceutically acceptable salts of the second antisense agent (e.g. second dsRNAi agent). If the second antisense agent (e.g., second dsRNAi agent) has, for example, at least one basic center, they can form acid addition salts. Corresponding acid addition salts can also be formed having, if desired, an additionally present basic center. Active substances having an acid group, e.g., COOH, can form salts with bases. The second antisense agent (e.g., second dsRNAi agent) or pharmaceutically acceptable salts thereof may also be used in form of a hydrate or include other solvents used for crystallization. In some embodiments, the second antisense agent (e.g., second dsRNAi agent) is a sodium salt. In some embodiments, the second antisense agent (e.g. second dsRNAi agent) is in a salt form (e.g., a pharmaceutically acceptable salt form), where the salt is sodium (Na+), ammonium (NHC), calcium (Ca2+), iron (Fe2+or Fe3+), magnesium (Mg2+), potassium (K+), pyridinium (CsHsNH+j, quaternary ammonium (NR4+, R being an alkyl group or an aryl group as described herein), or copper (Cu2+).[000191] In an aspect, the disclosure provides a second dsRNAi agent having sequences (e.g., antisense strand sequence) that can recognize a specific region of an HMGCR mRNA (e.g., humanPAT059887-PCT-SEC01HMGCR mRNA) and lead cleavage of the HMGCR mRNA and silencing of the gene. The second dsRNAi agent includes a sense strand and an antisense strand and each strand may range from 12 to 30 nucleotides in length. In some embodiments, each strand may have 15 to 30 nucleotides in length. In some embodiments, each strand may have 15 to 25 nucleotides in length. In some embodiments, the antisense strand may have 15 to 25 nucleotides in length. In some embodiments, the sense strand may have 15 to 25 nucleotides in length. In some embodiments, the antisense strand may have 15 to 23 nucleotides in length. In some embodiments, the sense strand may have 15 to 23 nucleotides in length. In some embodiments, the antisense strand may have 18 to 25 nucleotides in length. In some embodiments, the sense strand may have 18 to 25 nucleotides in length.[000192] In some embodiments, the sense strand may have 19 to 23 nucleotides in length. In some embodiments, the sense strand may have 21 to 23 nucleotides in length. In some embodiments, the sense strand may have 19 nucleotides in length. In some embodiments, the sense strand may have 20 nucleotides in length. In some embodiments, the sense strand may have 21 nucleotides in length. In some embodiments, the sense strand may have 22 nucleotides in length. In some embodiments, the sense strand may have 23 nucleotides in length.[000193] In some embodiments, the antisense strand may have 19 to 25 nucleotides in length. In some embodiments, the antisense strand may have 19 to 23 nucleotides in length. In some embodiments, the antisense strand may have 21 to 23 nucleotides in length. In some embodiments, the antisense strand may have 23 to 25 nucleotides in length. In some embodiments, the antisense strand may have 19 nucleotides in length. In some embodiments, the antisense strand may have 20 nucleotides in length. In some embodiments, the antisense strand may have 21 nucleotides in length. In some embodiments, the antisense strand may have 22 nucleotides in length. In some embodiments, the antisense strand may have 23 nucleotides in length. In some embodiments, the antisense strand may have 24 nucleotides in length. In some embodiments, the antisense strand may have 25 nucleotides in length.[000194] In some embodiments, the sense strand is 21 to 23 nucleotides in length and the antisense strand is 23 to 25 nucleotides in length. In some embodiments, the sense strand is 21 nucleotides in length and the antisense strand is 23 nucleotides in length. In some embodiments, the sense strand is 22 nucleotides in length and the antisense strand is 24 nucleotides in length. InPAT059887-PCT-SEC01 some embodiments, the sense strand is 23 nucleotides in length and the antisense strand is 25 nucleotides in length.[000195] In an aspect, a second dsRNAi agent as described herein forms a double-stranded(or “duplex”) region made between a sense strand and an antisense strand and having 10 to 25 nucleotide pairs in length. The double stranded or duplex region are loaded into the RISC complex and subsequent specific degradation of the sense strand occurs during the RISC pathway. In some embodiments, the double stranded region has 10 nucleotide base pairs in length. In some embodiments, the double stranded region has 11 nucleotide base pairs in length. In some embodiments, the double stranded region has 12 nucleotide base pairs in length. In some embodiments, the double stranded region has 13 nucleotide base pairs in length. In some embodiments, the double stranded region has 14 nucleotide base pairs in length. In some embodiments, the double stranded region has 15 nucleotide base pairs in length. In some embodiments, the double stranded region has 16 nucleotide base pairs in length. In some embodiments, the double stranded region has 17 nucleotide base pairs in length. In some embodiments, the double stranded region has 18 nucleotide base pairs in length. In some embodiments, the double stranded region has 19 nucleotide base pairs in length. In some embodiments, the double stranded region has 20 nucleotide base pairs in length. In some embodiments, the double stranded region has 21 nucleotide base pairs in length. In some embodiments, the double stranded region has 22 nucleotide base pairs in length. In some embodiments, the double stranded region has 23 nucleotide base pairs in length.[000196] In an aspect, a second dsRNAi agent as described herein may include at least one single-stranded nucleotide overhang, for example, for increasing in vivo effectiveness of the second dsRNAi agent and having substantially improved inhibition of the target genes. In certain aspect, the second dsRNAi agent may contain one or more extra nucleotides constituting overhang regions that locate other than the double stranded region at the 3 '-end, 5 '-end, or both ends of either stand or both strands (sense and antisense strands). In some embodiments, the overhang region may exist at the 3 '-end, 5 '-end, or both ends of the sense strand. In some embodiments, the overhang region may exist at the 3'-end, 5'-end, or both ends of the antisense strand. In some embodiments, the antisense strand may have a greater length than a length in the sense strand. In some embodiments, the antisense strand may have a shorter length than a length in the sense strand.PAT059887-PCT-SEC01[000197] In some embodiments, the second dsRNAi agent may contain one or more extra nucleotides constituting overhang regions at the 3'-end, 5'-end, or both ends of the antisense strand. In some embodiments, the overhang region in the antisense strand may consist of 1-6 nucleotides in length, for example, 1 nucleotide, 2 nucleotides, 3 nucleotides, 4 nucleotides, 5 nucleotides, or 6 nucleotides in length. In some embodiments, the second dsRNAi agent may contain one or more extra nucleotides constituting overhang regions at the 3'-end, 5'-end, or both ends of the sense strand. In some embodiments, the overhang region may consist of 1-6 nucleotides in length, for example, 1 nucleotide, 2 nucleotides, 3 nucleotides, 4 nucleotides, 5 nucleotides, or 6 nucleotides in length.[000198] In some embodiments, the antisense strand may include one-nucleotide overhang at the 5’ end. In some embodiments, the antisense strand may include one-nucleotide overhang at the 3 ’ end. In some embodiments, the antisense strand may include two-nucleotides overhang. In some embodiments, the antisense contains two-nucleotides overhang at the 5’ end. In some embodiments, the antisense contains two-nucleotides overhang at the 3’ end. In some embodiments, the antisense contains one-nucleotide overhang at the 5’ end and one-nucleotide overhang at the 3’ end. In some embodiments, the antisense strand may include three-nucleotide overhang. In some embodiments, the antisense contains three-nucleotides overhang at the 5’ end. In some embodiments, the antisense contains three-nucleotides overhang at the3 ’ end. In some embodiments, the antisense contains two-nucleotides overhang at the 5’ end and one-nucleotide overhang at the 3 ’ end. In some embodiments, the antisense contains two nucleotides overhang at the 3’ end and one-nucleotide overhang at the 5’ end.[000199] In certain aspect, a second dsRNAi agent as described herein may include at least one blunt end, e.g., for increasing in vivo stability with resistance to degradation in physiological surroundings. In some embodiments, the second dsRNAi agent may have a blunt end at the 3'- end, 5 '-end, or both ends of the duplex. In some embodiments, the second dsRNAi agent includes one overhang (e.g., at 3’ end of antisense strand) and one blunt end (e.g., at 5’ end of antisense strand). In some embodiments, the second dsRNAi agent includes a blunt end at the 5'-end of the sense strand (and at 3 ’ end of the antisense strand) and contain overhang nucleotide(s) at the other end. In some embodiments, the second dsRNAi agent may have a blunt end at the 3 '-end of the sense strand (and at 5’ end of the antisense strand) and contain overhang nucleotide(s) at the other end.PAT059887-PCT-SEC01[000200] The sequences of the single strands (i.e., sense strand and antisense strand) of the second dsRNAi agent can be selected by selecting a target region and a length in the HMGCR mRNA. In certain aspect, a second dsRNAi agent as described herein may target a nucleotide region selected from regions of (i) 50-250 and (ii) 2400-2600 of a human HMGCR mRNA sequence that has at least about 85% (e.g., about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99% or 100%) identity to SEQ ID NO: 793 (human HMGCR isoform, transcript variant 1, mRNA (GenBank: NM_000859.3)). In some embodiments, the target region is selected from regions of (i) 100-200 and (ii) 2500-2600 of a human HMGCR mRNA sequence that has at least about 85% (e.g., about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99% or 100%) identity to SEQ ID NO: 793 (human HMGCR isoform, transcript variant 1, mRNA (GenBank: NM_000859.3)).[000201] In certain aspect, an antisense strand of the second dsRNAi agent as described herein targets a nucleotide region selected from regions of (i) 50-250 and (ii) 2400-2600 of a human HMGCR mRNA sequence that has at least about 85% (e.g., about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99% or 100%) identity to SEQ ID NO: 793 (human HMGCR isoform, transcript variant 1, mRNA (GenBank: NM 000859.3)). In some embodiments, the antisense strand of the second dsRNAi agent as described herein targets a nucleotide region selected from regions of (i) 100-200 and (ii) 2500-2600 of a human HMGCR mRNA sequence that has at least about 85% (e.g., about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99% or 100%) identity to SEQ ID NO: 793 (human HMGCR isoform, transcript variant 1, mRNA (GenBank: NM_000859.3)).[000202] In some embodiments, the antisense strand targets a region of 50-25 Oth nucleotides in a human HMGCR mRNA sequence that has at least about 85% (e.g., about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99% or 100%) identity to SEQ ID NO: 793 (human HMGCR isoform, transcript variant 1, mRNA (GenBank: NM 000859.3)). In some embodiments, the antisense strand targets a region of 100-200th nucleotides in a human HMGCRPAT059887-PCT-SEC01 mRNA sequence that has at least about 85% (e.g., about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99% or 100%) identity to SEQ ID NO: 793 (human HMGCR isoform, transcript variant 1, mRNA (GenBank: NM_000859.3)). In some embodiments, the antisense strand targets a region of 100- 150th nucleotides in a human HMGCR mRNA sequence that has at least about 85% (e.g., about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99% or 100%) identity to SEQ ID NO: 793 (human HMGCR isoform, transcript variant 1, mRNA (GenBank: NM_000859.3)).[000203] In some embodiments, the antisense strand targets a region of 2400-2600th nucleotides in a human HMGCR mRNA sequence that has at least about 85% (e.g., about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99% or 100%) identity to SEQ ID NO: 793 (human HMGCR isoform, transcript variant 1, mRNA (GenBank: NM 000859.3)). In some embodiments, the antisense strand targets a region of 2500-2600th nucleotides in a human HMGCR mRNA sequence that has at least about 85% (e.g., about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99% or 100%) identity to SEQ ID NO: 793 (human HMGCR isoform, transcript variant 1, mRNA (GenBank: NM 000859.3)). In some embodiments, the antisense strand targets a region of 2550-2600th nucleotides in a human HMGCR mRNA sequence that has at least about 85% (e.g., about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99% or 100%) identity to SEQ ID NO: 793 (human HMGCR isoform, transcript variant 1, mRNA (GenBank: NM_000859.3)).[000204] In certain aspect, the target HMGCR mRNA sequence may range from 12 to 30 nucleotides, from 15 to 30 nucleotides, from 18 to 30 nucleotides, from 18 to 25 nucleotides, from 18 to 23 nucleotides. In some embodiments, the target HMGCR mRNA sequence may have 15 nucleotides in length. In some embodiments, the target HMGCR mRNA sequence may have 16 nucleotides in length. In some embodiments, the target HMGCR mRNA sequence may have 17 nucleotides in length. In some embodiments, the target HMGCR mRNA sequence may have 18 nucleotides in length. In some embodiments, the target HMGCR mRNA sequence may have 19PAT059887-PCT-SEC01 nucleotides in length. In some embodiments, the target HMGCR mRNA sequence may have 20 nucleotides in length. In some embodiments, the target HMGCR mRNA sequence may have 21 nucleotides in length. In some embodiments, the target HMGCR mRNA sequence may have 22 nucleotides in length. In some embodiments, the target HMGCR mRNA sequence may have 23 nucleotides in length.[000205] In certain aspect, exemplary second dsRNAi agent sequences including sense strands and antisense strands targeting the above indicated HMGCR mRNA (SEQ ID NO: 793, or GenBank: NM_000859.3) are in Table 3.Table 3PAT059887-PCT-SEC01PAT059887-PCT-SEC01PAT059887-PCT-SEC01PAT059887-PCT-SEC01PAT059887-PCT-SEC01PAT059887-PCT-SEC01PAT059887-PCT-SEC01PAT059887-PCT-SEC01PAT059887-PCT-SEC01PAT059887-PCT-SEC01Table 3A. Additional exemplary second dsRNAi agent sequences including sense strands and antisense strands targeting HMGCR.PAT059887-PCT-SEC01[000206] Homo sapiens HMGCR, transcript variant 1, mRNA : GenBank: NM 000859.3 (SEQ ID NO: 793)1 ccttccgctc cgcgactgcg ttaactggag ccaggctgag cgtcggcgcc ggggttcggt61 ggcctctagt gagatctgga ggatccaagg attctgtagc tacaatgttg tcaagacttt121 ttcgaatgca tggcctcttt gtggcctccc atccctggga agtcatagtg gggacagtga181 cactgaccat ctgcatgatg tccatgaaca tgtttactgg taacaataag atctgtggtt241 ggaattatga atgtccaaag tttgaagagg atgttttgag cagtgacatt ataattctga301 caataacacg atgcatagcc atcctgtata tttacttcca gttccagaat ttacgtcaac361 ttggatcaaa atatattttg ggtattgctg gccttttcac aattttctca agttttgtat421 tcagtacagt tgtcattcac ttcttagaca aagaattgac aggcttgaat gaagctttgc481 cctttttcct acttttgatt gacctttcca gagcaagcac attagcaaag tttgccctca541 gttccaactc acaggatgaa gtaagggaaa atattgctcg tggaatggca attttaggtc601 ctacgtttac cctcgatgct cttgttgaat gtcttgtgat tggagttggt accatgtcag661 gggtacgtca gcttgaaatt atgtgctgct ttggctgcat gtcagttctt gccaactact721 tcgtgttcat gactttcttc ccagcttgtg tgtccttggt attagagctt tctcgggaaa781 gccgcgaggg tcgtccaatt tggcagctca gccattttgc ccgagtttta gaagaagaag841 aaaataagcc gaatcctgta actcagaggg tcaagatgat tatgtctcta ggcttggttc901 ttgttcatgc tcacagtcgc tggatagctg atccttctcc tcaaaacagt acagcagata961 cttctaaggt ttcattagga ctggatgaaa atgtgtccaa gagaattgaa ccaagtgttt1021 ccctctggca gttttatctc tctaaaatga tcagcatgga tattgaacaa gttattaccc1081 taagtttagc tctccttctg gctgtcaagt acatcttctt tgaacaaaca gagacagaat1141 ctacactctc attaaaaaac cctatcacat ctcctgtagt gacacaaaag aaagtcccag1201 acaattgttg tagacgtgaa cctatgctgg tcagaaataa ccagaaatgt gattcagtag1261 aggaagagac agggataaac cgagaaagaa aagttgaggt tataaaaccc ttagtggctg1321 aaacagatac cccaaacaga gctacatttg tggttggtaa ctcctcctta ctcgatactt1381 catcagtact ggtgacacag gaacctgaaa ttgaacttcc cagggaacct cggcctaatg1441 aagaatgtct acagatactt gggaatgcag agaaaggtgc aaaattcctt agtgatgctg1501 agatcatcca gttagtcaat gctaagcata tcccagccta caagttggaa actctgatgg1561 aaactcatga gcgtggtgta tctattcgcc gacagttact ttccaagaag ctttcagaacPAT059887-PCT-SEC011621 cttcttctct ccagtaccta ccttacaggg attataatta ctccttggtg atgggagctt1681 gttgtgagaa tgttattgga tatatgccca tccctgttgg agtggcagga cccctttgct1741 tagatgaaaa agaatttcag gttccaatgg caacaacaga aggttgtctt gtggccagca1801 ccaatagagg ctgcagagca ataggtcttg gtggaggtgc cagcagccga gtccttgcag1861 atgggatgac tcgtggccca gttgtgcgtc ttccacgtgc ttgtgactct gcagaagtga1921 aagcctggct cgaaacatct gaagggttcg cagtgataaa ggaggcattt gacagcacta1981 gcagatttgc acgtctacag aaacttcata caagtatagc tggacgcaac ctttatatcc2041 gtttccagtc caggtcaggg gatgccatgg ggatgaacat gatttcaaag ggtacagaga2101 aagcactttc aaaacttcac gagtatttcc ctgaaatgca gattctagcc gttagtggta2161 actattgtac tgacaagaaa cctgctgcta taaattggat agagggaaga ggaaaatctg2221 ttgtttgtga agctgtcatt ccagccaagg ttgtcagaga agtattaaag actaccacag2281 aggctatgat tgaggtcaac attaacaaga atttagtggg ctctgccatg gctgggagca2341 taggaggcta caacgcccat gcagcaaaca ttgtcaccgc catctacatt gcctgtggac2401 aggatgcagc acagaatgtt ggtagttcaa actgtattac tttaatggaa gcaagtggtc2461 ccacaaatga agatttatat atcagctgca ccatgccatc tatagagata ggaacggtgg2521 gtggtgggac caacctacta cctcagcaag cctgtttgca gatgctaggt gttcaaggag2581 catgcaaaga taatcctggg gaaaatgccc ggcagcttgc ccgaattgtg tgtgggaccg2641 taatggctgg ggaattgtca cttatggcag cattggcagc aggacatctt gtcaaaagtc2701 acatgattca caacaggtcg aagatcaatt