Sirna capable of inhibiting expression of coagulation factor xi and use thereof

Abstract

The present disclosure belongs to the field of biomedicines, and specifically relates to a nucleic acid capable of inhibiting the expression of a coagulation factor XI (factor XI), a pharmaceutical composition containing the nucleic acid, and an siRNA conjugate. Specifically, provided in the present disclosure is a double-stranded oligonucleotide capable of inhibiting the expression of FXI. The double-stranded oligonucleotide comprises a sense strand and an antisense strand, wherein the sense strand and the antisense strand are at least partially reverse-complementary to form a double-stranded region, the antisense strand is at least partially complementary to a segment of nucleotides within FXI-transcribed mRNA, the length of the sense strand does not exceed 21 nucleotides, the length of the antisense strand does not exceed 23 nucleotides, and the antisense strand comprises a sequence of at least 17 contiguous nucleotides that differs from any one of the nucleotide sequences as set forth in SEQ ID NOs: 175-347 and 706-714 by no more than 4, 3, 2, or 1 nucleotides. The oligonucleotide prepared in the present disclosure has a good inhibitory effect on the expression of the coagulation factor XI both in vitro and in vivo.

Description

siRNA inhibiting expression of coagulation factor XI and uses thereof TECHNICAL FIELD

[0001] The present disclosure belongs to the field of biological medicine, and particularly relates to a nucleic acid capable of inhibiting expression of coagulation factor XI (factor XI) and a pharmaceutical composition containing the nucleic acid and an siRNA conjugate. The present disclosure also relates to the use of the nucleic acid, the pharmaceutical composition and the siRNA conjugate in treating various cardiovascular diseases. BACKGROUND

[0002] FXIa factor is a plasma serine protease mainly synthesized by hepatocytes and circulates in the form of zymogen (FXI), and is a key component of the intrinsic coagulation pathway. The risk of thrombosis in people with FXI deficiency is significantly reduced. Warfarin is a commonly used anticoagulant drug in clinical practice, which exerts a strong anticoagulant effect by antagonizing vitamin K-dependent coagulation factors II, VII, IX and X. However, it is significantly affected by diet and drugs and requires monitoring of the international normalized ratio. It also has a potential risk of bleeding. Studies have shown that about 2.1% of patients taking warfarin for anticoagulation in atrial fibrillation patients experience major bleeding events each year, of which about 1.15% of patients experience significant gastrointestinal bleeding each year, and about 0.58% of patients experience intracranial hemorrhage each year. Therefore, it is of great clinical significance to develop an anticoagulant drug that has good anticoagulant effect and reduces the risk of bleeding for the thrombin pathway. Blocking FXI will specifically block the intrinsic thrombin pathway without affecting the activity of the extrinsic pathway, reducing the impact on hemostatic function.

[0003] In 1998, two American scientists, Andrew Fire and Craig Mello, discovered a new biological mechanism, i.e., small RNA molecules can mediate the degradation of specific mRNA (Fire, Andrew, et al. nature 391.6669 (1998): 806-811.). When RNA molecules exist in a double-stranded form in cells, this mechanism is activated, i.e., RNA interference occurs. This discovery heralds the beginning of a new research field, and the two scientists have won the Nobel Prize in Physiology or Medicine in 2006. When double-stranded RNA binds to the protein complex Dicer, Dicer cuts the dsRNA into fragments, and another protein complex RISC binds to these fragments. One strand of the siRNA double strand is removed, but the other strand is still complexed with the RISC (RNA-induced silencing complex) complex. RISC recognizes and degrades the mRNA of the target gene through the guidance of single-stranded RNA, inhibits the expression of specific proteins, and thus specifically causes gene silencing.

[0004] RNA interference opens up a new field of application of gene technology. Double-stranded RNA molecules have been artificially designed to silence specific genes in humans, animals or plants. This artificially designed double-stranded RNA molecule (small interfering RNA, siRNA) for gene silencing is introduced into cells and activates the RNA interference mechanism to degrade the corresponding mRNA. At present, this method is an important research tool in biology and biomedicine. In addition, a large number of siRNA drugs have been developed to treat viral infections, cardiovascular diseases, cancers, endocrine disorders and other diseases, most of which are in the research and development stage or have been approved for marketing. siRNA therapies show good therapeutic effect. Since the first siRNA drug was launched in 2018, at least four siRNA drugs have been approved for marketing in the European Union or the United States. Therefore, using RNA interference technology to inhibit the expression of specific target genes has become an effective way to treat diseases.

[0005] The key to developing siRNA drugs for inhibiting FXI gene expression and treating thrombotic diseases lies in finding suitable siRNA sequences, modifying them and effective delivery systems. Therefore, it is urgent to develop more superior siRNA drugs in order to achieve the purpose of functional cure. SUMMARY

[0006] In order to solve the problems existing in the prior art, the purpose of the present disclosure is to provide a nucleic acid capable of inhibiting the expression of coagulation factor XI (FXI) and a pharmaceutical composition containing the nucleic acid and an siRNA conjugate. The present disclosure also relates to the use of these nucleic acids, pharmaceutical compositions and siRNA conjugates in the treatment of various cardiovascular diseases.

[0007] In one aspect, the present disclosure provides a double-stranded oligonucleotide for inhibiting the expression of FXI, the double-stranded oligonucleotide comprising a sense strand and an antisense strand, wherein the sense strand and the antisense strand are at least partially reverse complementary to form a double-stranded region, the antisense strand is at least partially complementary to a stretch of nucleotides in a FXI transcripted mRNA, the length of the sense strand is no more than 21 nucleotides, the length of the antisense strand is no more than 23 nucleotides, and the antisense strand comprises at least 17 contiguous nucleotides differing by no more than 4, 3, 2 or 1 nucleotides from the nucleotide sequence as set forth in any one of SEQ ID NOs: 1010-2017, SEQ ID NOs: 2601-2834.

[0008] In another aspect, the present disclosure provides a composition comprising the aforementioned double-stranded oligonucleotide or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier.

[0009] In another aspect, the present disclosure provides a cell comprising the aforementioned double-stranded oligonucleotide.

[0010] In another aspect, the present disclosure provides a method for inhibiting expression of a blood coagulation factor XI gene in vitro, the method comprising contacting an effective amount of the aforementioned siRNA and / or the aforementioned pharmaceutical composition with a cell.

[0011] In another aspect, the present disclosure provides a kit, wherein the kit contains the aforementioned double-stranded oligonucleotide and / or the aforementioned pharmaceutical composition.

[0012] In another aspect, the present disclosure provides use of the aforementioned double-stranded oligonucleotide and / or the aforementioned composition in the manufacture of a medicament for preventing or treating a disease.

[0013] In another aspect, the present disclosure provides a method for treating or preventing a disease or disorder in a subject, wherein the method comprises administering to the subject an amount of the aforementioned oligonucleotide and / or the aforementioned composition sufficient to inhibit expression of a blood coagulation factor XI gene in the subject.

[0014] The oligonucleotide prepared by the present disclosure has a good inhibitory effect on expression of a blood coagulation factor XI gene in vitro and in vivo. BRIEF DESCRIPTION OF DRAWINGS

[0015] Figure 1 shows the inhibition of FXI mRNA expression in HepG2 cells by unmodified siRNA sequences F0029 to 29 (1 nM).

[0016] Figure 2 shows the inhibition of FXI mRNA expression in HepG2 cells by unmodified siRNA sequences F0054 to 29 (1 nM).

[0017] Figure 3 shows the inhibition of FXI mRNA expression in HepG2 cells by unmodified siRNA sequences F0290 to 29 (1 nM).

[0018] Figure 4 shows the inhibition of FXI mRNA expression in HepG2 cells by unmodified siRNA sequences F0362 to 29 (1 nM).

[0019] Figure 5 shows the inhibition of FXI mRNA expression in HepG2 cells by unmodified siRNA sequences F0670 to 29 (1 nM).

[0020] Figure 6 shows the inhibition of FXI mRNA expression in HepG2 cells by unmodified siRNA sequences F0051 to 28 (1 nM).

[0021] Figure 7 shows the inhibition of FXI mRNA expression in HepG2 cells (0.25 nM) for unmodified siRNA sequences F0035 et seq. 22.

[0022] Figure 8 shows the inhibition of FXI mRNA expression in HepG2 cells (0.25 nM) for unmodified siRNA sequences F0379 et seq. 12.

[0023] Figure 9 shows the inhibition of FXI mRNA expression in HepG2 cells (0.25 nM) for unmodified siRNA sequences F0069 et seq. 21.

[0024] Figure 10 shows the inhibition of FXI mRNA expression in HepG2 cells (0.25 nM) for unmodified siRNA sequences F0378 et seq. 19.

[0025] Figure 11 shows the inhibition of FXI mRNA expression in HepG2 cells (0.25 nM) for unmodified siRNA sequences F0029 et seq. 12.

[0026] Figure 12 shows the inhibition of FXI mRNA expression in HepG2 cells (0.25 nM) for unmodified siRNA sequences F0198 et seq. 13.

[0027] Figure 13 shows the inhibition of FXI mRNA expression in HepG2 cells (0.25 nM) for unmodified siRNA sequences F0330 et seq. 13.

[0028] Figure 14 shows the inhibition of FXI mRNA expression in HepG2 cells (0.25 nM) for unmodified siRNA sequences F0360 et seq. 14.

[0029] Figure 15 shows the inhibition of FXI mRNA expression in HepG2 cells (0.25 nM) for unmodified siRNA sequences F0507 et seq. 14.

[0030] Figure 16 shows the inhibition of FXI mRNA expression in HepG2 cells (0.25 nM) for unmodified siRNA sequences F0667 et seq. 14.

[0031] Figure 17 shows the inhibition of FXI mRNA expression in HepG2 cells (0.25 nM) for unmodified siRNA sequences F0702 et seq. 14.

[0032] Figure 18 shows the inhibition of FXI mRNA expression in HepG2 cells by five unmodified siRNA sequences, F0854, at 0.25 nM.

[0033] Figures 19-22 show the IC50determination of the preferred chemically modified 17 siRNAs of the disclosure for inhibition of FXI mRNA expression in HepG2 cells.

[0034] Figures 23-26 show the inhibition activity of the preferred chemically modified 12 siRNAs of the disclosure for FXI mRNA in cynomolgus monkey primary hepatocytes.

[0035] Figure 27 shows the knockdown effect of the preferred chemically modified 14 siRNAs of the disclosure for hFXI in AAV mice.

[0036] Figure 28 shows the inhibition of the expression effect of siRNA conjugates on FXI protein concentration in plasma in a TG mouse model.

[0037] Figure 29 shows the inhibition effect of siRNA conjugates on FXI activity in cynomolgus monkeys. DETAILED DESCRIPTION

[0038] I. Definitions

[0039] In the present disclosure, unless otherwise indicated, the scientific and technical terms used herein have the meanings that would be generally understood by one of ordinary skill in the art. Also, the terms related to protein and nucleic acid chemistry, molecular biology, cell and tissue culture, microbiology, immunology, and laboratory procedures steps used herein are terms and procedures widely used in the respective fields. Also, for better understanding of the present disclosure, the definitions and explanations of the related terms are provided below.

[0040] As used herein, the term "about" or "approximately," as applied to one or more of the values of a parameter, refers to a value that is similar to a stated reference value. In certain embodiments, unless otherwise stated or otherwise clear from context, the term "approximately" or "about" means falling within 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less in either direction (greater than or less than) of the stated reference value (unless such number would exceed 100% of the possible values). As used herein, "optional" or "optionally" means that the subsequently described event or circumstance can or can not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.

[0041] As used herein, the term "strand" refers to a single, continuous sequence of nucleotides linked together by internucleotide bonds (e.g., phosphodiester bonds, phosphorothioate bonds). In some embodiments, a strand has two free ends, e.g., a 5'-end and a 3'-end.

[0042] As used herein, the term "siRNA" is a class of double-stranded RNA molecules that can mediate the silencing of a target RNA (e.g., mRNA, e.g., a transcript of a gene encoding a protein) that is complementary to it. siRNAs are typically double-stranded, comprising an antisense strand that is complementary to a target RNA, and a sense strand that is complementary to the antisense strand. For convenience, such mRNA is also referred to herein as mRNA to be silenced. Such gene is also referred to as target gene. Typically, the RNA to be silenced is an endogenous gene or a pathogen gene. In addition, RNAs other than mRNA (e.g., tRNA) and viral RNA can also be targeted.

[0043] As used herein, the term "antisense strand" refers to one strand of an siRNA that comprises a region that is fully or substantially complementary to a target sequence.

[0044] As used herein, the term "complementary" refers to the structural relationship between nucleotides (e.g., on opposite nucleic acids or on opposite regions of a single nucleic acid strand) that allows the nucleotides to form base pairs with each other. For example, a purine nucleotide of one nucleic acid that is complementary to a pyrimidine nucleotide of an opposite nucleic acid can base pair together by forming hydrogen bonds with each other. In some embodiments, complementary nucleotides can base pair in a Watson-Crick manner or in any other manner that allows for the formation of a stable duplex. In some embodiments, two nucleic acids can have nucleotide sequences that are complementary to each other so as to form a region of complementarity. As described herein, the term "region of complementarity" refers to a region on an antisense strand that is fully or substantially complementary to a target mRNA sequence. Where the region of complementarity is not fully complementary to the target sequence, mismatches can be located in the interior or in the terminal regions of the molecule. Typically, the most tolerated mismatches are located in the terminal regions, e.g., within 5, 4, 3, 2, or 1 nucleotides of the 5' and / or 3' end. The portion of the antisense strand that is most sensitive to mismatches is referred to as the "seed region." For example, in an siRNA comprising 19 nt, the 19th position (from 5' to 3') can tolerate some mismatches. The terms "complementary," "fully complementary," and "substantially complementary" can be used with respect to base pairing between a sense strand and an antisense strand of an siRNA, or between an antisense strand of an siRNA agent and a target sequence.

[0045] As used herein, the term "difference" means that one nucleotide sequence has a "nucleotide difference" from another nucleotide sequence, meaning that the base identity of a nucleotide at the same position in the former has changed as compared to the latter, e.g., where the nucleotide base in the latter is A, a nucleotide base at the corresponding position in the former is U, C, G, or T, a nucleotide difference is recognized to exist at that position between the two nucleotide sequences. In some embodiments, a nucleotide difference is also recognized to exist at a position where an abasic nucleotide or nucleotide analog is substituted for the nucleotide at the position.

[0046] As used herein, the term "mismatch" means that in a double-stranded nucleic acid, the bases at the corresponding positions are not paired in a complementary fashion.

[0047] As used herein, the term "comprise" and other forms of the term "comprise" are used in an open-ended sense, and are not limited to the inclusion of only the recited elements. The term "comprise" and other forms of the term "comprise" are used in an open-ended sense, and are not limited to the inclusion of only the recited elements. As used in this specification, the terms "comprises", "comprising", "includes", "including", "has", "having" or variants thereof are used synonymously with the term "comprising" and are intended not to exclude additional non-recited elements or method steps. As used in this specification, the term "comprises" or "comprising" or similar terms, when used in a graphical depiction of a process, indicates that the process includes at least the recited steps, but can also include additional steps. As used in this specification, the term "comprises" or "comprising" or similar terms, when used in the context of a compound, composition, or device, means that the compound, composition, or device includes at least the recited features or components, but can also include additional features or components. As used in this specification, the term "comprises" or "comprising" or similar terms, when used in the context of a double-stranded oligonucleotide set, means that the sense strand / antisense strand includes at least the recited sequences, but can also include additional sequences.

[0048] As used herein, the term "sense strand" refers to one strand of an siRNA that includes a region that is substantially complementary to a region that is the term antisense strand as defined herein.

[0049] As used herein, a "nucleoside" is a compound consisting of a purine or pyrimidine base, and either ribose or deoxyribose, and a "nucleotide" is a compound consisting of a purine or pyrimidine base, ribose or deoxyribose, and a phosphate. An "oligonucleotide" refers to a nucleic acid molecule (RNA or DNA) having, for example, a length of less than 100, 200, 300, or 400 nucleotides. An oligonucleotide can comprise ribonucleotides, deoxyribonucleotides, and / or modified nucleotides, including, for example, modified ribonucleotides. An oligonucleotide can be single-stranded or double-stranded. An oligonucleotide can or can not have a duplex region. As a non-limiting example, an oligonucleotide can be, but is not limited to, a small interfering RNA (siRNA), a microRNA (miRNA), a short hairpin RNA (shRNA), a Dicer substrate interfering RNA (dsiRNA), an antisense oligonucleotide, a short siRNA, or a single-stranded siRNA. In some embodiments, a double-stranded oligonucleotide is an RNAi oligonucleotide.

[0050] As used herein, a "base" is the basic building block of synthetic nucleosides, nucleotides, and nucleic acids, which contains nitrogen in its constituent elements, also known as a "nitrogen-containing base." Herein, unless otherwise specified, capital letters A, U, T, G, and C represent the base composition of a nucleotide, which are adenine, uracil, thymine, guanine, and cytosine, respectively, with specific structures as follows:

[0051] In some embodiments, m represents that the nucleotide adjacent to its left is a sugar ring 2'-OCH3 modified nucleotide, such as: Am, Um, Gm, and Cm represent A, U, G, and C with sugar ring 2'-OCH3 modification, respectively, with specific structures as follows:

[0052] f represents that the nucleotide adjacent to its left is a sugar ring 2'-f modified nucleotide, such as: Af, Uf, Gf, and Cf represent A, U, G, and C with sugar ring 2'-f modification, respectively, with specific structures as follows:

[0053] "s" represents that the two nucleotides adjacent to its left and right are linked by phosphorothioate, with specific structures as follows:

[0054] wherein X represents: 2'-OCH3 or 2'-f modification.

[0055] P represents that the nucleotide adjacent to its left is a sugar ring 5'-phosphate modified nucleotide, with specific structures as follows:

[0056] VP represents that the nucleotide adjacent to its left is a sugar ring 5'-vinylphosphate modified nucleotide, with specific structures as follows:

[0057] Im represents a nucleotide whose left side is a sugar ring 2'-0CH3 modified

[0058] If represents a nucleotide whose left side is a sugar ring 2'-f modified

[0059] As used herein, the term "fluoro-modified nucleotide" refers to a nucleotide in which the hydroxyl group at the 2' position of the ribose group is replaced with a fluorine, "non-fluoro-modified nucleotide" refers to a nucleotide or nucleotide analog in which the hydroxyl group at the 2' position of the ribose group is replaced with a non-fluorine group; "nucleotide analog" refers to a nucleotide that is capable of being substituted for a nucleotide in a nucleic acid, but differs in structure from an adenine ribonucleotide, a uracil ribonucleotide, a guanine ribonucleotide, a cytosine ribonucleotide, and a thymine deoxyribonucleotide.

[0060] As used herein, the term "deoxyribonucleotide" refers to a nucleotide having a hydrogen at the 2' position of the pentose sugar as compared to a ribonucleotide. A modified deoxyribonucleotide is a deoxyribonucleotide having one or more modifications or substitutions (including modifications or substitutions in or of the sugar, phosphate group, or base or modifications or substitutions of the sugar, phosphate group, or base) in addition to at the 2' position.

[0061] As used herein, the term "double-stranded oligonucleotide" refers to an oligonucleotide that is in substantially duplex form. In some embodiments, one or more duplex regions of a double-stranded oligonucleotide are formed by complementary base pairing between antiparallel sequences of nucleotides of covalently separate nucleic acid strands. In some embodiments, one or more duplex regions of a double-stranded oligonucleotide are formed by complementary base pairing between antiparallel sequences of nucleotides of covalently linked nucleic acid strands. In some embodiments, one or more duplex regions of a double-stranded oligonucleotide are formed by complementary base pairing of antiparallel sequences of nucleotides that are provided together, e.g., via a hairpin, from a single nucleic acid strand. In some embodiments, a double-stranded oligonucleotide comprises two covalently separate nucleic acid strands that are fully duplexed with each other. However, in some embodiments, a double-stranded oligonucleotide comprises two covalently separate nucleic acid strands that are partially duplexed, e.g., with overhangs at one or both ends. In some embodiments, a double-stranded oligonucleotide comprises antiparallel sequences of nucleotides that are partially complementary, and thus, can have one or more mismatches, which can include internal mismatches or terminal mismatches.

[0062] Substantially all of the nucleotides of an iRNA of the application are modified. For example, substantially all of the nucleotides of the sense strand are modified nucleotides, and / or substantially all of the nucleotides of the antisense strand are modified nucleotides, and / or substantially all of the nucleotides of both the sense strand and the antisense strand are modified nucleotides. In other embodiments of the application, all of the nucleotides of an iRNA of the application are modified nucleotides. For example, all of the nucleotides of the sense strand are modified nucleotides, and / or all of the nucleotides of the antisense strand are modified nucleotides, and / or all of the nucleotides of both the sense strand and the antisense strand are modified nucleotides. In this context, "substantially reverse complementary" means that there are no more than 3 base mismatches between the two nucleotide sequences in question; "essentially reverse complementary" means that there are no more than 1 base mismatch between the two nucleotide sequences; and "completely reverse complementary" means that there are no base mismatches between the two nucleotide sequences.

[0063] As used herein, a nucleotide sequence has a "nucleotide difference" with another nucleotide sequence if the base identity of a nucleotide at a corresponding position is changed when compared between the two sequences, e.g., if a nucleotide base is A in one sequence, and the corresponding nucleotide base is U, G, C, or T in the other sequence, then the two sequences are said to have a nucleotide difference at that position. In some embodiments, a nucleotide difference is also said to occur at a position when an abasic nucleotide or its equivalent is substituted for the nucleotide at that position.

[0064] As used herein, the terms "coagulation factor XI", "coagulation factor 11", "factor XI", "factor 11", "FXI", and "F11" are used interchangeably.

[0065] As used herein, the term "pharmaceutically acceptable carrier" is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, its use in the compositions is contemplated. Pharmaceutically acceptable carriers include diluents, fillers, salts, buffers, stabilizers, solubilizers, and other materials well known in the art. Exemplary pharmaceutically acceptable carriers are described in U.S. Pat. No. 5,211,657, while other carriers are known to those of skill in the art. Such formulations can typically contain salts, buffers, preservatives, compatible carriers, and optionally other therapeutic agents. When used in medicine, the salts should be pharmaceutically acceptable, but non-pharmaceutically acceptable salts can conveniently be used to prepare pharmaceutically acceptable salts thereof, without excluding them from the scope of the application. Such pharmacologically and pharmaceutically acceptable salts include, but are not limited to, salts derived from the following acids: hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, maleic, acetic, salicylic, citric, formic, malonic, succinic, and the like. In addition, pharmaceutically acceptable salts can be prepared as alkali metal salts or alkaline earth metal salts, such as sodium salts, potassium salts, or calcium salts.

[0066] As used herein, the term "inhibit" is used interchangeably with "reduce," "silence," "down-regulate," and other similar terms, and includes inhibition at any level.

[0067] As used herein, the term "treatment" includes inhibition, slowing, stopping, or reversing the progression or severity of an existing symptom or condition. Thus, treatment includes prevention, therapy, and / or cure. In addition, "therapeutic method," "treatment," "amelioration," or "improvement" can be used interchangeably herein. Prevention refers to preventing potential disease and / or preventing the worsening of symptoms or development of disease. As used herein, "therapeutic effect" means an effect resulting from treatment of an individual that alters, usually improves, or ameliorates symptoms of a disease or disease condition, or cures the disease or disease condition. As used herein, "therapeutically effective amount" or "therapeutically effective dose" means an amount of a substance, compound, material, or composition comprising a compound that, after administration to a subject, is at least sufficient to produce a therapeutic effect. Thus, it is an amount necessary to prevent, cure, ameliorate, retard, or partially retard symptoms of a disease or disorder. As used herein, "prophylactically effective amount" or "prophylactically effective dose" means an amount of a substance, compound, material, or composition comprising a compound that, when administered to a subject, will have the intended prophylactic effect, e.g., prevent or delay the onset of a disease or symptoms, reduce the likelihood of the onset of a disease or symptoms. A fully prophylactically effective dose does not necessarily occur with the administration of one dose, and can only occur after administration of a series of doses. Thus, a prophylactically effective amount can be administered in one or more administrations.

[0068] As used herein, the term "patient" refers to any animal, such as a mammal or marsupial. The presently disclosed subject matter includes, but is not limited to, humans, non-human primates (e.g., rhesus or other types of macaques), mice, pigs, horses, donkeys, cows, sheep, rats, and any species of poultry.

[0069] As used herein, "prevent" and "prevention" are used interchangeably. These terms refer to methods of obtaining beneficial or desired results, including but not limited to prophylactic benefit. To obtain "prophylactic benefit," a conjugate or composition can be administered to a patient at risk of suffering from a particular disease, or to a patient reporting one or more pathological symptoms of a disease, even though a diagnosis of this disease can not have been made.

[0070] As used herein, the term "walk," i.e., genome walking technology, is a molecular biology technique used to explore and clone unknown regions flanking a known DNA sequence. It is commonly used in genome sequencing projects to determine the upstream regulatory regions of a gene, sequences between genes, or other parts of the genome.

[0071] II. DETAILED DESCRIPTION

[0072] In some embodiments of the present disclosure, the single nucleotide of the sense strand or antisense strand is not necessarily a single modification, any position of the nucleotide can be modified without competing for the modification site, and multiple modifications can exist simultaneously. For example, in some embodiments, the modified nucleotide at the 2' position has a methoxy modification or a nucleotide with a fluorine modification, which means that the 2nd position of the ribonucleotide is replaced by a methoxy or fluorine, and for example, the 2'-methoxy modified nucleotide at the 5' end of the antisense strand can also contain a VP modification.

[0073] In one aspect, the present disclosure provides a double-stranded oligonucleotide for inhibiting the expression of FXI, the double-stranded oligonucleotide comprising a sense strand and an antisense strand, wherein the sense strand and the antisense strand at least partially reverse complement to form a double-stranded region, the antisense strand is at least partially complementary to a stretch of nucleotides in a FXI transcribed mRNA, the sense strand has a length of no more than 21 nucleotides, the antisense strand has a length of no more than 23 nucleotides, and the antisense strand comprises at least 17 contiguous nucleotides of a sequence of no more than 4, 3, 2, or 1 nucleotide difference from a nucleotide sequence as set forth in any one of SEQ ID NOs: 175-347.

[0074] In some embodiments, the sense strand comprises at least 17 contiguous nucleotides of a sequence of no more than 4, 3, 2, 1 nucleotide difference from a nucleotide sequence as set forth in any one of SEQ ID NOs: 1-173.

[0075] In some embodiments, the sense strand and the antisense strand are substantially reverse complementary, substantially fully reverse complementary, or fully reverse complementary.

[0076] In some embodiments, the sense strand and the antisense strand are 17-23 nucleotides in length, preferably 17-21 nucleotides in length, more preferably 19-21 nucleotides in length.

[0077] In some embodiments, the antisense strand is 21, 22, or 23 nucleotides in length.

[0078] In some embodiments, the antisense strand has a nucleotide sequence as shown in any one of SEQ ID NOs: 175-347, SEQ ID NOs: 706-714, or a fragment thereof.

[0079] In some embodiments, the sense strand is 19, 20, or 21 nucleotides in length.

[0080] In some embodiments, the sense strand has a nucleotide sequence as shown in any one of SEQ ID NOs: 1-173, SEQ ID NOs: 697-705, or a fragment thereof.