tacaagacct ccaaggagct tgcaccaaga2761 agacagcctg aatagcccga cagttctgaa ctggaacatg ggcattgggt tctaaaggac2821 taacataaaa tctgtgaatt aaaaaagctc aatgcattgt cttgtggagg atgaatagat2881 gtgatcactg agacagccac ttggtttttg gctctttcag agaggtctca ggttctttcc2941 atgcagactc ctcagatctg aacacagttt agtgctttac atgctgtgct ctttgaagag3001 atttcaacaa gaatattgta tgttaaagca tcagagatgg taatctacag ctcacctctg3061 aaggcaaata taagctggga aaaaagtttt gatgaaattc ttgaagttca tggtgatcag3121 tgcaattgac cttctccctc actcctgcca gttgaaaatg gatttttaaa ttatactgta3181 gctgatgaaa ctcctgattt tgtagttaat ttattaagtc tgggatgtag aacttcaaga3241 agtaagagct aagttctaag ttcatgtttg taaattaata cttcatttgg tgctggtcta3301 ttttgatttt ggggggtaat cagcattatt cttcagaagg ggacctgttt tcttcaaggg3361 aagaaacact cttattccca aactacagaa taatgtgtta aacatgctaa atagttctat3421 caggaaaaca aatcactgta tttatctccg caggctattt gttcagagag gccttttgttPAT059887-PCT-SEC013481 taaatataaa tgtttaaata taaatgtttg tctggattgg ctataacatg tctttcagca3541 ttaggctttt aagaaacaca gggttttgta ttctttacta aagatatcag agctcttaat 3601 gttgcttaga tgagggtgac tgtcaagtac aagcaagact gggaccttag aaatcattgt 3661 agaaacacag ttttgaaaga aaaataccat gtctctaagc caactttaat tgcttaaaag 3721 acatttttat ttagttgaaa aatctagttt tttttgtaaa ctgtatcaaa tctgtatatg 3781 ttgtaataaa acttatgcta gtttattgga agtgttcaag aaataaaaat caacttgtgt 3841 actgataaaa tactctagcc tgggccagag aagataatgt tctttaatgt tgtccaggaa 3901 accctggctt gcttgccgag cctaatgaaa gggaaagtca gctttcagag ccagtgaagg 3961 agccacgtga atggccctag aactgtgcct agttcctgtg gccaggaggt tggtgactga 4021 aacattcaca cagggctctt tgatggaccc acgaacgctc ttagctttct cagggggtca 4081 gcagagttat tgaatcttaa ttttttttaa tgtacaagtt ttgtataaat aataaagaac 4141 tccttatttt gtattacatc taatgcttca agtgttgctc ttggaaagct gatgatgtct 4201 cttgtagaag atggactctg aaaaacattc caggaaacca tggcagcatg gagagcctct 4261 tagtgattgt gtctgcattg ttattgtgga agatttacct tttctgttgt acgtaaagct 4321 taaattgctt ttgttgtgac tttttagcca gtgacttttt ctgagctttt catggaagtg 4381 gcagtgaaaa atatgttgag tgttcatttt agtgactgta attaatatct tgctggatta 4441 atgttttgta caattactaa attgtataca ttttgttata gaatactttt ttctagtttc 4501 agtaaataat gaaaaggaag ttaataccaa[000207] In Tables 3 and 3 A, each code (leter, e.g., A, G, C, and U) represents a single ribonucleotide in the second dsRNAi agent. In some embodiments, the sequence list may be inclusive of any possible, additional modifications in a nucleobase, a ribose sugar ring, and / or a phosphate group (i.e., internucleoside linkage). In some embodiments, the last nucleotide from the 5’ end (or the first nucleotide from 3’ end) in each strand (sense strand and antisense strand) may have not include a phosphate group as being hydrolyzed or processed, e.g., during the synthesis of the oligonucleotides. In some embodiments, a phosphate group in the last nucleotide from the 5 ’ end (or the first nucleotide from 3 ’ end) in the sense strand may be added as a functional group for conjugation with a ligand.[000208] In some embodiments, the second dsRNAi agent includes a sense strand having 10 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 794-1198 or 2432-2440. In some embodiments, the second dsRNAiPAT059887-PCT-SEC01 agent includes an antisense strand having 10 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of SEQ ID NOs: 1199-1603 or 2441-2449. In some embodiments, the second dsRNAi agent includes a sense strand having 11 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 794-1198 or 2432-2440. In some embodiments, the second dsRNAi agent includes an antisense strand having 11 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 1199-1603 or 2441-2449. In some embodiments, the second dsRNAi agent includes a sense strand having 12 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 794-1198 or 2432-2440. In some embodiments, the second dsRNAi agent includes an antisense strand having 12 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 1199-1603 or 2441-2449. In some embodiments, the second dsRNAi agent includes a sense strand having 13 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 794-1198 or 2432-2440. In some embodiments, the second dsRNAi agent includes an antisense strand having 13 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 1199-1603 or 2441-2449. In some embodiments, the second dsRNAi agent includes a sense strand having 14 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 794-1198 or 2432-2440. In some embodiments, the second dsRNAi agent includes an antisense strand having 14 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 1199- 1603 or 2441-2449. In some embodiments, the second dsRNAi agent includes a sense strand having 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 794-1198 or 2432-2440. In some embodiments, the second dsRNAi agent includes an antisense strand having 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 1199-1603 or 2441- 2449. In some embodiments, the second dsRNAi agent includes a sense strand having 16 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 794-1198 or 2432-2440. In some embodiments, the second dsRNAi agent includes an antisense strand having 16 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 1199-1603 or 2441-2449.PAT059887-PCT-SEC01In some embodiments, the second dsRNAi agent includes a sense strand having 17 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 794-1198 or 2432-2440. In some embodiments, the second dsRNAi agent includes an antisense strand having 17 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 1199-1603 or 2441-2449. In some embodiments, the second dsRNAi agent includes a sense strand having 18 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 794-1198 or 2432-2440. In some embodiments, the second dsRNAi agent includes an antisense strand having 18 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 1199-1603 or 2441-2449. In some embodiments, the second dsRNAi agent includes a sense strand having 19 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 794-1198 or 2432-2440. In some embodiments, the second dsRNAi agent includes an antisense strand having 19 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 1199-1603 or 2441-2449. In some embodiments, the second dsRNAi agent includes a sense strand having 20 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 794-1198 or 2432-2440. In some embodiments, the second dsRNAi agent includes an antisense strand having 20 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 1199-1603 or 2441-2449. In some embodiments, the second dsRNAi agent includes a sense strand having 21 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 794-1198 or 2432-2440. In some embodiments, the second dsRNAi agent includes an antisense strand having 21 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 1199- 1603 or 2441-2449. In some embodiments, the second dsRNAi agent includes an antisense strand having 22 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 1199-1603 or 2441-2449. In some embodiments, the second dsRNAi agent includes an antisense strand having 23 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 1199-1603 or 2441- 2449.PAT059887-PCT-SEC01[000209] In some embodiments, the second dsRNAi agent includes an antisense strand having 10 contiguous nucleotides differing by no more than 2 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 1199-1603 or 2441-2449. In some embodiments, the second dsRNAi agent includes a sense strand having 11 contiguous nucleotides differing by no more than 2 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 794-1198 or 2432-2440. In some embodiments, the second dsRNAi agent includes an antisense strand having 11 contiguous nucleotides differing by no more than 2 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 1199-1603 or 2441-2449. In some embodiments, the second dsRNAi agent includes a sense strand having 12 contiguous nucleotides differing by no more than 2 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 794-1198 or 2432-2440. In some embodiments, the second dsRNAi agent includes an antisense strand having 12 contiguous nucleotides differing by no more than 2 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 1199- 1603 or 2441-2449. In some embodiments, the second dsRNAi agent includes a sense strand having 13 contiguous nucleotides differing by no more than 2 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 794-1198 or 2432-2440. In some embodiments, the second dsRNAi agent includes an antisense strand having 13 contiguous nucleotides differing by no more than 2 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 1199-1603 or 2441- 2449. In some embodiments, the second dsRNAi agent includes a sense strand having 14 contiguous nucleotides differing by no more than 2 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 794-1198 or 2432-2440. In some embodiments, the second dsRNAi agent includes an antisense strand having 14 contiguous nucleotides differing by no more than 2 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 1199-1603 or 2441-2449. In some embodiments, the second dsRNAi agent includes a sense strand having 15 contiguous nucleotides differing by no more than 2 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 794-1198 or 2432-2440. In some embodiments, the second dsRNAi agent includes an antisense strand having 15 contiguous nucleotides differing by no more than 2 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 1199-1603 or 2441-2449. In some embodiments, the second dsRNAi agent includes a sense strand having 16 contiguous nucleotides differing by no more than 2 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 794-1198 or 2432-2440. In some embodiments, the second dsRNAi agent includes an antisense strand having 16 contiguous nucleotides differing by no more than 2 nucleotides from thePAT059887-PCT-SEC01 nucleotide sequence selected from SEQ ID NOs: 1199-1603 or 2441-2449. In some embodiments, the second dsRNAi agent includes a sense strand having 17 contiguous nucleotides differing by no more than 2 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 794-1198 or 2432-2440. In some embodiments, the second dsRNAi agent includes an antisense strand having 17 contiguous nucleotides differing by no more than 2 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 1199-1603 or 2441-2449. In some embodiments, the second dsRNAi agent includes a sense strand having 18 contiguous nucleotides differing by no more than 2 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 794-1198 or 2432-2440. In some embodiments, the second dsRNAi agent includes an antisense strand having 18 contiguous nucleotides differing by no more than 2 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 1199-1603 or 2441-2449. In some embodiments, the second dsRNAi agent includes a sense strand having 19 contiguous nucleotides differing by no more than 2 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 794-1198 or 2432-2440. In some embodiments, the second dsRNAi agent includes an antisense strand having 19 contiguous nucleotides differing by no more than 2 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 1199- 1603 or 2441-2449. In some embodiments, the second dsRNAi agent includes a sense strand having 20 contiguous nucleotides differing by no more than 2 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 794-1198 or 2432-2440. In some embodiments, the second dsRNAi agent includes an antisense strand having 20 contiguous nucleotides differing by no more than 2 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 1199-1603 or 2441- 2449. In some embodiments, the second dsRNAi agent includes a sense strand having 21 contiguous nucleotides differing by no more than 2 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 794-1198 or 2432-2440. In some embodiments, the second dsRNAi agent includes an antisense strand having 21 contiguous nucleotides differing by no more than 2 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 1199-1603 or 2441-2449. In some embodiments, the second dsRNAi agent includes an antisense strand having 22 contiguous nucleotides differing by no more than 2 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 1199-1603 or 2441-2449. In some embodiments, the second dsRNAi agent includes an antisense strand having 23 contiguous nucleotides differing by no more than 2 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 1199-1603 or 2441-2449.PAT059887-PCT-SEC01[000210] In some embodiments, the second dsRNAi agent includes a sense strand having 10 contiguous nucleotides differing by no more than 1 nucleotide from the nucleotide sequence selected from SEQ ID NOs: 794-1198 or 2432-2440. In some embodiments, the second dsRNAi agent includes an antisense strand having 10 contiguous nucleotides differing by no more than 1 nucleotide from the nucleotide sequence selected from SEQ ID NOs: 1199-1603 or 2441-2449. In some embodiments, the second dsRNAi agent includes a sense strand having 11 contiguous nucleotides differing by no more than 1 nucleotide from the nucleotide sequence selected from SEQ ID NOs: 794-1198 or 2432-2440. In some embodiments, the second dsRNAi agent includes an antisense strand having 11 contiguous nucleotides differing by no more than 1 nucleotide from the nucleotide sequence selected from SEQ ID NOs: 1199-1603 or 2441-2449. In some embodiments, the second dsRNAi agent includes a sense strand having 12 contiguous nucleotides differing by no more than 1 nucleotide from the nucleotide sequence selected from SEQ ID NOs: 794-1198 or 2432-2440. In some embodiments, the second dsRNAi agent includes an antisense strand having 12 contiguous nucleotides differing by no more than 1 nucleotide from the nucleotide sequence selected from SEQ ID NOs: 1199-1603 or 2441-2449. In some embodiments, the second dsRNAi agent includes a sense strand having 13 contiguous nucleotides differing by no more than 1 nucleotide from the nucleotide sequence selected from SEQ ID NOs: 794-1198 or 2432-2440. In some embodiments, the second dsRNAi agent includes an antisense strand having 13 contiguous nucleotides differing by no more than 1 nucleotide from the nucleotide sequence selected from SEQ ID NOs: 1199-1603 or 2441-2449. In some embodiments, the second dsRNAi agent includes a sense strand having 14 contiguous nucleotides differing by no more than 1 nucleotide from the nucleotide sequence selected from SEQ ID NOs: 794-1198 or 2432-2440. In some embodiments, the second dsRNAi agent includes an antisense strand having 14 contiguous nucleotides differing by no more than 1 nucleotide from the nucleotide sequence selected from SEQ ID NOs: 1199-1603 or 2441-2449. In some embodiments, the second dsRNAi agent includes a sense strand having 15 contiguous nucleotides differing by no more than 1 nucleotide from the nucleotide sequence selected from SEQ ID NOs: 794-1198 or 2432-2440. In some embodiments, the second dsRNAi agent includes an antisense strand having 15 contiguous nucleotides differing by no more than 1 nucleotide from the nucleotide sequence selected from SEQ ID NOs: 1199- 1603 or 2441-2449. In some embodiments, the second dsRNAi agent includes a sense strand having 16 contiguous nucleotides differing by no more than 1 nucleotide from the nucleotidePAT059887-PCT-SEC01 sequence selected from SEQ ID NOs: 794-1198 or 2432-2440. In some embodiments, the second dsRNAi agent includes an antisense strand having 16 contiguous nucleotides differing by no more than 1 nucleotide from the nucleotide sequence selected from SEQ ID NOs: 1199-1603 or 2441- 2449. In some embodiments, the second dsRNAi agent includes a sense strand having 17 contiguous nucleotides differing by no more than 1 nucleotide from the nucleotide sequence selected from SEQ ID NOs: 794-1198 or 2432-2440. In some embodiments, the second dsRNAi agent includes an antisense strand having 17 contiguous nucleotides differing by no more than 1 nucleotide from the nucleotide sequence selected from SEQ ID NOs: 1199-1603 or 2441-2449. In some embodiments, the second dsRNAi agent includes a sense strand having 18 contiguous nucleotides differing by no more than 1 nucleotide from the nucleotide sequence selected from SEQ ID NOs: 794-1198 or 2432-2440. In some embodiments, the second dsRNAi agent includes an antisense strand having 18 contiguous nucleotides differing by no more than 1 nucleotide from the nucleotide sequence selected from SEQ ID NOs: 1199-1603 or 2441-2449. In some embodiments, the second dsRNAi agent includes a sense strand having 19 contiguous nucleotides differing by no more than 1 nucleotide from the nucleotide sequence selected from SEQ ID NOs: 794-1198 or 2432-2440. In some embodiments, the second dsRNAi agent includes an antisense strand having 19 contiguous nucleotides differing by no more than 1 nucleotide from the nucleotide sequence selected from SEQ ID NOs: 1199-1603 or 2441-2449. In some embodiments, the second dsRNAi agent includes a sense strand having 20 contiguous nucleotides differing by no more than 1 nucleotide from the nucleotide sequence selected from SEQ ID NOs: 794-1198 or 2432-2440. In some embodiments, the second dsRNAi agent includes an antisense strand having 20 contiguous nucleotides differing by no more than 1 nucleotide from the nucleotide sequence selected from SEQ ID NOs: 1199-1603 or 2441-2449. In some embodiments, the second dsRNAi agent includes a sense strand having 21 contiguous nucleotides differing by no more than 1 nucleotide from the nucleotide sequence selected from SEQ ID NOs: 794-1198 or 2432-2440. In some embodiments, the second dsRNAi agent includes an antisense strand having 21 contiguous nucleotides differing by no more than 1 nucleotide from the nucleotide sequence selected from SEQ ID NOs: 1199-1603 or 2441-2449. In some embodiments, the second dsRNAi agent includes an antisense strand having 22 contiguous nucleotides differing by no more than 1 nucleotide from the nucleotide sequence selected from SEQ ID NOs: 1199-1603 or 2441-2449. In some embodiments, the second dsRNAi agent includes an antisense strand having 23 contiguousPAT059887-PCT-SEC01 nucleotides differing by no more than 1 nucleotide from the nucleotide sequence selected from SEQ ID NOs: 1199-1603 or 2441-2449.