[0081] In some embodiments, the sense strand and the antisense strand of the double- stranded oligonucleotide are selected from any one of the following combinations, respectively:

[0082] (1) the sense strand has a sequence as set forth in SEQ ID NO: 31, and the antisense strand has a sequence as set forth in SEQ ID NO: 205;

[0083] (2) the sense strand has a sequence as set forth in SEQ ID NO: 82, and the antisense strand has a sequence as set forth in SEQ ID NO: 256;

[0084] (3) the sense strand has a sequence as set forth in SEQ ID NO: 104, and the antisense strand has a sequence as set forth in SEQ ID NO: 278;

[0085] (4) the sense strand has a sequence as set forth in SEQ ID NO: 90, and the antisense strand has a sequence as set forth in SEQ ID NO: 264;

[0086] (5) the sense strand has a sequence as set forth in SEQ ID NO: 47, and the antisense strand has a sequence as set forth in SEQ ID NO: 221;

[0087] (6) the sense strand has a sequence as set forth in SEQ ID NO: 2, and the antisense strand has a sequence as set forth in SEQ ID NO: 176;

[0088] (7) a sense strand having the sequence of SEQ ID NO: 698, and an antisense strand having the sequence of SEQ ID NO: 707;

[0089] (8) a sense strand having the sequence of SEQ ID NO: 701, and an antisense strand having the sequence of SEQ ID NO: 710;

[0090] (9) a sense strand having the sequence of SEQ ID NO: 22, and an antisense strand having the sequence of SEQ ID NO: 196;

[0091] (10) a sense strand having the sequence of SEQ ID NO: 25, and an antisense strand having the sequence of SEQ ID NO: 199;

[0092] (11) a sense strand having the sequence of SEQ ID NO: 48, and an antisense strand having the sequence of SEQ ID NO: 222;

[0093] (12) a sense strand having the sequence of SEQ ID NO: 102, and an antisense strand having the sequence of SEQ ID NO: 276;

[0094] (13) a sense strand having the sequence of SEQ ID NO: 91, and an antisense strand having the sequence of SEQ ID NO: 265;

[0095] (14) a sense strand having the sequence of SEQ ID NO: 92, and an antisense strand having the sequence of SEQ ID NO: 266;

[0096] (15) a sense strand having the sequence of SEQ ID NO: 3, and an antisense strand having the sequence of SEQ ID NO: 177;

[0097] (16) a sense strand having the sequence of SEQ ID NO: 5, and an antisense strand having the sequence of SEQ ID NO: 179;

[0098] (17) a sense strand having the sequence of SEQ ID NO: 6, and an antisense strand having the sequence of SEQ ID NO: 180;

[0099] (18) a sense strand having the sequence of SEQ ID NO: 88, and an antisense strand having the sequence of SEQ ID NO: 262;

[0100] (19) a sense strand having the sequence of SEQ ID NO: 94, and an antisense strand having the sequence of SEQ ID NO: 268;

[0101] (20) a sense strand having the sequence of SEQ ID NO: 140, and an antisense strand having the sequence of SEQ ID NO: 314;

[0102] (21) a sense strand having the sequence of SEQ ID NO: 144, and an antisense strand having the sequence of SEQ ID NO: 318;

[0103] (22) a sense strand having the sequence of SEQ ID NO: 697, and an antisense strand having the sequence of SEQ ID NO: 706;

[0104] (23) a sense strand having the sequence of SEQ ID NO: 699, and an antisense strand having the sequence of SEQ ID NO: 708;

[0105] (24) a sense strand having the sequence of SEQ ID NO: 700, and an antisense strand having the sequence of SEQ ID NO: 709;

[0106] (25) a sense strand having the sequence of SEQ ID NO: 702, and an antisense strand having the sequence of SEQ ID NO: 711;

[0107] (26) a sense strand having the sequence of SEQ ID NO: 703, and an antisense strand having the sequence of SEQ ID NO: 712;

[0108] (27) a sense strand having the sequence of SEQ ID NO: 704, and an antisense strand having the sequence of SEQ ID NO: 713;

[0109] (28) a sense strand having the sequence of SEQ ID NO: 705, and an antisense strand having the sequence of SEQ ID NO: 714;

[0110] (29) a sense strand having the sequence of SEQ ID NO: 1, and an antisense strand having the sequence of SEQ ID NO: 175;

[0111] (30) a sense strand having the sequence of SEQ ID NO: 4, and an antisense strand having the sequence of SEQ ID NO: 178;

[0112] (31) a sense strand having the sequence of SEQ ID NO: 7, and an antisense strand having the sequence of SEQ ID NO: 181 ;

[0113] (32) a sense strand having the sequence of SEQ ID NO: 8, and an antisense strand having the sequence of SEQ ID NO: 182;

[0114] (33) a sense strand having the sequence of SEQ ID NO: 9, and an antisense strand having the sequence of SEQ ID NO: 183;

[0115] (34) a sense strand having the sequence of SEQ ID NO: 10, and an antisense strand having the sequence of SEQ ID NO: 184;

[0116] (35) a sense strand having the sequence of SEQ ID NO: 11, and an antisense strand having the sequence of SEQ ID NO: 185;

[0117] (36) a sense strand having the sequence of SEQ ID NO: 12, and an antisense strand having the sequence of SEQ ID NO: 186;

[0118] (37) a sense strand having the sequence of SEQ ID NO: 13, and an antisense strand having the sequence of SEQ ID NO: 187;

[0119] (38) a sense strand having the sequence of SEQ ID NO: 14, and an antisense strand having the sequence of SEQ ID NO: 188;

[0120] (39) a sense strand having the sequence of SEQ ID NO: 15, and an antisense strand having the sequence of SEQ ID NO: 189;

[0121] (40) a sense strand having the sequence of SEQ ID NO: 16, and an antisense strand having the sequence of SEQ ID NO: 190;

[0122] (41) a sense strand having the sequence of SEQ ID NO: 17, and an antisense strand having the sequence of SEQ ID NO: 191 ;

[0123] (42) a sense strand having the sequence of SEQ ID NO: 18, and an antisense strand having the sequence of SEQ ID NO: 192;

[0124] (43) a sense strand having the sequence of SEQ ID NO: 19, and an antisense strand having the sequence of SEQ ID NO: 193;

[0125] (44) a sense strand having the sequence of SEQ ID NO: 20, and an antisense strand having the sequence of SEQ ID NO: 194;

[0126] (45) a sense strand having the sequence of SEQ ID NO: 21, and an antisense strand having the sequence of SEQ ID NO: 195;

[0127] (46) a sense strand having the sequence of SEQ ID NO: 23, and an antisense strand having the sequence of SEQ ID NO: 197;

[0128] (47) a sense strand having the sequence of SEQ ID NO: 24, and an antisense strand having the sequence of SEQ ID NO: 198;

[0129] (48) a sense strand having the sequence of SEQ ID NO: 26, and an antisense strand having the sequence of SEQ ID NO: 200;

[0130] (49) a sense strand having the sequence of SEQ ID NO: 27, and an antisense strand having the sequence of SEQ ID NO: 201;

[0131] (50) a sense strand having the sequence of SEQ ID NO: 28, and an antisense strand having the sequence of SEQ ID NO: 202;

[0132] (51) a sense strand having the sequence of SEQ ID NO: 29, and an antisense strand having the sequence of SEQ ID NO: 203;

[0133] (52) a sense strand having the sequence of SEQ ID NO: 30, and an antisense strand having the sequence of SEQ ID NO: 204;

[0134] (53) a sense strand having the sequence of SEQ ID NO: 32, and an antisense strand having the sequence of SEQ ID NO: 206;

[0135] (54) a sense strand having the sequence of SEQ ID NO: 33, and an antisense strand having the sequence of SEQ ID NO: 207;

[0136] (55) a sense strand having the sequence of SEQ ID NO: 34, and an antisense strand having the sequence of SEQ ID NO: 208;

[0137] (56) a sense strand having the sequence of SEQ ID NO: 35, and an antisense strand having the sequence of SEQ ID NO: 209;

[0138] (57) a sense strand having the sequence of SEQ ID NO: 36, and an antisense strand having the sequence of SEQ ID NO: 210;

[0139] (58) a sense strand having the sequence of SEQ ID NO: 37, and an antisense strand having the sequence of SEQ ID NO: 211;

[0140] (59) a sense strand having the sequence of SEQ ID NO: 38, and an antisense strand having the sequence of SEQ ID NO: 212;

[0141] (60) a sense strand having the sequence of SEQ ID NO: 39, and an antisense strand having the sequence of SEQ ID NO: 213;

[0142] (61) a sense strand having the sequence of SEQ ID NO: 40, and an antisense strand having the sequence of SEQ ID NO: 214;

[0143] (62) a sense strand having the sequence of SEQ ID NO: 41, and an antisense strand having the sequence of SEQ ID NO: 215;

[0144] (63) a sense strand having the sequence of SEQ ID NO: 42, and an antisense strand having the sequence of SEQ ID NO: 216;

[0145] (64) a sense strand having the sequence of SEQ ID NO: 43, and an antisense strand having the sequence of SEQ ID NO: 217;

[0146] (65) a sense strand having the sequence of SEQ ID NO: 44, and an antisense strand having the sequence of SEQ ID NO: 218;

[0147] (66) a sense strand having the sequence of SEQ ID NO: 45, and an antisense strand having the sequence of SEQ ID NO: 219;

[0148] (67) a sense strand having the sequence of SEQ ID NO: 46, and an antisense strand having the sequence of SEQ ID NO: 220;

[0149] (68) a sense strand having the sequence of SEQ ID NO: 49, and an antisense strand having the sequence of SEQ ID NO: 223;

[0150] (69) a sense strand having the sequence of SEQ ID NO: 50, and an antisense strand having the sequence of SEQ ID NO: 224;

[0151] (70) a sense strand having the sequence of SEQ ID NO: 51, and an antisense strand having the sequence of SEQ ID NO: 225;

[0152] (71) a sense strand having the sequence of SEQ ID NO: 52, and an antisense strand having the sequence of SEQ ID NO: 226;

[0153] (72) a sense strand having the sequence of SEQ ID NO: 53, and an antisense strand having the sequence of SEQ ID NO: 227;

[0154] (73) a sense strand having the sequence of SEQ ID NO: 54, and an antisense strand having the sequence of SEQ ID NO: 228;

[0155] (74) a sense strand having the sequence of SEQ ID NO: 55, and an antisense strand having the sequence of SEQ ID NO: 229;

[0156] (75) a sense strand having the sequence of SEQ ID NO: 56, and an antisense strand having the sequence of SEQ ID NO: 230;

[0157] (76) a sense strand having the sequence of SEQ ID NO: 57, and an antisense strand having the sequence of SEQ ID NO: 231;

[0158] (77) a sense strand having the sequence of SEQ ID NO: 58, and an antisense strand having the sequence of SEQ ID NO: 232;

[0159] (78) a sense strand having the sequence of SEQ ID NO: 59, and an antisense strand having the sequence of SEQ ID NO: 233;

[0160] (79) a sense strand having the sequence of SEQ ID NO: 60, and an antisense strand having the sequence of SEQ ID NO: 234;

[0161] (80) a sense strand having the sequence of SEQ ID NO: 61, and an antisense strand having the sequence of SEQ ID NO: 235;

[0162] (81) a sense strand having the sequence of SEQ ID NO: 62, and an antisense strand having the sequence of SEQ ID NO: 236;

[0163] (82) a sense strand having the sequence of SEQ ID NO: 63, and an antisense strand having the sequence of SEQ ID NO: 237;

[0164] (83) a sense strand having the sequence of SEQ ID NO: 64, and an antisense strand having the sequence of SEQ ID NO: 238;

[0165] (84) a sense strand having the sequence of SEQ ID NO: 65, and an antisense strand having the sequence of SEQ ID NO: 239;

[0166] (85) a sense strand having the sequence of SEQ ID NO: 66, and an antisense strand having the sequence of SEQ ID NO: 240;

[0167] (86) a sense strand having the sequence of SEQ ID NO: 67, and an antisense strand having the sequence of SEQ ID NO: 241;

[0168] (87) a sense strand having the sequence of SEQ ID NO: 68, and an antisense strand having the sequence of SEQ ID NO: 242;

[0169] (88) a sense strand having the sequence of SEQ ID NO: 69, and an antisense strand having the sequence of SEQ ID NO: 243;

[0170] (89) a sense strand having the sequence of SEQ ID NO: 70, and an antisense strand having the sequence of SEQ ID NO: 244;

[0171] (90) a sense strand having the sequence of SEQ ID NO: 71, and an antisense strand having the sequence of SEQ ID NO: 245;

[0172] (91) the sense strand having the sequence of SEQ ID NO: 72, and the antisense strand having the sequence of SEQ ID NO: 246;

[0173] (92) the sense strand having the sequence of SEQ ID NO: 73, and the antisense strand having the sequence of SEQ ID NO: 247;

[0174] (93) the sense strand having the sequence of SEQ ID NO: 74, and the antisense strand having the sequence of SEQ ID NO: 248;

[0175] (94) the sense strand having the sequence of SEQ ID NO: 75, and the antisense strand having the sequence of SEQ ID NO: 249;

[0176] (95) the sense strand having the sequence of SEQ ID NO: 76, and the antisense strand having the sequence of SEQ ID NO: 250;

[0177] (96) the sense strand having the sequence of SEQ ID NO: 77, and the antisense strand having the sequence of SEQ ID NO: 251 ;

[0178] (97) the sense strand having the sequence of SEQ ID NO: 78, and the antisense strand having the sequence of SEQ ID NO: 252;

[0179] (98) the sense strand having the sequence of SEQ ID NO: 79, and the antisense strand having the sequence of SEQ ID NO: 253;

[0180] (99) the sense strand having the sequence of SEQ ID NO: 80, and the antisense strand having the sequence of SEQ ID NO: 254;

[0181] (100) the sense strand having the sequence of SEQ ID NO: 81, and the antisense strand having the sequence of SEQ ID NO: 255;

[0182] (101) the sense strand having the sequence of SEQ ID NO: 83, and the antisense strand having the sequence of SEQ ID NO: 257;

[0183] (102) the sense strand having the sequence of SEQ ID NO: 84, and the antisense strand having the sequence of SEQ ID NO: 258;

[0184] (103) a sense strand having the sequence of SEQ ID NO: 85, and an antisense strand having the sequence of SEQ ID NO: 259;

[0185] (104) a sense strand having the sequence of SEQ ID NO: 86, and an antisense strand having the sequence of SEQ ID NO: 260;

[0186] (105) a sense strand having the sequence of SEQ ID NO: 87, and an antisense strand having the sequence of SEQ ID NO: 261;

[0187] (106) a sense strand having the sequence of SEQ ID NO: 89, and an antisense strand having the sequence of SEQ ID NO: 263;

[0188] (107) a sense strand having the sequence of SEQ ID NO: 93, and an antisense strand having the sequence of SEQ ID NO: 267;

[0189] (108) a sense strand having the sequence of SEQ ID NO: 95, and an antisense strand having the sequence of SEQ ID NO: 269;

[0190] (109) a sense strand having the sequence of SEQ ID NO: 96, and an antisense strand having the sequence of SEQ ID NO: 270;

[0191] (110) a sense strand having the sequence of SEQ ID NO: 97, and an antisense strand having the sequence of SEQ ID NO: 271;

[0192] (111) a sense strand having the sequence of SEQ ID NO: 98, and an antisense strand having the sequence of SEQ ID NO: 272;

[0193] (112) a sense strand having the sequence of SEQ ID NO: 99, and an antisense strand having the sequence of SEQ ID NO: 273;

[0194] (113) a sense strand having the sequence of SEQ ID NO: 100, and an antisense strand having the sequence of SEQ ID NO: 274;

[0195] (114) a sense strand having the sequence of SEQ ID NO: 101, and an antisense strand having the sequence of SEQ ID NO: 275;

[0196] (115) a sense strand having the sequence of SEQ ID NO: 103, and an antisense strand having the sequence of SEQ ID NO: 277;

[0197] (116) a sense strand having the sequence of SEQ ID NO: 105, and an antisense strand having the sequence of SEQ ID NO: 279;

[0198] (117) a sense strand having the sequence of SEQ ID NO: 106, and an antisense strand having the sequence of SEQ ID NO: 280;

[0199] (118) a sense strand having the sequence of SEQ ID NO: 107, and an antisense strand having the sequence of SEQ ID NO: 281 ;

[0200] (119) a sense strand having the sequence of SEQ ID NO: 108, and an antisense strand having the sequence of SEQ ID NO: 282;

[0201] (120) a sense strand having the sequence of SEQ ID NO: 109, and an antisense strand having the sequence of SEQ ID NO: 283;

[0202] (121) a sense strand having the sequence of SEQ ID NO: 110, and an antisense strand having the sequence of SEQ ID NO: 284;

[0203] (122) a sense strand having the sequence of SEQ ID NO: 111, and an antisense strand having the sequence of SEQ ID NO: 285;

[0204] (123) a sense strand having the sequence of SEQ ID NO: 112, and an antisense strand having the sequence of SEQ ID NO: 286;

[0205] (124) a sense strand having the sequence of SEQ ID NO: 113, and an antisense strand having the sequence of SEQ ID NO: 287;

[0206] (125) a sense strand having the sequence of SEQ ID NO: 114, and an antisense strand having the sequence of SEQ ID NO: 288;

[0207] (126) a sense strand having the sequence of SEQ ID NO: 115, and an antisense strand having the sequence of SEQ ID NO: 289;

[0208] (127) a sense strand having the sequence of SEQ ID NO: 116, and an antisense strand having the sequence of SEQ ID NO: 290;

[0209] (128) a sense strand having the sequence of SEQ ID NO: 117, and an antisense strand having the sequence of SEQ ID NO: 291 ;

[0210] (129) a sense strand having the sequence of SEQ ID NO: 118, and an antisense strand having the sequence of SEQ ID NO: 292;

[0211] (130) a sense strand having the sequence of SEQ ID NO: 119, and an antisense strand having the sequence of SEQ ID NO: 293;

[0212] (131) a sense strand having the sequence of SEQ ID NO: 120, and an antisense strand having the sequence of SEQ ID NO: 294;

[0213] (132) a sense strand having the sequence of SEQ ID NO: 121, and an antisense strand having the sequence of SEQ ID NO: 295;

[0214] (133) a sense strand having the sequence of SEQ ID NO: 122, and an antisense strand having the sequence of SEQ ID NO: 296;

[0215] (134) a sense strand having the sequence of SEQ ID NO: 123, and an antisense strand having the sequence of SEQ ID NO: 297;

[0216] (135) a sense strand having the sequence of SEQ ID NO: 124, and an antisense strand having the sequence of SEQ ID NO: 298;

[0217] (136) a sense strand having the sequence of SEQ ID NO: 125, and an antisense strand having the sequence of SEQ ID NO: 299;

[0218] (137) a sense strand having the sequence of SEQ ID NO: 126, and an antisense strand having the sequence of SEQ ID NO: 300;

[0219] (138) a sense strand having the sequence of SEQ ID NO: 127, and an antisense strand having the sequence of SEQ ID NO: 301;

[0220] (139) a sense strand having the sequence of SEQ ID NO: 128, and an antisense strand having the sequence of SEQ ID NO: 302;

[0221] (140) a sense strand having the sequence of SEQ ID NO: 129, and an antisense strand having the sequence of SEQ ID NO: 303;

[0222] (141) a sense strand having the sequence of SEQ ID NO: 130, and an antisense strand having the sequence of SEQ ID NO: 304;

[0223] (142) a sense strand having the sequence of SEQ ID NO: 131, and an antisense strand having the sequence of SEQ ID NO: 305;

[0224] (143) a sense strand having the sequence of SEQ ID NO: 132, and an antisense strand having the sequence of SEQ ID NO: 306;

[0225] (144) a sense strand having the sequence of SEQ ID NO: 133, and an antisense strand having the sequence of SEQ ID NO: 307;

[0226] (145) a sense strand having the sequence of SEQ ID NO: 134, and an antisense strand having the sequence of SEQ ID NO: 308;

[0227] (146) a sense strand having the sequence of SEQ ID NO: 135, and an antisense strand having the sequence of SEQ ID NO: 309;

[0228] (147) a sense strand having the sequence of SEQ ID NO: 136, and an antisense strand having the sequence of SEQ ID NO: 310;

[0229] (148) a sense strand having the sequence of SEQ ID NO: 137, and an antisense strand having the sequence of SEQ ID NO: 311;

[0230] (149) a sense strand having the sequence of SEQ ID NO: 138, and an antisense strand having the sequence of SEQ ID NO: 312;

[0231] (150) a sense strand having the sequence of SEQ ID NO: 139, and an antisense strand having the sequence of SEQ ID NO: 313;

[0232] (151) a sense strand having the sequence of SEQ ID NO: 141, and an antisense strand having the sequence of SEQ ID NO: 315;

[0233] (152) a sense strand having the sequence of SEQ ID NO: 142, and an antisense strand having the sequence of SEQ ID NO: 316;

[0234] (153) a sense strand having the sequence of SEQ ID NO: 143, and an antisense strand having the sequence of SEQ ID NO: 317;

[0235] (154) a sense strand having the sequence of SEQ ID NO: 145, and an antisense strand having the sequence of SEQ ID NO: 319;

[0236] (155) a sense strand having the sequence of SEQ ID NO: 146, and an antisense strand having the sequence of SEQ ID NO: 320;

[0237] (156) a sense strand having the sequence of SEQ ID NO: 147, and an antisense strand having the sequence of SEQ ID NO: 321;

[0238] (157) a sense strand having the sequence of SEQ ID NO: 148, and an antisense strand having the sequence of SEQ ID NO: 322;

[0239] (158) a sense strand having the sequence of SEQ ID NO: 149, and an antisense strand having the sequence of SEQ ID NO: 323;

[0240] (159) a sense strand having the sequence of SEQ ID NO: 150, and an antisense strand having the sequence of SEQ ID NO: 324;

[0241] (160) a sense strand having the sequence of SEQ ID NO: 151, and an antisense strand having the sequence of SEQ ID NO: 325;

[0242] (161) a sense strand having the sequence of SEQ ID NO: 152, and an antisense strand having the sequence of SEQ ID NO: 326;

[0243] (162) a sense strand having the sequence of SEQ ID NO: 153, and an antisense strand having the sequence of SEQ ID NO: 327;

[0244] (163) a sense strand having the sequence of SEQ ID NO: 154, and an antisense strand having the sequence of SEQ ID NO: 328;

[0245] (164) a sense strand having the sequence of SEQ ID NO: 155, and an antisense strand having the sequence of SEQ ID NO: 329;

[0246] (165) a sense strand having the sequence of SEQ ID NO: 156, and an antisense strand having the sequence of SEQ ID NO: 330;

[0247] (166) a sense strand having the sequence of SEQ ID NO: 157, and an antisense strand having the sequence of SEQ ID NO: 331 ;

[0248] (167) a sense strand having the sequence of SEQ ID NO: 158, and an antisense strand having the sequence of SEQ ID NO: 332;

[0249] (168) a sense strand having the sequence of SEQ ID NO: 159, and an antisense strand having the sequence of SEQ ID NO: 333;

[0250] (169) a sense strand having the sequence of SEQ ID NO: 160, and an antisense strand having the sequence of SEQ ID NO: 334;

[0251] (170) a sense strand having the sequence of SEQ ID NO: 161, and an antisense strand having the sequence of SEQ ID NO: 335;

[0252] (171) a sense strand having the sequence of SEQ ID NO: 162, and an antisense strand having the sequence of SEQ ID NO: 336;

[0253] (172) a sense strand having the sequence of SEQ ID NO: 163, and an antisense strand having the sequence of SEQ ID NO: 337;

[0254] (173) a sense strand having the sequence of SEQ ID NO: 164, and an antisense strand having the sequence of SEQ ID NO: 338;

[0255] (174) a sense strand having the sequence of SEQ ID NO: 165, and an antisense strand having the sequence of SEQ ID NO: 339;

[0256] (175) a sense strand having the sequence of SEQ ID NO: 166, and an antisense strand having the sequence of SEQ ID NO: 340;

[0257] (176) a sense strand having the sequence of SEQ ID NO: 167, and an antisense strand having the sequence of SEQ ID NO: 341 ;

[0258] (177) a sense strand having the sequence of SEQ ID NO: 168, and an antisense strand having the sequence of SEQ ID NO: 342;

[0259] (178) a sense strand having the sequence of SEQ ID NO: 169, and an antisense strand having the sequence of SEQ ID NO: 343;

[0260] (179) a sense strand having the sequence of SEQ ID NO: 170, and an antisense strand having the sequence of SEQ ID NO: 344;

[0261] (180) a sense strand having the sequence of SEQ ID NO: 171, and an antisense strand having the sequence of SEQ ID NO: 345;

[0262] (181) a sense strand having the sequence of SEQ ID NO: 172, and an antisense strand having the sequence of SEQ ID NO: 346; or

[0263] (182) a sense strand having the sequence of SEQ ID NO: 173, and an antisense strand having the sequence of SEQ ID NO: 347;

[0264] wherein the antisense strand is 21, 22, or 23 nucleotides in length, and the sense strand is 19, 20, or 21 nucleotides in length.

[0265] In some embodiments, the sense and antisense strands of the double stranded oligonucleotide are selected from any of the following combinations, respectively:

[0266] (1) a sense strand having the sequence of SEQ ID NO: 31, and an antisense strand having the sequence of SEQ ID NO: 205;

[0267] (2) a sense strand having the sequence of SEQ ID NO: 82, and an antisense strand having the sequence of SEQ ID NO: 256;

[0268] (3) a sense strand having the sequence of SEQ ID NO: 104, and an antisense strand having the sequence of SEQ ID NO: 278;

[0269] (4) the sense strand of the sequence as shown in SEQ ID NO: 90, and the antisense strand of the sequence as shown in SEQ ID NO: 264;

[0270] (5) the sense strand of the sequence as shown in SEQ ID NO: 47, and the antisense strand of the sequence as shown in SEQ ID NO: 221 ;

[0271] (6) the sense strand of the sequence as shown in SEQ ID NO: 2, and the antisense strand of the sequence as shown in SEQ ID NO: 176;

[0272] (7) the sense strand of the sequence as shown in SEQ ID NO: 698, and the antisense strand of the sequence as shown in SEQ ID NO: 707;

[0273] (8) the sense strand of the sequence as shown in SEQ ID NO: 701, and the antisense strand of the sequence as shown in SEQ ID NO: 710;

[0274] (9) the sense strand of the sequence as shown in SEQ ID NO: 22, and the antisense strand of the sequence as shown in SEQ ID NO: 196;

[0275] (10) the sense strand of the sequence as shown in SEQ ID NO: 25, and the antisense strand of the sequence as shown in SEQ ID NO: 199;

[0276] (11) the sense strand of the sequence as shown in SEQ ID NO: 48, and the antisense strand of the sequence as shown in SEQ ID NO: 222;

[0277] (12) the sense strand of the sequence as shown in SEQ ID NO: 102, and the antisense strand of the sequence as shown in SEQ ID NO: 276;

[0278] (13) the sense strand of the sequence as shown in SEQ ID NO: 91, and the antisense strand of the sequence as shown in SEQ ID NO: 265;

[0279] (14) the sense strand of the sequence as shown in SEQ ID NO: 92, and the antisense strand of the sequence as shown in SEQ ID NO: 266;

[0280] (15) the sense strand of the sequence as shown in SEQ ID NO: 3, and the antisense strand of the sequence as shown in SEQ ID NO: 177;

[0281] (16) the sense strand of the sequence as shown in SEQ ID NO: 5, and the antisense strand of the sequence as shown in SEQ ID NO: 179;

[0282] (17) the sense strand of the sequence recited in SEQ ID NO: 6, and the antisense strand of the sequence recited in SEQ ID NO: 180;

[0283] (18) the sense strand of the sequence recited in SEQ ID NO: 88, and the antisense strand of the sequence recited in SEQ ID NO: 262;

[0284] (19) the sense strand of the sequence recited in SEQ ID NO: 94, and the antisense strand of the sequence recited in SEQ ID NO: 268;

[0285] (20) the sense strand of the sequence recited in SEQ ID NO: 140, and the antisense strand of the sequence recited in SEQ ID NO: 314;

[0286] (21) the sense strand of the sequence recited in SEQ ID NO: 144, and the antisense strand of the sequence recited in SEQ ID NO: 318;

[0287] (22) the sense strand of the sequence recited in SEQ ID NO: 697, and the antisense strand of the sequence recited in SEQ ID NO: 706;

[0288] (23) the sense strand of the sequence recited in SEQ ID NO: 699, and the antisense strand of the sequence recited in SEQ ID NO: 708;

[0289] (24) the sense strand of the sequence recited in SEQ ID NO: 700, and the antisense strand of the sequence recited in SEQ ID NO: 709;

[0290] (25) the sense strand of the sequence recited in SEQ ID NO: 702, and the antisense strand of the sequence recited in SEQ ID NO: 711;

[0291] (26) the sense strand of the sequence recited in SEQ ID NO: 703, and the antisense strand of the sequence recited in SEQ ID NO: 712;

[0292] (27) the sense strand of the sequence recited in SEQ ID NO: 704, and the antisense strand of the sequence recited in SEQ ID NO: 713;

[0293] (28) the sense strand of the sequence recited in SEQ ID NO: 705, and the antisense strand of the sequence recited in SEQ ID NO: 714;

[0294] (29) the sense strand of the sequence recited in SEQ ID NO: 1, and the antisense strand of the sequence recited in SEQ ID NO: 175;

[0295] (30) the sense strand of the sequence as shown in SEQ ID NO: 4, and the antisense strand of the sequence as shown in SEQ ID NO: 178;

[0296] (31) the sense strand of the sequence as shown in SEQ ID NO: 7, and the antisense strand of the sequence as shown in SEQ ID NO: 181 ;

[0297] (32) the sense strand of the sequence as shown in SEQ ID NO: 8, and the antisense strand of the sequence as shown in SEQ ID NO: 182;

[0298] (33) the sense strand of the sequence as shown in SEQ ID NO: 9, and the antisense strand of the sequence as shown in SEQ ID NO: 183;

[0299] (34) the sense strand of the sequence as shown in SEQ ID NO: 10, and the antisense strand of the sequence as shown in SEQ ID NO: 184;

[0300] (35) the sense strand of the sequence as shown in SEQ ID NO: 11, and the antisense strand of the sequence as shown in SEQ ID NO: 185;

[0301] (36) the sense strand of the sequence as shown in SEQ ID NO: 12, and the antisense strand of the sequence as shown in SEQ ID NO: 186;

[0302] (37) the sense strand of the sequence as shown in SEQ ID NO: 13, and the antisense strand of the sequence as shown in SEQ ID NO: 187;

[0303] (38) the sense strand of the sequence as shown in SEQ ID NO: 14, and the antisense strand of the sequence as shown in SEQ ID NO: 188;

[0304] (39) the sense strand of the sequence as shown in SEQ ID NO: 15, and the antisense strand of the sequence as shown in SEQ ID NO: 189;

[0305] (40) the sense strand of the sequence as shown in SEQ ID NO: 16, and the antisense strand of the sequence as shown in SEQ ID NO: 190;

[0306] (41) the sense strand of the sequence as shown in SEQ ID NO: 17, and the antisense strand of the sequence as shown in SEQ ID NO: 191 ;

[0307] (42) the sense strand of the sequence as shown in SEQ ID NO: 18, and the antisense strand of the sequence as shown in SEQ ID NO: 192;

[0308] (43) the sense strand of the sequence recited in SEQ ID NO: 19, and the antisense strand of the sequence recited in SEQ ID NO: 193;

[0309] (44) the sense strand of the sequence recited in SEQ ID NO: 20, and the antisense strand of the sequence recited in SEQ ID NO: 194;

[0310] (45) the sense strand of the sequence recited in SEQ ID NO: 21, and the antisense strand of the sequence recited in SEQ ID NO: 195;

[0311] (46) the sense strand of the sequence recited in SEQ ID NO: 23, and the antisense strand of the sequence recited in SEQ ID NO: 197;

[0312] (47) the sense strand of the sequence recited in SEQ ID NO: 24, and the antisense strand of the sequence recited in SEQ ID NO: 198;

[0313] (48) the sense strand of the sequence recited in SEQ ID NO: 26, and the antisense strand of the sequence recited in SEQ ID NO: 200;

[0314] (49) the sense strand of the sequence recited in SEQ ID NO: 27, and the antisense strand of the sequence recited in SEQ ID NO: 201;

[0315] (50) the sense strand of the sequence recited in SEQ ID NO: 28, and the antisense strand of the sequence recited in SEQ ID NO: 202;

[0316] (51) the sense strand of the sequence recited in SEQ ID NO: 29, and the antisense strand of the sequence recited in SEQ ID NO: 203;

[0317] (52) the sense strand of the sequence recited in SEQ ID NO: 30, and the antisense strand of the sequence recited in SEQ ID NO: 204;

[0318] (53) the sense strand of the sequence recited in SEQ ID NO: 32, and the antisense strand of the sequence recited in SEQ ID NO: 206;

[0319] (54) the sense strand of the sequence recited in SEQ ID NO: 33, and the antisense strand of the sequence recited in SEQ ID NO: 207;

[0320] (55) the sense strand of the sequence recited in SEQ ID NO: 34, and the antisense strand of the sequence recited in SEQ ID NO: 208;

[0321] (56) the sense strand of the sequence recited in SEQ ID NO: 35, and the antisense strand of the sequence recited in SEQ ID NO: 209;

[0322] (57) the sense strand of the sequence recited in SEQ ID NO: 36, and the antisense strand of the sequence recited in SEQ ID NO: 210;

[0323] (58) the sense strand of the sequence recited in SEQ ID NO: 37, and the antisense strand of the sequence recited in SEQ ID NO: 211;

[0324] (59) the sense strand of the sequence recited in SEQ ID NO: 38, and the antisense strand of the sequence recited in SEQ ID NO: 212;

[0325] (60) the sense strand of the sequence recited in SEQ ID NO: 39, and the antisense strand of the sequence recited in SEQ ID NO: 213;

[0326] (61) the sense strand of the sequence recited in SEQ ID NO: 40, and the antisense strand of the sequence recited in SEQ ID NO: 214;

[0327] (62) the sense strand of the sequence recited in SEQ ID NO: 41, and the antisense strand of the sequence recited in SEQ ID NO: 215;

[0328] (63) the sense strand of the sequence recited in SEQ ID NO: 42, and the antisense strand of the sequence recited in SEQ ID NO: 216;

[0329] (64) the sense strand of the sequence recited in SEQ ID NO: 43, and the antisense strand of the sequence recited in SEQ ID NO: 217;

[0330] (65) the sense strand of the sequence recited in SEQ ID NO: 44, and the antisense strand of the sequence recited in SEQ ID NO: 218;

[0331] (66) the sense strand of the sequence recited in SEQ ID NO: 45, and the antisense strand of the sequence recited in SEQ ID NO: 219;

[0332] (67) the sense strand of the sequence recited in SEQ ID NO: 46, and the antisense strand of the sequence recited in SEQ ID NO: 220;

[0333] (68) the sense strand of the sequence recited in SEQ ID NO: 49, and the antisense strand of the sequence recited in SEQ ID NO: 223;

[0334] (69) the sense strand of the sequence recited in SEQ ID NO: 50, and the antisense strand of the sequence recited in SEQ ID NO: 224;

[0335] (70) the sense strand of the sequence recited in SEQ ID NO: 51, and the antisense strand of the sequence recited in SEQ ID NO: 225;

[0336] (71) the sense strand of the sequence recited in SEQ ID NO: 52, and the antisense strand of the sequence recited in SEQ ID NO: 226;

[0337] (72) the sense strand of the sequence recited in SEQ ID NO: 53, and the antisense strand of the sequence recited in SEQ ID NO: 227;

[0338] (73) the sense strand of the sequence recited in SEQ ID NO: 54, and the antisense strand of the sequence recited in SEQ ID NO: 228;

[0339] (74) the sense strand of the sequence recited in SEQ ID NO: 55, and the antisense strand of the sequence recited in SEQ ID NO: 229;

[0340] (75) the sense strand of the sequence recited in SEQ ID NO: 56, and the antisense strand of the sequence recited in SEQ ID NO: 230;

[0341] (76) the sense strand of the sequence recited in SEQ ID NO: 57, and the antisense strand of the sequence recited in SEQ ID NO: 231;

[0342] (77) the sense strand of the sequence recited in SEQ ID NO: 58, and the antisense strand of the sequence recited in SEQ ID NO: 232;

[0343] (78) the sense strand of the sequence recited in SEQ ID NO: 59, and the antisense strand of the sequence recited in SEQ ID NO: 233;

[0344] (79) the sense strand of the sequence recited in SEQ ID NO: 60, and the antisense strand of the sequence recited in SEQ ID NO: 234;

[0345] (80) the sense strand of the sequence recited in SEQ ID NO: 61, and the antisense strand of the sequence recited in SEQ ID NO: 235;

[0346] (81) the sense strand of the sequence recited in SEQ ID NO: 62, and the antisense strand of the sequence recited in SEQ ID NO: 236;

[0347] (82) the sense strand of the sequence recited in SEQ ID NO: 63, and the antisense strand of the sequence recited in SEQ ID NO: 237;

[0348] (83) the sense strand of the sequence recited in SEQ ID NO: 64, and the antisense strand of the sequence recited in SEQ ID NO: 238;

[0349] (84) the sense strand of the sequence recited in SEQ ID NO: 65, and the antisense strand of the sequence recited in SEQ ID NO: 239;

[0350] (85) the sense strand of the sequence recited in SEQ ID NO: 66, and the antisense strand of the sequence recited in SEQ ID NO: 240;

[0351] (86) the sense strand of the sequence recited in SEQ ID NO: 67, and the antisense strand of the sequence recited in SEQ ID NO: 241;

[0352] (87) the sense strand of the sequence recited in SEQ ID NO: 68, and the antisense strand of the sequence recited in SEQ ID NO: 242;

[0353] (88) the sense strand of the sequence recited in SEQ ID NO: 69, and the antisense strand of the sequence recited in SEQ ID NO: 243;

[0354] (89) the sense strand of the sequence recited in SEQ ID NO: 70, and the antisense strand of the sequence recited in SEQ ID NO: 244;

[0355] (90) the sense strand of the sequence recited in SEQ ID NO: 71, and the antisense strand of the sequence recited in SEQ ID NO: 245;

[0356] (91) the sense strand of the sequence recited in SEQ ID NO: 72, and the antisense strand of the sequence recited in SEQ ID NO: 246;

[0357] (92) the sense strand of the sequence recited in SEQ ID NO: 73, and the antisense strand of the sequence recited in SEQ ID NO: 247;

[0358] (93) the sense strand of the sequence recited in SEQ ID NO: 74, and the antisense strand of the sequence recited in SEQ ID NO: 248;

[0359] (94) the sense strand of the sequence recited in SEQ ID NO: 75, and the antisense strand of the sequence recited in SEQ ID NO: 249;

[0360] (95) the sense strand of the sequence recited in SEQ ID NO: 76, and the antisense strand of the sequence recited in SEQ ID NO: 250;

[0361] (96) the sense strand of the sequence recited in SEQ ID NO: 77, and the antisense strand of the sequence recited in SEQ ID NO: 251 ;

[0362] (97) the sense strand of the sequence recited in SEQ ID NO: 78, and the antisense strand of the sequence recited in SEQ ID NO: 252;

[0363] (98) the sense strand of the sequence recited in SEQ ID NO: 79, and the antisense strand of the sequence recited in SEQ ID NO: 253;

[0364] (99) the sense strand of the sequence recited in SEQ ID NO: 80, and the antisense strand of the sequence recited in SEQ ID NO: 254;

[0365] (100) the sense strand of the sequence recited in SEQ ID NO: 81, and the antisense strand of the sequence recited in SEQ ID NO: 255;

[0366] (101) the sense strand of the sequence recited in SEQ ID NO: 83, and the antisense strand of the sequence recited in SEQ ID NO: 257;

[0367] (102) the sense strand of the sequence recited in SEQ ID NO: 84, and the antisense strand of the sequence recited in SEQ ID NO: 258;

[0368] (103) the sense strand of the sequence recited in SEQ ID NO: 85, and the antisense strand of the sequence recited in SEQ ID NO: 259;

[0369] (104) the sense strand of the sequence recited in SEQ ID NO: 86, and the antisense strand of the sequence recited in SEQ ID NO: 260;

[0370] (105) the sense strand of the sequence recited in SEQ ID NO: 87, and the antisense strand of the sequence recited in SEQ ID NO: 261;

[0371] (106) the sense strand of the sequence recited in SEQ ID NO: 89, and the antisense strand of the sequence recited in SEQ ID NO: 263;

[0372] (107) the sense strand of the sequence recited in SEQ ID NO: 93, and the antisense strand of the sequence recited in SEQ ID NO: 267;

[0373] (108) the sense strand of the sequence recited in SEQ ID NO: 95, and the antisense strand of the sequence recited in SEQ ID NO: 269;

[0374] (109) the sense strand of the sequence recited in SEQ ID NO: 96, and the antisense strand of the sequence recited in SEQ ID NO: 270;

[0375] (110) the sense strand of the sequence recited in SEQ ID NO: 97, and the antisense strand of the sequence recited in SEQ ID NO: 271;

[0376] (111) the sense strand of the sequence recited in SEQ ID NO: 98, and the antisense strand of the sequence recited in SEQ ID NO: 272;

[0377] (112) the sense strand of the sequence recited in SEQ ID NO: 99, and the antisense strand of the sequence recited in SEQ ID NO: 273;

[0378] (113) the sense strand of the sequence recited in SEQ ID NO: 100, and the antisense strand of the sequence recited in SEQ ID NO: 274;

[0379] (114) the sense strand of the sequence recited in SEQ ID NO: 101, and the antisense strand of the sequence recited in SEQ ID NO: 275;

[0380] (115) the sense strand of the sequence recited in SEQ ID NO: 103, and the antisense strand of the sequence recited in SEQ ID NO: 277;

[0381] (116) the sense strand of the sequence recited in SEQ ID NO: 105, and the antisense strand of the sequence recited in SEQ ID NO: 279;

[0382] (117) the sense strand of the sequence recited in SEQ ID NO: 106, and the antisense strand of the sequence recited in SEQ ID NO: 280;

[0383] (118) the sense strand of the sequence recited in SEQ ID NO: 107, and the antisense strand of the sequence recited in SEQ ID NO: 281;

[0384] (119) the sense strand of the sequence recited in SEQ ID NO: 108, and the antisense strand of the sequence recited in SEQ ID NO: 282;

[0385] (120) the sense strand of the sequence recited in SEQ ID NO: 109, and the antisense strand of the sequence recited in SEQ ID NO: 283;

[0386] (121) the sense strand of the sequence as shown in SEQ ID NO: 110, and the antisense strand of the sequence as shown in SEQ ID NO: 284;

[0387] (122) the sense strand of the sequence as shown in SEQ ID NO: 111, and the antisense strand of the sequence as shown in SEQ ID NO: 285;

[0388] (123) the sense strand of the sequence as shown in SEQ ID NO: 112, and the antisense strand of the sequence as shown in SEQ ID NO: 286;

[0389] (124) the sense strand of the sequence as shown in SEQ ID NO: 113, and the antisense strand of the sequence as shown in SEQ ID NO: 287;

[0390] (125) the sense strand of the sequence as shown in SEQ ID NO: 114, and the antisense strand of the sequence as shown in SEQ ID NO: 288;

[0391] (126) the sense strand of the sequence as shown in SEQ ID NO: 115, and the antisense strand of the sequence as shown in SEQ ID NO: 289;

[0392] (127) the sense strand of the sequence as shown in SEQ ID NO: 116, and the antisense strand of the sequence as shown in SEQ ID NO: 290;

[0393] (128) the sense strand of the sequence as shown in SEQ ID NO: 117, and the antisense strand of the sequence as shown in SEQ ID NO: 291;

[0394] (129) the sense strand of the sequence as shown in SEQ ID NO: 118, and the antisense strand of the sequence as shown in SEQ ID NO: 292;

[0395] (130) the sense strand of the sequence as shown in SEQ ID NO: 119, and the antisense strand of the sequence as shown in SEQ ID NO: 293;

[0396] (131) the sense strand of the sequence as shown in SEQ ID NO: 120, and the antisense strand of the sequence as shown in SEQ ID NO: 294;

[0397] (132) the sense strand of the sequence as shown in SEQ ID NO: 121, and the antisense strand of the sequence as shown in SEQ ID NO: 295;

[0398] (133) the sense strand of the sequence as shown in SEQ ID NO: 122, and the antisense strand of the sequence as shown in SEQ ID NO: 296;

[0399] (134) the sense strand of the sequence as shown in SEQ ID NO: 123, and the antisense strand of the sequence as shown in SEQ ID NO: 297;

[0400] (135) the sense strand of the sequence as shown in SEQ ID NO: 124, and the antisense strand of the sequence as shown in SEQ ID NO: 298;

[0401] (136) the sense strand of the sequence as shown in SEQ ID NO: 125, and the antisense strand of the sequence as shown in SEQ ID NO: 299;

[0402] (137) the sense strand of the sequence as shown in SEQ ID NO: 126, and the antisense strand of the sequence as shown in SEQ ID NO: 300;

[0403] (138) the sense strand of the sequence as shown in SEQ ID NO: 127, and the antisense strand of the sequence as shown in SEQ ID NO: 301;

[0404] (139) the sense strand of the sequence as shown in SEQ ID NO: 128, and the antisense strand of the sequence as shown in SEQ ID NO: 302;

[0405] (140) the sense strand of the sequence as shown in SEQ ID NO: 129, and the antisense strand of the sequence as shown in SEQ ID NO: 303;

[0406] (141) the sense strand of the sequence as shown in SEQ ID NO: 130, and the antisense strand of the sequence as shown in SEQ ID NO: 304;

[0407] (142) the sense strand of the sequence as shown in SEQ ID NO: 131, and the antisense strand of the sequence as shown in SEQ ID NO: 305;

[0408] (143) the sense strand of the sequence as shown in SEQ ID NO: 132, and the antisense strand of the sequence as shown in SEQ ID NO: 306;

[0409] (144) the sense strand of the sequence as shown in SEQ ID NO: 133, and the antisense strand of the sequence as shown in SEQ ID NO: 307;

[0410] (145) the sense strand of the sequence as shown in SEQ ID NO: 134, and the antisense strand of the sequence as shown in SEQ ID NO: 308;

[0411] (146) the sense strand of the sequence recited in SEQ ID NO: 135, and the antisense strand of the sequence recited in SEQ ID NO: 309;

[0412] (147) the sense strand of the sequence recited in SEQ ID NO: 136, and the antisense strand of the sequence recited in SEQ ID NO: 310;

[0413] (148) the sense strand of the sequence recited in SEQ ID NO: 137, and the antisense strand of the sequence recited in SEQ ID NO: 311;

[0414] (149) the sense strand of the sequence recited in SEQ ID NO: 138, and the antisense strand of the sequence recited in SEQ ID NO: 312;

[0415] (150) the sense strand of the sequence recited in SEQ ID NO: 139, and the antisense strand of the sequence recited in SEQ ID NO: 313;

[0416] (151) the sense strand of the sequence recited in SEQ ID NO: 141, and the antisense strand of the sequence recited in SEQ ID NO: 315;

[0417] (152) the sense strand of the sequence recited in SEQ ID NO: 142, and the antisense strand of the sequence recited in SEQ ID NO: 316;

[0418] (153) the sense strand of the sequence recited in SEQ ID NO: 143, and the antisense strand of the sequence recited in SEQ ID NO: 317;

[0419] (154) the sense strand of the sequence recited in SEQ ID NO: 145, and the antisense strand of the sequence recited in SEQ ID NO: 319;

[0420] (155) the sense strand of the sequence recited in SEQ ID NO: 146, and the antisense strand of the sequence recited in SEQ ID NO: 320;

[0421] (156) the sense strand of the sequence recited in SEQ ID NO: 147, and the antisense strand of the sequence recited in SEQ ID NO: 321;

[0422] (157) the sense strand of the sequence recited in SEQ ID NO: 148, and the antisense strand of the sequence recited in SEQ ID NO: 322;

[0423] (158) the sense strand of the sequence recited in SEQ ID NO: 149, and the antisense strand of the sequence recited in SEQ ID NO: 323;

[0424] (159) the sense strand of the sequence as shown in SEQ ID NO: 150, and the antisense strand of the sequence as shown in SEQ ID NO: 324;

[0425] (160) the sense strand of the sequence as shown in SEQ ID NO: 151, and the antisense strand of the sequence as shown in SEQ ID NO: 325;

[0426] (161) the sense strand of the sequence as shown in SEQ ID NO: 152, and the antisense strand of the sequence as shown in SEQ ID NO: 326;

[0427] (162) the sense strand of the sequence as shown in SEQ ID NO: 153, and the antisense strand of the sequence as shown in SEQ ID NO: 327;

[0428] (163) the sense strand of the sequence as shown in SEQ ID NO: 154, and the antisense strand of the sequence as shown in SEQ ID NO: 328;

[0429] (164) the sense strand of the sequence as shown in SEQ ID NO: 155, and the antisense strand of the sequence as shown in SEQ ID NO: 329;

[0430] (165) the sense strand of the sequence as shown in SEQ ID NO: 156, and the antisense strand of the sequence as shown in SEQ ID NO: 330;

[0431] (166) the sense strand of the sequence as shown in SEQ ID NO: 157, and the antisense strand of the sequence as shown in SEQ ID NO: 331;

[0432] (167) the sense strand of the sequence as shown in SEQ ID NO: 158, and the antisense strand of the sequence as shown in SEQ ID NO: 332;

[0433] (168) the sense strand of the sequence as shown in SEQ ID NO: 159, and the antisense strand of the sequence as shown in SEQ ID NO: 333;

[0434] (169) the sense strand of the sequence as shown in SEQ ID NO: 160, and the antisense strand of the sequence as shown in SEQ ID NO: 334;

[0435] (170) the sense strand of the sequence as shown in SEQ ID NO: 161, and the antisense strand of the sequence as shown in SEQ ID NO: 335;

[0436] (171) the sense strand of the sequence as shown in SEQ ID NO: 162, and the antisense strand of the sequence as shown in SEQ ID NO: 336;

[0437] (172) the sense strand of the sequence as shown in SEQ ID NO: 163, and the antisense strand of the sequence as shown in SEQ ID NO: 337;

[0438] (173) the sense strand of the sequence as shown in SEQ ID NO: 164, and the antisense strand of the sequence as shown in SEQ ID NO: 338;

[0439] (174) the sense strand of the sequence as shown in SEQ ID NO: 165, and the antisense strand of the sequence as shown in SEQ ID NO: 339;

[0440] (175) the sense strand of the sequence as shown in SEQ ID NO: 166, and the antisense strand of the sequence as shown in SEQ ID NO: 340;

[0441] (176) the sense strand of the sequence as shown in SEQ ID NO: 167, and the antisense strand of the sequence as shown in SEQ ID NO: 341;

[0442] (177) the sense strand of the sequence as shown in SEQ ID NO: 168, and the antisense strand of the sequence as shown in SEQ ID NO: 342;

[0443] (178) the sense strand of the sequence as shown in SEQ ID NO: 169, and the antisense strand of the sequence as shown in SEQ ID NO: 343;

[0444] (179) the sense strand of the sequence as shown in SEQ ID NO: 170, and the antisense strand of the sequence as shown in SEQ ID NO: 344;

[0445] (180) the sense strand of the sequence as shown in SEQ ID NO: 171, and the antisense strand of the sequence as shown in SEQ ID NO: 345;

[0446] (181) the sense strand of the sequence as shown in SEQ ID NO: 172, and the antisense strand of the sequence as shown in SEQ ID NO: 346; or

[0447] (182) the sense strand of the sequence as shown in SEQ ID NO: 173, and the antisense strand of the sequence as shown in SEQ ID NO: 347;

[0448] wherein the antisense strand is 21, 22, or 23 nucleotides in length, and the sense strand is 19, 20, or 21 nucleotides in length.

[0449] In some embodiments, the sense and antisense strands of the double stranded oligonucleotide are selected from any one of the following combinations, respectively:

[0450] (1) a sense strand having the sequence of SEQ ID NO: 31, and an antisense strand having the sequence of SEQ ID NO: 205;

[0451] (2) a sense strand having the sequence of SEQ ID NO: 82, and an antisense strand having the sequence of SEQ ID NO: 256;

[0452] (3) a sense strand having the sequence of SEQ ID NO: 104, and an antisense strand having the sequence of SEQ ID NO: 278;

[0453] (4) a sense strand having the sequence of SEQ ID NO: 90, and an antisense strand having the sequence of SEQ ID NO: 264;

[0454] (5) a sense strand having the sequence of SEQ ID NO: 47, and an antisense strand having the sequence of SEQ ID NO: 221;

[0455] (6) a sense strand having the sequence of SEQ ID NO: 2, and an antisense strand having the sequence of SEQ ID NO: 176;

[0456] (7) a sense strand having the sequence of SEQ ID NO: 22, and an antisense strand having the sequence of SEQ ID NO: 196;

[0457] (8) a sense strand having the sequence of SEQ ID NO: 25, and an antisense strand having the sequence of SEQ ID NO: 199;

[0458] (9) a sense strand having the sequence of SEQ ID NO: 48, and an antisense strand having the sequence of SEQ ID NO: 222;

[0459] (10) a sense strand having the sequence of SEQ ID NO: 102, and an antisense strand having the sequence of SEQ ID NO: 276;

[0460] (11) a sense strand having the sequence of SEQ ID NO: 3, and an antisense strand having the sequence of SEQ ID NO: 177;

[0461] (12) a sense strand having the sequence of SEQ ID NO: 5, and an antisense strand having the sequence of SEQ ID NO: 179;

[0462] (13) a sense strand having the sequence of SEQ ID NO: 6, and an antisense strand having the sequence of SEQ ID NO: 180;

[0463] (14) a sense strand having the sequence of SEQ ID NO: 88, and an antisense strand having the sequence of SEQ ID NO: 262;

[0464] (15) a sense strand having the sequence of SEQ ID NO: 94, and an antisense strand having the sequence of SEQ ID NO: 268;

[0465] (16) a sense strand having the sequence of SEQ ID NO: 140, and an antisense strand having the sequence of SEQ ID NO: 314; or

[0466] (17) a sense strand having the sequence of SEQ ID NO: 144, and an antisense strand having the sequence of SEQ ID NO: 318;

[0467] wherein the antisense strand is 21, 22, or 23 nucleotides in length, and the sense strand is 19, 20, or 21 nucleotides in length.