[000211] In some embodiments, the second dsRNAi agent includes (i) a sense strand having 15 contiguous nucleotides differing by no more than one, two or three nucleotides from the nucleotide sequence selected from SEQ ID NOs: 794-1198 or 2432-2440 and (ii) an antisense strand forming a duplex with the sense strand of (i) and having 15 contiguous nucleotides differing by no more than one, two or three nucleotides from the nucleotide sequence selected from SEQ ID NOs: 1199- 1603 or 2441-2449. In some embodiments, the second dsRNAi agent includes (i) a sense strand having 16 contiguous nucleotides differing by no more than one, two or three from the nucleotide sequence selected from SEQ ID NOs: 794-1198 or 2432-2440 and (ii) an antisense strand forming a duplex with the sense strand of (i) and having 16 contiguous nucleotides differing by no more than one, two or three nucleotides from the nucleotide sequence selected from SEQ ID NOs: 1199- 1603 or 2441-2449. In some embodiments, the second dsRNAi agent includes (i) a sense strand having 17 contiguous nucleotides differing by no more than one, two or three nucleotides from the nucleotide sequence selected from SEQ ID NOs: 794-1198 or 2432-2440 and (ii) an antisense strand forming a duplex with the sense strand of (i) and having 17 contiguous nucleotides differing by no more than one, two or three nucleotides from the nucleotide sequence selected from SEQ ID NOs: 1199-1603 or 2441-2449. In some embodiments, the second dsRNAi agent includes (i) a sense strand having 18 contiguous nucleotides differing by no more than one, two or three nucleotides from the nucleotide sequence selected from SEQ ID NOs: 794-1198 or 2432-2440 and (ii) an antisense strand forming a duplex with the sense strand of (i) and having 18 contiguous nucleotides differing by no more than one, two or three nucleotides from the nucleotide sequence selected from SEQ ID NOs: 1199-1603 or 2441-2449. In some embodiments, the second dsRNAi agent includes (i) a sense strand having 19 contiguous nucleotides differing by no more than one, two or three nucleotides from the nucleotide sequence selected from SEQ ID NOs: 794-1198 or 2432-2440 and (ii) an antisense strand forming a duplex with the sense strand of (i) and having 19 contiguous nucleotides differing by no more than one, two or three nucleotides from the nucleotide sequence selected from SEQ ID NOs: 1199-1603 or 2441-2449. In some embodiments, the second dsRNAi agent includes (i) a sense strand having 20 contiguous nucleotides differing by no more than one, two or three nucleotides from the nucleotide sequence selected from SEQ ID NOs: 794- 1198 or 2432-2440 and (ii) an antisense strand forming a duplex with the sense strand of (i) andPAT059887-PCT-SEC01 having 20 contiguous nucleotides differing by no more than one, two or three nucleotides from the nucleotide sequence selected from SEQ ID NOs: 1199-1603 or 2441-2449. In some embodiments, the second dsRNAi agent includes (i) a sense strand having 21 contiguous nucleotides differing by no more than one, two or three nucleotides from the nucleotide sequence selected from SEQ ID NOs: 794-1198 or 2432-2440 and (ii) an antisense strand forming a duplex with the sense strand of (i) and having 21 contiguous nucleotides differing by no more than one, two or three nucleotides from the nucleotide sequence selected from SEQ ID NOs: 1199-1603 or 2441-2449. In some embodiments, the second dsRNAi agent includes (i) a sense strand having 21 contiguous nucleotides differing by no more than one, two or three nucleotides from the nucleotide sequence selected from SEQ ID NOs: 794-1198 or 2432-2440 and (ii) an antisense strand forming a duplex with the sense strand of (i) and having 22 contiguous nucleotides differing by no more than one, two or three nucleotides from the nucleotide sequence selected from SEQ ID NOs: 1199-1603 or 2441-2449. In some embodiments, the second dsRNAi agent includes (i) a sense strand having 21 contiguous nucleotides differing by no more than one, two or three nucleotides from the nucleotide sequence selected from SEQ ID NOs: 794-1198 or 2432-2440 and (ii) an antisense strand forming a duplex with the sense strand of (i) and having 23 contiguous nucleotides differing by no more than one, two or three nucleotides from the nucleotide sequence selected from SEQ ID NOs: 1199- 1603 or 2441-2449.[000212] In certain aspect, when a sense strand or an antisense strand of a second dsRNAi agent in above paragraphs is differing by a certain number of nucleotides (e.g., one, two or three nucleotides) from a specific sequence (e.g., SEQ ID NOs: 794-1603 or 2432-2449), it is meant by that the sense strand or the antisense strand of the second dsRNAi agent includes one, two or three nucleotides having different nucleobases compared to the nucleobases of the nucleotides at the corresponding positions of the specific sequence (e.g., SEQ ID NOs: 794-1603 or 2432-2449). [000213] Additional suitable second dsRNAi agents are described in WO 2024 / 260434 and WO 2025 / 188589, the entire contents of which are incorporated herein by reference.Combinations I[000214] Also provided herein are combinations that include a first dsRNAi agent and a second dsRNAi agent, wherein the first dsRNAi agent is selected from Tables 1-2 or SEQ ID NOs: 3 to 792 and the second dsRNAi agent is selected from Table 3 or SEQ ID NOs: 794 to 1603. AlsoPAT059887-PCT-SEC01 provided herein are combinations that include a first dsRNAi agent and a second dsRNAi agent, wherein the first dsRNAi agent is selected from Tables 1, 2 or 2A or SEQ ID NOs: 3-792 or 2348-2431 and the second dsRNAi agent is selected from Tables 3 or 3 A or SEQ ID NOs: 794-1603 or 2432-2449. In some embodiments, the first dsRNAi agent comprises a sense strand comprising a sequence selected from SEQ ID NOs: 3-381 and 761-776 and an antisense strand comprising a sequence selected from SEQ ID NOs: 382-760 and 777-792; and the second dsRNAi agent comprises a sense strand comprising a sequence selected from SEQ ID NOs: 794-1198 and an antisense strand comprising a sequence selected from SEQ ID NOs: 1199-1603. In some embodiments, the first dsRNAi agent comprises a sense strand comprising a sequence selected from SEQ ID NOs: 3-381, 761-776, and 2348-2389 and an antisense strand comprising a sequence selected from SEQ ID NOs: 382-760, 777-792, and 2390-2431; and the second dsRNAi agent comprises a sense strand comprising a sequence selected from SEQ ID NOs: 794-1198 and 2432- 2440 and an antisense strand comprising a sequence selected from SEQ ID NOs: 1199-1603 and 2441-2449. In some embodiments, the first dsRNAi agent comprises a sense strand selected from SEQ ID NOs: 3-381 and 761-776 and an antisense strand selected from SEQ ID NOs: 382-760 and 777-792; and the second dsRNAi agent comprises a sense strand selected from SEQ ID NOs: 794-1198 and an antisense strand selected from SEQ ID NO: 1199-1603. In some embodiments, the first dsRNAi agent comprises a sense strand selected from SEQ ID NOs: 3-381, 761-776, and 2348-2389 and an antisense strand selected from SEQ ID NOs: 382-760, 777-792, and 2390-2431; and the second dsRNAi agent comprises a sense strand selected from SEQ ID NOs: 794-1198 and 2432-2440 and an antisense strand selected from SEQ ID NO: 1199-1603 and 2441-2449.[000215] Also provided herein are combinations that include a first dsRNAi agent and a second dsRNAi agent, where the first dsRNAi agent is selected from:(a) a dsRNAi agent comprising a sense strand consisting of SEQ ID NO: 761 and an antisense strand consisting of SEQ ID NO: 777; and(b) a dsRNAi agent comprising a sense strand consisting of SEQ ID NO: 772 and an antisense strand consisting of SEQ ID NO: 788; and the second dsRNAi agent is selected from Table 3 or SEQ ID NOs: 794-1603.[000216] Also provided herein are combinations that include a first dsRNAi agent and a second dsRNAi agent, where the first dsRNAi agent is selected from:(a) a dsRNAi agent comprising a sense strand consisting of SEQ ID NO: 761 andPAT059887-PCT-SEC01 an antisense strand consisting of SEQ ID NO: 777; and(b) a dsRNAi agent comprising a sense strand consisting of SEQ ID NO: 772 and an antisense strand consisting of SEQ ID NO: 788; and the second dsRNAi agent is selected from Tables 3 or 3A or SEQ ID NOs: 794-1603 or 2432- 2449.[000217] In some embodiments, the combination includes a first dsRNAi agent and a second dsRNAi agent, where the first dsRNAi agent is selected from:(a) a dsRNAi agent comprising a sense strand consisting of SEQ ID NO: 761 and an antisense strand consisting of SEQ ID NO: 777; and(b) a dsRNAi agent comprising a sense strand consisting of SEQ ID NO: 772 and an antisense strand consisting of SEQ ID NO: 788; and the second dsRNAi agent comprises a sense strand comprising a sequence selected from SEQ ID NOs: 794-1198 and an antisense strand comprising a sequence selected from SEQ ID NO: 1199-1603.[000218] In some embodiments, the combination includes a first dsRNAi agent and a second dsRNAi agent, where the first dsRNAi agent is selected from:(a) a dsRNAi agent comprising a sense strand consisting of SEQ ID NO: 761 and an antisense strand consisting of SEQ ID NO: 777; and(b) a dsRNAi agent comprising a sense strand consisting of SEQ ID NO: 772 and an antisense strand consisting of SEQ ID NO: 788; and the second dsRNAi agent comprises a sense strand comprising a sequence selected from SEQ ID NOs: 794-1198 or 2432-2440 and an antisense strand comprising a sequence selected from SEQ ID NO: 1199-1603 or 2441-2449.[000219] In some embodiments, the combination includes a first dsRNAi agent and a second dsRNAi agent, where the first dsRNAi agent is selected from:(a) a dsRNAi agent comprising a sense strand consisting of SEQ ID NO: 761 and an antisense strand consisting of SEQ ID NO: 777; and(b) a dsRNAi agent comprising a sense strand consisting of SEQ ID NO: 772 and an antisense strand consisting of SEQ ID NO: 788; and the second dsRNAi agent comprises a sense strand selected from SEQ ID NOs: 794-1198 and an antisense strand selected from SEQ ID NOs: 1199-1603.PAT059887-PCT-SEC01[000220] In some embodiments, the combination includes a first dsRNAi agent and a second dsRNAi agent, where the first dsRNAi agent is selected from:(a) a dsRNAi agent comprising a sense strand consisting of SEQ ID NO: 761 and an antisense strand consisting of SEQ ID NO: 777; and(b) a dsRNAi agent comprising a sense strand consisting of SEQ ID NO: 772 and an antisense strand consisting of SEQ ID NO: 788; and the second dsRNAi agent comprises a sense strand selected from SEQ ID NOs: 794-1198 or 2432-2440 and an antisense strand selected from SEQ ID NOs: 1199-1603 or 2441-2449.[000221] Also provided herein are combinations that include a first dsRNAi agent and a second dsRNAi agent, wherein the first dsRNAi agent is selected from Tables 1-2 or SEQ ID NOs: 3-792 and the second dsRNAi agent is selected from:(a) a dsRNAi agent comprising a sense strand consisting of SEQ ID NO: 796 and an antisense strand consisting of SEQ ID NO: 1201;(b) a dsRNAi agent comprising a sense strand consisting of SEQ ID NO: 799 and an antisense strand consisting of SEQ ID NO: 1204; and(c) a dsRNAi agent comprising a sense strand consisting of SEQ ID NO: 1077 and an antisense strand consisting of SEQ ID NO: 1482.[000222] Also provided herein are combinations that include a first dsRNAi agent and a second dsRNAi agent, wherein the first dsRNAi agent is selected from Tables 1, 2 or 2A or SEQ ID NOs: 3-792 or 2348-2431 and the second dsRNAi agent is selected from:(a) a dsRNAi agent comprising a sense strand consisting of SEQ ID NO: 796 and an antisense strand consisting of SEQ ID NO: 1201;(b) a dsRNAi agent comprising a sense strand consisting of SEQ ID NO: 799 and an antisense strand consisting of SEQ ID NO: 1204; and(c) a dsRNAi agent comprising a sense strand consisting of SEQ ID NO: 1077 and an antisense strand consisting of SEQ ID NO: 1482.[000223] In some embodiments, combinations include a first dsRNAi agent and a second dsRNAi agent, where the first dsRNAi agent comprises a sense strand comprising a sequence selected from SEQ ID NOs: 3-381 and 761-776 and an antisense strand comprising a sequence selected from SEQ ID NOs: 382-760 and 777-792; and the second dsRNAi agent is selected from:PAT059887-PCT-SEC01(a) a dsRNAi agent comprising a sense strand consisting of SEQ ID NO: 796 and an antisense strand consisting of SEQ ID NO: 1201;(b) a dsRNAi agent comprising a sense strand consisting of SEQ ID NO: 799 and an antisense strand consisting of SEQ ID NO: 1204; and(c) a dsRNAi agent comprising a sense strand consisting of SEQ ID NO: 1077 and an antisense strand consisting of SEQ ID NO: 1482.[000224] In some embodiments, combinations include a first dsRNAi agent and a second dsRNAi agent, where the first dsRNAi agent comprises a sense strand comprising a sequence selected from SEQ ID NOs: 3-381, 761-776 and 2348-2389 and an antisense strand comprising a sequence selected from SEQ ID NOs: 382-760, 777-792 and 2390-2431; and the second dsRNAi agent is selected from:(a) a dsRNAi agent comprising a sense strand consisting of SEQ ID NO: 796 and an antisense strand consisting of SEQ ID NO: 1201;(b) a dsRNAi agent comprising a sense strand consisting of SEQ ID NO: 799 and an antisense strand consisting of SEQ ID NO: 1204; and(c) a dsRNAi agent comprising a sense strand consisting of SEQ ID NO: 1077 and an antisense strand consisting of SEQ ID NO: 1482.[000225] In some embodiments, combinations include a first dsRNAi agent and a second dsRNAi agent, where the first dsRNAi agent comprises a sense strand selected from SEQ ID Nos 3-381 and 761-776 and an antisense strand selected from SEQ ID NO: 382-760 and 777-792; and the second dsRNAi agent is selected from:(a) a dsRNAi agent comprising a sense strand consisting of SEQ ID NO: 796 and an antisense strand consisting of SEQ ID NO: 1201;(b) a dsRNAi agent comprising a sense strand consisting of SEQ ID NO: 799 and an antisense strand consisting of SEQ ID NO: 1204; and(c) a dsRNAi agent comprising a sense strand consisting of SEQ ID NO: 1077 and an antisense strand consisting of SEQ ID NO: 1482.[000226] In some embodiments, combinations include a first dsRNAi agent and a second dsRNAi agent, where the first dsRNAi agent comprises a sense strand selected from SEQ ID NOs: 3-381, 761-776 and 2348-2389 and an antisense strand selected from SEQ ID NO: 382-760, 777- 792 and 2390-2431; and the second dsRNAi agent is selected from:PAT059887-PCT-SEC01(a) a dsRNAi agent comprising a sense strand consisting of SEQ ID NO: 796 and an antisense strand consisting of SEQ ID NO: 1201;(b) a dsRNAi agent comprising a sense strand consisting of SEQ ID NO: 799 and an antisense strand consisting of SEQ ID NO: 1204; and(c) a dsRNAi agent comprising a sense strand consisting of SEQ ID NO: 1077 and an antisense strand consisting of SEQ ID NO: 1482.[000227] Also provided herein are combinations that include a first dsRNAi agent and a second dsRNAi agent, where the first dsRNAi agent is selected from:(a) a dsRNAi agent comprising a sense strand consisting of SEQ ID NO: 761 and an antisense strand consisting of SEQ ID NO: 777; and(b) a dsRNAi agent comprising a sense strand consisting of SEQ ID NO: 772 and an antisense strand consisting of SEQ ID NO: 788; and the second dsRNAi agent is selected from:(a) a dsRNAi agent comprising a sense strand consisting of SEQ ID NO: 796 and an antisense strand consisting of SEQ ID NO: 1201;(b) a dsRNAi agent comprising a sense strand consisting of SEQ ID NO: 799 and an antisense strand consisting of SEQ ID NO: 1204; and(c) a dsRNAi agent comprising a sense strand consisting of SEQ ID NO: 1077 and an antisense strand consisting of SEQ ID NO: 1482.[000228] In some embodiments, the first dsRNAi agent comprises:(a) a sense strand consisting of SEQ ID NO: 761 and an antisense strand consisting of SEQ ID NO: 777; or(b) a sense strand consisting of SEQ ID NO: 772 and an antisense strand consisting of SEQ ID NO: 788.[000229] In some embodiments, the second dsRNAi agent comprises:(a) a sense strand consisting of SEQ ID NO: 796 and an antisense strand consisting of SEQ ID NO: 1201;(b) a sense strand consisting of SEQ ID NO: 799 and an antisense strand consisting of SEQ ID NO: 1204; or(c) a sense strand consisting of SEQ ID NO: 1077 and an antisense strand consisting of SEQ ID NO: 1482.PAT059887-PCT-SEC01[000230] In some embodiments, the first dsRNAi agent comprises:(a) a sense strand consisting of SEQ ID NO: 761 and an antisense strand consisting of SEQ ID NO: 777; or(b) a sense strand consisting of SEQ ID NO: 772 and an antisense strand consisting of SEQ ID NO: 788; and the second dsRNAi agent comprises:(a) a sense strand consisting of SEQ ID NO: 796 and an antisense strand consisting of SEQ ID NO: 1201;(b) a sense strand consisting of SEQ ID NO: 799 and an antisense strand consisting of SEQ ID NO: 1204; or(c) a sense strand consisting of SEQ ID NO: 1077 and an antisense strand consisting of SEQ ID NO: 1482.Modifications[000231] In one embodiment, the first dsRNAi agent comprises a modified nucleotide. In one embodiment, the second dsRNAi agent comprises a modified nucleotide. In one embodiment, the first dsRNAi agent and the second dsRNAi agent comprise a modified nucleotide.