[0468] In some embodiments, the sense strand and the antisense strand of the double- stranded oligonucleotide are selected from any one of the following combinations, respectively:

[0469] (1) a sense strand having the sequence of SEQ ID NO: 31, and an antisense strand having the sequence of SEQ ID NO: 205;

[0470] (2) a sense strand having the sequence of SEQ ID NO: 82, and an antisense strand having the sequence of SEQ ID NO: 256;

[0471] (3) a sense strand having the sequence of SEQ ID NO: 104, and an antisense strand having the sequence of SEQ ID NO: 278;

[0472] (4) a sense strand having the sequence of SEQ ID NO: 90, and an antisense strand having the sequence of SEQ ID NO: 264;

[0473] (5) a sense strand having the sequence of SEQ ID NO: 47, and an antisense strand having the sequence of SEQ ID NO: 221;

[0474] (6) a sense strand having the sequence of SEQ ID NO: 2, and an antisense strand having the sequence of SEQ ID NO: 176;

[0475] (7) a sense strand as set forth in SEQ ID NO: 22, and an antisense strand as set forth in SEQ ID NO: 196;

[0476] (8) a sense strand as set forth in SEQ ID NO: 25, and an antisense strand as set forth in SEQ ID NO: 199;

[0477] (9) a sense strand as set forth in SEQ ID NO: 48, and an antisense strand as set forth in SEQ ID NO: 222;

[0478] (10) a sense strand as set forth in SEQ ID NO: 102, and an antisense strand as set forth in SEQ ID NO: 276;

[0479] (11) a sense strand as set forth in SEQ ID NO: 3, and an antisense strand as set forth in SEQ ID NO: 177;

[0480] (12) a sense strand as set forth in SEQ ID NO: 5, and an antisense strand as set forth in SEQ ID NO: 179;

[0481] (13) a sense strand as set forth in SEQ ID NO: 6, and an antisense strand as set forth in SEQ ID NO: 180;

[0482] (14) a sense strand as set forth in SEQ ID NO: 88, and an antisense strand as set forth in SEQ ID NO: 262;

[0483] (15) a sense strand as set forth in SEQ ID NO: 94, and an antisense strand as set forth in SEQ ID NO: 268;

[0484] (16) a sense strand as set forth in SEQ ID NO: 140, and an antisense strand as set forth in SEQ ID NO: 314; or

[0485] (17) a sense strand as set forth in SEQ ID NO: 144, and an antisense strand as set forth in SEQ ID NO: 318;

[0486] wherein the antisense strand is 21, 22, or 23 nucleotides in length, and the sense strand is 19, 20, or 21 nucleotides in length.

[0487] In some embodiments, the sense strand and the antisense strand of the double- stranded oligonucleotide are selected from any one of the following combinations, respectively:

[0488] (1) a sense strand having the sequence of SEQ ID NO: 698, and an antisense strand having the sequence of SEQ ID NO: 707;

[0489] (2) a sense strand having the sequence of SEQ ID NO: 701, and an antisense strand having the sequence of SEQ ID NO: 710;

[0490] (3) a sense strand having the sequence of SEQ ID NO: 91, and an antisense strand having the sequence of SEQ ID NO: 265;

[0491] (4) a sense strand having the sequence of SEQ ID NO: 92, and an antisense strand having the sequence of SEQ ID NO: 266;

[0492] (5) a sense strand having the sequence of SEQ ID NO: 697, and an antisense strand having the sequence of SEQ ID NO: 706;

[0493] (6) a sense strand having the sequence of SEQ ID NO: 699, and an antisense strand having the sequence of SEQ ID NO: 708;

[0494] (7) a sense strand having the sequence of SEQ ID NO: 700, and an antisense strand having the sequence of SEQ ID NO: 709;

[0495] (8) a sense strand having the sequence of SEQ ID NO: 702, and an antisense strand having the sequence of SEQ ID NO: 711;

[0496] (9) a sense strand having the sequence of SEQ ID NO: 703, and an antisense strand having the sequence of SEQ ID NO: 712;

[0497] (10) a sense strand having the sequence of SEQ ID NO: 704, and an antisense strand having the sequence of SEQ ID NO: 713; or

[0498] (11) a sense strand having the sequence of SEQ ID NO: 705, and an antisense strand having the sequence of SEQ ID NO: 714;

[0499] wherein the antisense strand is 21, 22, or 23 nucleotides in length, and the sense strand is 19, 20, or 21 nucleotides in length.

[0500] In some embodiments, the sense and antisense strands of the double stranded oligonucleotide are selected from any of the following combinations, respectively:

[0501] (1) a sense strand of the sequence as shown in SEQ ID NO: 698, and an antisense strand of the sequence as shown in SEQ ID NO: 707;

[0502] (2) a sense strand of the sequence as shown in SEQ ID NO: 701, and an antisense strand of the sequence as shown in SEQ ID NO: 710;

[0503] (3) a sense strand of the sequence as shown in SEQ ID NO: 91, and an antisense strand of the sequence as shown in SEQ ID NO: 265;

[0504] (4) a sense strand of the sequence as shown in SEQ ID NO: 92, and an antisense strand of the sequence as shown in SEQ ID NO: 266;

[0505] (5) a sense strand of the sequence as shown in SEQ ID NO: 697, and an antisense strand of the sequence as shown in SEQ ID NO: 706;

[0506] (6) a sense strand of the sequence as shown in SEQ ID NO: 699, and an antisense strand of the sequence as shown in SEQ ID NO: 708;

[0507] (7) a sense strand of the sequence as shown in SEQ ID NO: 700, and an antisense strand of the sequence as shown in SEQ ID NO: 709;

[0508] (8) a sense strand of the sequence as shown in SEQ ID NO: 702, and an antisense strand of the sequence as shown in SEQ ID NO: 711;

[0509] (9) a sense strand of the sequence as shown in SEQ ID NO: 703, and an antisense strand of the sequence as shown in SEQ ID NO: 712;

[0510] (10) a sense strand of the sequence as shown in SEQ ID NO: 704, and an antisense strand of the sequence as shown in SEQ ID NO: 713; or

[0511] (11) a sense strand of the sequence as shown in SEQ ID NO: 705, and an antisense strand of the sequence as shown in SEQ ID NO: 714;

[0512] wherein the antisense strand is 21, 22, or 23 nucleotides in length, and the sense strand is 19, 20, or 21 nucleotides in length.

[0513] In some embodiments, the sense and antisense strands of the double- stranded oligonucleotide are selected from any one of the following combinations, respectively:

[0514] (1) a sense strand has the sequence of SEQ ID NO: 31, and an antisense strand has the sequence of SEQ ID NO: 205;

[0515] (2) a sense strand has the sequence of SEQ ID NO: 82, and an antisense strand has the sequence of SEQ ID NO: 256;

[0516] (3) a sense strand has the sequence of SEQ ID NO: 104, and an antisense strand has the sequence of SEQ ID NO: 278;

[0517] (4) a sense strand has the sequence of SEQ ID NO: 90, and an antisense strand has the sequence of SEQ ID NO: 264;

[0518] (5) a sense strand has the sequence of SEQ ID NO: 47, and an antisense strand has the sequence of SEQ ID NO: 221;

[0519] (6) a sense strand has the sequence of SEQ ID NO: 2, and an antisense strand has the sequence of SEQ ID NO: 176;

[0520] (7) a sense strand has the sequence of SEQ ID NO: 22, and an antisense strand has the sequence of SEQ ID NO: 196;

[0521] (8) a sense strand has the sequence of SEQ ID NO: 25, and an antisense strand has the sequence of SEQ ID NO: 199;

[0522] (9) a sense strand has the sequence of SEQ ID NO: 48, and an antisense strand has the sequence of SEQ ID NO: 222;

[0523] (10) a sense strand has the sequence of SEQ ID NO: 91, and an antisense strand has the sequence of SEQ ID NO: 265;

[0524] (11) a sense strand has the sequence of SEQ ID NO: 92, and an antisense strand has the sequence of SEQ ID NO: 266; or

[0525] (12) a sense strand has the sequence of SEQ ID NO: 102, and an antisense strand has the sequence of SEQ ID NO: 276;

[0526] wherein the antisense strand has a length of 21, 22, or 23 nucleotides, and the sense strand has a length of 19, 20, or 21 nucleotides.

[0527] In some embodiments, the sense strand and the antisense strand of the double stranded oligonucleotide are selected from any one of the following combinations, respectively:

[0528] (1) a sense strand of the sequence as shown in SEQ ID NO: 31, and an antisense strand of the sequence as shown in SEQ ID NO: 205;

[0529] (2) a sense strand of the sequence as shown in SEQ ID NO: 82, and an antisense strand of the sequence as shown in SEQ ID NO: 256;

[0530] (3) a sense strand of the sequence as shown in SEQ ID NO: 104, and an antisense strand of the sequence as shown in SEQ ID NO: 278;

[0531] (4) a sense strand of the sequence as shown in SEQ ID NO: 90, and an antisense strand of the sequence as shown in SEQ ID NO: 264;

[0532] (5) a sense strand of the sequence as shown in SEQ ID NO: 47, and an antisense strand of the sequence as shown in SEQ ID NO: 221;

[0533] (6) a sense strand of the sequence as shown in SEQ ID NO: 2, and an antisense strand of the sequence as shown in SEQ ID NO: 176;

[0534] (7) a sense strand of the sequence as shown in SEQ ID NO: 22, and an antisense strand of the sequence as shown in SEQ ID NO: 196;

[0535] (8) a sense strand of the sequence as shown in SEQ ID NO: 25, and an antisense strand of the sequence as shown in SEQ ID NO: 199;

[0536] (9) a sense strand of the sequence as shown in SEQ ID NO: 48, and an antisense strand of the sequence as shown in SEQ ID NO: 222;

[0537] (10) a sense strand of the sequence as shown in SEQ ID NO: 91, and an antisense strand of the sequence as shown in SEQ ID NO: 265;

[0538] (11) a sense strand of the sequence as shown in SEQ ID NO: 92, and an antisense strand of the sequence as shown in SEQ ID NO: 266; or

[0539] (12) a sense strand of the sequence as shown in SEQ ID NO: 102, and an antisense strand of the sequence as shown in SEQ ID NO: 276;

[0540] wherein the length of the antisense strand is 21, 22, or 23 nucleotides, and the length of the sense strand is 19, 20, or 21 nucleotides.

[0541] In some embodiments, the sense strand and the antisense strand of the double- stranded oligonucleotide are selected from any one of the following combinations, respectively:

[0542] (1) the sense strand has the sequence of SEQ ID NO: 31, and the antisense strand has the sequence of SEQ ID NO: 205;

[0543] (2) the sense strand has the sequence of SEQ ID NO: 82, and the antisense strand has the sequence of SEQ ID NO: 256;

[0544] (3) the sense strand has the sequence of SEQ ID NO: 104, and the antisense strand has the sequence of SEQ ID NO: 278;

[0545] (4) the sense strand has the sequence of SEQ ID NO: 90, and the antisense strand has the sequence of SEQ ID NO: 264;

[0546] (5) the sense strand has the sequence of SEQ ID NO: 47, and the antisense strand has the sequence of SEQ ID NO: 221;

[0547] (6) the sense strand has the sequence of SEQ ID NO: 2, and the antisense strand has the sequence of SEQ ID NO: 176;

[0548] (7) the sense strand has the sequence of SEQ ID NO: 698, and the antisense strand has the sequence of SEQ ID NO: 707; or

[0549] (8) the sense strand has the sequence of SEQ ID NO: 701, and the antisense strand has the sequence of SEQ ID NO: 710;

[0550] wherein the length of the antisense strand is 21, 22, or 23 nucleotides, and the length of the sense strand is 19, 20, or 21 nucleotides.

[0551] In some embodiments, the sense strand and the antisense strand of the double- stranded oligonucleotide are selected from any one of the following combinations, respectively:

[0552] (1) the sense strand has the sequence of SEQ ID NO: 31, and the antisense strand has the sequence of SEQ ID NO: 205;

[0553] (2) the sense strand of the sequence as shown in SEQ ID NO: 82, and the antisense strand of the sequence as shown in SEQ ID NO: 256;

[0554] (3) the sense strand of the sequence as shown in SEQ ID NO: 104, and the antisense strand of the sequence as shown in SEQ ID NO: 278;

[0555] (4) the sense strand of the sequence as shown in SEQ ID NO: 90, and the antisense strand of the sequence as shown in SEQ ID NO: 264;

[0556] (5) the sense strand of the sequence as shown in SEQ ID NO: 47, and the antisense strand of the sequence as shown in SEQ ID NO: 221;

[0557] (6) the sense strand of the sequence as shown in SEQ ID NO: 2, and the antisense strand of the sequence as shown in SEQ ID NO: 176;

[0558] (7) the sense strand of the sequence as shown in SEQ ID NO: 698, and the antisense strand of the sequence as shown in SEQ ID NO: 707; or

[0559] (8) the sense strand of the sequence as shown in SEQ ID NO: 701, and the antisense strand of the sequence as shown in SEQ ID NO: 710;

[0560] wherein the antisense strand is 21, 22, or 23 nucleotides in length, and the sense strand is 19, 20, or 21 nucleotides in length.

[0561] In some embodiments, the double stranded oligonucleotide comprises modified nucleotides.

[0562] In some embodiments, at least a portion of the nucleotides of each of the sense strand and the antisense strand of the double stranded oligonucleotide are independently modified nucleotides. In some embodiments, each nucleotide of the sense strand or the antisense strand is a modified nucleotide.

[0563] In some embodiments, the modified nucleotides are selected from 2'-methoxy modified nucleotides, 2'-fluoro modified nucleotides, 2'-deoxy nucleotides, inosine or hypoxanthine nucleotides, 5'-phosphate nucleotides, 2',3'-seco nucleotide mimics, locked nucleotides (LNA), unlocked nucleic acid nucleotides (UNA), glycol nucleic acid nucleotides (GNA), bicyclic nucleic acids (BNA), 2'-F-arabinonucleotides, 2'-methoxyethyl nucleotides, abasic nucleotides, ribothymidine, inverted nucleotides, inverted abasic nucleotides (Invab), inverted 2'-OMe nucleotides, inverted 2'-deoxy nucleotides, 2'-amino modified nucleotides, 2'-alkyl modified nucleotides, morpholino nucleotides, 3'-OMe nucleotides, phosphate group modified nucleotides, terminal nucleotides linked to a cholesteryl derivative or dodecanoic acid bisdecylamide group, 2'-amino modified nucleotides, phosphoramidates, non-natural base containing nucleotides, or 5'-phosphate mimic modified nucleotides.

[0564] In some embodiments, the sense strand and the antisense strand each independently comprise at least one internucleotide linkage.

[0565] In some embodiments, the internucleotide linkage is a phosphorothioate linkage.

[0566] In some embodiments, the 5'-phosphate mimic is selected from 5'-oxymethylphosphonate, 5'-vinylphosphonate, 5'-vinylphosphonate, 5' vinylphosphonate-2'-N-acetyl, or 5'-malonylphosphonate.

[0567] In some embodiments, the nucleotide at the 7th, 8th, 9thposition from the 5' end of the sense strand is a 2'-fluoro modified nucleotide, and one and only one of the nucleotides at the 5th, 11th, or 12thposition is a 2'-fluoro modified nucleotide.

[0568] In some embodiments, the nucleotide at the 2nd, 6th, 7th, 14th, 16thposition from the 5' end of the antisense strand is a 2'-fluoro modified nucleotide, and one and only one of the nucleotides at the 4thor 5thposition is a 2'-fluoro modified nucleotide.

[0569] In some embodiments, there is a phosphorothioate linkage between the 1stnucleotide and the 2ndnucleotide, and between the 2ndnucleotide and the 3rdnucleotide from the 5' end of the sense strand.

[0570] In some embodiments, there is a phosphorothioate linkage between the 1stand 2ndnucleotides, between the 2ndand 3rdnucleotides, between the 19thand 20thnucleotides, between the 20thand 21stnucleotides from the 5' terminus of the antisense strand.

[0571] In some embodiments, the modification type of the double-stranded oligonucleotide is selected from any one of the following combinations:

[0572] (1) the nucleotides at positions 5, 7, 8, 9 from the 5' terminus of the sense strand are 2'-fluoro-modified nucleotides, and the rest of the nucleotides are 2'-methoxy-modified nucleotides, and there is a phosphorothioate linkage between the 1stand 2ndnucleotides, between the 2ndand 3rdnucleotides from the 5' terminus of the sense strand; the nucleotides at positions 2, 4, 6, 7, 10, 12, 14, 16 from the 5' terminus of the antisense strand are 2'-fluoro-modified nucleotides, and the rest of the nucleotides are 2'-methoxy-modified nucleotides, and there is a phosphorothioate linkage between the 1stand 2ndnucleotides, between the 2ndand 3rdnucleotides, between the 19thand 20thnucleotides, between the 20thand 21stnucleotides from the 5' terminus of the antisense strand;

[0573] (2) the nucleotides at positions 7, 8, 9, 12 from the 5' terminus of the sense strand are 2'-fluoro-modified nucleotides, and the rest of the nucleotides are 2'-methoxy-modified nucleotides, and there is a phosphorothioate linkage between the 1stand 2ndnucleotides, between the 2ndand 3rdnucleotides from the 5' terminus of the sense strand; the nucleotides at positions 2, 4, 6, 7, 10, 12, 14, 16 from the 5' terminus of the antisense strand are 2'-fluoro-modified nucleotides, and the rest of the nucleotides are 2'-methoxy-modified nucleotides, and there is a phosphorothioate linkage between the 1stand 2ndnucleotides, between the 2ndand 3rdnucleotides, between the 19thand 20thnucleotides, between the 20thand 21stnucleotides from the 5' terminus of the antisense strand; or

[0574] (3) the 7th, 8th, 9th, 11th nucleotides from the 5' end of the sense strand are 2'-fluoro-modified nucleotides, and the rest of the nucleotides are 2'-methoxy-modified nucleotides, and there is a phosphorothioate linkage between the 1st and 2nd nucleotides, and between the 2nd and 3rd nucleotides from the 5' end of the sense strand; the 2nd, 5th, 6th, 7th, 14th, 16th nucleotides from the 5' end of the antisense strand are 2'-fluoro-modified nucleotides, and the rest of the nucleotides are 2'-methoxy-modified nucleotides, and there is a phosphorothioate linkage between the 1st and 2nd nucleotides, between the 2nd and 3rd nucleotides, between the 19th and 20th nucleotides, and between the 20th and 21st nucleotides from the 5' end of the antisense strand.

[0575] In some embodiments, the 7th, 8th, 9th, 12th nucleotides from the 5' end of the sense strand are 2'-fluoro-modified nucleotides, and the rest of the nucleotides are 2'-methoxy-modified nucleotides, and there is a phosphorothioate linkage between the 1st and 2nd nucleotides, and between the 2nd and 3rd nucleotides from the 5' end of the sense strand; the 2nd, 4th, 6th, 7th, 10th, 12th, 14th, 16th nucleotides from the 5' end of the antisense strand are 2'-fluoro-modified nucleotides, and the rest of the nucleotides are 2'-methoxy-modified nucleotides, and there is a phosphorothioate linkage between the 1st and 2nd nucleotides, between the 2nd and 3rd nucleotides, between the 19th and 20th nucleotides, and between the 20th and 21st nucleotides from the 5' end of the antisense strand.

[0576] In some embodiments, the sense strand and the antisense strand of the double- stranded oligonucleotide are selected from any one of the following combinations, respectively, or comprise at least 17 contiguous nucleotide sequences that differ by no more than 4, 3, 2, or 1 nucleotides from the nucleotide sequences set forth in any one of the following combinations:

[0577] (1) the sense strand has the sequence set forth in SEQ ID NO: 379, and the antisense strand has the sequence set forth in SEQ ID NO: 553;

[0578] (2) the sense strand has the sequence set forth in SEQ ID NO: 430, and the antisense strand has the sequence set forth in SEQ ID NO: 604;

[0579] (3) the sense strand has the sequence set forth in SEQ ID NO: 452, and the antisense strand has the sequence set forth in SEQ ID NO: 626;

[0580] (4) a sense strand having the sequence of SEQ ID NO: 438, and an antisense strand having the sequence of SEQ ID NO: 612;

[0581] (5) a sense strand having the sequence of SEQ ID NO: 395, and an antisense strand having the sequence of SEQ ID NO: 569;

[0582] (6) a sense strand having the sequence of SEQ ID NO: 350, and an antisense strand having the sequence of SEQ ID NO: 524;

[0583] (7) a sense strand having the sequence of SEQ ID NO: 716, and an antisense strand having the sequence of SEQ ID NO: 725;

[0584] (8) a sense strand having the sequence of SEQ ID NO: 719, and an antisense strand having the sequence of SEQ ID NO: 728;

[0585] (9) a sense strand having the sequence of SEQ ID NO: 370, and an antisense strand having the sequence of SEQ ID NO: 544;

[0586] (10) a sense strand having the sequence of SEQ ID NO: 373, and an antisense strand having the sequence of SEQ ID NO: 547;

[0587] (11) a sense strand having the sequence of SEQ ID NO: 396, and an antisense strand having the sequence of SEQ ID NO: 570;

[0588] (12) a sense strand having the sequence of SEQ ID NO: 450, and an antisense strand having the sequence of SEQ ID NO: 624;

[0589] (13) a sense strand having the sequence of SEQ ID NO: 439, and an antisense strand having the sequence of SEQ ID NO: 613;

[0590] (14) a sense strand having the sequence of SEQ ID NO: 440, and an antisense strand having the sequence of SEQ ID NO: 614;

[0591] (15) a sense strand having the sequence of SEQ ID NO: 351, and an antisense strand having the sequence of SEQ ID NO: 525;

[0592] (16) a sense strand having the sequence of SEQ ID NO: 353, and an antisense strand having the sequence of SEQ ID NO: 527;

[0593] (17) a sense strand having the sequence of SEQ ID NO: 354, and an antisense strand having the sequence of SEQ ID NO: 528;

[0594] (18) a sense strand having the sequence of SEQ ID NO: 436, and an antisense strand having the sequence of SEQ ID NO: 610;

[0595] (19) a sense strand having the sequence of SEQ ID NO: 442, and an antisense strand having the sequence of SEQ ID NO: 616;

[0596] (20) a sense strand having the sequence of SEQ ID NO: 488, and an antisense strand having the sequence of SEQ ID NO: 662;

[0597] (21) a sense strand having the sequence of SEQ ID NO: 492, and an antisense strand having the sequence of SEQ ID NO: 666;

[0598] (22) a sense strand having the sequence of SEQ ID NO: 715, and an antisense strand having the sequence of SEQ ID NO: 724;

[0599] (23) a sense strand having the sequence of SEQ ID NO: 717, and an antisense strand having the sequence of SEQ ID NO: 726;

[0600] (24) a sense strand having the sequence of SEQ ID NO: 718, and an antisense strand having the sequence of SEQ ID NO: 727;

[0601] (25) a sense strand having the sequence of SEQ ID NO: 720, and an antisense strand having the sequence of SEQ ID NO: 729;

[0602] (26) a sense strand having the sequence of SEQ ID NO: 721, and an antisense strand having the sequence of SEQ ID NO: 730;

[0603] (27) a sense strand having the sequence of SEQ ID NO: 722, and an antisense strand having the sequence of SEQ ID NO: 731;

[0604] (28) a sense strand having the sequence of SEQ ID NO: 723, and an antisense strand having the sequence of SEQ ID NO: 732;

[0605] (29) a sense strand having the sequence of SEQ ID NO: 349, and an antisense strand having the sequence of SEQ ID NO: 523;

[0606] (30) a sense strand having the sequence of SEQ ID NO: 352, and an antisense strand having the sequence of SEQ ID NO: 526;

[0607] (31) a sense strand having the sequence of SEQ ID NO: 355, and an antisense strand having the sequence of SEQ ID NO: 529;

[0608] (32) a sense strand having the sequence of SEQ ID NO: 356, and an antisense strand having the sequence of SEQ ID NO: 530;

[0609] (33) a sense strand having the sequence of SEQ ID NO: 357, and an antisense strand having the sequence of SEQ ID NO: 531;

[0610] (34) a sense strand having the sequence of SEQ ID NO: 358, and an antisense strand having the sequence of SEQ ID NO: 532;

[0611] (35) a sense strand having the sequence of SEQ ID NO: 359, and an antisense strand having the sequence of SEQ ID NO: 533;

[0612] (36) a sense strand having the sequence of SEQ ID NO: 360, and an antisense strand having the sequence of SEQ ID NO: 534;

[0613] (37) a sense strand having the sequence of SEQ ID NO: 361, and an antisense strand having the sequence of SEQ ID NO: 535;

[0614] (38) a sense strand having the sequence of SEQ ID NO: 362, and an antisense strand having the sequence of SEQ ID NO: 536;

[0615] (39) a sense strand having the sequence of SEQ ID NO: 363, and an antisense strand having the sequence of SEQ ID NO: 537;

[0616] (40) a sense strand having the sequence of SEQ ID NO: 364, and an antisense strand having the sequence of SEQ ID NO: 538;

[0617] (41) a sense strand having the sequence of SEQ ID NO: 365, and an antisense strand having the sequence of SEQ ID NO: 539;

[0618] (42) a sense strand having the sequence of SEQ ID NO: 366, and an antisense strand having the sequence of SEQ ID NO: 540;

[0619] (43) a sense strand having the sequence of SEQ ID NO: 367, and an antisense strand having the sequence of SEQ ID NO: 541;

[0620] (44) a sense strand having the sequence of SEQ ID NO: 368, and an antisense strand having the sequence of SEQ ID NO: 542;

[0621] (45) a sense strand having the sequence of SEQ ID NO: 369, and an antisense strand having the sequence of SEQ ID NO: 543;

[0622] (46) a sense strand having the sequence of SEQ ID NO: 371, and an antisense strand having the sequence of SEQ ID NO: 545;

[0623] (47) a sense strand having the sequence of SEQ ID NO: 372, and an antisense strand having the sequence of SEQ ID NO: 546;

[0624] (48) a sense strand having the sequence of SEQ ID NO: 374, and an antisense strand having the sequence of SEQ ID NO: 548;

[0625] (49) a sense strand having the sequence of SEQ ID NO: 375, and an antisense strand having the sequence of SEQ ID NO: 549;

[0626] (50) a sense strand having the sequence of SEQ ID NO: 376, and an antisense strand having the sequence of SEQ ID NO: 550;

[0627] (51) a sense strand having the sequence of SEQ ID NO: 377, and an antisense strand having the sequence of SEQ ID NO: 551;

[0628] (52) a sense strand having the sequence of SEQ ID NO: 378, and an antisense strand having the sequence of SEQ ID NO: 552;

[0629] (53) a sense strand having the sequence of SEQ ID NO: 380, and an antisense strand having the sequence of SEQ ID NO: 554;

[0630] (54) a sense strand having the sequence of SEQ ID NO: 381, and an antisense strand having the sequence of SEQ ID NO: 555;

[0631] (55) a sense strand having the sequence of SEQ ID NO: 382, and an antisense strand having the sequence of SEQ ID NO: 556;

[0632] (56) a sense strand having the sequence of SEQ ID NO: 383, and an antisense strand having the sequence of SEQ ID NO: 557;

[0633] (57) a sense strand having the sequence of SEQ ID NO: 384, and an antisense strand having the sequence of SEQ ID NO: 558;

[0634] (58) a sense strand having the sequence of SEQ ID NO: 385, and an antisense strand having the sequence of SEQ ID NO: 559;

[0635] (59) a sense strand having the sequence of SEQ ID NO: 386, and an antisense strand having the sequence of SEQ ID NO: 560;

[0636] (60) a sense strand having the sequence of SEQ ID NO: 387, and an antisense strand having the sequence of SEQ ID NO: 561;

[0637] (61) a sense strand having the sequence of SEQ ID NO: 388, and an antisense strand having the sequence of SEQ ID NO: 562;

[0638] (62) a sense strand having the sequence of SEQ ID NO: 389, and an antisense strand having the sequence of SEQ ID NO: 563;

[0639] (63) a sense strand having the sequence of SEQ ID NO: 390, and an antisense strand having the sequence of SEQ ID NO: 564;

[0640] (64) a sense strand having the sequence of SEQ ID NO: 391, and an antisense strand having the sequence of SEQ ID NO: 565;

[0641] (65) a sense strand having the sequence of SEQ ID NO: 392, and an antisense strand having the sequence of SEQ ID NO: 566;

[0642] (66) a sense strand having the sequence of SEQ ID NO: 393, and an antisense strand having the sequence of SEQ ID NO: 567;

[0643] (67) a sense strand having the sequence of SEQ ID NO: 394, and an antisense strand having the sequence of SEQ ID NO: 568;

[0644] (68) a sense strand having the sequence of SEQ ID NO: 397, and an antisense strand having the sequence of SEQ ID NO: 571;

[0645] (69) a sense strand having the sequence of SEQ ID NO: 398, and an antisense strand having the sequence of SEQ ID NO: 572;

[0646] (70) a sense strand having the sequence of SEQ ID NO: 399, and an antisense strand having the sequence of SEQ ID NO: 573;

[0647] (71) a sense strand having the sequence of SEQ ID NO: 400, and an antisense strand having the sequence of SEQ ID NO: 574;

[0648] (72) a sense strand having the sequence of SEQ ID NO: 401, and an antisense strand having the sequence of SEQ ID NO: 575;

[0649] (73) a sense strand having the sequence of SEQ ID NO: 402, and an antisense strand having the sequence of SEQ ID NO: 576;

[0650] (74) a sense strand having the sequence of SEQ ID NO: 403, and an antisense strand having the sequence of SEQ ID NO: 577;

[0651] (75) a sense strand having the sequence of SEQ ID NO: 404, and an antisense strand having the sequence of SEQ ID NO: 578;

[0652] (76) a sense strand having the sequence of SEQ ID NO: 405, and an antisense strand having the sequence of SEQ ID NO: 579;

[0653] (77) a sense strand having the sequence of SEQ ID NO: 406, and an antisense strand having the sequence of SEQ ID NO: 580;

[0654] (78) a sense strand having the sequence of SEQ ID NO: 407, and an antisense strand having the sequence of SEQ ID NO: 581;

[0655] (79) a sense strand having the sequence of SEQ ID NO: 408, and an antisense strand having the sequence of SEQ ID NO: 582;

[0656] (80) a sense strand having the sequence of SEQ ID NO: 409, and an antisense strand having the sequence of SEQ ID NO: 583;

[0657] (81) a sense strand having the sequence of SEQ ID NO: 410, and an antisense strand having the sequence of SEQ ID NO: 584;

[0658] (82) a sense strand having the sequence of SEQ ID NO: 411, and an antisense strand having the sequence of SEQ ID NO: 585;

[0659] (83) a sense strand having the sequence of SEQ ID NO: 412, and an antisense strand having the sequence of SEQ ID NO: 586;

[0660] (84) a sense strand having the sequence of SEQ ID NO: 413, and an antisense strand having the sequence of SEQ ID NO: 587;

[0661] (85) a sense strand having the sequence of SEQ ID NO: 414, and an antisense strand having the sequence of SEQ ID NO: 588;

[0662] (86) a sense strand having the sequence of SEQ ID NO: 415, and an antisense strand having the sequence of SEQ ID NO: 589;

[0663] (87) a sense strand having the sequence of SEQ ID NO: 416, and an antisense strand having the sequence of SEQ ID NO: 590;

[0664] (88) a sense strand having the sequence of SEQ ID NO: 417, and an antisense strand having the sequence of SEQ ID NO: 591 ;

[0665] (89) a sense strand having the sequence of SEQ ID NO: 418, and an antisense strand having the sequence of SEQ ID NO: 592;

[0666] (90) a sense strand having the sequence of SEQ ID NO: 419, and an antisense strand having the sequence of SEQ ID NO: 593;

[0667] (91) a sense strand having the sequence of SEQ ID NO: 420, and an antisense strand having the sequence of SEQ ID NO: 594;

[0668] (92) a sense strand having the sequence of SEQ ID NO: 421, and an antisense strand having the sequence of SEQ ID NO: 595;

[0669] (93) a sense strand having the sequence of SEQ ID NO: 422, and an antisense strand having the sequence of SEQ ID NO: 596;

[0670] (94) a sense strand having the sequence of SEQ ID NO: 423, and an antisense strand having the sequence of SEQ ID NO: 597;

[0671] (95) a sense strand having the sequence of SEQ ID NO: 424, and an antisense strand having the sequence of SEQ ID NO: 598;

[0672] (96) a sense strand having the sequence of SEQ ID NO: 425, and an antisense strand having the sequence of SEQ ID NO: 599;

[0673] (97) a sense strand having the sequence of SEQ ID NO: 426, and an antisense strand having the sequence of SEQ ID NO: 600;

[0674] (98) a sense strand having the sequence of SEQ ID NO: 427, and an antisense strand having the sequence of SEQ ID NO: 601;

[0675] (99) a sense strand having the sequence of SEQ ID NO: 428, and an antisense strand having the sequence of SEQ ID NO: 602;

[0676] (100) the sense strand having the sequence of SEQ ID NO: 429, and the antisense strand having the sequence of SEQ ID NO: 603;

[0677] (101) the sense strand having the sequence of SEQ ID NO: 431, and the antisense strand having the sequence of SEQ ID NO: 605;

[0678] (102) the sense strand having the sequence of SEQ ID NO: 432, and the antisense strand having the sequence of SEQ ID NO: 606;

[0679] (103) the sense strand having the sequence of SEQ ID NO: 433, and the antisense strand having the sequence of SEQ ID NO: 607;

[0680] (104) the sense strand having the sequence of SEQ ID NO: 434, and the antisense strand having the sequence of SEQ ID NO: 608;

[0681] (105) the sense strand having the sequence of SEQ ID NO: 435, and the antisense strand having the sequence of SEQ ID NO: 609;

[0682] (106) the sense strand having the sequence of SEQ ID NO: 437, and the antisense strand having the sequence of SEQ ID NO: 611;

[0683] (107) the sense strand having the sequence of SEQ ID NO: 441, and the antisense strand having the sequence of SEQ ID NO: 615;

[0684] (108) the sense strand having the sequence of SEQ ID NO: 443, and the antisense strand having the sequence of SEQ ID NO: 617;

[0685] (109) the sense strand having the sequence of SEQ ID NO: 444, and the antisense strand having the sequence of SEQ ID NO: 618;

[0686] (110) the sense strand having the sequence of SEQ ID NO: 445, and the antisense strand having the sequence of SEQ ID NO: 619;

[0687] (111) the sense strand having the sequence of SEQ ID NO: 446, and the antisense strand having the sequence of SEQ ID NO: 620;

[0688] (112) a sense strand having the sequence of SEQ ID NO: 447, and an antisense strand having the sequence of SEQ ID NO: 621 ;

[0689] (113) a sense strand having the sequence of SEQ ID NO: 448, and an antisense strand having the sequence of SEQ ID NO: 622;

[0690] (114) a sense strand having the sequence of SEQ ID NO: 449, and an antisense strand having the sequence of SEQ ID NO: 623;

[0691] (115) a sense strand having the sequence of SEQ ID NO: 451, and an antisense strand having the sequence of SEQ ID NO: 625;

[0692] (116) a sense strand having the sequence of SEQ ID NO: 453, and an antisense strand having the sequence of SEQ ID NO: 627;

[0693] (117) a sense strand having the sequence of SEQ ID NO: 454, and an antisense strand having the sequence of SEQ ID NO: 628;

[0694] (118) a sense strand having the sequence of SEQ ID NO: 455, and an antisense strand having the sequence of SEQ ID NO: 629;

[0695] (119) a sense strand having the sequence of SEQ ID NO: 456, and an antisense strand having the sequence of SEQ ID NO: 630;

[0696] (120) a sense strand having the sequence of SEQ ID NO: 457, and an antisense strand having the sequence of SEQ ID NO: 631 ;

[0697] (121) a sense strand having the sequence of SEQ ID NO: 458, and an antisense strand having the sequence of SEQ ID NO: 632;

[0698] (122) a sense strand having the sequence of SEQ ID NO: 459, and an antisense strand having the sequence of SEQ ID NO: 633;

[0699] (123) a sense strand having the sequence of SEQ ID NO: 460, and an antisense strand having the sequence of SEQ ID NO: 634;

[0700] (124) a sense strand having the sequence of SEQ ID NO: 461, and an antisense strand having the sequence of SEQ ID NO: 635;

[0701] (125) a sense strand having the sequence of SEQ ID NO: 462, and an antisense strand having the sequence of SEQ ID NO: 636;

[0702] (126) a sense strand having the sequence of SEQ ID NO: 463, and an antisense strand having the sequence of SEQ ID NO: 637;

[0703] (127) a sense strand having the sequence of SEQ ID NO: 464, and an antisense strand having the sequence of SEQ ID NO: 638;

[0704] (128) a sense strand having the sequence of SEQ ID NO: 465, and an antisense strand having the sequence of SEQ ID NO: 639;

[0705] (129) a sense strand having the sequence of SEQ ID NO: 466, and an antisense strand having the sequence of SEQ ID NO: 640;

[0706] (130) a sense strand having the sequence of SEQ ID NO: 467, and an antisense strand having the sequence of SEQ ID NO: 641;

[0707] (131) a sense strand having the sequence of SEQ ID NO: 468, and an antisense strand having the sequence of SEQ ID NO: 642;

[0708] (132) a sense strand having the sequence of SEQ ID NO: 469, and an antisense strand having the sequence of SEQ ID NO: 643;

[0709] (133) a sense strand having the sequence of SEQ ID NO: 470, and an antisense strand having the sequence of SEQ ID NO: 644;

[0710] (134) a sense strand having the sequence of SEQ ID NO: 471, and an antisense strand having the sequence of SEQ ID NO: 645;

[0711] (135) a sense strand having the sequence of SEQ ID NO: 472, and an antisense strand having the sequence of SEQ ID NO: 646;

[0712] (136) a sense strand having the sequence of SEQ ID NO: 473, and an antisense strand having the sequence of SEQ ID NO: 647;

[0713] (137) a sense strand having the sequence of SEQ ID NO: 474, and an antisense strand having the sequence of SEQ ID NO: 648;

[0714] (138) a sense strand having the sequence of SEQ ID NO: 475, and an antisense strand having the sequence of SEQ ID NO: 649;

[0715] (139) a sense strand having the sequence of SEQ ID NO: 476, and an antisense strand having the sequence of SEQ ID NO: 650;

[0716] (140) a sense strand having the sequence of SEQ ID NO: 477, and an antisense strand having the sequence of SEQ ID NO: 651;

[0717] (141) a sense strand having the sequence of SEQ ID NO: 478, and an antisense strand having the sequence of SEQ ID NO: 652;

[0718] (142) a sense strand having the sequence of SEQ ID NO: 479, and an antisense strand having the sequence of SEQ ID NO: 653;

[0719] (143) a sense strand having the sequence of SEQ ID NO: 480, and an antisense strand having the sequence of SEQ ID NO: 654;

[0720] (144) a sense strand having the sequence of SEQ ID NO: 481, and an antisense strand having the sequence of SEQ ID NO: 655;

[0721] (145) a sense strand having the sequence of SEQ ID NO: 482, and an antisense strand having the sequence of SEQ ID NO: 656;

[0722] (146) a sense strand having the sequence of SEQ ID NO: 483, and an antisense strand having the sequence of SEQ ID NO: 657;

[0723] (147) a sense strand having the sequence of SEQ ID NO: 484, and an antisense strand having the sequence of SEQ ID NO: 658;

[0724] (148) a sense strand having the sequence of SEQ ID NO: 485, and an antisense strand having the sequence of SEQ ID NO: 659;

[0725] (149) a sense strand having the sequence of SEQ ID NO: 486, and an antisense strand having the sequence of SEQ ID NO: 660;

[0726] (150) a sense strand having the sequence of SEQ ID NO: 487, and an antisense strand having the sequence of SEQ ID NO: 661 ;

[0727] (151) a sense strand having the sequence of SEQ ID NO: 489, and an antisense strand having the sequence of SEQ ID NO: 663;

[0728] (152) a sense strand having the sequence of SEQ ID NO: 490, and an antisense strand having the sequence of SEQ ID NO: 664;

[0729] (153) a sense strand having the sequence of SEQ ID NO: 491, and an antisense strand having the sequence of SEQ ID NO: 665;

[0730] (154) a sense strand having the sequence of SEQ ID NO: 493, and an antisense strand having the sequence of SEQ ID NO: 667;

[0731] (155) a sense strand having the sequence of SEQ ID NO: 494, and an antisense strand having the sequence of SEQ ID NO: 668;

[0732] (156) a sense strand having the sequence of SEQ ID NO: 495, and an antisense strand having the sequence of SEQ ID NO: 669;

[0733] (157) a sense strand having the sequence of SEQ ID NO: 496, and an antisense strand having the sequence of SEQ ID NO: 670;

[0734] (158) a sense strand having the sequence of SEQ ID NO: 497, and an antisense strand having the sequence of SEQ ID NO: 671 ;

[0735] (159) a sense strand having the sequence of SEQ ID NO: 498, and an antisense strand having the sequence of SEQ ID NO: 672;

[0736] (160) a sense strand having the sequence of SEQ ID NO: 499, and an antisense strand having the sequence of SEQ ID NO: 673;

[0737] (161) a sense strand having the sequence of SEQ ID NO: 500, and an antisense strand having the sequence of SEQ ID NO: 674;

[0738] (162) a sense strand having the sequence of SEQ ID NO: 501, and an antisense strand having the sequence of SEQ ID NO: 675;

[0739] (163) a sense strand having the sequence of SEQ ID NO: 502, and an antisense strand having the sequence of SEQ ID NO: 676;

[0740] (164) a sense strand having the sequence of SEQ ID NO: 503, and an antisense strand having the sequence of SEQ ID NO: 677;

[0741] (165) a sense strand having the sequence of SEQ ID NO: 504, and an antisense strand having the sequence of SEQ ID NO: 678;

[0742] (166) a sense strand having the sequence of SEQ ID NO: 505, and an antisense strand having the sequence of SEQ ID NO: 679;

[0743] (167) a sense strand having the sequence of SEQ ID NO: 506, and an antisense strand having the sequence of SEQ ID NO: 680;

[0744] (168) a sense strand having the sequence of SEQ ID NO: 507, and an antisense strand having the sequence of SEQ ID NO: 681;

[0745] (169) a sense strand having the sequence of SEQ ID NO: 508, and an antisense strand having the sequence of SEQ ID NO: 682;

[0746] (170) a sense strand having the sequence of SEQ ID NO: 509, and an antisense strand having the sequence of SEQ ID NO: 683;

[0747] (171) a sense strand having the sequence of SEQ ID NO: 510, and an antisense strand having the sequence of SEQ ID NO: 684;

[0748] (172) a sense strand having the sequence of SEQ ID NO: 511, and an antisense strand having the sequence of SEQ ID NO: 685;

[0749] (173) a sense strand having the sequence of SEQ ID NO: 512, and an antisense strand having the sequence of SEQ ID NO: 686;

[0750] (174) a sense strand having the sequence of SEQ ID NO: 513, and an antisense strand having the sequence of SEQ ID NO: 687;

[0751] (175) a sense strand having the sequence of SEQ ID NO: 514, and an antisense strand having the sequence of SEQ ID NO: 688;

[0752] (176) a sense strand having the sequence of SEQ ID NO: 515, and an antisense strand having the sequence of SEQ ID NO: 689;

[0753] (177) a sense strand having the sequence of SEQ ID NO: 516, and an antisense strand having the sequence of SEQ ID NO: 690;

[0754] (178) a sense strand having the sequence of SEQ ID NO: 517, and an antisense strand having the sequence of SEQ ID NO: 691;

[0755] (179) a sense strand having the sequence of SEQ ID NO: 518, and an antisense strand having the sequence of SEQ ID NO: 692;

[0756] (180) a sense strand having the sequence of SEQ ID NO: 519, and an antisense strand having the sequence of SEQ ID NO: 693;

[0757] (181) a sense strand having the sequence of SEQ ID NO: 520, and an antisense strand having the sequence of SEQ ID NO: 694; or

[0758] (182) a sense strand having the sequence of SEQ ID NO: 521, and an antisense strand having the sequence of SEQ ID NO: 695.

[0759] In some embodiments, the sense strand and the antisense strand of the double stranded oligonucleotide are selected from any one of the following combinations, or the sense strand and the antisense strand of the double stranded oligonucleotide comprise at least 17 contiguous nucleotides sequences differing by no more than 4, 3, 2, or 1 nucleotides from the nucleotide sequences set forth in any one of the following combinations:

[0760] (1) the sense strand of the sequence set forth in SEQ ID NO: 379, and the antisense strand of the sequence set forth in SEQ ID NO: 553;

[0761] (2) the sense strand of the sequence set forth in SEQ ID NO: 430, and the antisense strand of the sequence set forth in SEQ ID NO: 604;

[0762] (3) the sense strand of the sequence set forth in SEQ ID NO: 452, and the antisense strand of the sequence set forth in SEQ ID NO: 626;

[0763] (4) the sense strand of the sequence set forth in SEQ ID NO: 438, and the antisense strand of the sequence set forth in SEQ ID NO: 612;

[0764] (5) the sense strand of the sequence set forth in SEQ ID NO: 395, and the antisense strand of the sequence set forth in SEQ ID NO: 569;

[0765] (6) the sense strand of the sequence set forth in SEQ ID NO: 350, and the antisense strand of the sequence set forth in SEQ ID NO: 524;

[0766] (7) the sense strand of the sequence set forth in SEQ ID NO: 716, and the antisense strand of the sequence set forth in SEQ ID NO: 725;

[0767] (8) the sense strand of the sequence set forth in SEQ ID NO: 719, and the antisense strand of the sequence set forth in SEQ ID NO: 728;

[0768] (9) the sense strand of the sequence set forth in SEQ ID NO: 370, and the antisense strand of the sequence set forth in SEQ ID NO: 544;

[0769] (10) the sense strand of the sequence set forth in SEQ ID NO: 373, and the antisense strand of the sequence set forth in SEQ ID NO: 547;

[0770] (11) the sense strand of the sequence set forth in SEQ ID NO: 396, and the antisense strand of the sequence set forth in SEQ ID NO: 570;

[0771] (12) the sense strand of the sequence set forth in SEQ ID NO: 450, and the antisense strand of the sequence set forth in SEQ ID NO: 624;

[0772] (13) the sense strand of the sequence set forth in SEQ ID NO: 439, and the antisense strand of the sequence set forth in SEQ ID NO: 613;

[0773] (14) the sense strand of the sequence set forth in SEQ ID NO: 440, and the antisense strand of the sequence set forth in SEQ ID NO: 614;

[0774] (15) the sense strand of the sequence set forth in SEQ ID NO: 351, and the antisense strand of the sequence set forth in SEQ ID NO: 525;

[0775] (16) the sense strand of the sequence set forth in SEQ ID NO: 353, and the antisense strand of the sequence set forth in SEQ ID NO: 527;

[0776] (17) the sense strand of the sequence set forth in SEQ ID NO: 354, and the antisense strand of the sequence set forth in SEQ ID NO: 528;

[0777] (18) the sense strand of the sequence set forth in SEQ ID NO: 436, and the antisense strand of the sequence set forth in SEQ ID NO: 610;

[0778] (19) the sense strand of the sequence set forth in SEQ ID NO: 442, and the antisense strand of the sequence set forth in SEQ ID NO: 616;

[0779] (20) the sense strand of the sequence set forth in SEQ ID NO: 488, and the antisense strand of the sequence set forth in SEQ ID NO: 662;

[0780] (21) the sense strand of the sequence set forth in SEQ ID NO: 492, and the antisense strand of the sequence set forth in SEQ ID NO: 666;

[0781] (22) the sense strand of the sequence set forth in SEQ ID NO: 715, and the antisense strand of the sequence set forth in SEQ ID NO: 724;

[0782] (23) the sense strand of the sequence set forth in SEQ ID NO: 717, and the antisense strand of the sequence set forth in SEQ ID NO: 726;

[0783] (24) the sense strand of the sequence set forth in SEQ ID NO: 718, and the antisense strand of the sequence set forth in SEQ ID NO: 727;

[0784] (25) the sense strand of the sequence recited in SEQ ID NO: 720, and the antisense strand of the sequence recited in SEQ ID NO: 729;

[0785] (26) the sense strand of the sequence recited in SEQ ID NO: 721, and the antisense strand of the sequence recited in SEQ ID NO: 730;

[0786] (27) the sense strand of the sequence recited in SEQ ID NO: 722, and the antisense strand of the sequence recited in SEQ ID NO: 731;

[0787] (28) the sense strand of the sequence recited in SEQ ID NO: 723, and the antisense strand of the sequence recited in SEQ ID NO: 732;

[0788] (29) the sense strand of the sequence recited in SEQ ID NO: 349, and the antisense strand of the sequence recited in SEQ ID NO: 523;

[0789] (30) the sense strand of the sequence recited in SEQ ID NO: 352, and the antisense strand of the sequence recited in SEQ ID NO: 526;

[0790] (31) the sense strand of the sequence recited in SEQ ID NO: 355, and the antisense strand of the sequence recited in SEQ ID NO: 529;

[0791] (32) the sense strand of the sequence recited in SEQ ID NO: 356, and the antisense strand of the sequence recited in SEQ ID NO: 530;

[0792] (33) the sense strand of the sequence recited in SEQ ID NO: 357, and the antisense strand of the sequence recited in SEQ ID NO: 531;

[0793] (34) the sense strand of the sequence recited in SEQ ID NO: 358, and the antisense strand of the sequence recited in SEQ ID NO: 532;

[0794] (35) the sense strand of the sequence recited in SEQ ID NO: 359, and the antisense strand of the sequence recited in SEQ ID NO: 533;

[0795] (36) the sense strand of the sequence recited in SEQ ID NO: 360, and the antisense strand of the sequence recited in SEQ ID NO: 534;

[0796] (37) the sense strand of the sequence recited in SEQ ID NO: 361, and the antisense strand of the sequence recited in SEQ ID NO: 535;

[0797] (38) the sense strand of the sequence recited in SEQ ID NO: 362, and the antisense strand of the sequence recited in SEQ ID NO: 536;

[0798] (39) the sense strand of the sequence recited in SEQ ID NO: 363, and the antisense strand of the sequence recited in SEQ ID NO: 537;

[0799] (40) the sense strand of the sequence recited in SEQ ID NO: 364, and the antisense strand of the sequence recited in SEQ ID NO: 538;

[0800] (41) the sense strand of the sequence recited in SEQ ID NO: 365, and the antisense strand of the sequence recited in SEQ ID NO: 539;

[0801] (42) the sense strand of the sequence recited in SEQ ID NO: 366, and the antisense strand of the sequence recited in SEQ ID NO: 540;

[0802] (43) the sense strand of the sequence recited in SEQ ID NO: 367, and the antisense strand of the sequence recited in SEQ ID NO: 541;

[0803] (44) the sense strand of the sequence recited in SEQ ID NO: 368, and the antisense strand of the sequence recited in SEQ ID NO: 542;

[0804] (45) the sense strand of the sequence recited in SEQ ID NO: 369, and the antisense strand of the sequence recited in SEQ ID NO: 543;

[0805] (46) the sense strand of the sequence recited in SEQ ID NO: 371, and the antisense strand of the sequence recited in SEQ ID NO: 545;

[0806] (47) the sense strand of the sequence recited in SEQ ID NO: 372, and the antisense strand of the sequence recited in SEQ ID NO: 546;

[0807] (48) the sense strand of the sequence recited in SEQ ID NO: 374, and the antisense strand of the sequence recited in SEQ ID NO: 548;

[0808] (49) the sense strand of the sequence recited in SEQ ID NO: 375, and the antisense strand of the sequence recited in SEQ ID NO: 549;

[0809] (50) the sense strand of the sequence recited in SEQ ID NO: 376, and the antisense strand of the sequence recited in SEQ ID NO: 550;

[0810] (51) the sense strand of the sequence recited in SEQ ID NO: 377, and the antisense strand of the sequence recited in SEQ ID NO: 551 ;

[0811] (52) the sense strand of the sequence recited in SEQ ID NO: 378, and the antisense strand of the sequence recited in SEQ ID NO: 552;

[0812] (53) the sense strand of the sequence recited in SEQ ID NO: 380, and the antisense strand of the sequence recited in SEQ ID NO: 554;

[0813] (54) the sense strand of the sequence recited in SEQ ID NO: 381, and the antisense strand of the sequence recited in SEQ ID NO: 555;

[0814] (55) the sense strand of the sequence recited in SEQ ID NO: 382, and the antisense strand of the sequence recited in SEQ ID NO: 556;

[0815] (56) the sense strand of the sequence recited in SEQ ID NO: 383, and the antisense strand of the sequence recited in SEQ ID NO: 557;

[0816] (57) the sense strand of the sequence recited in SEQ ID NO: 384, and the antisense strand of the sequence recited in SEQ ID NO: 558;

[0817] (58) the sense strand of the sequence recited in SEQ ID NO: 385, and the antisense strand of the sequence recited in SEQ ID NO: 559;

[0818] (59) the sense strand of the sequence recited in SEQ ID NO: 386, and the antisense strand of the sequence recited in SEQ ID NO: 560;

[0819] (60) the sense strand of the sequence recited in SEQ ID NO: 387, and the antisense strand of the sequence recited in SEQ ID NO: 561;

[0820] (61) the sense strand of the sequence recited in SEQ ID NO: 388, and the antisense strand of the sequence recited in SEQ ID NO: 562;

[0821] (62) the sense strand of the sequence recited in SEQ ID NO: 389, and the antisense strand of the sequence recited in SEQ ID NO: 563;

[0822] (63) the sense strand of the sequence recited in SEQ ID NO: 390, and the antisense strand of the sequence recited in SEQ ID NO: 564;

[0823] (64) the sense strand of the sequence recited in SEQ ID NO: 391, and the antisense strand of the sequence recited in SEQ ID NO: 565;

[0824] (65) the sense strand of the sequence recited in SEQ ID NO: 392, and the antisense strand of the sequence recited in SEQ ID NO: 566;

[0825] (66) the sense strand of the sequence recited in SEQ ID NO: 393, and the antisense strand of the sequence recited in SEQ ID NO: 567;

[0826] (67) the sense strand of the sequence recited in SEQ ID NO: 394, and the antisense strand of the sequence recited in SEQ ID NO: 568;

[0827] (68) the sense strand of the sequence recited in SEQ ID NO: 397, and the antisense strand of the sequence recited in SEQ ID NO: 571;