[000232] In an aspect, the disclosure provides a set of modification patterns determined or arranged by modified nucleotides in dsRNA(s) described herein. Aside from or in addition to the nucleobase sequences, various arrangements of modified nucleotides and the modification patterns thereof can be introduced, for example, to increase stability in a biological or physiological surrounding, to facilitate or promote cleavage by the RN A- induced silencing complex, and / or to mitigate or reduce off-targeting risk (e.g., to PCSK9 off-targeting risk and / or to HMGCR off- targeting risk).[000233] In an aspect, the disclosure provides dsRNA agent(s) that are partially (e.g., greater than about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, or 45% of the total nucleotides), substantially (e.g., greater than about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% of the total nucleotides), or entirely made of modified nucleotides, which can provide improved resistance to chemical and / or nuclease digestion and increased in vivo stability thereby imposing a longer in vivo half-life. Further, increasing the in vivo half-life of dsRNA(s) results in enhanced bioavailability and enhanced effectiveness in inhibiting expression or activity of a target gene (e.g.,PAT059887-PCT-SEC01 human PCSK9 and / or human HMGCR). For example, the stability of dsRNA(s) in blood or serum may be determined, e.g., by its susceptibility to degradation by the cellular enzymes, which may be dependent on the characteristics (e.g., sequences, modification, modification pattern, or other chemical moieties) of each strand (i.e., sense strand or antisense strand) of the dsRNA. In certain aspects, the efficiency of dsRNA(s) as a therapeutic agent may be improved by increasing the in vivo stability (e.g., in blood or serum) of dsRNA(s) while maintaining the ability of the dsRNA(s) to mediate RNA interference in vivo.Modified Nucleotides[000234] The modified nucleotides as used herein contain one or more modifications, for example, the modified nucleotides contain at least one chemical modification or replacement in an internucleoside linkage (“linkage”), a nucleobase, and / or a sugar moiety of the nucleotide. Nonlimiting examples include a 2'-modification on a ribose sugar ring (e.g., 2'-deoxy, 2'-O-alkyl, 2'- halo, 2'-O-alkoxyalkyl, 2'-O-amino alkyl, etc.), 3 '-modification (e.g., substitution) in backbone phosphate group (or phosphodiester linkage), or 4'-modification on a ribose sugar ring (e.g., 4'- thio RNA). Also, other non-limiting examples of modifications may include one or more modifications selected from a deoxy modification, a 2'-O-alkyl modification, a 2'-halo modification, a 2'-5 '-linkage modification, a conformationally restricting modification, an abasic modification, a 2'-amino-modification, a 2'-O-allyl modification, 2'-C-alkyl modification, a 2'-O- alkoxyalkyl modification, a morpholino modification, a modification containing a phosphoramidate group, a non-natural nucleobase modification, a modification in a tetrahydropyran, a threofuranosyl nucleotide (TNA) modification, a modification containing a 1,5- anhydrohexitol, a modification containing a cyclohexyl, a modification containing a cyclohexenyl, a modification containing a phosphorothioate group, a modification containing a methylphosphonate group, a modification containing an alkylphosphate, a modification containing a phosphonate, a modification containing an alkylphosphonate, a modification to form a thermally destabilizing nucleotide, a glycol nucleic acid (GNA) modification, and a 2-O-(N- methylacetamide) modification. For example, a modified nucleotide may include a single modification, or two or more modifications at the positions at which the chemical modification groups do not hinder or intervene each other.PAT059887-PCT-SEC01[000235] In some embodiments, each of the modified nucleotides is independently selected from TNA, GNA, LNA, 2'-O-alkoxyalkyl modified nucleotide, 2'-O-alkyl modified nucleotide, 2'-O- allyl modified nucleotide, 2'-C-alkyl modified nucleotide, 2'-halo modified nucleotide, and 2'- deoxy modified nucleotide (DNA). In some embodiments, each of the modified nucleotides contain independently selected from TNA modification, GNA modification, LNA modification, 2'-O-alkoxyalkyl modification, 2'-O-alkyl modification, 2'-O-allyl modification, 2'-C-alkyl modification, 2'-halo modification, and 2'-deoxy modification (DNA). The term alkyl, alkoxyl, allyl, amino, and halo can be interpreted as described above. In some embodiments, the modified nucleotides include at least one TN As. In some embodiments, the modified nucleotides include at least one GNAs. In some embodiments, the modified nucleotides include at least one LNAs. In some embodiments, the modified nucleotides include at least one 2'-O-alkoxyalkyl modified nucleotides. In some embodiments, the modified nucleotides include at least one 2'-O-alkyl modified nucleotides. In some embodiments, the modified nucleotides include at least one 2'-O- allyl modified nucleotides. In some embodiments, the modified nucleotides include at least one 2'-C-alkyl modified nucleotides. In some embodiments, the modified nucleotides include at least one 2'-halo (e.g., -F) modified nucleotides. In some embodiments, the modified nucleotides include at least one 2'-deoxy modified nucleotides (DNA).[000236] In some embodiments, the modified nucleotide may be a bicyclic (or bridged) nucleic acid (“BNA”) having a covalent linkage between the 2' and 4' carbons on a ribose sugar. In some embodiments, the modified nucleotide is a locked RNA (“LNA”) having covalent linkage of a bicyclic sugar modification is a 4'-CH2-O-2' linkage (methylene oxy), also known as “LNA havingpharmaceutically acceptable salt thereof, wherein ® is an attachment point to the adjacent nucleotides.[000237] In some embodiments, a ribose ring may be replaced with a glycol moiety linked to aseO phosphate and the GNA includes a moiety of , or a pharmaceutically acceptable saltPAT059887-PCT-SEC01 ase thereof. In some embodiments, the GNA may have a structureor a pharmaceutically acceptable salt thereof. In some embodiments, the phosphodiester linkage in the GNA may be modified, e.g., with phosphorothioate group and modified GNA may have the ase structure. or a pharmaceutically acceptable salt thereof. The GNA may further include one or more substituents replacing hydrogen(s) and such modified GNA may be encompassed by the definition of GNA herein.[000238] In some embodiments, a ribose pentofuranosyl ring may be replaced with a threofuranosyl ring linked to the phosphate and a threofuranosyl nucleotide (TNA) may include apharmaceutically acceptable salt thereof. In some embodiments, the TNA may have a structurepharmaceutically acceptable salt thereof. In some embodiments, the phosphodiester linkage in the TNA may be modified, e.g., with phosphorothioate group and modified TNA may include a structurepharmaceutically acceptable salt thereof. The TNA may further include one or more substituents at 1', 3' and / or 4' positions and such modified TNA may be encompassed by the definition of TNA herein.PAT059887-PCT-SEC01[000239] In certain aspects, the modified nucleotide may include a heterocyclic group (e.g., 5 to 6 membered heterocycloalkyl ring) in place of a ribose ring. In some embodiments, the ribose ring may be replaced with a morpholinyl ring, e.g., to form an morpholino oligonucleotide. In some embodiments, the ribose ring may be replaced with an arabinose ring.[000240] In certain aspects, the modified nucleotides contain one or more modification groups at 2' position on the ribose ring by replacing 2'-OH. In some embodiments, the modification group may include one or more selected from hydrogen (i.e. deoxy), halogen (e.g., -F), substituted or unsubstituted alkyl (e.g., C1-C12 alkyl), substituted or unsubstituted heteroalkyl (e.g., -O-(Ci-Ci2 alkyl), -N-(Ci-Ci2 alkyl), -C(O)NH-(Ci-Ci2 alkyl), -NHC(O)-(Ci-Ci2 alkyl), and -C(O)-(Ci-Ci2 alkyl)). In some embodiments, the modification group may be hydrogen, -F, -O-alkyl (e.g., C1-C4 alkyl), or -O-alkoxyalkyl (e.g., -O-(Ci-C4 alkylene)-(Ci-C4 alkoxyl)). Any of the alkyl, heteroalkyl, alkylene in the disclosure are optionally substituted with one or more of hydroxyl (- OH), C1-C3 alkyl (e.g., methyl, or ethyl), amine (e.g., monoamine or diamine), alkoxyl (e.g., -O- CH3 (OMe) or -O-CH2CH3 (OEt)), halogen (e.g., -F) or the like.[000241] In certain aspects, the modified nucleotides may include one or more of 2'-deoxy modification, 2'-O-alkyl modification, 2'-O-subsituted alkyl modification, 2'-O-alkoxyalkyl modification, and 2'-O-aminoalkyl modification. In some embodiments, the modified nucleotides may include one or more of 2'-deoxy modification, 2'-O-alkyl modification, 2'-O-subsituted alkyl modification, 2'-O-alkoxyalkyl modification, and 2'-O-aminoalkyl modification. In some embodiments, the modified nucleotides include at least one GNAs. In some embodiments, the modified nucleotides include at least one 2'-O-alkoxyalkyl modifications. In some embodiments, the modified nucleotides include at least one 2'-O-alkyl modifications. In some embodiments, the modified nucleotides include at least one 2'-O-allyl modifications. In some embodiments, the modified nucleotides include at least one 2'-C-alkyl modifications. In some embodiments, the modified nucleotides include at least one 2'-halo (e.g., -F) modifications. In some embodiments, the modified nucleotides include at least one 2'-deoxy modifications (DNA). In some embodiments, the modified nucleotides do not include 2'-deoxy modifications (DNA).[000242] In certain aspects, the modified nucleotides may include one or more of 2'-deoxy nucleotide (DNA), 2'-O-methyl (2'-OMe) modification, 2'-flouro (2'-F) modification, 2'-O- methoxyethyl (2'-0-M0E or “2'-M0E”) modification, 2'-O-aminopropyl (2'-O-AP) modification, 2'-O-dimethylaminoethyl (2'-O-DMAOE) modification, 2'-O-dimethylaminopropyl (2'-O-PAT059887-PCT-SEC01DMAP) modification, 2'-O-dimethylaminoethyloxyethyl (2'-0-DMAE0E) modification, and 2'- O-N-methylacetamido (2'-0-NMA) modification. In some embodiments, the modified nucleotides may include at least one 2'-deoxy modification (DNA). In some embodiments, the modified nucleotides may include at least one 2'-O-methyl (2'-0Me) modification. In some embodiments, the modified nucleotides may include at least one 2'-flouro (2'-F) modification. In some embodiments, the modified nucleotides may include at least one 2'-O-methoxyethyl (2'-O- MOE or “2'-M0E”) modification. In some embodiments, the modified nucleotides may include at least one 2'-O-aminopropyl (2'-O-AP) modification. In some embodiments, the modified nucleotides may include at least one 2'-O-dimethylaminoethyl (2'-0-DMA0E) modification. In some embodiments, the modified nucleotides may include at least one 2'-O-dimethylaminopropyl (2'-0-DMAP) modification. In some embodiments, the modified nucleotides may include at least one 2'-O-dimethylaminoethyloxyethyl (2'-0-DMAE0E) modification. In some embodiments, the modified nucleotides may include at least one 2'-O-N-methylacetamido (2'-0-NMA) modification.[000243] In some embodiments, each modified nucleotide containing a modification on a 2' sugar ring may optionally contain a phosphorothioate group at 5' or 3' linkage. In some embodiments, each modified nucleotide containing a modification on a 2' sugar ring may optionally contain a modification such as an abasic modification (absence of a nucleobase) or methylated nucleobase modification at nucleobase (e.g., thymine (T) or 5-methyl cytosine (5mC)).[000244] In certain aspects, the dsRNA agent(s) are partially (e.g., greater than about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, or 45% of the total nucleotides), substantially (e.g., greater than about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% of the total nucleotides), or entirely made of modified nucleotides containing the modification on 2' sugar ring. In some embodiments, the dsRNA(s) are partially (e.g., greater than about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, or 45% of the total nucleotides) made of modified nucleotides containing the modification on 2' sugar ring. In some embodiments, the dsRNA agent(s) are substantially (e.g., greater than about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% of the total nucleotides) made of modified nucleotides containing the modification on 2' sugar ring. In some embodiments, the dsRNA agent(s) include greater than about 80% of modified nucleotides containing the modification on 2' sugar ring based on the total nucleotides. In some embodiments,PAT059887-PCT-SEC01 the dsRNA agent(s) include greater than about 85% of modified nucleotides containing the modification on 2' sugar ring based on the total nucleotides. In some embodiments, the dsRNA agent(s) include greater than about 90% of modified nucleotides containing the modification on 2' sugar ring based on the total nucleotides. In some embodiments, the dsRNA agent(s) include greater than about 95% of modified nucleotides containing the modification on 2' sugar ring based on the total nucleotides. In some embodiments, the dsRNA agent(s) are entirely made of modified nucleotides containing the modification on 2' sugar ring.[000245] In certain aspects, the modified nucleotide may include a modification in a phosphate or phosphodiester linkage, in other words, an internucleoside linkage modification (e.g., phosphorothioate, phosphorodithioate, methylphosphonate, methylene phosphonate, or vinyl phosphonate (VP) linkage). In some embodiments, the linkage modification may include phosphorothioate (PS) having a structurewhich may be an Rp isomer or an Sp isomer. In some embodiments, the linkage modification may include phosphorothioate (PS) having a structurewhich may be a stereopure Rp isomer. In some embodiments, the linkage modification may include phosphorothioate (PS) having a structurewhich may be a stereopure Sp isomer.[000246] For example, the modified nucleotide including 3'-PS modification can be representedpharmaceutically acceptable salt thereof, wherein R represents H, OH or a substituent (e.g., -F -CTh -OMe or MOFI and is an attachment nomt to the adiacentPAT059887-PCT-SEC01 nucleotides. In some embodiments, the 3'-PS group may be a stereopure Sp isomer. In some embodiments, the 3'-PS group may be a stereopure Rp isomer .[000247] In certain aspects, the dsRNAi agent(s) may be entirely made of modified nucleotides having one or more internucleoside linkage modification and / or modifications in the sugar moieties of the nucleotides.[000248] In certain aspects, the first nucleotide from the 5' end of each strand (e.g., sense strand and antisense strand) may include an additional phosphate group or a variant thereof (e.g., phosphorothioate, phosphorodithioate, methylphosphonate, methylene phosphonate, or vinyl phosphonate (VP)) attached or linked to the 5' terminal group of the first nucleotide.[000249] In some embodiments, the first nucleotide from the 5' end of each strand (e.g., sense strand and antisense strand) includes a 5'-vinyl phosphonate (5'-VP) group that is a chemical0=Fmoiety having the structure of V or a pharmaceutically acceptable salt thereof, wherein represents the point of attachment to the 5' carbon of the pentofuranosyl sugar of a nucleotide.In some embodiments, the first nucleotide from the 5' end of each strand (e.g., sense strand and antisense strand) may include (E)-vinyl phosphonate (VP) having a structure of, or a pharmaceutically acceptable salt thereof, wherein represents the point of attachment to the 4' carbon of the pentofuranosyl sugar. In some embodiments, the first nucleotide from the 5' end of each strand (e.g., sense strand and antisense strand) may include (Z)-vinyl phosphonate having a structure ofor a pharmaceutically acceptable salt thereof, wherein » represents the point of attachment to the 4' carbon of the pentofuranosyl sugar.[000250] In certain aspects, one or more of the modified nucleotides contain a 2' modification (e.g., 2'-0Me, 2'-F, 2'-M0E, 2'-deoxy, etc.) and an internucleoside linkage modification (e.g., phosphorothioate or (E)-vinyl phosphonate). In some embodiments, one or more of the modified nucleotides contain 2'-0Me modification and phosphorothioate group. In some embodiments, one or more of the modified nucleotides contain 2'-0Me modification and (E)-vinyl phosphonate group. In some embodiments, one or more of the modified nucleotides contain 2'-F modificationPAT059887-PCT-SEC01 and phosphorothioate group. In some embodiments, one or more of the modified nucleotides contain 2'-F and (E)-vinyl phosphonate group. In some embodiments, one or more of the modified nucleotides contain 2'-M0E modification and phosphorothioate group. In some embodiments, one or more of the modified nucleotides contain 2'-M0E modification and (E)-vinyl phosphonate group. In some embodiments, one or more of the modified nucleotides contain 2'-deoxy modification and phosphorothioate group. In some embodiments, one or more of the modified nucleotides contain 2'-0Me modification and (E)-vinyl phosphonate group. In some embodiments, one or more of the modified nucleotides are GNA containing (E)-vinyl phosphonate group. In some embodiments, one or more of the modified nucleotides are GNA containing a phosphorothioate group. In some embodiments, one or more of the modified nucleotides are TNA containing (E)-vinyl phosphonate group. In some embodiments, one or more of the modified nucleotides are TNA containing a phosphorothioate group.