[0828] (69) the sense strand of the sequence recited in SEQ ID NO: 398, and the antisense strand of the sequence recited in SEQ ID NO: 572;

[0829] (70) the sense strand of the sequence recited in SEQ ID NO: 399, and the antisense strand of the sequence recited in SEQ ID NO: 573;

[0830] (71) the sense strand of the sequence recited in SEQ ID NO: 400, and the antisense strand of the sequence recited in SEQ ID NO: 574;

[0831] (72) the sense strand of the sequence recited in SEQ ID NO: 401, and the antisense strand of the sequence recited in SEQ ID NO: 575;

[0832] (73) the sense strand of the sequence recited in SEQ ID NO: 402, and the antisense strand of the sequence recited in SEQ ID NO: 576;

[0833] (74) the sense strand of the sequence recited in SEQ ID NO: 403, and the antisense strand of the sequence recited in SEQ ID NO: 577;

[0834] (75) the sense strand of the sequence recited in SEQ ID NO: 404, and the antisense strand of the sequence recited in SEQ ID NO: 578;

[0835] (76) the sense strand of the sequence recited in SEQ ID NO: 405, and the antisense strand of the sequence recited in SEQ ID NO: 579;

[0836] (77) the sense strand of the sequence recited in SEQ ID NO: 406, and the antisense strand of the sequence recited in SEQ ID NO: 580;

[0837] (78) the sense strand of the sequence recited in SEQ ID NO: 407, and the antisense strand of the sequence recited in SEQ ID NO: 581 ;

[0838] (79) the sense strand of the sequence recited in SEQ ID NO: 408, and the antisense strand of the sequence recited in SEQ ID NO: 582;

[0839] (80) the sense strand of the sequence recited in SEQ ID NO: 409, and the antisense strand of the sequence recited in SEQ ID NO: 583;

[0840] (81) the sense strand of the sequence recited in SEQ ID NO: 410, and the antisense strand of the sequence recited in SEQ ID NO: 584;

[0841] (82) the sense strand of the sequence recited in SEQ ID NO: 411, and the antisense strand of the sequence recited in SEQ ID NO: 585;

[0842] (83) the sense strand of the sequence recited in SEQ ID NO: 412, and the antisense strand of the sequence recited in SEQ ID NO: 586;

[0843] (84) the sense strand of the sequence recited in SEQ ID NO: 413, and the antisense strand of the sequence recited in SEQ ID NO: 587;

[0844] (85) the sense strand of the sequence recited in SEQ ID NO: 414, and the antisense strand of the sequence recited in SEQ ID NO: 588;

[0845] (86) the sense strand of the sequence recited in SEQ ID NO: 415, and the antisense strand of the sequence recited in SEQ ID NO: 589;

[0846] (87) the sense strand of the sequence recited in SEQ ID NO: 416, and the antisense strand of the sequence recited in SEQ ID NO: 590;

[0847] (88) the sense strand of the sequence recited in SEQ ID NO: 417, and the antisense strand of the sequence recited in SEQ ID NO: 591;

[0848] (89) the sense strand of the sequence recited in SEQ ID NO: 418, and the antisense strand of the sequence recited in SEQ ID NO: 592;

[0849] (90) the sense strand of the sequence recited in SEQ ID NO: 419, and the antisense strand of the sequence recited in SEQ ID NO: 593;

[0850] (91) the sense strand of the sequence recited in SEQ ID NO: 420, and the antisense strand of the sequence recited in SEQ ID NO: 594;

[0851] (92) the sense strand of the sequence recited in SEQ ID NO: 421, and the antisense strand of the sequence recited in SEQ ID NO: 595;

[0852] (93) the sense strand of the sequence recited in SEQ ID NO: 422, and the antisense strand of the sequence recited in SEQ ID NO: 596;

[0853] (94) the sense strand of the sequence recited in SEQ ID NO: 423, and the antisense strand of the sequence recited in SEQ ID NO: 597;

[0854] (95) the sense strand of the sequence recited in SEQ ID NO: 424, and the antisense strand of the sequence recited in SEQ ID NO: 598;

[0855] (96) the sense strand of the sequence recited in SEQ ID NO: 425, and the antisense strand of the sequence recited in SEQ ID NO: 599;

[0856] (97) the sense strand of the sequence recited in SEQ ID NO: 426, and the antisense strand of the sequence recited in SEQ ID NO: 600;

[0857] (98) the sense strand of the sequence recited in SEQ ID NO: 427, and the antisense strand of the sequence recited in SEQ ID NO: 601;

[0858] (99) the sense strand of the sequence recited in SEQ ID NO: 428, and the antisense strand of the sequence recited in SEQ ID NO: 602;

[0859] (100) the sense strand of the sequence recited in SEQ ID NO: 429, and the antisense strand of the sequence recited in SEQ ID NO: 603;

[0860] (101) the sense strand of the sequence recited in SEQ ID NO: 431, and the antisense strand of the sequence recited in SEQ ID NO: 605;

[0861] (102) the sense strand of the sequence recited in SEQ ID NO: 432, and the antisense strand of the sequence recited in SEQ ID NO: 606;

[0862] (103) the sense strand of the sequence as shown in SEQ ID NO: 433, and the antisense strand of the sequence as shown in SEQ ID NO: 607;

[0863] (104) the sense strand of the sequence as shown in SEQ ID NO: 434, and the antisense strand of the sequence as shown in SEQ ID NO: 608;

[0864] (105) the sense strand of the sequence as shown in SEQ ID NO: 435, and the antisense strand of the sequence as shown in SEQ ID NO: 609;

[0865] (106) the sense strand of the sequence as shown in SEQ ID NO: 437, and the antisense strand of the sequence as shown in SEQ ID NO: 611;

[0866] (107) the sense strand of the sequence as shown in SEQ ID NO: 441, and the antisense strand of the sequence as shown in SEQ ID NO: 615;

[0867] (108) the sense strand of the sequence as shown in SEQ ID NO: 443, and the antisense strand of the sequence as shown in SEQ ID NO: 617;

[0868] (109) the sense strand of the sequence as shown in SEQ ID NO: 444, and the antisense strand of the sequence as shown in SEQ ID NO: 618;

[0869] (110) the sense strand of the sequence as shown in SEQ ID NO: 445, and the antisense strand of the sequence as shown in SEQ ID NO: 619;

[0870] (111) the sense strand of the sequence as shown in SEQ ID NO: 446, and the antisense strand of the sequence as shown in SEQ ID NO: 620;

[0871] (112) the sense strand of the sequence as shown in SEQ ID NO: 447, and the antisense strand of the sequence as shown in SEQ ID NO: 621;

[0872] (113) the sense strand of the sequence as shown in SEQ ID NO: 448, and the antisense strand of the sequence as shown in SEQ ID NO: 622;

[0873] (114) the sense strand of the sequence as shown in SEQ ID NO: 449, and the antisense strand of the sequence as shown in SEQ ID NO: 623;

[0874] (115) the sense strand of the sequence as shown in SEQ ID NO: 451, and the antisense strand of the sequence as shown in SEQ ID NO: 625;

[0875] (116) the sense strand of the sequence as shown in SEQ ID NO: 453, and the antisense strand of the sequence as shown in SEQ ID NO: 627;

[0876] (117) the sense strand of the sequence as shown in SEQ ID NO: 454, and the antisense strand of the sequence as shown in SEQ ID NO: 628;

[0877] (118) the sense strand of the sequence as shown in SEQ ID NO: 455, and the antisense strand of the sequence as shown in SEQ ID NO: 629;

[0878] (119) the sense strand of the sequence as shown in SEQ ID NO: 456, and the antisense strand of the sequence as shown in SEQ ID NO: 630;

[0879] (120) the sense strand of the sequence as shown in SEQ ID NO: 457, and the antisense strand of the sequence as shown in SEQ ID NO: 631;

[0880] (121) the sense strand of the sequence as shown in SEQ ID NO: 458, and the antisense strand of the sequence as shown in SEQ ID NO: 632;

[0881] (122) the sense strand of the sequence as shown in SEQ ID NO: 459, and the antisense strand of the sequence as shown in SEQ ID NO: 633;

[0882] (123) the sense strand of the sequence as shown in SEQ ID NO: 460, and the antisense strand of the sequence as shown in SEQ ID NO: 634;

[0883] (124) the sense strand of the sequence as shown in SEQ ID NO: 461, and the antisense strand of the sequence as shown in SEQ ID NO: 635;

[0884] (125) the sense strand of the sequence as shown in SEQ ID NO: 462, and the antisense strand of the sequence as shown in SEQ ID NO: 636;

[0885] (126) the sense strand of the sequence as shown in SEQ ID NO: 463, and the antisense strand of the sequence as shown in SEQ ID NO: 637;

[0886] (127) the sense strand of the sequence as shown in SEQ ID NO: 464, and the antisense strand of the sequence as shown in SEQ ID NO: 638;

[0887] (128) the sense strand of the sequence recited in SEQ ID NO: 465, and the antisense strand of the sequence recited in SEQ ID NO: 639;

[0888] (129) the sense strand of the sequence recited in SEQ ID NO: 466, and the antisense strand of the sequence recited in SEQ ID NO: 640;

[0889] (130) the sense strand of the sequence recited in SEQ ID NO: 467, and the antisense strand of the sequence recited in SEQ ID NO: 641;

[0890] (131) the sense strand of the sequence recited in SEQ ID NO: 468, and the antisense strand of the sequence recited in SEQ ID NO: 642;

[0891] (132) the sense strand of the sequence recited in SEQ ID NO: 469, and the antisense strand of the sequence recited in SEQ ID NO: 643;

[0892] (133) the sense strand of the sequence recited in SEQ ID NO: 470, and the antisense strand of the sequence recited in SEQ ID NO: 644;

[0893] (134) the sense strand of the sequence recited in SEQ ID NO: 471, and the antisense strand of the sequence recited in SEQ ID NO: 645;

[0894] (135) the sense strand of the sequence recited in SEQ ID NO: 472, and the antisense strand of the sequence recited in SEQ ID NO: 646;

[0895] (136) the sense strand of the sequence recited in SEQ ID NO: 473, and the antisense strand of the sequence recited in SEQ ID NO: 647;

[0896] (137) the sense strand of the sequence recited in SEQ ID NO: 474, and the antisense strand of the sequence recited in SEQ ID NO: 648;

[0897] (138) the sense strand of the sequence recited in SEQ ID NO: 475, and the antisense strand of the sequence recited in SEQ ID NO: 649;

[0898] (139) the sense strand of the sequence recited in SEQ ID NO: 476, and the antisense strand of the sequence recited in SEQ ID NO: 650;

[0899] (140) the sense strand of the sequence recited in SEQ ID NO: 477, and the antisense strand of the sequence recited in SEQ ID NO: 651;

[0900] (141) the sense strand of the sequence recited in SEQ ID NO: 478, and the antisense strand of the sequence recited in SEQ ID NO: 652;

[0901] (142) the sense strand of the sequence recited in SEQ ID NO: 479, and the antisense strand of the sequence recited in SEQ ID NO: 653;

[0902] (143) the sense strand of the sequence recited in SEQ ID NO: 480, and the antisense strand of the sequence recited in SEQ ID NO: 654;

[0903] (144) the sense strand of the sequence recited in SEQ ID NO: 481, and the antisense strand of the sequence recited in SEQ ID NO: 655;

[0904] (145) the sense strand of the sequence recited in SEQ ID NO: 482, and the antisense strand of the sequence recited in SEQ ID NO: 656;

[0905] (146) the sense strand of the sequence recited in SEQ ID NO: 483, and the antisense strand of the sequence recited in SEQ ID NO: 657;

[0906] (147) the sense strand of the sequence recited in SEQ ID NO: 484, and the antisense strand of the sequence recited in SEQ ID NO: 658;

[0907] (148) the sense strand of the sequence recited in SEQ ID NO: 485, and the antisense strand of the sequence recited in SEQ ID NO: 659;

[0908] (149) the sense strand of the sequence recited in SEQ ID NO: 486, and the antisense strand of the sequence recited in SEQ ID NO: 660;

[0909] (150) the sense strand of the sequence recited in SEQ ID NO: 487, and the antisense strand of the sequence recited in SEQ ID NO: 661;

[0910] (151) the sense strand of the sequence recited in SEQ ID NO: 489, and the antisense strand of the sequence recited in SEQ ID NO: 663;

[0911] (152) the sense strand of the sequence recited in SEQ ID NO: 490, and the antisense strand of the sequence recited in SEQ ID NO: 664;

[0912] (153) the sense strand of the sequence recited in SEQ ID NO: 491, and the antisense strand of the sequence recited in SEQ ID NO: 665;

[0913] (154) the sense strand of the sequence as shown in SEQ ID NO: 493, and the antisense strand of the sequence as shown in SEQ ID NO: 667;

[0914] (155) the sense strand of the sequence as shown in SEQ ID NO: 494, and the antisense strand of the sequence as shown in SEQ ID NO: 668;

[0915] (156) the sense strand of the sequence as shown in SEQ ID NO: 495, and the antisense strand of the sequence as shown in SEQ ID NO: 669;

[0916] (157) the sense strand of the sequence as shown in SEQ ID NO: 496, and the antisense strand of the sequence as shown in SEQ ID NO: 670;

[0917] (158) the sense strand of the sequence as shown in SEQ ID NO: 497, and the antisense strand of the sequence as shown in SEQ ID NO: 671;

[0918] (159) the sense strand of the sequence as shown in SEQ ID NO: 498, and the antisense strand of the sequence as shown in SEQ ID NO: 672;

[0919] (160) the sense strand of the sequence as shown in SEQ ID NO: 499, and the antisense strand of the sequence as shown in SEQ ID NO: 673;

[0920] (161) the sense strand of the sequence as shown in SEQ ID NO: 500, and the antisense strand of the sequence as shown in SEQ ID NO: 674;

[0921] (162) the sense strand of the sequence as shown in SEQ ID NO: 501, and the antisense strand of the sequence as shown in SEQ ID NO: 675;

[0922] (163) the sense strand of the sequence as shown in SEQ ID NO: 502, and the antisense strand of the sequence as shown in SEQ ID NO: 676;

[0923] (164) the sense strand of the sequence as shown in SEQ ID NO: 503, and the antisense strand of the sequence as shown in SEQ ID NO: 677;

[0924] (165) the sense strand of the sequence as shown in SEQ ID NO: 504, and the antisense strand of the sequence as shown in SEQ ID NO: 678;

[0925] (166) the sense strand of the sequence recited in SEQ ID NO: 505, and the antisense strand of the sequence recited in SEQ ID NO: 679;

[0926] (167) the sense strand of the sequence recited in SEQ ID NO: 506, and the antisense strand of the sequence recited in SEQ ID NO: 680;

[0927] (168) the sense strand of the sequence recited in SEQ ID NO: 507, and the antisense strand of the sequence recited in SEQ ID NO: 681;

[0928] (169) the sense strand of the sequence recited in SEQ ID NO: 508, and the antisense strand of the sequence recited in SEQ ID NO: 682;

[0929] (170) the sense strand of the sequence recited in SEQ ID NO: 509, and the antisense strand of the sequence recited in SEQ ID NO: 683;

[0930] (171) the sense strand of the sequence recited in SEQ ID NO: 510, and the antisense strand of the sequence recited in SEQ ID NO: 684;

[0931] (172) the sense strand of the sequence recited in SEQ ID NO: 511, and the antisense strand of the sequence recited in SEQ ID NO: 685;

[0932] (173) the sense strand of the sequence recited in SEQ ID NO: 512, and the antisense strand of the sequence recited in SEQ ID NO: 686;

[0933] (174) the sense strand of the sequence recited in SEQ ID NO: 513, and the antisense strand of the sequence recited in SEQ ID NO: 687;

[0934] (175) the sense strand of the sequence recited in SEQ ID NO: 514, and the antisense strand of the sequence recited in SEQ ID NO: 688;

[0935] (176) the sense strand of the sequence recited in SEQ ID NO: 515, and the antisense strand of the sequence recited in SEQ ID NO: 689;

[0936] (177) the sense strand of the sequence recited in SEQ ID NO: 516, and the antisense strand of the sequence recited in SEQ ID NO: 690;

[0937] (178) the sense strand of the sequence recited in SEQ ID NO: 517, and the antisense strand of the sequence recited in SEQ ID NO: 691;

[0938] (179) the sense strand of the sequence as shown in SEQ ID NO: 518, and the antisense strand of the sequence as shown in SEQ ID NO: 692;

[0939] (180) the sense strand of the sequence as shown in SEQ ID NO: 519, and the antisense strand of the sequence as shown in SEQ ID NO: 693;

[0940] (181) the sense strand of the sequence as shown in SEQ ID NO: 520, and the antisense strand of the sequence as shown in SEQ ID NO: 694; or

[0941] (182) the sense strand of the sequence as shown in SEQ ID NO: 521, and the antisense strand of the sequence as shown in SEQ ID NO: 695.

[0942] In some embodiments, the sense strand and the antisense strand of the double stranded oligonucleotide are selected from any one of the following combinations; or the sense strand and the antisense strand of the double stranded oligonucleotide comprise at least 17 contiguous nucleotides of difference of no more than 4, 3, 2, or 1 nucleotides from the nucleotide sequences set forth in any one of the following combinations:

[0943] (1) the sense strand having the sequence as shown in SEQ ID NO: 379, and the antisense strand having the sequence as shown in SEQ ID NO: 553;

[0944] (2) the sense strand having the sequence as shown in SEQ ID NO: 430, and the antisense strand having the sequence as shown in SEQ ID NO: 604;

[0945] (3) the sense strand having the sequence as shown in SEQ ID NO: 452, and the antisense strand having the sequence as shown in SEQ ID NO: 626;

[0946] (4) the sense strand having the sequence as shown in SEQ ID NO: 438, and the antisense strand having the sequence as shown in SEQ ID NO: 612;

[0947] (5) the sense strand having the sequence as shown in SEQ ID NO: 395, and the antisense strand having the sequence as shown in SEQ ID NO: 569;

[0948] (6) the sense strand having the sequence as shown in SEQ ID NO: 350, and the antisense strand having the sequence as shown in SEQ ID NO: 524;

[0949] (7) the sense strand having the sequence as shown in SEQ ID NO: 370, and the antisense strand having the sequence as shown in SEQ ID NO: 544;

[0950] (8) a sense strand having the sequence of SEQ ID NO: 373, and an antisense strand having the sequence of SEQ ID NO: 547;

[0951] (9) a sense strand having the sequence of SEQ ID NO: 396, and an antisense strand having the sequence of SEQ ID NO: 570;

[0952] (10) a sense strand having the sequence of SEQ ID NO: 450, and an antisense strand having the sequence of SEQ ID NO: 624;

[0953] (11) a sense strand having the sequence of SEQ ID NO: 351, and an antisense strand having the sequence of SEQ ID NO: 525;

[0954] (12) a sense strand having the sequence of SEQ ID NO: 353, and an antisense strand having the sequence of SEQ ID NO: 527;

[0955] (13) a sense strand having the sequence of SEQ ID NO: 354, and an antisense strand having the sequence of SEQ ID NO: 528;

[0956] (14) a sense strand having the sequence of SEQ ID NO: 436, and an antisense strand having the sequence of SEQ ID NO: 610;

[0957] (15) a sense strand having the sequence of SEQ ID NO: 442, and an antisense strand having the sequence of SEQ ID NO: 616;

[0958] (16) a sense strand having the sequence of SEQ ID NO: 488, and an antisense strand having the sequence of SEQ ID NO: 662; or

[0959] (17) a sense strand having the sequence of SEQ ID NO: 492, and an antisense strand having the sequence of SEQ ID NO: 666.

[0960] In some embodiments, the sense strand and the antisense strand of the double stranded oligonucleotide are selected from any one of the following combinations, or the sense strand and the antisense strand of the double stranded oligonucleotide comprise at least 17 contiguous nucleotides sequences that differ by no more than 4, 3, 2, or 1 nucleotides from the nucleotide sequences set forth in any one of the following combinations:

[0961] (1) the sense strand of the sequence as shown in SEQ ID NO: 379, and the antisense strand of the sequence as shown in SEQ ID NO: 553;

[0962] (2) the sense strand of the sequence as shown in SEQ ID NO: 430, and the antisense strand of the sequence as shown in SEQ ID NO: 604;

[0963] (3) the sense strand of the sequence as shown in SEQ ID NO: 452, and the antisense strand of the sequence as shown in SEQ ID NO: 626;

[0964] (4) the sense strand of the sequence as shown in SEQ ID NO: 438, and the antisense strand of the sequence as shown in SEQ ID NO: 612;

[0965] (5) the sense strand of the sequence as shown in SEQ ID NO: 395, and the antisense strand of the sequence as shown in SEQ ID NO: 569;

[0966] (6) the sense strand of the sequence as shown in SEQ ID NO: 350, and the antisense strand of the sequence as shown in SEQ ID NO: 524;

[0967] (7) the sense strand of the sequence as shown in SEQ ID NO: 370, and the antisense strand of the sequence as shown in SEQ ID NO: 544;

[0968] (8) the sense strand of the sequence as shown in SEQ ID NO: 373, and the antisense strand of the sequence as shown in SEQ ID NO: 547;

[0969] (9) the sense strand of the sequence as shown in SEQ ID NO: 396, and the antisense strand of the sequence as shown in SEQ ID NO: 570;

[0970] (10) the sense strand of the sequence as shown in SEQ ID NO: 450, and the antisense strand of the sequence as shown in SEQ ID NO: 624;

[0971] (11) the sense strand of the sequence as shown in SEQ ID NO: 351, and the antisense strand of the sequence as shown in SEQ ID NO: 525;

[0972] (12) the sense strand of the sequence as shown in SEQ ID NO: 353, and the antisense strand of the sequence as shown in SEQ ID NO: 527;

[0973] (13) the sense strand of the sequence as shown in SEQ ID NO: 354, and the antisense strand of the sequence as shown in SEQ ID NO: 528;

[0974] (14) the sense strand of the sequence set forth in SEQ ID NO: 436, and the antisense strand of the sequence set forth in SEQ ID NO: 610;

[0975] (15) the sense strand of the sequence set forth in SEQ ID NO: 442, and the antisense strand of the sequence set forth in SEQ ID NO: 616;

[0976] (16) the sense strand of the sequence set forth in SEQ ID NO: 488, and the antisense strand of the sequence set forth in SEQ ID NO: 662; or

[0977] (17) the sense strand of the sequence set forth in SEQ ID NO: 492, and the antisense strand of the sequence set forth in SEQ ID NO: 666.

[0978] In some embodiments, the sense strand and the antisense strand of the double stranded oligonucleotide are selected from any one of the following combinations; or the sense strand and the antisense strand of the double stranded oligonucleotide comprise at least 17 contiguous nucleotides of sequence that differs by no more than 4, 3, 2, or 1 nucleotides from the nucleotide sequences set forth in any one of the following combinations:

[0979] (1) the sense strand of the sequence set forth in SEQ ID NO: 379, and the antisense strand of the sequence set forth in SEQ ID NO: 553;

[0980] (2) the sense strand of the sequence set forth in SEQ ID NO: 430, and the antisense strand of the sequence set forth in SEQ ID NO: 604;

[0981] (3) the sense strand of the sequence set forth in SEQ ID NO: 452, and the antisense strand of the sequence set forth in SEQ ID NO: 626;

[0982] (4) the sense strand of the sequence set forth in SEQ ID NO: 395, and the antisense strand of the sequence set forth in SEQ ID NO: 569;

[0983] (5) the sense strand of the sequence set forth in SEQ ID NO: 438, and the antisense strand of the sequence set forth in SEQ ID NO: 612;

[0984] (6) the sense strand of the sequence set forth in SEQ ID NO: 350, and the antisense strand of the sequence set forth in SEQ ID NO: 524;

[0985] (7) the sense strand of the sequence set forth in SEQ ID NO: 370, and the antisense strand of the sequence set forth in SEQ ID NO: 544;

[0986] (8) a sense strand having a sequence as set forth in SEQ ID NO: 373, and an antisense strand having a sequence as set forth in SEQ ID NO: 547;

[0987] (9) a sense strand having a sequence as set forth in SEQ ID NO: 396, and an antisense strand having a sequence as set forth in SEQ ID NO: 570;

[0988] (10) a sense strand having a sequence as set forth in SEQ ID NO: 439, and an antisense strand having a sequence as set forth in SEQ ID NO: 613;

[0989] (11) a sense strand having a sequence as set forth in SEQ ID NO: 440, and an antisense strand having a sequence as set forth in SEQ ID NO: 614; or

[0990] (12) a sense strand having a sequence as set forth in SEQ ID NO: 450, and an antisense strand having a sequence as set forth in SEQ ID NO: 624.

[0991] In some embodiments, the sense strand and the antisense strand of the double stranded oligonucleotide are selected from any one of the following combinations; or the sense strand and the antisense strand of the double stranded oligonucleotide comprise at least 17 contiguous nucleotides of sequence that differs by no more than 4, 3, 2, or 1 nucleotides from the nucleotide sequences set forth in any one of the following combinations:

[0992] (1) a sense strand of sequence as set forth in SEQ ID NO: 379, and an antisense strand of sequence as set forth in SEQ ID NO: 553;

[0993] (2) a sense strand of sequence as set forth in SEQ ID NO: 430, and an antisense strand of sequence as set forth in SEQ ID NO: 604;

[0994] (3) a sense strand of sequence as set forth in SEQ ID NO: 452, and an antisense strand of sequence as set forth in SEQ ID NO: 626;

[0995] (4) a sense strand of sequence as set forth in SEQ ID NO: 395, and an antisense strand of sequence as set forth in SEQ ID NO: 569;

[0996] (5) a sense strand of sequence as set forth in SEQ ID NO: 438, and an antisense strand of sequence as set forth in SEQ ID NO: 612;

[0997] (6) a sense strand of sequence as set forth in SEQ ID NO: 350, and an antisense strand of sequence as set forth in SEQ ID NO: 524;

[0998] (7) a sense strand as set forth in SEQ ID NO: 370, and an antisense strand as set forth in SEQ ID NO: 544;

[0999] (8) a sense strand as set forth in SEQ ID NO: 373, and an antisense strand as set forth in SEQ ID NO: 547;

[1000] (9) a sense strand as set forth in SEQ ID NO: 396, and an antisense strand as set forth in SEQ ID NO: 570;

[1001] (10) a sense strand as set forth in SEQ ID NO: 439, and an antisense strand as set forth in SEQ ID NO: 613;

[1002] (11) a sense strand as set forth in SEQ ID NO: 440, and an antisense strand as set forth in SEQ ID NO: 614; or

[1003] (12) a sense strand as set forth in SEQ ID NO: 450, and an antisense strand as set forth in SEQ ID NO: 624.