[000251] In certain aspects, the modified nucleotides contain one or more modifications on a modified nucleobase. In some embodiments, one or more of the modified nucleotides may include thymine (“T”) nucleobase (“ribothymidine” or “5-methyluridine”) in the ribonucleotide (e.g., including 2'-OH). In some embodiments, one or more of the modified nucleotides may include methylcytosine nucleobase (e.g., 5-methylcytidine or N4- methylcytidine). In certain aspects, one or more of the modified nucleotides may contain no nucleobase or be abasic.Sense Strand (SS)[000252] In certain aspects, a sense strand of the dsRNA agent(s) as described herein are substantially (e.g., greater than about 80%, 85%, 90%, or 95% of the total nucleotides) made of modified nucleotides. In another certain aspect, the sense strand is entirely made of modified nucleotides.[000253] In certain aspects, a sense strand of the dsRNA agent(s) as described herein includes two or more 2'-M0E modifications. In some embodiments, the sense strand includes two, four, six or eight 2'-M0E modifications. In some embodiments, the sense strand includes two 2'- MOE modifications. In some embodiments, the sense strand includes four 2'-M0E modifications. In some embodiments, the sense strand includes six 2'-M0E modifications. In some embodiments, the sense strand includes eight 2'-M0E modifications.PAT059887-PCT-SEC01[000254] In some embodiments, the 2'-MOE modified nucleotides in the sense strand as described herein include a structurepharmaceutically acceptable salt thereof, whereinis an attachment point to a linkage (e.g., phosphate or phosphor othioate group) or the adjacent nucleotides and “Base” is a nucleobase.[000255] In some embodiments, the 2'-M0E modified nucleotides in the sense strand as described herein include a structurepharmaceutically acceptable salt thereof, whereinis an attachment point to a terminal group (e.g., H, OH, or salt) or the adjacent nucleotides and “Base” is a nucleobase. In some embodiments, the 2'-M0E modified nucleotides in the sense strand as described herein include apharmaceutically acceptable salt thereof.[000256] In some embodiments, the 2'-M0E modified nucleotides include a structure ofthereof, whereinis an attachment point to a terminal group (e.g., H, OH, or salt) or thePAT059887-PCT-SEC01 adjacent nucleotides. In some embodiments, the 2'-M0E modified nucleotides include apharmaceutically acceptable salt thereof. In some embodiments, the 2'-M0E modified nucleotides include apharmaceutically acceptable salt thereof.[000257] In some embodiments, the 2'-M0E modified nucleotides include a nucleotide havingacceptable salt thereof, wherein1is an attachment point to a terminal group (e.g., H, OH, or salt) or the adjacent nucleotides. In some embodiments, the 2'-M0E modified nucleotidesPAT059887-PCT-SEC01 include a nucleotide having a structurepharmaceutically acceptable salt thereof. In some embodiments, the 2'-M0E modified nucleotides include a nucleotide having a structurepharmaceutically acceptable salt thereof. In some embodiments, the 2'-M0E modified nucleotides include a nucleotide having a structurepharmaceutically acceptable salt thereof.[000258] In some embodiments, the 2'-M0E modified nucleotides in the sense strand as described herein include a nucleotide having a structurePAT059887-PCT-SEC01pharmaceutically acceptable salt thereof, wherein1is an attachment point to a terminal group (e.g., H, OH, or salt) or the adjacent nucleotides. In some embodiments, the 2'-M0E modified nucleotides in the sense strand as described herein include a nucleotide having a structurepharmaceutically acceptable salt thereof.[000259] In some embodiments, the 2'-M0E modified nucleotides include a nucleotide havingacceptable salt thereof, wherein71is an attachment point to a terminal group (e.g., H, OH, or salt) or the adjacent nucleotides. In some embodiments, the 2'-M0E modified nucleotidesPAT059887-PCT-SEC01 include a nucleotide having a structurepharmaceutically acceptable salt thereof.[000260] In certain aspects, at least one of the 2'-M0E modified nucleotides in the sense strand as described herein has a structurepharmaceutically acceptable salt thereof, whereinis an attachment point to a terminal group (e.g., H, OH, or salt) or the adjacent nucleotides. In some embodiments, at least one of the 2'-M0E modified nucleotides in the sense strand as described herein has a structurepharmaceutically acceptable salt thereof.PAT059887-PCT-SEC01[000261] In some embodiments, the first nucleotide from the 5' end of the sense strand includes a structurepharmaceutically acceptable salt thereof. In some embodiments, the first nucleotide from the 5' end of the sense strand includes a structurepharmaceutically acceptable salt thereof.[000262] In some embodiments, the first nucleotide from the 3' end of the sense strand includes a structurepharmaceutically acceptable salt thereof. In some embodiments, the first nucleotide from the 3' end of the sense strand includes a structurePAT059887-PCT-SEC01acceptable salt thereof, whereinis an attachment point to a ligand. In some embodiments, the first nucleotide from the 3' end of the sense strand includes a structureor a pharmaceutically acceptable salt thereof.[000263] In certain aspects, at least one of the 2'-M0E modified nucleotides in the sense strand as described herein has a structurepharmaceutically acceptable salt thereof, whereinis an attachment point to a terminal group (e.g., H, OH, or salt) or the adjacent nucleotides. In somePAT059887-PCT-SEC01 embodiments, at least one of the 2'-M0E modified nucleotides in the sense strand as described herein has a structurepharmaceutically acceptable salt thereof.[000264] In some embodiments, the first nucleotide from the 5' end of the sense strand includes a structurepharmaceutically acceptable salt thereof. In some embodiments, the first nucleotide from the 5' end of the sense strand includes a structurepharmaceutically acceptable salt thereof.[000265] In some embodiments, the first nucleotide from the 3' end of the sense strandpharmaceutically acceptable salt thereof. In some embodiments, the first nucleotide from the 3' end of the sensePAT059887-PCT-SEC01 strand includes a structurepharmaceutically acceptable salt thereof, wherein1is an attachment point to a ligand. In some embodiments, the first nucleotide from the 3' end of the sense strand includes a structurepharmaceutically acceptable salt thereof.PAT059887-PCT-SEC01[000266] In certain aspects, at least one of the 2'-M0E modified nucleotides in the sense strand as described herein has a structurepharmaceutically acceptable salt thereof, wherein1is an attachment point to a terminal group (e.g., H, OH, or salt) or the adjacent nucleotides. In some embodiments, at least one of the 2'-M0E modified nucleotides in the sense strand as described herein has a structurepharmaceutically acceptable salt thereof.[000267] In some embodiments, the first nucleotide from the 5' end of the sense strandpharmaceutically acceptable salt thereof. In some embodiments, the first nucleotide from the 5'PAT059887-PCT-SEC01 end of the sense strand includes a structurepharmaceutically acceptable salt thereof.[000268] In some embodiments, the first nucleotide from the 3' end of the sense strand has a structurepharmaceutically acceptable salt thereof. In some embodiments, the first nucleotide from the 3' end of the sensePAT059887-PCT-SEC01, or a pharmaceutically acceptable salt thereof, wherein > is an attachment point to a ligand. In some embodiments, the first nucleotide from the 3' end of the sense strand has a structurepharmaceutically acceptable salt thereof.[000269] In certain aspects, at least one of the 2'-M0E modified nucleotides in the sense strand as described herein has a structureacceptable salt thereof, whereinis an attachment point to a terminal group (e.g., H, OH, or salt) or the adjacent nucleotides. In some embodiments, at least one of the 2'-M0E modifiedPAT059887-PCT-SEC01 nucleotides in the sense strand as described herein has a structure ofpharmaceutically acceptable salt thereof.[000270] In some embodiments, the first nucleotide from the 5' end of the sense strand includes a structurepharmaceutically acceptable salt thereof. In some embodiments, the first nucleotide from the 5' end of the sense strand includes a structurepharmaceutically acceptable salt thereof.[000271] In some embodiments, the first nucleotide from the 3' end of the sense strand has apharmaceutically acceptable salt thereof. In some embodiments, the first nucleotide from the 3' end of the sense strand has a structure ofPAT059887-PCT-SEC01acceptable salt thereof, wherein1is an attachment point to a ligand. In some embodiments, the first nucleotide from the 3' end of the sense strand has a structure ofpharmaceutically acceptable salt thereof.[000272] In certain aspects, the 2'-M0E modified nucleotides locate at both 5' and 3' ends of a sense strand so as to form a structural confinement (“2'-M0E clamp”) at the sense strand termini. In some embodiments, the 2'-M0E clamps may be symmetric and having the same number of 2'- MOE modified nucleotides at both 5' and 3' ends of the sense strand. For example, the sense strand includes one 2'-M0E modified nucleotide at 5' end and one 2'-M0E modified nucleotide at 3' end; two 2'-M0E modified nucleotides at 5' end and two 2'-M0E modified nucleotides at 3'PAT059887-PCT-SEC01 end; or three 2'-M0E modified nucleotides at 5' end and three 2'-M0E modified nucleotides at 3' end. In some embodiments, the 2'-M0E clamps may be asymmetric and having different numbers of 2'-M0E nucleotides at 5' and 3' ends of the sense strand. For example, the sense strand includes one 2'-M0E modified nucleotide at 5' end only; one 2'-M0E modified nucleotide at 3' end only; two 2'-M0E modified nucleotides at 5' end only; two 2'-M0E modified nucleotides at 3' end only; one 2'-M0E modified nucleotide at 5' end and two 2'-M0E modified nucleotides at 3' end; or two 2'-M0E modified nucleotides at 5' end and one 2'-M0E modified nucleotide at 3' end.[000273] In certain aspects, the sense strand includes one 2'-M0E modified nucleotide at 5' end and one 2'-M0E modified nucleotide at 3' end. In some embodiments, the sense strand includes only one 2'-M0E modified nucleotide at 5' end and only one 2'-M0E modified nucleotide at 3' end. In some embodiments, the sense strand includes only one 2'-M0E modified nucleotide at 5' end. In some embodiments, the sense strand includes only one 2'-M0E modified nucleotide at 3' end.[000274] In certain aspects, the sense strand includes at least two contiguous 2'-M0E modified nucleotides at 5' end and at least two 2'-M0E modified nucleotides at 3' end. In some embodiments, the sense strand includes only two 2'-M0E modified nucleotides at 5' end and only two 2'-M0E modified nucleotides at 3' end. In some embodiments, the sense strand includes only two 2'-M0E modified nucleotides at 5' end. In some embodiments, the sense strand includes only two 2'-M0E modified nucleotides at 3' end.[000275] Alternatively, in certain aspects, a sense strand of the dsRNA agent(s) as described herein includes two or more TNAs. In some embodiments, the sense strand includes two, four, six or eight TNAs. In some embodiments, the sense strand includes two TNAs. In some embodiments, the sense strand includes four TNAs. In some embodiments, the sense strand includes six TNAs. In some embodiments, the sense strand includes eight TNAs.[000276] In certain aspects, the sense strand includes at least two contiguous TNAs at 5' end and at least two TNAs at 3' end. In some embodiments, the sense strand includes only two TNAs at 5' end and only two TNAs at 3' end. In some embodiments, the sense strand includes only two TNAs at 5' end. In some embodiments, the sense strand includes only two TNAs at 3' end.PAT059887-PCT-SEC01[000277] In some embodiments, the TNAs in the sense strand as described herein include a structurepharmaceutically acceptable salt thereof, wherein is an attachment point to a linkage (e.g., phosphate or phosphorothioate group) or the adjacent nucleotides and “Base” is a nucleobase.[000278] In some embodiments, the TNAs in the sense strand as described herein include a structurepharmaceutically acceptable salt thereof, wherein is an attachment point to a terminal group (e.g., H, OH, or salt) or the adjacent nucleotides and “Base” is a nucleobase. In some embodiments, the TNAs in the dsRNA agent(s) as described herein include a structurepharmaceutically acceptable salt thereof.[000279] In some embodiments, the TNAs include a structurepharmaceutically acceptable salt thereof,PAT059887-PCT-SEC01 wherein is an attachment point to a terminal group (e.g., H, OH, or salt) or the adjacent nucleotides. In some embodiments, the TNAs include a structurepharmaceutically acceptable salt thereof.[000280] In some embodiments, the TNAs include a nucleotide having a structure ofpharmaceutically acceptable salt thereof, wherein1is an attachment point to a terminal group (e.g., H, OH, or salt) or the adjacent nucleotides. In some embodiments, the TNAs include a nucleotide having apharmaceutically acceptable salt thereof.[000281] In some embodiments, the TNAs in the dsRNA agent(s) as described herein include a nucleotide having a structurePAT059887-PCT-SEC01pharmaceutically acceptable salt thereof, whereinis an attachment point to a terminal group (e.g., H, OH, or salt) or the adjacent nucleotides. In some embodiments, the TNAs in the dsRNA agent(s) as described herein include a nucleotide having a structurepharmaceutically acceptable salt thereof.[000282] In some embodiments, the TNAs include a nucleotide having a structure ofpharmaceutically acceptable salt thereof, whereinis an attachment point to a terminal group(e.g., H, OH, or salt) or the adjacent nucleotides. In some embodiments, the TNAs include a nucleotide having a structurepharmaceutically acceptable salt thereof.PAT059887-PCT-SEC01[000283] In certain aspects, at least one of the TNAs in the sense strand as described hereinpharmaceutically acceptable salt thereof, whereinis an attachment point to a terminal group(e.g., H, OH, or salt) or the adjacent nucleotides. In some embodiments, at least one of theTNAs in the sense strand as described herein has a structurepharmaceutically acceptable salt thereof.[000284] In some embodiments, the first nucleotide from the 5' end of the sense strand includes a structurepharmaceutically acceptable salt thereof. In some embodiments, the first nucleotide from the 5' end of the sense strand includes a structurepharmaceutically acceptable salt thereof.PAT059887-PCT-SEC01[000285] In some embodiments, the first nucleotide from the 3' end of the sense strand includes a structurepharmaceutically acceptable salt thereof. In some embodiments, the first nucleotide from the 3' end of the senseacceptable salt thereof andis an attachment point to a ligand. In some embodiments, the first nucleotide from the 3' end of the sense strand includes a structurepharmaceutically acceptable salt thereof.PAT059887-PCT-SEC01[000286] In certain aspects, at least one of the TNAs in the sense strand as described hereinpharmaceutically acceptable salt thereof, whereinis an attachment point to a terminal group(e.g., H, OH, or salt) or the adjacent nucleotides. In some embodiments, at least one of theTNAs in the sense strand as described herein has a structurepharmaceutically acceptable salt thereof.[000287] In some embodiments, the first nucleotide from the 5' end of the sense strand includes a structurepharmaceutically acceptable salt thereof. In some embodiments, the first nucleotide from the 5' end of the sense strand includes a structurepharmaceutically acceptable salt thereof.PAT059887-PCT-SEC01[000288] In some embodiments, the first nucleotide from the 3' end of the sense strandacceptable salt thereof. In some embodiments, the first nucleotide from the 3' end of the senseacceptable salt thereof andis an attachment point to a ligand. In some embodiments, the first nucleotide from the 3' end of the sense strand includes a structurepharmaceutically acceptable salt thereof.PAT059887-PCT-SEC01[000289] In certain aspects, at least one of the TNAs in the sense strand as described hereinpharmaceutically acceptable salt thereof, whereinis an attachment point to a terminal group (e.g., H, OH, or salt) or the adjacent nucleotides. In some embodiments, at least one of theTNAs in the sense strand as described herein has a structurepharmaceutically acceptable salt thereof.[000290] In some embodiments, the first nucleotide from the 5' end of the sense strand includes a structurepharmaceutically acceptable salt thereof. In some embodiments, the first nucleotide from the 5' end of the sense strand includes a structurepharmaceutically acceptable salt thereof.PAT059887-PCT-SEC01[000291] In some embodiments, the first nucleotide from the 3' end of the sense strand includes a structurepharmaceutically acceptable salt thereof. In some embodiments, the first nucleotide from the 3' end of the sense strand includes a structure, or a pharmaceutically acceptable salt thereof andis an attachment point to a ligand. In some embodiments, the first nucleotide from the 3' end of the sense strand includes a structurepharmaceutically acceptable salt thereof.PAT059887-PCT-SEC01[000292] In certain aspects, at least one of the TNAs in the sense strand as described herein has a structurepharmaceutically acceptable salt thereof, whereinis an attachment point to a terminal group (e.g., H, OH, or salt) or the adjacent nucleotides. In some embodiments, at least one of the TNAs in the sense strand as described herein has a structure ofpharmaceutically acceptable salt thereof.[000293] In some embodiments, the first nucleotide from the 5' end of the sense strand includes a structurepharmaceutically acceptable salt thereof. In some embodiments, the first nucleotide from the 5'PAT059887-PCT-SEC01 end of the sense strand includes a structurepharmaceutically acceptable salt thereof.[000294] In some embodiments, the first nucleotide from the 3' end of the sense strand includes a structurepharmaceutically acceptable salt thereof. In some embodiments, the first nucleotide from the 3' end of the sense strand includes a structurePAT059887-PCT-SEC01 salt thereof andis an attachment point to a ligand. In some embodiments, the first nucleotide o^O^N^N^NH2from the 3' end of the sense strand includes a structure of OH , or a pharmaceutically acceptable salt thereof.[000295] In certain aspects, the TN As locate at both 5' and 3' ends of a sense strand so as to form a structural confinement (“TNA clamp”) at the sense strand termini. In some embodiments, the TNA clamps may be symmetric and having the same number of TN As at both 5' and 3' ends of the sense strand. For example, the sense strand includes one TNA at 5' end and one TNA at 3' end; two TNAs at 5' end and two TNAs at 3' end; or three TNAs at 5' end and three TNAs at 3' end. In some embodiments, the TNA clamps may be asymmetric and having different numbers of TNAs at 5' and 3' ends of the sense strand. For example, the sense strand includes one TNA at 5' end only; one TNA at 3' end only; two TNAs at 5' end only; two TNAs at 3' end only; one TNA at 5' end and two TNAs at 3' end; or two TNAs at 5' end and one TNA at 3' end.[000296] In certain aspects, the sense strand includes one TNA at 5' end and one TNA at 3' end. In some embodiments, the sense strand includes only one TNA at 5' end and only one TNA at 3' end. In some embodiments, the sense strand includes only one TNA at 5' end. In some embodiments, the sense strand includes only one TNA at 3' end.[000297] In certain aspects, the sense strand includes at least two contiguous TNAs at 5' end and at least two TNAs at 3' end. In some embodiments, the sense strand includes only two TNAs at 5' end and only two TNAs at 3' end. In some embodiments, the sense strand includes only two TNAs at 5' end. In some embodiments, the sense strand includes only two TNAs at 3' end.[000298] In certain aspects, the sense strand of the dsRNA agent(s) as described herein includes two or more 2'-F modifications. In some embodiments, the sense strand of the dsRNA agent(s) includes two, three, four, five, six, seven, or eight 2'-F modified nucleotides. In some embodiments, the sense strand includes two 2'-F modified nucleotides. In some embodiments, the sense strand includes three 2'-F modified nucleotides. In some embodiments, the sense strand includes four 2'-F modified nucleotides. In some embodiments, the sense strand includesPAT059887-PCT-SEC01 five 2'-F modified nucleotides. In some embodiments, the sense strand includes six 2'-F modified nucleotides. In some embodiments, the sense strand includes seven 2'-F modified nucleotides. In some embodiments, the sense strand includes eight 2'-F modified nucleotides. In some embodiments, two contiguous 2'-F modified nucleotides locate in the sense strand. In some embodiments, three contiguous 2'-F modified nucleotides locate in the sense strand. In some embodiments, four contiguous 2'-F modified nucleotides locate in the sense strand. [000299] In certain aspects, a sense strand of the dsRNA agent(s) as described herein includes one, two, three, or four 2'-deoxy modifications (DNA). In some embodiments, the sense strand of the dsRNA agent(s) includes one 2'-deoxy modified nucleotide. In some embodiments, the sense strand includes two 2'-deoxy modified nucleotides. In some embodiments, the sense strand includes three 2'-deoxy modified nucleotides. In some embodiments, the sense strand includes four 2'-deoxy modified nucleotides.[000300] In certain aspects, a sense strand of the dsRNA agent(s) as described herein includes one, two, three, or four deoxythymidines (dT). In some embodiments, the sense strand of the dsRNA agent(s) includes one deoxythymidine (dT). In some embodiments, the sense strand includes two deoxy thymidines. In some embodiments, the sense strand includes three deoxythymidines (dT). In some embodiments, the sense strand includes four deoxythymidines. [000301] In some embodiments, the sense strand includes 2'-OMe modified nucleotides in the remaining positions in the sense strand.[000302] In certain aspects, the sense strand includes one to six phosphorothioate (PS) linkages between nucleosides. In some embodiments, the sense strand includes one, two, three, or four phosphorothioate (PS) linkages between nucleosides.[000303] In certain aspects, a sense strand of the dsRNA agent(s) as described herein includes one or more of TNAs, one or more of 2'-F modified nucleotides, one or more of 2'-deoxy modified nucleotides, and one or more of 2'-0Me modified nucleotides. In certain aspects, a sense strand of the dsRNA agent(s) as described herein consists of one or more of TNAs, one or more of 2'-F modified nucleotides, one or more of 2'-deoxy modified nucleotides, and one or more of 2'-0Me modified nucleotides.PAT059887-PCT-SEC01Antisense Strand (AS)[000304] In certain aspects, an antisense strand of the dsRNA agent(s) as described herein are substantially (e.g., greater than about 80%, 85%, 90%, or 95% of the total nucleotides) made of modified nucleotides. In another certain aspect, the antisense strand is entirely made of modified nucleotides.[000305] In certain aspects, the first nucleotide from the 5' end of the antisense strand may contain an additional phosphate group or a variant thereof (e.g., phosphor othioate, phosphorodithioate, methylphosphonate, methylene phosphonate, or vinyl phosphonate (VP)) attached or linked to the 5' terminal group of the first nucleotide) attached or linked to the 5' terminal group of the first nucleotide.[000306] In certain aspects, the antisense strand includes 5'-vinyl phosphonate (5'-VP) group at the first nucleotide from the 5' end in the antisense strand. The “5'-VP” is a chemical moietyO=P\_§having the structure of V or a pharmaceutically acceptable salt thereof, where the wavy line represent the point of attachment to the 5' carbon of the pentofuranosyl sugar of a nucleotide.[000307] In some embodiments, the first nucleotide from the 5' end in the antisense strandO=P, includes (E)-vinyl phosphonate (VP) having a structure of, or a pharmaceutically acceptable salt thereof, wherein the wavy line presents the point of attachment to the 4' carbon of the pentofuranosyl sugar of a nucleotide. In some embodiments, the first nucleotide from the 5'OH„. ,end in the antisense strand includes (Z)-vinyl phosphonate having a structure of \= / , or a pharmaceutically acceptable salt thereof, wherein the wavy line presents the point of attachment to the 4' carbon of the pentofuranosyl sugar of a nucleotide.PAT059887-PCT-SEC01[000308] In some embodiments, the first nucleotide from the 5' end of the antisense strand haspharmaceutically acceptable salt thereof. In some embodiments, the first nucleotide from the 5' end of the Base antisense strand has a structureor a pharmaceutically acceptable salt thereof. In some embodiments, the first nucleotide from the 5' end of the antisense strand has apharmaceutically acceptable salt thereof. In some embodiments, the first nucleotide from the 5' end of the antisense strand has a structure ofpharmaceutically acceptable salt thereof.PAT059887-PCT-SEC01[000309] In some embodiments, the first nucleotide from the 5' end of the antisense strand haspharmaceutically acceptable salt thereof, whereinis an attachment point to the adjacent nucleotides. In some embodiments, the first nucleotide from the 5' end of the antisense strand has a structure ofpharmaceutically acceptable salt thereof. In some embodiments, the first nucleotide from the 5' end of the antisense strand has a structure ofpharmaceutically acceptable salt thereof, whereinis an attachment point to the adjacent nucleotides. In some embodiments,PAT059887-PCT-SEC01 the first nucleotide from the 5' end of the antisense strand has a structure ofpharmaceutically acceptable salt thereof.[000310] In certain aspects, the antisense strand of the dsRNA agent(s) as described herein includes two or more 2'-F modifications. In some embodiments, the antisense strand of the dsRNA agent(s) includes two, three, four, five, six, seven, or eight 2'-F modified nucleotides. In some embodiments, the antisense strand includes two 2'-F modified nucleotides. In some embodiments, the antisense strand includes three 2'-F modified nucleotides. In some embodiments, the antisense strand includes four 2'-F modified nucleotides. In some embodiments, the antisense strand includes five 2'-F modified nucleotides. In some embodiments, the antisense strand includes six 2'-F modified nucleotides. In some embodiments, the antisense strand includes seven 2'-F modified nucleotides. In some embodiments, the antisense strand includes eight 2'-F modified nucleotides. In some embodiments, two contiguous 2'-F modified nucleotides locate in the antisense strand. In some embodiments, three contiguous 2'-F modified nucleotides locate in the antisense strand. In some embodiments, four contiguous 2'-F modified nucleotides locate in the antisense strand.[000311] In certain aspects, the antisense strand is 23 nucleotides in length.[000312] In certain aspects, an antisense strand of the dsRNA agent(s) as described herein does not include a 2'-M0E modification. Alternatively, in certain aspects, the antisense strand includes one to four 2'-M0E modified nucleotides. In some embodiments, the antisense strand includes one 2'-M0E modified nucleotide. In some embodiments, the antisense strand includes two 2'-M0E modified nucleotides. In some embodiments, the antisense strand includes three 2'- MOE modified nucleotides. In some embodiments, the antisense strand includes four 2'-M0E modified nucleotides.[000313] In certain aspects, the antisense strand includes at least one GNA. In some embodiments, the antisense strand includes only one GNA.PAT059887-PCT-SEC01[000314] In certain aspects, the antisense strand includes at least one TNA. In some embodiments, the antisense strand includes only one TNA.[000315] In certain aspects, the antisense strand includes at least one 2'-deoxy modified nucleotide (e.g., dT, dA, dG, or dC). In some embodiments, the antisense strand includes only one 2'-deoxy modified nucleotide (e.g., dT, dA, dG, or dC).[000316] In certain aspects, the antisense strand includes two, three, or four phosphorothioate (PS) linkages between nucleosides.[000317] In certain aspects, the antisense strand includes two to eight phosphorothioate (PS) linkages between nucleosides.[000318] In certain aspects, the antisense strand includes 5'-(E)-VP modified nucleotide at the first nucleotide from 5' end of the antisense strand. In some embodiments, the antisense strand includes a 5'-(E)-VP-2'-OMe modified nucleotide at the first nucleotide from 5' end of the antisense strand.[000319] Exemplary first dsRNA agents (siRNA) with modified nucleotides, including sense strands and antisense strands targeting the above indicated PCSK9 mRNA, are shown in Table 4.Table 4: Examples of modified nucleotide sequence of PCSK9 siRNAPAT059887-PCT-SEC01PAT059887-PCT-SEC01PAT059887-PCT-SEC01PAT059887-PCT-SEC01PAT059887-PCT-SEC01PAT059887-PCT-SEC01PAT059887-PCT-SEC01[000320] Table A below shows codes in the nucleotide sequences in Table 4 and the following Tables in the disclosure.Table A p: phosphodiester linkage pOOl: phosphorothioate (PS) linkageSS: sense strand AS: antisense strandA 1039 or X2171: inverted abasic nucleotide _A002: 2'-deoxy adenosine (dA) G002: 2'-deoxy guanosine (dG)A004: adenosine / 2'-0Me G004: guanosine / 2'-0MeA005: adenosine / 2'-M0E G005: guanosine / 2'-M0EA007: adenosine / 2'-F G007: guanosine / 2'-FA042: adenosine TNA G042: guanosine TNAA1016: adenosine GNA G1016: guanosine GNAX033A1027: Adenosine / 5'-(E)-VP-2'-Ome X033G1027: guanosine / 5'-(E)-VP-2'-OMeX033A1032: Adenosine / 5,-(E)-VP-2’-MOEPAT059887-PCT-SEC01C002: 2'-deoxy cytidine (dC) T002: 2'-deoxy thymidine (dT)C004: cytidine / 2'-0Me U004: uridine / 2'-0MeC005: 5 -methyl -cytidine / 2'-M0E T005: ribothymidine (5-methyl uridine) / 2'-M0EC007: cytidine / 2'-F U007: uridine / 2'-FC042: cytidine TNA U042: uridine TNACl 016: cytosine GNA U1016: uridine GNAX033C1027: cytidine / 5'-(E)-VP-2'-OMe X033U1027: uridine / 5,-(E)-VP-2'-OMe[000321] The sequences and sequence lists including modified nucleosides (e.g., RNA, RNA modified at a 2'-OH sugar moiety, or RNA modified at a nucleobase) in the disclosure (e.g., Tables 4 and 7) are indicated with codes defined in Table A unless otherwise indicated. Each code consists of a letter representing a type of the nucleobase, e.g., “A”, “G”, “C”,“U,” or “T” and a numeric code representing a type of modification on a sugar ring.[000322] For example, if a nucleoside is coded as “T005”, it is meant by a RNA nucleoside including a 2'-M0E ribose sugar moiety and a thymine (or methylated uracil) as “T” indicates a thymine (or methylated uracil) nucleobase and “005” indicates a 2'-M0E substituent at 2'-OH position on the ribose sugar ring.[000323] In particular example, if a nucleoside is coded as “C005”, it is meant by a RNA nucleoside including a 5-methylated cytosine and a 2'-M0E sugar moiety as “C” indicates a type of specific nucleobase that can exist in combination with a 2'-M0E sugar moiety and “005” indicates a 2'-M0E substituent at 2'-OH position on the ribose sugar ring.[000324] In another example, if a nucleoside is coded as “A042”, it is meant by a RNA nucleoside including an adenine and a threofuranosyl sugar ring as “A” indicates a type of adenine and “042” indicates a threofuranosyl ring replacing the ribose sugar ring.[000325] In some embodiments, the first dsRNA agent includes a sense strand having 10 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 1604-1656 or 2324-2329. In some embodiments, the first dsRNA agent includes an antisense strand having 10 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of SEQ ID NOs: 1657-1709 or 2330-2335. In some embodiments, the first dsRNA agent includes a sense strand having 11 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 1604-1656 or 2324-2329. In some embodiments, the first dsRNA agent includes an antisense strand having 11 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 1657-1709 or 2330-2335. In some embodiments,PAT059887-PCT-SEC01 the first dsRNA agent includes a sense strand having 12 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 1604-1656 or 2324-2329. In some embodiments, the first dsRNA agent includes an antisense strand having 12 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 1657-1709 or 2330-2335. In some embodiments, the first dsRNA agent includes a sense strand having 13 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 1604-1656 or 2324-2329. In some embodiments, the first dsRNA agent includes an antisense strand having 13 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 1657-1709 or 2330-2335. In some embodiments, the first dsRNA agent includes a sense strand having 14 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 1604-1656 or 2324-2329. In some embodiments, the first dsRNA agent includes an antisense strand having 14 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 1657-1709 or 2330-2335. In some embodiments, the first dsRNA agent includes a sense strand having 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 1604-1656 or 2324-2329. In some embodiments, the first dsRNA agent includes an antisense strand having 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 1657-1709 or 2330-2335. In some embodiments, the first dsRNA agent includes a sense strand having 16 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 1604-1656 or 2324-2329. In some embodiments, the first dsRNA agent includes an antisense strand having 16 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 1657-1709 or 2330-2335. In some embodiments, the first dsRNA agent includes a sense strand having 17 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 1604-1656 or 2324-2329. In some embodiments, the first dsRNA agent includes an antisense strand having 17 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 1657-1709 or 2330-2335. In some embodiments, the first dsRNA agent includes a sense strand having 18 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 1604-1656 orPAT059887-PCT-SEC012324-2329. In some embodiments, the first dsRNA agent includes an antisense strand having 18 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 1657-1709 or 2330-2335. In some embodiments, the first dsRNA agent includes a sense strand having 19 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 1604-1656 or 2324-2329. In some embodiments, the first dsRNA agent includes an antisense strand having 19 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 1657-1709 or 2330-2335. In some embodiments, the first dsRNA agent includes a sense strand having 20 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 1604-1656 or 2324-2329. In some embodiments, the first dsRNA agent includes an antisense strand having 20 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 1657-1709 or 2330-2335. In some embodiments, the first dsRNA agent includes a sense strand having 21 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 1604-1656 or 2324-2329. In some embodiments, the first dsRNA agent includes an antisense strand having 21 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 1657-1709 or 2330-2335. In some embodiments, the first dsRNA agent includes an antisense strand having 22 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 1657-1709 or 2330-2335. In some embodiments, the first dsRNA agent includes an antisense strand having 23 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 1657-1709 or 2330-2335.