[1004] In some embodiments, the sense strand and the antisense strand of the double stranded oligonucleotide comprise at least 17 contiguous nucleotides of any one of the following combinations; or the sense strand and the antisense strand of the double stranded oligonucleotide comprise at least 17 contiguous nucleotides of no more than 4, 3, 2, or 1 nucleotides different from the nucleotide sequences set forth in any one of the following combinations:

[1005] (1) a sense strand having the sequence set forth in SEQ ID NO: 379, and an antisense strand having the sequence set forth in SEQ ID NO: 553;

[1006] (2) a sense strand having the sequence set forth in SEQ ID NO: 430, and an antisense strand having the sequence set forth in SEQ ID NO: 604;

[1007] (3) a sense strand having the sequence set forth in SEQ ID NO: 452, and an antisense strand having the sequence set forth in SEQ ID NO: 626;

[1008] (4) a sense strand having the sequence set forth in SEQ ID NO: 395, and an antisense strand having the sequence set forth in SEQ ID NO: 569;

[1009] (5) a sense strand having the sequence set forth in SEQ ID NO: 438, and an antisense strand having the sequence set forth in SEQ ID NO: 612;

[1010] (6) a sense strand having a sequence as set forth in SEQ ID NO: 350, and an antisense strand having a sequence as set forth in SEQ ID NO: 524;

[1011] (7) a sense strand having a sequence as set forth in SEQ ID NO: 716, and an antisense strand having a sequence as set forth in SEQ ID NO: 725; or

[1012] (8) a sense strand having a sequence as set forth in SEQ ID NO: 719, and an antisense strand having a sequence as set forth in SEQ ID NO: 728.

[1013] In some embodiments, the sense strand and the antisense strand of the double stranded oligonucleotide comprise any of the following combinations, respectively; or the sense strand and the antisense strand of the double stranded oligonucleotide comprise at least 17 contiguous nucleotides sequences of no more than 4, 3, 2, or 1 nucleotides different from the nucleotide sequences set forth in any of the following combinations:

[1014] (1) a sense strand having a sequence as set forth in SEQ ID NO: 379, and an antisense strand having a sequence as set forth in SEQ ID NO: 553;

[1015] (2) a sense strand having a sequence as set forth in SEQ ID NO: 430, and an antisense strand having a sequence as set forth in SEQ ID NO: 604;

[1016] (3) a sense strand having a sequence as set forth in SEQ ID NO: 452, and an antisense strand having a sequence as set forth in SEQ ID NO: 626;

[1017] (4) a sense strand having a sequence as set forth in SEQ ID NO: 395, and an antisense strand having a sequence as set forth in SEQ ID NO: 569;

[1018] (5) a sense strand having a sequence as set forth in SEQ ID NO: 438, and an antisense strand having a sequence as set forth in SEQ ID NO: 612;

[1019] (6) a sense strand having a sequence as set forth in SEQ ID NO: 350, and an antisense strand having a sequence as set forth in SEQ ID NO: 524;

[1020] (7) a sense strand having a sequence as set forth in SEQ ID NO: 716, and an antisense strand having a sequence as set forth in SEQ ID NO: 725; or

[1021] (8) a sense strand having a sequence as set forth in SEQ ID NO: 719, and an antisense strand having a sequence as set forth in SEQ ID NO: 728.

[1022] In some embodiments, at least one nucleotide of the double stranded oligonucleotide is conjugated to one or more targeting ligands.

[1023] In some embodiments, the targeting ligand is conjugated to the sense strand of the oligonucleotide.

[1024] In some embodiments, the targeting ligand is conjugated to any one nucleotide of the sense strand of the oligonucleotide.

[1025] In some embodiments, the targeting ligand is conjugated to the 5' end of the sense strand of the oligonucleotide.

[1026] In some embodiments, the targeting ligand is conjugated to the sense strand of the double stranded oligonucleotide at the 3'-end.

[1027] In some embodiments, the targeting ligand comprises a protein, a carbohydrate, or a lipid.

[1028] In some embodiments, the protein is selected from the group consisting of a natural protein, a synthetic polyamino acid, and an antibody.

[1029] In some embodiments, the natural protein is selected from the group consisting of human serum albumin, low density lipoprotein, or globulin.

[1030] In some embodiments, the synthetic polyamino acid is selected from the group consisting of polylysine, poly L-aspartic acid, poly L-glutamic acid, styrene-maleic anhydride copolymer, poly(L-lactic-co-ethylene glycol) copolymer, divinyl ether-maleic anhydride copolymer, N-(2-hydroxypropyl)methacrylamide copolymer, polyethylene glycol, polyvinyl alcohol, polyurethane, poly(2-ethylacrylic acid), N-isopropyl acrylamide polymer, or polyphosphazene.

[1031] In some embodiments, the carbohydrate is selected from the group consisting of dextran, pullulan, chitin, chitosan, inulin, cyclodextrin, an aminosugar, or hyaluronic acid.

[1032] In some embodiments, the lipid is selected from the group consisting of a fatty acid, a sterol, or a phospholipid.

[1033] In some embodiments, the fatty acid is selected from the group consisting of decanoic acid, octanoic acid, lauric acid, palmitic acid, myristic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, arachidonic acid, or eicosanoic acid.

[1034] In some embodiments, the sterol is selected from the group consisting of cholesterol, cholesteryl, cholestanol, stigmasterol, cholestanic acid, or ergosterol.

[1035] In some embodiments, the phospholipid is selected from the group consisting of di-hexadecyl-rac-glycerol or triethyl-amine 1,2-di-O-hexadecyl-rac-glycerol-3-hydrogen phosphonate.

[1036] In some embodiments, the targeting ligand comprises an aminosugar.

[1037] In some embodiments, the targeting ligand comprises an N-acetylgalactosamine (GalNAc) moiety.

[1038] In some embodiments, the GalNac moiety is a monovalent GalNAc moiety, a bivalent GalNAc moiety, a trivalent GalNAc moiety, or a tetravalent GalNAc moiety.

[1039] In some embodiments, the targeting ligand has the following structure:

[1040] In some embodiments, the targeting ligand has the following structure:

[1041] In some embodiments, the 3’ terminal end of the sense strand of the double- stranded oligonucleotide is conjugated to a targeting ligand of the following structure:

[1042] In some embodiments, the sense strand and the antisense strand of the double- stranded oligonucleotide are selected from any one of the following combinations, respectively; or the sense strand and the antisense strand of the double-stranded oligonucleotide comprise at least a 17 contiguous nucleotide sequence that differs by no more than 4, 3, 2, or 1 nucleotides from the nucleotide sequence set forth in any one of the following combinations:

[1043] (1) the sense strand has the sequence of SEQ ID NO: 379, and the antisense strand has the sequence of SEQ ID NO: 553;

[1044] (2) the sense strand has the sequence of SEQ ID NO: 430, and the antisense strand has the sequence of SEQ ID NO: 604;

[1045] (3) the sense strand has the sequence of SEQ ID NO: 452, and the antisense strand has the sequence of SEQ ID NO: 626;

[1046] (4) the sense strand has the sequence of SEQ ID NO: 395, and the antisense strand has the sequence of SEQ ID NO: 569;

[1047] (5) the sense strand has the sequence of SEQ ID NO: 438, and the antisense strand has the sequence of SEQ ID NO: 612;

[1048] (6) a sense strand having a sequence as set forth in SEQ ID NO: 350, and an antisense strand having a sequence as set forth in SEQ ID NO: 524;

[1049] (7) a sense strand having a sequence as set forth in SEQ ID NO: 716, and an antisense strand having a sequence as set forth in SEQ ID NO: 725; or

[1050] (8) a sense strand having a sequence as set forth in SEQ ID NO: 719, and an antisense strand having a sequence as set forth in SEQ ID NO: 728.

[1051] In some embodiments, the sense strand and the antisense strand of the double stranded oligonucleotide are selected from any one of the following combinations; or the sense strand and the antisense strand of the double stranded oligonucleotide comprise at least 17 contiguous nucleotides of sequence that differs by no more than 4, 3, 2, or 1 nucleotides from the nucleotide sequences set forth in any one of the following combinations:

[1052] (1) a sense strand having a sequence as set forth in SEQ ID NO: 379, and an antisense strand having a sequence as set forth in SEQ ID NO: 553;

[1053] (2) a sense strand having a sequence as set forth in SEQ ID NO: 430, and an antisense strand having a sequence as set forth in SEQ ID NO: 604;

[1054] (3) a sense strand having a sequence as set forth in SEQ ID NO: 452, and an antisense strand having a sequence as set forth in SEQ ID NO: 626;

[1055] (4) a sense strand having a sequence as set forth in SEQ ID NO: 395, and an antisense strand having a sequence as set forth in SEQ ID NO: 569;

[1056] (5) a sense strand having a sequence as set forth in SEQ ID NO: 438, and an antisense strand having a sequence as set forth in SEQ ID NO: 612;

[1057] (6) a sense strand having a sequence as set forth in SEQ ID NO: 350, and an antisense strand having a sequence as set forth in SEQ ID NO: 524;

[1058] (7) a sense strand having a sequence as set forth in SEQ ID NO: 716, and an antisense strand having a sequence as set forth in SEQ ID NO: 725; or

[1059] (8) a sense strand having a sequence as set forth in SEQ ID NO: 719, and an antisense strand having a sequence as set forth in SEQ ID NO: 728.

[1060] In another aspect, the present disclosure provides a composition comprising the foregoing double-stranded oligonucleotide or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier.

[1061] In some embodiments, the composition further comprises one or more additional therapeutic components.

[1062] In some embodiments, the composition is packaged in a kit, container, wrapper, dispenser, pre-filled syringe, or vial.

[1063] In some embodiments, the composition is formulated for ocular, vaginal, rectal, intranasal, transdermal, subcutaneous administration, intravenous drip, intra-arterial, translymphatic, intrabronchial, intrapleural, intraperitoneal, intracerebrospinal, or intramuscular injection, pulmonary, intrathecal, or intraventricular administration.

[1064] In another aspect, the present disclosure provides a cell comprising the foregoing double-stranded oligonucleotide.

[1065] In another aspect, the present disclosure provides a method of inhibiting expression of a blood coagulation factor XI gene in vitro, the method comprising contacting an effective amount of the foregoing double-stranded oligonucleotide and / or the foregoing composition with a cell.

[1066] In another aspect, the present disclosure provides a kit comprising the foregoing double-stranded oligonucleotide and / or the foregoing composition.

[1067] In another aspect, the present disclosure provides use of the foregoing double-stranded oligonucleotide and / or the foregoing composition in the manufacture of a medicament for preventing or treating a disease.

[1068] In some embodiments, the disease is a thromboembolic disease and / or ischemic stroke.

[1069] In some embodiments, the thromboembolic disease comprises one or more of deep vein thrombosis, venous or arterial thrombosis, pulmonary embolism, myocardial infarction, stroke, thrombosis caused by atrial fibrillation, thrombosis after cardiovascular bypass, thrombosis after knee and hip joint replacement, and thrombosis associated with chronic kidney disease or end-stage kidney disease.

[1070] In some embodiments, the thrombosis associated with chronic kidney disease or end-stage kidney disease comprises dialysis-associated thrombosis, or other procoagulant states.

[1071] In another aspect, the present disclosure provides a method of treating or preventing a disease or condition in a subject, wherein the method comprises administering to the subject an amount of the foregoing oligonucleotide and / or the foregoing composition sufficient to inhibit expression of a blood coagulation factor XI gene in the subject.

[1072] In some embodiments, the disease is a thromboembolic disease and / or ischemic stroke.

[1073] In some embodiments, the thromboembolic disease comprises one or more of deep vein thrombosis, venous or arterial thrombosis, pulmonary embolism, myocardial infarction, stroke, thrombosis resulting from atrial fibrillation, thrombosis after cardiovascular bypass, thrombosis after knee and hip joint replacement, thrombosis associated with chronic kidney disease or end-stage renal disease.

[1074] In some embodiments, the thrombosis associated with chronic kidney disease or end-stage renal disease comprises dialysis-associated thrombosis, or other procoagulant states.

[1075] For purposes of clarity and brevity, features described as part of some embodiments herein that are identical or separate will be understood to encompass some embodiments having all or some of the described features in combination.

[1076] Hereinafter, the present disclosure will be described in more detail with reference to specific examples, however, the examples are for illustrative purposes only and do not limit the effect of the present disclosure.

[1077] Examples

[1078] The structure of the compound is determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS). The chemical shift δ is given in 10-6 (ppm) units. The determination of NMR is carried out with a Bruker nuclear magnetic instrument, and the determination solvent is deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD), and the internal standard is tetramethylsilane (TMS).

[1079] The determination of LCMS is carried out with Agilent 1260 Infinity II (ESI) mass spectrometer, Waters UPLC H Class plus (ESI), or Shimadzu LCMS-2020 (ESI).

[1080] High performance liquid chromatography (HPLC) analysis uses Agilent 1260 or Shimadzu LC-20AD.

[1081] Preparative high performance liquid chromatography (pre-HPLC) uses GILSON GX-281 or Agilent 1260 Infinity II preparative liquid.

[1082] Chiral preparation uses supercritical fluid chromatography (SFC), and the instrument uses Shimadzu LC-30Adsf or Shimadzu LC-20AD.

[1083] Thin layer chromatography silica gel plate uses Anhui Liangchen Silicon Source Material Co., Ltd. GF254 acrylic adhesive silica gel plate. The silica gel plate used in thin layer chromatography has a specification of 0.2 mm, and the silica gel plate used in thin layer chromatography separation and purification of products has a specification of 0.5 mm.

[1084] Column chromatography generally uses 200-300 mesh silica gel from Anhui Liangchen Silicon Source Material Co., Ltd. as a carrier.

[1085] The determination of the average inhibition rate of the kinase and the IC50 value uses a SpectraMax i3X enzyme marker (MD, USA).

[1086] Known starting materials of the present disclosure can be synthesized according to methods known in the art or purchased from companies such as Bide Pharmaceutical, Leyan, Shaoyuan Chemical Technology, and Anning Chemicals.

[1087] In the following examples, unless otherwise specified, the reactions were carried out under an argon or nitrogen atmosphere.

[1088] An argon or nitrogen atmosphere refers to a reaction bottle connected to an argon or nitrogen balloon with a volume of about 1 L.

[1089] A hydrogen atmosphere refers to a reaction bottle connected to a hydrogen balloon with a volume of about 1 L.

[1090] The hydrogenation reaction is usually vacuumed, filled with hydrogen, and repeated 3 times.

[1091] An oxygen atmosphere refers to a reaction bottle connected to an oxygen balloon with a volume of about 1 L.

[1092] In the following examples, unless otherwise specified, the solution refers to an aqueous solution, and the reaction temperature is room temperature, which is 20-30°C.

[1093] The reaction progress in the examples is monitored by thin layer chromatography (TLC). The developing agent used in the reaction, the eluent system of column chromatography used for purification of compounds, and the developing agent system of thin layer chromatography include: A: dichloromethane / methanol system, B: petroleum ether / ethyl acetate system. The volume ratio of the solvents is adjusted according to the polarity of the compounds, and a small amount of triethylamine and acetic acid or other basic or acidic reagents can also be added for adjustment.

[1094] Example 1: Preparation of compound 2

[1095] First step

[1096] Dissolve 2a (5.00 g, 34.9 mmol) in 20 mL of ethanol, add ethyl 2-bromoacetate (5.83 g, 34.9 mmol), stir at 80 °C for 15 hours. Concentrate the reaction solution by distillation under reduced pressure, add 25 mL of isopropyl alcohol to the obtained residue, purify by recrystallization to obtain the title product 2b (7.34 g, yield: 91%) in the form of a yellow solid.

[1097] MS m / z (ESI): 230.1 [M+1].

[1098] Second step

[1099] Dissolve 2b (6.84 g, 29.7 mmol) in 50 mL of acetonitrile, protect under nitrogen, add 2-cyclopentenone (11.7 g, 142 mmol) and triethylamine (3.31 g, 32.6 mmol), stir at 25 °C for 24 hours under nitrogen protection. Add 50 mL of water to the reaction solution, extract the reaction solution with ethyl acetate (80 mL x 3), wash the organic phase with saturated sodium chloride solution (60 mL x 2), then dry over anhydrous sodium sulfate, filter, concentrate the filtrate by distillation under reduced pressure, purify the obtained residue by silica gel column chromatography with developing system B to obtain the title product 2c (5.81 g, yield: 61%) in the form of a yellow solid.

[1100] MS m / z (ESI): 312.1 [M+1].

[1101] Third step

[1102] Dissolve 2c (5.31 g, 16.5 mmol) in 60 mL of toluene, protect under nitrogen, add tributyltin hydride (11.9 g, 40.9 mmol) and azobisisobutyronitrile (543 mg, 3.31 mmol), react at 120 °C for 6 hours under nitrogen protection. Concentrate the reaction solution by distillation under reduced pressure, add 80 mL of ethyl acetate and hydrochloric acid (1 N, 40 mL) to the obtained residue, let the obtained liquid stand at 25 °C for 14 hours, suck off the organic phase, wash the remaining aqueous phase with ethyl acetate (100 mL x 3), obtain the crude title product 2d (3.27 g) in the form of a yellow liquid without purification, directly use the product in the next step reaction.

[1103] Fourth step

[1104] To 2d (3.27 g, 16.6 mmol) was added sodium bicarbonate solution (25 mL), acetonitrile (25 mL), 9-fluorenylmethyl-N-succinimidyl carbonate (6.71 g, 19.9 mmol), and the reaction was stirred at 25 °C for 2 h under nitrogen atmosphere. The reaction was extracted with ethyl acetate (80 mL x 3), and the organic phase was washed with saturated sodium chloride solution (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated by distillation under reduced pressure. The residue was purified by silica gel column chromatography with the developing system B to give the title product 2e (2.01 g, yield: 27%) as a yellow oil.

[1105] 2e (2.01 g, 4.80 mmol) was separated by SFC (separation condition: column: DAICEL CHIRALPAK AD (250 mm x 30 mm, 10 pm); mobile phase: A-carbon dioxide: B-methanol, isocratic elution: B: 35%), to give single configuration compound 2e-1 and single configuration compound 2e-2.

[1106] 2e-1 (shorter retention time)

[1107] Yellow gum, 775 mg, yield: 39%. SFC analysis: retention time 1.830 min. (column: Chiralpak AD-3 50 x 4.6 mm I.D., 3 pm, mobile phase: A-carbon dioxide, B-methanol (0.05% diethylamine), gradient elution: B: 5-40%, flow rate: 3 mL / min, instrument: Shimadzu LC-30ADsf).

[1108] MS m / z (ESI): 420.1 [M+1].

[1109] 2e-2 (longer retention time)

[1110] Yellow gum, 750 mg, yield: 37%. SFC analysis: retention time 2.193 min. (column: Chiralpak AD-3 50 x 4.6 mm I.D., 3 pm, mobile phase: A-carbon dioxide, B-methanol (0.05% diethylamine), gradient elution: B: 5-40%, flow rate: 3 mL / min, instrument: Shimadzu LC-30ADsf).

[1111] MS m / z (ESI): 420.1 [M+1].

[1112] Fifth step

[1113] (R)-5,5-diphenyl-2-methyl-3,4-propanol-1,3,2-oxazaborolidine (79.3 mg, 286 pmol) was dissolved in 2 mL of toluene, protected by nitrogen, and cooled to 0 °C. Borane dimethyl sulfide complex (10 M, 171 pL) was added dropwise, and the reaction was allowed to proceed at 0 °C for 15 min. A toluene solution (8 mL) of 2e-1 (600 mg, 1.43 mmol) was then added, and the reaction was allowed to proceed at 0 °C for 30 min. 5 mL of methanol and 8 mL of water were added to the reaction at 0 °C, and the reaction was extracted with dichloromethane (10 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated by distillation under reduced pressure. The resulting residue was purified by silica gel column chromatography with developing system A to give the title product 2f (500 mg, yield: 81%) as a yellow oil.

[1114] MS m / z (ESI): 422.0 [M + 1].

[1115] Sixth step

[1116] 2f (500 mg, 1.15 mmol) was dissolved in 10 mL of tetrahydrofuran, protected by nitrogen, and cooled to 0 °C. A tetrahydrofuran solution (2 M, 864 pL) of lithium borohydride was added dropwise, and the reaction was stirred at 25 °C for 1 h. 1 mL of ammonium chloride solution and 5 mL of water were added at 0 °C, and the reaction was extracted with dichloromethane (8 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated by distillation under reduced pressure. The resulting residue was purified by silica gel column chromatography with developing system A to give the title product 2g (189 mg, yield: 63%) as a white solid.

[1117] MS m / z (ESI): 380.0 [M + 1].

[1118] Seventh step

[1119] 2g (25 mg, 64.57 pmol) was dissolved in 3 mL of dry pyridine, protected by nitrogen, and cooled to below 5 °C. A dichloromethane solution (5 mL) of 4,4'-dimethoxytrityl chloride (21.88 mg, 64.57 pmol) was then added slowly dropwise to the reaction, which was allowed to naturally rise to 25 °C and stirred for 12 h. The reaction was quenched by adding 1 mL of methanol, and the reaction was concentrated by distillation under reduced pressure. The resulting residue was purified by preparative high-performance liquid chromatography (separation conditions: column: InfinityLab Poroshell 120 SB-C18 21.2 x 250 mm, 4 pm; mobile phase: A-water (0.05% ammonium bicarbonate):B-acetonitrile, gradient elution: B%: 20%-100%) to give the title product 2h (27 mg, yield: 58%) as a white solid.

[1120] Eighth step

[1121] Dissolution of 2h (26 mg, 38 pmol) and hexahydropyridine (6 mg, 73 pmol) in 3 mL of N,N-dimethylformamide, reaction at 25 °C for 12 hours, the reaction solution was purified by reverse phase liquid chromatography (mobile phase: A-water (0.05% ammonium bicarbonate), B-acetonitrile; gradient elution: B%: 10%-80%) without purification, to obtain the title product 2i (16 mg, yield: 91%) in the form of a white solid.

[1122] Ninth step

[1123] Dissolution of 2i (15 mg, 31.00 pmol) and dodecanedioic acid monomethyl ester (7.58 mg, 31.02 pmol) in 2 mL of dichloromethane, addition of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (14.15 mg, 37.21 pmol) and N,N-diisopropylethylamine (20.03 mg, 155.0 pmol), reaction at 25 °C for 2 hours. Concentration of the reaction solution by distillation under reduced pressure, the obtained residue was purified by preparative high performance liquid chromatography (separation conditions: column: InfinityLab Poroshell 120 SB-C18 21.2 x 250 mm, 4 pm; mobile phase: A-water (0.05% ammonium bicarbonate): B-acetonitrile, gradient elution: B%: 30%-100%), to obtain the title product 2j (14 mg, yield: 62%) in the form of a white solid.

[1124] Tenth step

[1125] Dissolution of 2j (12 mg, 16.62 pmol) in 2 mL of tetrahydrofuran and 2 mL of water, addition of lithium hydroxide (1.99 mg, 83.09 pmol), reaction at 25 °C for 12 hours. Concentration of the reaction solution by distillation under reduced pressure, the obtained residue was purified by preparative high performance liquid chromatography (separation conditions: column: InfinityLab Poroshell 120 SB-C18 21.2 x 250 mm, 4 pm; mobile phase: A-water (0.05% ammonium bicarbonate): B-acetonitrile, gradient elution: B%: 10%-70%), to obtain the title product 2k (10 mg, yield: 85%) in the form of a white solid.

[1126] Eleventh step

[1127] Dissolve 2k (5 mg, 7.07 μmol) and 1g (14.71 mg, 7.07 μmol) in 2 mL of dichloromethane, add 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (4.03 mg, 10.6 μmol) and N,N-diisopropylethylamine (4.57 mg, 35.36 μmol), and react at 25°C for 2 hours. Concentrate the reaction solution by distillation under reduced pressure, and purify the obtained residue by preparative high-performance liquid chromatography (separation conditions: column: InfinityLab Poroshell 120 SB-C18 21.2 x 250 mm, 4 μm; mobile phase: A - water (0.05% ammonium bicarbonate) : B - acetonitrile, gradient elution: B%: 20% - 70%) to obtain the title product 2l (11 mg, yield: 55%) as a white solid.

[1128] Twelfth step

[1129] Dissolve 2l (10 mg, 3.94 μmol) in 3 mL of dichloromethane, add 4-dimethylaminopyridine (0.1 mg, 0.79 μmol), succinic anhydride (1.97 mg, 19.7 μmol), and N,N-diisopropylethylamine (5.09 mg, 39.4 μmol), and stir at 25°C for 15 hours. Concentrate the reaction solution by distillation under reduced pressure, and purify the obtained residue by preparative high-performance liquid chromatography (separation conditions: column: InfinityLab Poroshell 120 SB-C18 21.2 x 250 mm, 4 μm; mobile phase: A - water (0.05% ammonium bicarbonate) : B - acetonitrile, gradient elution: B%: 10% - 90%) to obtain the title product 2 (4 mg, yield: 36%) as a beige solid.

[1130] MS m / z (ESI): 1162.9 [1 / 2 (M-301)].

[1131] 1H NMR (400 MHz, CD3OD) δ 7.39 - 7.36 (m, 2H), 7.30 - 7.28 (m, 1H), 7.27 - 7.24 (m, 5H), 7.21 - 7.18 (m, 1H), 6.87 - 6.82 (m, 4H), 5.33 - 5.31 (m, 3H), 5.08 - 5.03 (m, 4H), 4.57 - 4.54 (m, 3H), 4.17 - 4.04 (m, 12H), 4.02 - 3.97 (m, 4H), 3.89 - 3.84 (m, 4H), 3.78 - 3.77 (m, 6H), 3.70 - 3.65 (m, 12H), 3.56 - 3.50 (m, 4H), 3.48 - 3.46 (m, 1H), 3.33 - 3.31 (m, 2H), 3.15 - 3.11 (m, 12H), 2.46 - 2.42 (m, 8H), 2.25 - 2.21 (m, 6H), 2.13 - 2.11 (m, 9H), 2.02 - 2.00 (m, 9H), 1.94 - 1.91 (m, 18H), 1.71 - 1.49 (m, 22H), 1.48 - 1.42 (m, 2H), 1.31 - 1.25 (m, 12H), 0.50 - 0.46 (m, 12H).

[1132] Example 2: Design and synthesis of coagulation factor XI siRNA

[1133] 1) siRNA design, siRNA was designed with human coagulation factor XI gene (NM_000128.4) as the target gene. The unmodified siRNA sense and antisense strands are shown in Table la; the modified siRNA sense and antisense strands are shown in Table lb.

[1134] 2) Unmodified siRNA synthesis, the unmodified sequence was synthesized by Suzhou Baisin Biotechnology Co., Ltd. and Nanjing Kingsun Biotech Co., Ltd. respectively through outsourcing.

[1135] 3) Modified siRNA synthesis, all siRNA sense and antisense strands contained in Table lb were synthesized by solid phase synthesis method respectively. Specifically, siRNA without ligand coupling was synthesized by LK-48 synthesizer (Lingkun Biotechnology) on a 500 nmol scale solid phase carrier through phosphoramidite chemistry. The solid phase carrier was controlled pore glass The auxiliary reagents and 2-cyanoethylphosphonamide monomers (2′-deoxy-2′-fluoro, 2′-O-methyl, RNA, DNA) were obtained from Wuhu Huaren Technology Co., Ltd. or Beijing Dinaxingke Biotechnology Co., Ltd. Additional phosphorusamide monomers were obtained through commercial procurement, self-preparation, or custom synthesis. A 50 mM solution of phosphorusamide monomer acetonitrile or a 1:1 acetonitrile:dichloromethane solution was provided in the synthesis. The deprotection reagent was a 3% trichloroacetic acid / dichloromethane solution, the reaction time was 30 s, and deprotection was performed 4 times. The activator used in the coupling reaction was a 0.25 M solution of 5-benzylthiotetrazole (BTT) acetonitrile, the reaction time was 160 s, and coupling was performed 3 times. Thiophosphate ester bonds were generated using a 50 mM 1:1 acetonitrile:pyridine solution prepared with N,N-dimethyl-N'-(3-thio-3H-1,2,4-dithiazo-5-yl)formamidin, the oxidation time was 120 s, and oxidation was performed 2 times. The capping agents used were 10% acetic anhydride / tetrahydrofuran solution and N-methylimidazole / pyridine / tetrahydrofuran solution, with a capping time of 20 seconds and two capping cycles. All sequences were de-capped at the end (“DMT Off”).