[000326] In some embodiments, the first dsRNA agent includes a sense strand having 10 contiguous nucleotides differing by no more than 2 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 1604-1656 or 2324-2329. In some embodiments, the first dsRNA agent includes an antisense strand having 10 contiguous nucleotides differing by no more than 2 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 1657-1709 or 2330-2335. In some embodiments, the first dsRNA agent includes a sense strand having 11 contiguous nucleotides differing by no more than 2 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 1604-1656 or 2324-2329. In some embodiments, the first dsRNA agent includes an antisense strand having 11 contiguous nucleotides differing by no more than 2 nucleotides fromPAT059887-PCT-SEC01 the nucleotide sequence selected from SEQ ID NOs: 1657-1709 or 2330-2335. In some embodiments, the first dsRNA agent includes a sense strand having 12 contiguous nucleotides differing by no more than 2 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 1604-1656 or 2324-2329. In some embodiments, the first dsRNA agent includes an antisense strand having 12 contiguous nucleotides differing by no more than 2 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 1657-1709 or 2330-2335. In some embodiments, the first dsRNA agent includes a sense strand having 13 contiguous nucleotides differing by no more than 2 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 1604-1656 or 2324-2329. In some embodiments, the first dsRNA agent includes an antisense strand having 13 contiguous nucleotides differing by no more than 2 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 1657-1709 or 2330-2335. In some embodiments, the first dsRNA agent includes a sense strand having 14 contiguous nucleotides differing by no more than 2 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 1604-1656 or 2324-2329. In some embodiments, the first dsRNA agent includes an antisense strand having 14 contiguous nucleotides differing by no more than 2 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 1657-1709 or 2330-2335. In some embodiments, the first dsRNA agent includes a sense strand having 15 contiguous nucleotides differing by no more than 2 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 1604-1656 or 2324-2329. In some embodiments, the first dsRNA agent includes an antisense strand having 15 contiguous nucleotides differing by no more than 2 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 1657-1709 or 2330-2335. In some embodiments, the first dsRNA agent includes a sense strand having 16 contiguous nucleotides differing by no more than 2 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 1604-1656 or 2324-2329. In some embodiments, the first dsRNA agent includes an antisense strand having 16 contiguous nucleotides differing by no more than 2 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 1657-1709 or 2330-2335. In some embodiments, the first dsRNA agent includes a sense strand having 17 contiguous nucleotides differing by no more than 2 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 1604-1656 or 2324-2329. In some embodiments, the first dsRNA agent includes an antisense strand having 17 contiguous nucleotides differing by no more than 2 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 1657-1709 or 2330-2335. In some embodiments, the first dsRNA agent includes a sense strand having 18 contiguous nucleotidesPAT059887-PCT-SEC01 differing by no more than 2 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 1604-1656 or 2324-2329. In some embodiments, the first dsRNA agent includes an antisense strand having 18 contiguous nucleotides differing by no more than 2 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 1657-1709 or 2330-2335. In some embodiments, the first dsRNA agent includes a sense strand having 19 contiguous nucleotides differing by no more than 2 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 1604-1656 or 2324-2329. In some embodiments, the first dsRNA agent includes an antisense strand having 19 contiguous nucleotides differing by no more than 2 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 1657-1709 or 2330-2335. In some embodiments, the first dsRNA agent includes a sense strand having 20 contiguous nucleotides differing by no more than 2 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 1604-1656 or 2324-2329. In some embodiments, the first dsRNA agent includes an antisense strand having 20 contiguous nucleotides differing by no more than 2 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 1657-1709 or 2330-2335. In some embodiments, the first dsRNA agent includes a sense strand having 21 contiguous nucleotides differing by no more than 2 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 1604-1656 or 2324-2329. In some embodiments, the first dsRNA agent includes an antisense strand having 21 contiguous nucleotides differing by no more than 2 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 1657-1709 or 2330-2335. In some embodiments, the first dsRNA agent includes an antisense strand having 22 contiguous nucleotides differing by no more than 2 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 1657-1709 or 2330-2335. In some embodiments, the first dsRNA agent includes an antisense strand having 23 contiguous nucleotides differing by no more than 2 nucleotides from the nucleotide sequence selected from SEQ ID NOs: 1657-1709 or 2330-2335.[000327] In some embodiments, the first dsRNA agent includes a sense strand having 10 contiguous nucleotides differing by no more than 1 nucleotide from the nucleotide sequence selected from SEQ ID NOs: 1604-1656 or 2324-2329. In some embodiments, the first dsRNA agent includes an antisense strand having 10 contiguous nucleotides differing by no more than 1 nucleotide from the nucleotide sequence selected from SEQ ID NOs: 1657-1709 or 2330-2335. In some embodiments, the first dsRNA agent includes a sense strand having 11 contiguous nucleotides differing by no more than 1 nucleotide from the nucleotide sequence selected from SEQ ID NOs: 1604-1656 or 2324-2329. In some embodiments, the first dsRNA agent includes anPAT059887-PCT-SEC01 antisense strand having 11 contiguous nucleotides differing by no more than 1 nucleotide from the nucleotide sequence selected from SEQ ID NOs: 1657-1709 or 2330-2335. In some embodiments, the first dsRNA agent includes a sense strand having 12 contiguous nucleotides differing by no more than 1 nucleotide from the nucleotide sequence selected from SEQ ID NOs: 1604-1656 or 2324-2329. In some embodiments, the first dsRNA agent includes an antisense strand having 12 contiguous nucleotides differing by no more than 1 nucleotide from the nucleotide sequence selected from SEQ ID NOs: 1657-1709 or 2330-2335. In some embodiments, the first dsRNA agent includes a sense strand having 13 contiguous nucleotides differing by no more than 1 nucleotide from the nucleotide sequence selected from SEQ ID NOs: 1604-1656 or 2324-2329. In some embodiments, the first dsRNA agent includes an antisense strand having 13 contiguous nucleotides differing by no more than 1 nucleotide from the nucleotide sequence selected from SEQ ID NOs: 1657-1709 or 2330-2335. In some embodiments, the first dsRNA agent includes a sense strand having 14 contiguous nucleotides differing by no more than 1 nucleotide from the nucleotide sequence selected from SEQ ID NOs: 1604-1656 or 2324-2329. In some embodiments, the first dsRNA agent includes an antisense strand having 14 contiguous nucleotides differing by no more than 1 nucleotide from the nucleotide sequence selected from SEQ ID NOs: 1657-1709 or 2330-2335. In some embodiments, the first dsRNA agent includes a sense strand having 15 contiguous nucleotides differing by no more than 1 nucleotide from the nucleotide sequence selected from SEQ ID NOs: 1604-1656 or 2324-2329. In some embodiments, the first dsRNA agent includes an antisense strand having 15 contiguous nucleotides differing by no more than 1 nucleotide from the nucleotide sequence selected from SEQ ID NOs: 1657-1709 or 2330-2335. In some embodiments, the first dsRNA agent includes a sense strand having 16 contiguous nucleotides differing by no more than 1 nucleotide from the nucleotide sequence selected from SEQ ID NOs: 1604-1656 or 2324-2329. In some embodiments, the first dsRNA agent includes an antisense strand having 16 contiguous nucleotides differing by no more than 1 nucleotide from the nucleotide sequence selected from SEQ ID NOs: 1657-1709 or 2330-2335. In some embodiments, the first dsRNA agent includes a sense strand having 17 contiguous nucleotides differing by no more than 1 nucleotide from the nucleotide sequence selected from SEQ ID NOs: 1604-1656 or 2324-2329. In some embodiments, the first dsRNA agent includes an antisense strand having 17 contiguous nucleotides differing by no more than 1 nucleotide from the nucleotide sequence selected from SEQ ID NOs: 1657-1709 or 2330-2335. In some embodiments, the first dsRNAPAT059887-PCT-SEC01 agent includes a sense strand having 18 contiguous nucleotides differing by no more than 1 nucleotide from the nucleotide sequence selected from SEQ ID NOs: 1604-1656 or 2324-2329. In some embodiments, the first dsRNA agent includes an antisense strand having 18 contiguous nucleotides differing by no more than 1 nucleotide from the nucleotide sequence selected from SEQ ID NOs: 1657-1709 or 2330-2335. In some embodiments, the first dsRNA agent includes a sense strand having 19 contiguous nucleotides differing by no more than 1 nucleotide from the nucleotide sequence selected from SEQ ID NOs: 1604-1656 or 2324-2329. In some embodiments, the first dsRNA agent includes an antisense strand having 19 contiguous nucleotides differing by no more than 1 nucleotide from the nucleotide sequence selected from SEQ ID NOs: 1657-1709 or 2330-2335. In some embodiments, the first dsRNA agent includes a sense strand having 20 contiguous nucleotides differing by no more than 1 nucleotide from the nucleotide sequence selected from SEQ ID NOs: 1604-1656 or 2324-2329. In some embodiments, the first dsRNA agent includes an antisense strand having 20 contiguous nucleotides differing by no more than 1 nucleotide from the nucleotide sequence selected from SEQ ID NOs: 1657-1709 or 2330-2335. In some embodiments, the first dsRNA agent includes a sense strand having 21 contiguous nucleotides differing by no more than 1 nucleotide from the nucleotide sequence selected from SEQ ID NOs: 1604-1656 or 2324-2329. In some embodiments, the first dsRNA agent includes an antisense strand having 21 contiguous nucleotides differing by no more than 1 nucleotide from the nucleotide sequence selected from SEQ ID NOs: 1657-1709 or 2330-2335. In some embodiments, the first dsRNA agent includes an antisense strand having 22 contiguous nucleotides differing by no more than 1 nucleotide from the nucleotide sequence selected from SEQ ID NOs: 1657-1709 or 2330-2335. In some embodiments, the first dsRNA agent includes an antisense strand having 23 contiguous nucleotides differing by no more than 1 nucleotide from the nucleotide sequence selected from SEQ ID NOs: 1657-1709 or 2330-2335.[000328] In some embodiments, the first dsRNA agent includes (i) a sense strand having 15 contiguous nucleotides differing by no more than one, two or three nucleotides from the nucleotide sequence selected from SEQ ID NOs: 1604-1656 or 2324-2329 and (ii) an antisense strand forming a duplex with the sense strand of (i) and having 15 contiguous nucleotides differing by no more than one, two or three nucleotides from the nucleotide sequence selected from SEQ ID NOs: 1657- 1709 or 2330-2335. In some embodiments, the first dsRNA agent includes (i) a sense strand having 16 contiguous nucleotides differing by no more than one, two or three from the nucleotidePAT059887-PCT-SEC01 sequence selected from SEQ ID NOs: 1604-1656 or 2324-2329 and (ii) an antisense strand forming a duplex with the sense strand of (i) and having 16 contiguous nucleotides differing by no more than one, two or three nucleotides from the nucleotide sequence selected from SEQ ID NOs: 1657- 1709 or 2330-2335. In some embodiments, the first dsRNA agent includes (i) a sense strand having 17 contiguous nucleotides differing by no more than one, two or three nucleotides from the nucleotide sequence selected from SEQ ID NOs: 1604-1656 or 2324-2329 and (ii) an antisense strand forming a duplex with the sense strand of (i) and having 17 contiguous nucleotides differing by no more than one, two or three nucleotides from the nucleotide sequence selected from SEQ ID NOs: 1657-1709 or 2330-2335. In some embodiments, the first dsRNA agent includes (i) a sense strand having 18 contiguous nucleotides differing by no more than one, two or three nucleotides from the nucleotide sequence selected from SEQ ID NOs: 1604-1656 or 2324-2329 and (ii) an antisense strand forming a duplex with the sense strand of (i) and having 18 contiguous nucleotides differing by no more than one, two or three nucleotides from the nucleotide sequence selected from SEQ ID NOs: 1657-1709 or 2330-2335. In some embodiments, the first dsRNA agent includes (i) a sense strand having 19 contiguous nucleotides differing by no more than one, two or three nucleotides from the nucleotide sequence selected from SEQ ID NOs: 1604-1656 or 2324-2329 and (ii) an antisense strand forming a duplex with the sense strand of (i) and having 19 contiguous nucleotides differing by no more than one, two or three nucleotides from the nucleotide sequence selected from SEQ ID NOs: 1657-1709 or 2330-2335. In some embodiments, the first dsRNA agent includes (i) a sense strand having 20 contiguous nucleotides differing by no more than one, two or three nucleotides from the nucleotide sequence selected from SEQ ID NOs: 1604- 1656 or 2324-2329 and (ii) an antisense strand forming a duplex with the sense strand of (i) and having 20 contiguous nucleotides differing by no more than one, two or three nucleotides from the nucleotide sequence selected from SEQ ID NOs: 1657-1709 or 2330-2335. In some embodiments, the first dsRNA agent includes (i) a sense strand having 21 contiguous nucleotides differing by no more than one, two or three nucleotides from the nucleotide sequence selected from SEQ ID NOs: 1604-1656 or 2324-2329 and (ii) an antisense strand forming a duplex with the sense strand of (i) and having 21 contiguous nucleotides differing by no more than one, two or three nucleotides from the nucleotide sequence selected from SEQ ID NOs: 1657-1709 or 2330-2335. In some embodiments, the first dsRNA agent includes (i) a sense strand having 21 contiguous nucleotides differing by no more than one, two or three nucleotides from the nucleotide sequence selected fromPAT059887-PCT-SEC01SEQ ID NOs: 1604-1656 or 2324-2329 and (ii) an antisense strand forming a duplex with the sense strand of (i) and having 22 contiguous nucleotides differing by no more than one, two or three nucleotides from the nucleotide sequence selected from SEQ ID NOs: 1657-1709 or 2330-2335. In some embodiments, the first dsRNA agent includes (i) a sense strand having 21 contiguous nucleotides differing by no more than one, two or three nucleotides from the nucleotide sequence selected from SEQ ID NOs: 1604-1656 or 2324-2329 and (ii) an antisense strand forming a duplex with the sense strand of (i) and having 23 contiguous nucleotides differing by no more than one, two or three nucleotides from the nucleotide sequence selected from SEQ ID NOs: 1657-1709 or 2330-2335.[000329] In certain aspects, when a sense strand or an antisense strand of a dsRNA in above paragraphs is differing by a certain number of nucleotides (e.g., one, two or three nucleotides) from a specific sequence (e.g., SEQ ID NOs: 1604-1709 or 2324-2335), it is meant by that the sense strand or the antisense strand includes one, two or three nucleotides, having different nucleobases and / or different modifications compared to the nucleobases and / or the modifications of the nucleotides at the corresponding positions of the specific sequence (e.g., SEQ ID NOs: 1604- 1709 or 2324-2335). In some embodiments, when a sense strand or an antisense strand is differing by a certain number of nucleotides (e.g., one, two or three nucleotides) from a specific sequence (e.g., SEQ ID NOs: 1604-1709 or 2324-2335), the sense strand or the antisense strand includes one, two, or three nucleotides, having different nucleobases compared to the nucleobases of the nucleotides at the corresponding positions of the specific sequence (e.g., SEQ ID NOs: 1604-1709 or 2324-2335). In some embodiments, when a sense strand or an antisense strand is differing by a certain number of nucleotides (e.g., one, two or three nucleotides) from a specific sequence (e.g., SEQ ID NOs: 1604-1709 or 2324-2335), the sense strand or the antisense strand includes one, two, or three nucleotides, having different modifications compared to the modifications of the nucleotides at the corresponding positions of the specific sequence (e.g., SEQ ID NOs: 1604-1709 or 2324-2335). In some embodiments, when a sense strand or an antisense strand is differing by a certain number of nucleotides (e.g., one, two or three nucleotides) from a specific sequence (e.g., SEQ ID NOs: 1604-1709 or 2324-2335), the sense strand or the antisense strand includes one, two, or three nucleotides having different nucleobases and different modifications compared to the nucleobases and the modifications of the nucleotides at the corresponding positions of the specific sequence (e.g., SEQ ID NOs: 1604-1709 or 2324-2335).PAT059887-PCT-SEC01[000330] In certain aspects, when a sense strand or an antisense strand of a dsRNA in above paragraphs is differing by a certain number of nucleotides (e.g., one, two or three nucleotides) from a specific sequence (e.g., SEQ ID NOs: 1604-1709 or 2324-2335), it is meant by that the sense strand or the antisense strand includes one, two or three nucleotides, having different nucleobases, different modifications, and / or different phosphate linkages (e.g...

Claims

PAT059887-PCT-SEC01WHAT IS CLAIMED:

1. A combination comprising a first antisense agent and a second antisense agent, wherein:(a) the first antisense agent is a proprotein convertase subtilisin kexin 9 (PCSK9) inhibitor; and(b) the second antisense agent is a 3 -hydroxy-3 -methylglutaryl-Co A reductase (HMGCR) inhibitor.

2. The combination of claim 1, wherein the first antisense agent is a double stranded RNAi (dsRNAi) agent.

3. The combination of claim 1 or claim 2, wherein the second antisense agent is a dsRNAi agent.

4. The combination of any one of claims 1 to 3, comprising a first double stranded RNAi (dsRNAi) agent and a second dsRNAi agent, wherein:(a) the first dsRNAi agent is a PCSK9 inhibitor; and(b) the second dsRNAi agent is an HMGCR inhibitor.

5. The combination of any one of claims 2 to 4, wherein one or more nucleotides in the sense strand and the antisense strand of the first dsRNAi agent are modified nucleotides.

6. The combination of any one of claims 3 to 5, wherein one or more nucleotides in the sense strand and the antisense strand of the second dsRNAi agent are modified nucleotides.

7. The combination of claim 5 or claim 6, wherein each of the one or more modified nucleotides independently comprises one or more modifications selected from a 2’ -deoxy modification, a 2’- O-alkyl modification, a 2'-halo modification, a threofuranosyl nucleotide (TNA) modification, a 2’ -5 ’-linkage modification, a conformationally restricting modification, an abasic modification, a 2’- amino-modifi cation, a 2’-O-allyl modification, 2’-C-alkyl modification, a 2’-O-alkoxyalkyl modification, a morpholino modification, a phosphoramidate modification, a non-natural nucleobase modification, a modification in a tetrahydropyran, a modification containing a 1,5- anhydrohexitol, a modification containing a cyclohexenyl, a modification containing aPAT059887-PCT-SEC01 phosphor othioate group, a modification containing a 5’-vinyl-phosphonate, a modification containing a 5 ’-phosphate, a modification to form a thermally destabilizing nucleotide, a glycol nucleic acid (GNA) modification, and a 2-O-(N-methylacetamide) modification.

8. The combination of claim 7, wherein each of the one or more modified nucleotides independently comprises one or more modifications selected from 2’ -deoxy modification, 2'-O- alkoxyalkyl modification, 2'-O-alkyl modification, 2'-O-allyl modification, 2'-C-alkyl modification, 2'-halo modification, modification containing a non-natural nucleobase, a GNA modification, and a TNA modification.

9. The combination of any one of claims 5 to 8, wherein the first and / or second dsRNAi agent comprises a 3’-phosphorothioate (PS) modification.

10. The combination of any one of claims 5 to 9, wherein each of the one or more modified nucleotides independently comprises one or more modifications selected from 2’ -deoxy modification, 2’-O-methyl (2’-0Me) modification, 2’-fluoro (2’-F) modification, 2’-O- methoxy ethyl (2 ’-MOE) modification, a modification containing a non-natural nucleobase, TNA, GNA, 3’-phosphorothioate (PS) modification, and 5’-vinyl-phosphonate (5 ’-VP) modification.

11. The combination of any one of claims 1 to 10, wherein the first dsRNAi agent further comprises a ligand.

12. The combination of any one of claims 1 to 11, wherein the second dsRNAi agent further comprises a ligand.

13. The combination of claim 11 or claim 12, wherein the ligand comprises a N- acetylgalactosamine (GalNAc) moiety.

14. The combination of any one of claims 11 to 13, wherein the ligand has a structure of:PAT059887-PCT-SEC01or a pharmaceutically acceptable salt thereof, wherein: each LI is independently a linker which may be same or different in each occurrence;L2 is a linker; n is an integer from 1 to 3; and is an attachment point to the sense strand or the antisense strand, or to a conjugate linker conjugated to the sense strand or the antisense strand.

15. The combination of claim 14, wherein the ligand comprises the following structure ofor a pharmaceutically acceptable salt thereof, wherein:PAT059887-PCT-SEC01 each pl, p2, p3, ql, q2, rl, r2 and r3 is independently an integer from 0 to 12; each nl, n2, and n3 is independently an integer from 1 to 3; and is an attachment point to L2.

16. The combination of any one of claims 11 to 13, wherein the ligand has a structure of:or a pharmaceutically acceptable salt thereof, wherein: each LI 1, L12, L13, L14, and L15 is an independently a linker;L2 is a linker; is an attachment point to the sense strand or the antisense strand, or to a conjugate linker conjugated to the sense strand or the antisense strand.

17. The combination of claim 16, wherein the ligand has a structure of:PAT059887-PCT-SEC01or a pharmaceutically acceptable salt thereof, wherein: each pl 1 and ql 1 is independently an integer from 0 to 12; each zl, z2, and z3 is independently an integer of 0 to 12; and is an attachment point to the sense strand or the antisense strand, or to a conjugate linker conjugated to the sense strand or the antisense strand.

18. The combination of any one of claims 11 to 17, wherein the ligand comprises the following structure:PAT059887-PCT-SEC01or a pharmaceutically acceptable salt thereof, wherein is an attachment point to the sense strand or the antisense strand or to a conjugate linker conjugated to the sense strand or the antisense strand.

19. The combination of claim 18, wherein the ligand is conjugated to 3’ end of the sense strand to form the following structure:PAT059887-PCT-SEC01acceptable salt thereof, wherein W is -OH or -SH.

20. The combination of claim 18, wherein the ligand is conjugated to 5’ end of the sense strand to form the following structure:PAT059887-PCT-SEC01 or a pharmaceutically acceptable salt thereof wherein W is -OH or -SH.

21. The combination of claim 19 or claim 20, wherein W is -OH.

22. The combination of any one of claims 1 to 21, wherein the first antisense agent (e.g., first dsRNAi agent) is in a pharmaceutically acceptable salt form.

23. The combination of any one of claims 1 to 22, wherein the second antisense agent (e.g., second dsRNAi agent) is in a pharmaceutically acceptable salt form.

24. The combination of claim 22 or claim 23, wherein the pharmaceutically acceptable salt is a sodium salt.

25. The combination of any one of claims 1 to 24, wherein the first antisense agent (e.g., first dsRNAi agent) and the second antisense agent (e.g., second dsRNAi agent) are provided as a mixture.

26. The combination of any one of claims 1 to 25, wherein the first antisense agent (e.g., first dsRNAi agent) and the second antisense agent (e.g., second dsRNAi agent) are formulated separately.

27. The combination of any one of claims 1 to 26, wherein: the first antisense agent comprises a sense strand selected from SEQ ID NOs: 3-381, 761-776, 2348-2389, 1604-1656, 2324-2329, 2450-2507, 2200-2256, 2336-2341, and 2606-2631; and an antisense strand selected from SEQ ID NOs: 382-760, 777-792, 2390-2431, 1657-1709, 2330- 2335, 2508-2565, 2257-2313, 2342-2347, and 2632-2657; and the second antisense agent comprises a sense strand selected from SEQ ID NOs: 794-1198, 2432-2438, 2439-2440, 1710-1950, 2192-2195, 2566-2582, 2600-2602, 2314-2317, and 2658- 2660; and an antisense strand selected from SEQ ID NOs: 1199-1603, 2441-2447, 2448-2449, 1951-2191, 2196-2199, 2583-2599, 2603-2605, 2318-2321, and 2661-2663.PAT059887-PCT-SEC0128. A pharmaceutical composition comprising the combination of any one of claims 1 to 27, and a pharmaceutically acceptable carrier.

29. The pharmaceutical composition of claim 28, wherein the pharmaceutical composition is in an aqueous solution form.

30. A method of inhibiting PCSK9 and / or HMGCR expression in a cell, the method comprising:(a) contacting the cell with the combination of any one of claims 1 to 27, or the pharmaceutical composition of any one of claim 28 or claim 29; and(b) maintaining the cell produced in step (a) for a time sufficient to obtain degradation of the mRNA transcript of a PCSK9 gene and / or an HMGCR gene, thereby inhibiting expression of the PCSK9 gene and / or the HMGCR gene in the cell.

31. A method of lowering a level of low-density lipoprotein cholesterol (LDL-C) in a subject in need thereof, comprising administering to the subject the combination of any one of claims 1 to 27, or the pharmaceutical composition of claim 28 or claim 29.

32. A method of treating lipidemia mediated by PCSK9 and / or HMGCR expression in a subject in need thereof, comprising administering to the subject the combination of any one of claims 1 to 27, or the pharmaceutical composition of claim 28 or claim 29.

33. A method of treating or preventing atherosclerotic cardiovascular disease (ASCVD) in a subject in need thereof, comprising administering to the subject the combination of any one of claims 1 to 27, or the pharmaceutical composition of claim 28 or claim 29.

34. A method of reducing or preventing cardiovascular event in a subject in need thereof, comprising administering to the subject the combination of any one of claims 1 to 27, or the pharmaceutical composition of any one of claim 28 or claim 29.PAT059887-PCT-SEC0135. The method of claim 34, wherein the cardiovascular event is cardiovascular death, non-fatal myocardial infarction (MI), non-fatal ischemic stroke, urgent coronary revascularization, coronary heart disease (CHD) death, or any combination thereof.

36. A method of reducing or preventing a major limb adverse event (MALE) in a subject in need thereof, comprising administering to the subject the combination of any one of claims 1 to 27, or the pharmaceutical composition of claim 28 or claim 29.

37. The method of claim 36, wherein the MALE is acute lower limb ischemia, lower limb amputation due to ischemia, urgent lower limb revascularization for ischemia, or any combination thereof.

38. The method of any one of claims 30 to 37, wherein the first antisense agent (e.g., first dsRNAi agent) and the second antisense agent (e.g., second dsRNAi agent) are administered to the subject concurrently.

39. The method of any one of claims 30 to 37, wherein the first antisense agent (e.g. first dsRNAi agent) and the second antisense agent (e.g., second dsRNAi agent) are administered to the subject sequentially.

40. The method of any one of claims 30 to 39, wherein the first antisense agent (e.g., first dsRNAi agent) and the second antisense agent (e.g. second dsRNAi agent) are administered to the subject subcutaneously or intravenously.

41. The method of any one of claims 30 to 40, wherein the subject is a human.

42. The method of any one of claims 30 to 41, wherein the subject has or is diagnosed with hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, mixed hyperlipidemia, congestive heart disease (CHD) or atherosclerosis.PAT059887-PCT-SEC0143. A kit comprising a first antisense agent (e.g., first dsRNAi agent) and a second antisense agent (e.g., second dsRNAi agent) as defined in any one of claims 1 to 27, or the pharmaceutical composition of any one of claims 28 or 29.

44. The kit of claim 43, wherein the first antisense agent (e.g., first dsRNAi agent) and the second antisense agent (e.g., second dsRNAi agent) are contained in a single vial.

45. The kit of claim 43, wherein the first antisense agent (e.g., first dsRNAi agent) and the second antisense agent (e.g., second dsRNAi) agent are contained in separate vials.

46. The kit of any one of claims 43 to 45, further comprising one or more applicators.

47. The kit of claim 46, wherein the one or more applicators are syringes.

48. The kit of claim 47, wherein the one or more applicators are pre-filled syringes.

49. A method of inhibiting PCSK9 and / or HMGCR expression in a cell, the method comprising:(a) contacting the cell with the second antisense agent of the combination of claims 1 to 27 or a pharmaceutical composition thereof; and(b) maintaining the cell produced in step (a) for a time sufficient to obtain degradation of the mRNA transcript of a PCSK9 gene and / or an HMGCR gene, thereby inhibiting expression of the PCSK9 gene and / or the HMGCR gene in the cell, wherein the cell has been contacted with the first antisense agent of the combination of claims 1 to 27 or a pharmaceutical composition thereof, prior to step (a).

50. A method of inhibiting PCSK9 and / or HMGCR expression in a cell, the method comprising:(a) contacting the cell with the first antisense agent of the combination of claims 1 to 27 or a pharmaceutical composition thereof; and(b) maintaining the cell produced in step (a) for a time sufficient to obtain degradation of the mRNA transcript of a PCSK9 gene and / or an HMGCR gene, thereby inhibiting expression of thePAT059887-PCT-SEC01PCSK9 gene and / or the HMGCR gene in the cell, wherein the cell has been contacted with the second antisense agent of the combination of claims 1 to 27 or a pharmaceutical composition thereof, prior to step (a).

51. A method of lowering a level of low-density lipoprotein cholesterol (LDL-C) in a subject in need thereof, comprising (a) administering to the subject the second antisense agent of the combination of claims 1 to 27 or a pharmaceutical composition thereof, wherein the subject has been administered with the first antisense agent of the combination of claims 1 to 27 or a pharmaceutical composition thereof, prior to step (a).

52. A method of lowering a level of low-density lipoprotein cholesterol (LDL-C) in a subject in need thereof, comprising (a) administering to the subject the first antisense agent of the combination of claims 1 to 27 or a pharmaceutical composition thereof, wherein the subject has been administered with the second antisense agent of the combination of claims 1 to 27 or a pharmaceutical composition thereof, prior to step (a).

53. A method of treating lipidemia mediated by PCSK9 and / or HMGCR expression in a subject in need thereof, comprising (a) administering to the subject the second antisense agent of the combination of claims 1 to 27 or a pharmaceutical composition thereof, wherein the subject has been administered with the first antisense agent of the combination of claims 1 to 27 or a pharmaceutical composition thereof, prior to step (a).

54. A method of treating lipidemia mediated by PCSK9 and / or HMGCR expression in a subject in need thereof, comprising (a) administering to the subject the first antisense agent of the combination of claims 1 to 27 or a pharmaceutical composition thereof, wherein the subject has been administered with the second antisense agent of the combination of claims 1 to 27 or a pharmaceutical composition thereof, prior to step (a).

55. A method of treating or preventing atherosclerotic cardiovascular disease (ASCVD) in a subject in need thereof, comprising (a) administering to the subject the second antisense agent ofPAT059887-PCT-SEC01 the combination of claims 1 to 27 or a pharmaceutical composition thereof, wherein the subject has been administered with the first antisense agent of the combination of claims 1 to 27 or a pharmaceutical composition thereof, prior to step (a).

56. A method of treating or preventing atherosclerotic cardiovascular disease (ASCVD) in a subject in need thereof, comprising (a) administering to the subject the first antisense agent of the combination of claims 1 to 27 or a pharmaceutical composition thereof, wherein the subject has been administered with the second antisense agent of the combination of claims 1 to 27 or a pharmaceutical composition thereof, prior to step (a).

57. A method of reducing or preventing cardiovascular event in a subject in need thereof, comprising (a) administering to the subject the second antisense agent of the combination of claims 1 to 27 or a pharmaceutical composition thereof, wherein the subject has been administered with the first antisense agent of the combination of claims 1 to 27 or a pharmaceutical composition thereof, prior to step (a).

58. A method of reducing or preventing cardiovascular event in a subject in need thereof, comprising (a) administering to the subject the first antisense agent of the combination of claims 1 to 27 or a pharmaceutical composition thereof, wherein the subject has been administered with the second antisense agent of the combination of claims 1 to 27 or a pharmaceutical composition thereof, prior to step (a).

59. The method of claim 57 or 58, wherein the cardiovascular event is cardiovascular death, non- fatal myocardial infarction (MI), non-fatal ischemic stroke, urgent coronary revascularization, coronary heart disease (CHD) death, or any combination thereof.

60. A method of reducing or preventing a major limb adverse event (MALE) in a subject in need thereof, comprising (a) administering to the subject the second antisense agent of the combination of claims 1 to 27 or a pharmaceutical composition thereof, wherein the subject hasPAT059887-PCT-SEC01 been administered with the first antisense agent of the combination of claims 1 to 27 or a pharmaceutical composition thereof, prior to step (a).

61. A method of reducing or preventing a major limb adverse event (MALE) in a subject in need thereof, comprising (a) administering to the subject the first antisense agent of the combination of claims 1 to 27 or a pharmaceutical composition thereof, wherein the subject has been administered with the second antisense agent of the combination of claims 1 to 27 or a pharmaceutical composition thereof, prior to step (a).

62. The method of claim 60 or 61, wherein the MALE is acute lower limb ischemia, lower limb amputation due to ischemia, urgent lower limb revascularization for ischemia, or any combination thereof.

63. The method of any one of claims 49 to 62, wherein the first antisense agent (e.g., first dsRNAi agent) and the second antisense agent (e.g. second dsRNAi agent) are administered to the subject subcutaneously or intravenously.

64. The method of any one of claims 49 to 63, wherein the subject is a human.

65. The method of any one of claims 49 to 64, wherein the subject has or is diagnosed with hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, mixed hyperlipidemia, congestive heart disease (CHD) or atherosclerosis.

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