[1136] After solid-phase synthesis, the solid-loaded oligonucleotides were treated with 500 μL of 3:1 ammonia:ethanol in a cryovial at 45 °C for 16 hours to induce cleavage on the solid support, followed by removal of additional unstable protecting groups. The oligonucleotides were precipitated with 10% v / v 5M NaCl solution and 3 volumes of anhydrous ethanol, centrifuged at 4 °C, and the supernatant was discarded. The oligonucleotides were reconstituted in dd-H₂O and purified using an Agilent 1260 HPLC system. The prepared solution was lyophilized and then desalted. Quantitative analysis was performed using LC-MS and UV spectroscopy. The concentration of the oligonucleotide solution was determined using a micro-spectrophotometer OD260.

[1137] Using enzyme-free water or DEPC water, dissolve equimolar amounts of the complementary sense and antisense strands from Table 1b, and then anneal to obtain the following siRNAs provided in this disclosure: as shown in Table 1b (a total of 174 siRNAs). Confirm the concentration and information of each double strand, and then adjust to the concentration required for the experiment.

[1138] Table 1a. Unmodified sense and antisense strand siRNA sequences of this disclosure

[1139] Table 1b. Modified sense and antisense siRNA sequences of this disclosure

[1140] Note: In the sequence, uppercase letters A, U, G, C, and T represent the base composition of nucleotides; lowercase letter m indicates that the nucleotide adjacent to the left of letter m is a methoxy-modified nucleotide; lowercase letter f indicates that the nucleotide adjacent to the left of letter f is a fluorinated nucleotide; lowercase letter s indicates that the two nucleotides adjacent to the left and right of letter s are linked by a thiophosphate group; uppercase letter P indicates that the nucleotide adjacent to the right of letter P is a 5'-phosphate nucleotide.

[1141] Table 1c shows the unmodified sense and antisense siRNA sequences disclosed herein.

[1142] Table 1d shows the modified sense and antisense siRNA sequences disclosed herein.

[1143] Note: In this context, uppercase letters A, U, G, C, and T represent the base composition of nucleotides; lowercase letter m indicates that the nucleotide adjacent to the left of letter m is a methoxy-modified nucleotide; lowercase letter f indicates that the nucleotide adjacent to the left of letter f is a fluorinated nucleotide; and lowercase letter s indicates that the two nucleotides adjacent to the left and right of letter s are linked by thiophosphate groups.

[1144] Example 3: Synthesis of siRNA conjugates

[1145] 1. Preparation of a custom-designed GalNAc mounting system

[1146] Weigh N,N-diisopropylethylamine (3 eq), dissolve it in anhydrous N,N-dimethylformamide, and prepare an N,N-diisopropylethylamine solution with a concentration of 8.1 mg / mL. Weigh 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (2 eq), dissolve it in anhydrous acetonitrile, and prepare a 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate solution with a concentration of 14.6 mg / mL. Dissolve the GalNAc compound (compound 2 above) in the above N,N-diisopropylethylamine N,N-dimethylformamide solution (3 eq), and then add the acetonitrile solution of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (2 eq). Take CPG (blank loading of 180 μmol / g, target loading of 40 μmol / g) and add it dropwise to the above mixed solution containing GalNAc. Shake gently to mix. Place the reaction solution on a shaker (temperature: 25℃, speed: 200 rpm) and shake overnight. Add dichloromethane to the reaction solution to flush the CPG adhering to the flask wall to the bottom. Wash the solution three times with dichloromethane and twice with anhydrous acetonitrile. After each wash, wait for the CPG to precipitate to the bottom of the flask, carefully aspirate the supernatant, and dry the solid obtained from the last wash under vacuum for 1 hour. Weigh 1 mg of 4-dimethylaminopyridine and add 1000 μL of anhydrous acetonitrile to prepare a 1 mg / mL acetonitrile solution of 4-dimethylaminopyridine; take 20 μL of N-methylimidazole and add 80 μL of anhydrous acetonitrile to prepare a CapA solution; take 40 μL of acetic anhydride and add 60 μL of anhydrous acetonitrile to prepare a CapB1 solution; take 60 μL of anhydrous pyridine and add 40 μL of anhydrous acetonitrile to prepare a CapB2 solution; add 65.4 μL of the above acetonitrile solution of 4-dimethylaminopyridine, 12.95 μL of CapA, 56.95 μL of CapB1, and 6.33 μL of CapB2 sequentially to a CPG support linked with different GalNAc compounds, and place the reaction solution on a shaker (temperature: 25℃, speed: 200 rpm) and shake for 2 hours. Anhydrous acetonitrile was added to the reaction solution to flush the CPG adhering to the bottle wall to the bottom of the bottle. The mixture was then washed three times with anhydrous acetonitrile. The solid was collected, dried under vacuum overnight, and CPG containing the GalNAc compound was obtained (labeled as CPG-2). The loading was then determined.

[1147] The structure of CPG-2 is listed below as an example:

[1148] 2.3′-Conjugated GalNAc siRNA Synthesis

[1149] Weigh out the immobilized GalNAc (i.e., the compound CPG-2 prepared in step 1 above), fill it into an empty column with a lower sieve, and then cover it with an upper sieve. Connect nucleoside monomers one by one in the nucleotide sequence from 3' to 5'. Each connection of a nucleoside monomer involves four steps: deprotection, coupling, capping, and oxidation or sulfidation. The procedure is standard in the art.

[1150] The auxiliary reagents and 2-cyanoethylphosphonamide monomers (2′-deoxy-2′-fluoro, 2′-O-methyl, RNA, DNA) were obtained from Wuhu Huaren Technology Co., Ltd. or Beijing Dinaxingke Biotechnology Co., Ltd. Additional phosphoramide monomers were obtained through commercial procurement, in-house preparation, or custom synthesis. A 50 mM solution of phosphoramide monomer acetonitrile or a 1:1 acetonitrile:dichloromethane solution was provided in the synthesis. The deprotection agent was a 3% trichloroacetic acid / dichloromethane solution, and the reaction time was 30 seconds, with four deprotection cycles. The activator used in the coupling reaction was a 0.25 M solution of 5-benzylthiotetrazole (BTT) acetonitrile, and the reaction time was 160 seconds, with three coupling cycles. Thiophosphate ester bonds were generated using a 50 mM acetonitrile:pyridine (1:1) solution prepared with N,N-dimethyl-N'-(3-thio-3H-1,2,4-dithiazo-5-yl)formamidin, with an oxidation time of 120 seconds, and two oxidation cycles. The capping agents used were a 10% acetic anhydride / tetrahydrofuran solution and an N-methylimidazole / pyridine / tetrahydrofuran solution. The capping time was 20 seconds, and the capping was performed twice. All sequences were de-capped at the end (“DMT Off”).

[1151] After solid-phase synthesis, the solid-loaded oligonucleotides were treated with 500 μL of ammonia:ethanol (3:1) in a cryovial at 45 °C for 16 hours to induce cleavage on the solid support, followed by removal of additional unstable protecting groups. Taking compound CPG-2 as an example, it was ligated to the sequence via the above solid-phase synthesis, and then subjected to aminolysis to remove some functional groups, resulting in NGN-2.

[1152] Oligonucleotides were precipitated with 10% v / v 5M sodium chloride solution and 3 volumes of anhydrous ethanol, centrifuged at 4°C, and the supernatant was discarded. The oligonucleotides were reconstituted in dd-H₂O and purified using an Agilent 1260 HPLC system. The prepared solution was lyophilized and then desalted. Quantitative analysis was performed using LC-MS and UV spectroscopy. The concentration of the oligonucleotide solution was determined using a micro-spectrophotometer (OD260). The sense and antisense strands were mixed in an equimolar ratio and incubated in a 95°C water bath for 5 min, then slowly brought to room temperature over 2–3 hours. The concentration and information of each duplex were confirmed, and then used for in vitro screening experiments.

[1153] 3. Preparation of siRNA conjugates with L96 coupling ligand

[1154] The synthesis of the coupling ligand L96 (GalNAc) was performed according to PCT publications WO2009073809 and WO2009082607 in this field. Compound L96 and TBTU (2 eq) were dissolved in DMF, followed by the addition of DIPA (4 eq) and shaking until the solution was clear. Then, a blank support (1 eq, 160 μmol / g) was added. The reaction mixture was prepared at 25°C and reacted on a shaker for 16 hours. A 2mg sample was taken and the DMT group was removed using 80ml of 3% trichloroacetic acid / dichloromethane solution. The Abs content of the solution was measured spectrophotometrically, and the loading was calculated to be 40-50 μmol / g. The reaction solution was filtered and dried under vacuum. The solid powder was added to a reaction flask containing DMF, followed by acetic anhydride (12 eq), N-methylimidazole (12 eq), and pyridine (20 eq). The mixture was shaken on a shaker at room temperature for 30 minutes, filtered, dried under vacuum for 16 hours, and then used for solid-phase synthesis.

[1155] Weigh 10-15 mg of the custom-loaded GalNAc (L96) and fill an empty column with a lower sieve, then cover with an upper sieve. Auxiliary reagents and 2-cyanoethylphosphonamide monomers (2′-deoxy-2′-fluoro, 2′-O-methyl, RNA, DNA) were obtained from Wuhu Huaren Technology Co., Ltd. or Beijing Dinaxingke Biotechnology Co., Ltd. Additional phosphorusamide monomers were obtained through commercial procurement, self-preparation, or custom synthesis. A 50 mM solution of phosphorusamide monomer acetonitrile or a 1:1 acetonitrile:dichloromethane solution was provided in the synthesis. The deprotection agent was a 3% trichloroacetic acid / dichloromethane solution, the reaction time was 30 seconds, and deprotection was performed 4 times. The activator used in the coupling reaction was a 0.25 M solution of 5-benzylthiotetrazole (BTT) acetonitrile, the reaction time was 160 seconds, and coupling was performed 3 times. Thiophosphate bonds were formed using a 50 mM 1:1 acetonitrile:pyridine solution prepared with N,N-dimethyl-N'-(3-thio-3H-1,2,4-dithiazo-5-yl)formamidin, with an oxidation time of 120 seconds and two oxidation cycles. Capping agents included a 10% acetic anhydride / tetrahydrofuran solution and an N-methylimidazolium / pyridine / tetrahydrofuran solution, with a capping time of 20 seconds and two capping cycles. All sequences underwent final de-DMT removal (“DMT Off”).

[1156] After solid-phase synthesis was completed, the solid-loaded oligonucleotides were treated with 500 μL of 3:1 ammonia:ethanol in a cryovial at 45 °C for 16 hours to cleave them on the solid support, and then additional unstable protecting groups were removed.

[1157] The oligonucleotides were precipitated with 10% v / v 5M NaCl solution and 3 volumes of anhydrous ethanol, centrifuged at 4°C, and the supernatant was discarded. The oligonucleotides were reconstituted in dd-H2O and purified using an Agilent 1260 HPLC system. The prepared solution was lyophilized and then desalted. Quantitative analysis was performed using LC-MS and UV spectroscopy. The concentration of the oligonucleotide solution was determined using a micro-spectrophotometer OD260.

[1158] Table 2. siRNA conjugates disclosed in this paper

[1159] Note: In the above sequences, uppercase letters A, U, G, C, and T represent the base composition of nucleotides; lowercase letter m indicates that the nucleotide adjacent to the left of letter m is a methoxy-modified nucleotide; lowercase letter f indicates that the nucleotide adjacent to the left of letter f is a fluorinated nucleotide; lowercase letter s indicates that the two nucleotides adjacent to the left and right of letter s are linked by a thiophosphate group; uppercase letter P indicates that the nucleotide adjacent to the right of letter P is a 5'-phosphate nucleotide; compound 2 or L10 is conjugated to the 3' end of the positive strand of each siRNA.

[1160] Example 4: Inhibition of FXI mRNA by siRNA in HepG2 cells

[1161] The effect of siRNA targeting coagulation factor FXI on the mRNA expression level of coagulation factor FXI was tested in vitro.

[1162] (1) Cell culture and plating: HepG2 cells were cultured in DMEM high glucose medium containing 10% fetal bovine serum and 1% non-essential amino acid NEAA at 37°C and 5% CO2. 24 hours before transfection, HepG2 cells were collected and seeded into 96-well plates at a density of 20,000 cells per well with 100 μL of medium per well.

[1163] (2) Transfection: Refer to the product instruction manual and use lipofectamine RNAiMAX (ThermoFisher, 13778150) to transfect siRNA. The final concentration of siRNA transfection is 10 nM, and three replicates are used.

[1164] (3) RNA extraction: Continue culturing cells for 24 hours, and use Thermo Fisher's automated nucleic acid extractor in conjunction with Tiangen's magnetic bead method tissue / cell / blood total RNA extraction kit (DP761) to extract RNA. Refer to the product instruction manual for specific steps.

[1165] (4) RNA reverse transcription to cDNA: using Novizan III. Reverse transcription was performed using the RT SuperMix for qPCR (+gDNAwiper) kit. A 10 μL reverse transcription reaction system was prepared according to the kit instructions to reverse transcribe total RNA from cells. The transcribed cDNA was then diluted 3-fold with 20 μL of DEPC water. The sample was used for subsequent experiments or stored at -20°C.

[1166] (5) qPCR: For each reverse transcription reaction system, 4 μL of the diluted cDNA solution was used as a template. A 10 μL qPCR reaction system was prepared using the reagents provided by the Novizan AceQ Universal U+Probe Master Mix V2 kit. The PCR primer sequences for amplifying the target gene FXI and the internal reference gene GAPDH are shown in Table 3, and the Taqman probe sequences for amplifying the target gene FXI and the internal reference gene GAPDH are shown in Table 4. The final concentration of each primer and probe was 10 μM. The real-time quantitative PCR system on the Taqman method was used for detection. The Ct values ​​of the target gene FXI and the internal reference gene GAPDH were obtained.

[1167] Table 3. PCR primer sequences

[1168] Table 4. Taqman probe sequences used in real-time quantitative PCR

[1169] Note: 6-FAM and VIC represent fluorescent groups, and BHQ1 represents quenching groups.

[1170] The expression levels of the target gene FXI in each test group and control group were relatively quantitatively calculated using the Ct (ΔΔCt) method. The calculation method is as follows:

[1171] ΔCt(test group) = Ct(target gene in test group) - ΔCt(internal reference gene in test group)

[1172] ΔCt(control group) = Ct(target gene in control group) - ΔCt(internal reference gene in control group)

[1173] ΔCt(test group) = ΔCt(test group) - ΔCt(control group average)

[1174] ΔCt(control group) = ΔCt(control group) - ΔCt(control group average)

[1175] Wherein, ΔCt (control group average) is the arithmetic mean of ΔCt (control group) for each of the three culture wells in the control group. Therefore, each culture well in both the test group and the control group corresponds to a ΔCt value. The relative expression level of FXI mRNA in the test group = 2 - ΔCt (test group) × 100%.

[1176] In HepG2 cells, the inhibitory effects of these 173 siRNAs (see Table 1a) on FXI mRNA at 1 nM and 0.25 nM were measured. The screening results for 1 nM are shown in Figures 1 to 6; the screening results for 0.25 nM are shown in Figures 7 to 18.

[1177] Simultaneously, 173 modified sequences were synthesized, as detailed in Table 1b. Following the above method, the inhibitory effect of these 173 sequences on FXI mRNA was determined, using the siRNAs shown in Table 1b. For each siRNA, the measured concentrations were 10.0, 2.0, 0.4, 0.08, 0.016, 0.032, and 0.00064 nM, totaling 7 concentrations, 5-fold dilutions, and 2 biological replicates. This paper discloses the IC50 values ​​of 17 selected siRNAs. 50 The assay results, as shown in Figures 19 to 22 and Table 5, indicate that the IC50 of the 17 selected siRNAs against FXI mRNA was significantly higher than that of the positive control RB-g1M1SP. 50 Equal to or better than.

[1178] Table 5. IC50 of 17 preferred sequences for FXI mRNA in HepG2 cells 50

[1179] Note: "Same number of plates" means that the experiment was conducted on the same 96-well plate and the data were obtained.

[1180] Based on the aforementioned 17 preferred sequences, a large-scale screening was conducted again around their target regions to obtain an additional 11 preferred sequences, the IC50 determination results of which are shown in Table 6.

[1181] Table 6. IC50 of the 11 selected modified sequences against FXI mRNA in HepG2 cells 50

[1182] Note: "Same number of plates" means that the experiment was conducted on the same 96-well plate and the data were obtained.

[1183] Example 5: Inhibitory activity of 12 chemically modified siRNAs against primary hepatocytes of cynomolgus monkeys.

[1184] Following the method in Example 4, the inhibitory effects of 12 chemically modified siRNAs (with sequences further preferred from Example 4) on FXI mRNA in primary cynomolgus monkey hepatocytes were determined, the only difference being that the cells used were primary cynomolgus monkey hepatocytes. The IC50 values ​​of these 12 siRNAs were... 50 The assay results, as shown in Figures 23 to 26 and Table 7, indicate that the IC50 of the selected 12 siRNAs against FXI mRNA was significantly higher than that of the positive control RB-g1M1SP. 50 Equal to or better than.

[1185] Table 7. IC50 of FXI mRNA in primary hepatocytes of cynomolgus monkeys after modification of the 12 preferred sequences. 50

[1186] Note: "Same number of plates" means that the experiment was conducted on the same 96-well plate and the data were obtained.

[1187] Example 6: Determination of the activity of siRNA conjugates in AAV mice (in vivo)

[1188] Preparation of AAV-virus of human FXI: (1) Construction of plasmids: The target gene - human FXI (NM_000128.4, a total of 3053bp) was inserted into the multiple cloning site of the pAAV-CMV vector using homologous recombination; (2) AAV-293 cells were trans-expressed with the adenovirus E1 gene. When three AAV plasmids were co-transfected: pAAV-CMV Vector containing the target gene expression promoter and two ITRs, pAAV-DJ Vecor containing the Rep and Cap genes of adenovirus, and pHelper Vector containing the E2A, E4 and VA genes of adenovirus, AAV-293 cells could produce infectious adenovirus-associated virus particles (Kimura T, Scientific Reports, 2019 Sep). 19;9(1):13601.);(3) AAV-DJ virus was packaged by co-transfection of AAV-293 cells with three plasmids, and then collected and purified to achieve the required viral titer (Guo P, J Virol Methods. 2012 Aug;183(2):139-46.).

[1189] AAV mice allow for the introduction of the full-length human FXI gene mRNA into mice for in vivo screening of siRNAs. Compared to the subsequent TG mice, AAV mice contain the complete human FXI gene, enabling screening of all siRNA conjugates disclosed herein. In contrast, commercially available TG mice only contain the CDS region that can be translated into protein, thus limiting the screening scope compared to AAV mice.

[1190] AAV-virus carrying human FXI was injected into mice via the tail vein to construct an AAV mouse model expressing human FXI. The mice used were C57BL / 6N, all male, and 6-8 weeks old. The expression level of human FXI in all mice was measured on day 14 after modeling. The human FXI protein content in the plasma of the mice was tested using the Factor XI Human ELISA Kit (Abcam, catalog number ab108834). The mice were then divided into groups of 4 mice each using a serpentine scattering method. After grouping, the mice were administered siRNA conjugates at a dose of 3 mg / kg via subcutaneous injection once. The conjugates were: compound 2-F4001, compound 2-F4002, compound 2-F4003, compound 2-F4004, compound 2-F4005, compound 2-F4006, compound 2-F4007, compound 2-F4010, compound 2-F4011, compound 2-F4013, compound 2-F4015, compound 2-F4016, compound 2-F4017, and compound 2-F4018.

[1191] The siRNA conjugates were provided in the form of 0.9% saline solution for injection containing 5 mg / mL of the siRNA conjugate (prepared to the required concentration and volume using 0.9% sodium chloride solution for injection before the experiment), with an administration volume of 5 mL / kg.

[1192] One group of mice was given 0.9% saline at a volume of 5 mL / kg, serving as the control group (vehicle). Blood samples were collected from the orbital venous plexus of mice before administration (day 0) and on days 6, 17, 24, and 31 after administration. At each time point, the expression level of FXI protein in mouse plasma was detected using an ELISA kit (Abcam, catalog number ab108834). The ELISA results are shown in Table 8 and Figure 27.

[1193] Table 8. Inhibition of plasma FXI protein expression by siRNA conjugates in AAV mouse model

[1194] ND. Not dertemined: Not detected

[1195] As can be seen from the above results, the siRNA conjugates disclosed herein all exhibited excellent inhibitory effects on human FXI protein expression in the AAV mouse model. Compounds 2-F4001 and 2-F4004 showed nearly 80% FXI protein inhibition rate on Day 24; in addition, compounds 2-F4005, 2-F4010, and 2-F4011 showed more than 80% FXI protein inhibition rate on Day 24; and compound 2-F4015 showed more than 90% FXI protein inhibition rate on Day 24. All of the above conjugates still achieved excellent FXI protein inhibition effects on Day 38.

[1196] Example 7: Determination of the activity of siRNA conjugates in humanized mice (in vivo)

[1197] The humanized FXI mice used in this embodiment were purchased from Shanghai Southern Model Biotechnology Co., Ltd., hereinafter referred to as TG mice. The purchased TG mice were C57BL / 6N, all male, 6-8 weeks old. The expression level of human FXI in all mice was measured on the day of administration (day 0). Then, the human FXI protein content in the plasma of these mice was tested using the Factor XI Human ELISA Kit (Abcam, catalog number ab108834). The mice were then divided into groups of four using a serpentine scattering method. After grouping, the mice were administered once subcutaneously at a dose of 3 mg / kg of siRNA conjugates: compound 2-F4010, compound 2-F4011, compound 2-F4014, compound 2-F4016, compound 2-F4017, compound 2-F4020, compound 2-F4021, and L10-siFXIg1M1SP. The preparation of the siRNA conjugate L10-siFXIg1M1SP was based on the authorized patent CN_113227376_B.

[1198] The siRNA conjugates were provided in the form of 0.9% saline solution for injection containing 5 mg / mL of the siRNA conjugate (prepared to the required concentration and volume using 0.9% sodium chloride solution for injection before the experiment), with an administration volume of 5 mL / kg.

[1199] One group of mice was given 0.9% saline at a volume of 5 mL / kg, serving as the control group (vehicle). Blood samples were collected from the orbital venous plexus of mice on days 7, 14, 21, and 28 after administration. At each time point, the expression level of FXI protein in mouse plasma was detected using an ELISA kit (Abcam, catalog number ab108834). The ELISA results are shown in Table 9 and Figure 28.

[1200] Table 9. Inhibition of plasma FXI protein expression by siRNA conjugates in TG mouse model

[1201] ND. Not dertemined: Not detected

[1202] As can be seen from the above results, the siRNA conjugates disclosed herein all showed excellent inhibitory effects on human FXI protein expression in the TG mouse model.

[1203] Example 8: Determination of the in vivo activity of siRNA conjugates in cynomolgus monkeys

[1204] Eight cynomolgus macaques (half male and half female) were randomly divided into two groups of four each, based on body weight. Each group received a single subcutaneous injection of 6 mg / kg of compound 2-F4010 or compound 2-F4015. The day of administration was defined as day 0 (D0) of the administration period. During the experiment, the general condition of the macaques in each group was observed daily; they were weighed every 1–2 weeks. Blood samples were collected on days 1 and 4 before administration for hematological testing, and on day 3 before administration for blood biochemical analysis. Efficacy testing was conducted on days 1 and 4 before administration, and on days 0, 3, 7, 14, 21, 28, 35, 42, 49, 63, 77, and 91 of the administration period for testing FXI activity and four coagulation parameters.

[1205] Blood collection method: Fasting for at least 12 hours before sampling, but water intake is permitted; collect 1.8 mL of blood from the anterior cubital vein or other suitable vein. Blood sample processing method: Anticoagulate blood samples with 3.2% sodium citrate at a ratio of 1:9. Store and transport at room temperature. Centrifuge at 2200×g for 10 minutes at 15–25℃ to separate plasma. Aliquot plasma samples into at least two tubes, 300 μL each. Freeze at -70–-86℃. Except for plasma samples to be tested on the same day, other samples should be temporarily stored at -70–-86℃ for later use. Plasma sample testing: Samples stored at 15–25℃ should be tested within 4 hours; samples stored at 2–8℃ should be tested within 8 hours; plasma frozen at -24–-18℃ should be tested within one week.

[1206] General Condition: During the experiment, the cynomolgus monkeys in all groups were in good general condition with no abnormalities observed. Weight: During the experiment, the weight of the cynomolgus monkeys in all groups remained stable with no significant abnormalities. Blood Biochemistry Tests: On day 3 before drug administration, blood biochemistry tests of the cynomolgus monkeys in all groups showed no abnormalities. Hematological Tests: On days 1 and 4 before drug administration, hematological tests of the cynomolgus monkeys in all groups showed no abnormalities.

[1207] FXI activity test results: From the 3rd day of the administration period, the plasma coagulation factor FXI activity (%) of each group of cynomolgus monkeys continued to decrease compared with the pre-administration level, and basically decreased to the lowest level on the 21st day of the administration period (see Figure 29 and Table 10 for details).

[1208] Table 10. Inhibitory effect of siRNA conjugates on plasma FXI enzyme activity in cynomolgus monkeys.

Claims

A double-stranded oligonucleotide for inhibiting FXI expression, the double-stranded oligonucleotide comprising a sense strand and an antisense strand, wherein, The sense strand and the antisense strand are at least partially anticomplementary to form a double-stranded region, the antisense strand is at least partially complementary to a nucleotide segment in the FXI transcribed mRNA, the sense strand is no more than 21 nucleotides in length, the antisense strand is no more than 23 nucleotides in length, and the antisense strand comprises at least 17 consecutive nucleotide sequences that differ from the nucleotide sequences shown in any one of SEQ ID NO:175-347 and SEQ ID NO:706-714 by no more than 4, 3, 2, or 1 nucleotides. According to claim 1, the double-stranded oligonucleotide, wherein, The positive chain comprises at least 17 consecutive nucleotide sequences that differ from the nucleotide sequences shown in any one of SEQ ID NO:1-173, SEQ ID NO:697-705 by no more than 4, 3, 2, or 1 nucleotides, respectively. According to claim 1 or 2, the double-stranded oligonucleotide, wherein, The justice chain and antisense chain are essentially oppositely complementary, essentially completely oppositely complementary, or completely oppositely complementary. The double-stranded oligonucleotide according to any one of claims 1-3, wherein, The length of the sense and antisense strands is 17-23 nucleotides, preferably 17-21 nucleotides, and more preferably 19-21 nucleotides. The double-stranded oligonucleotide according to any one of claims 1-4, wherein, The antisense strand is 21, 22, or 23 nucleotides in length; Preferably, the antisense strand has a nucleotide sequence or fragment thereof as shown in any of SEQ ID NO:175-347 or SEQ ID NO:706-714. The double-stranded oligonucleotide according to any one of claims 1-5, wherein, The length of the positive chain is 19, 20, or 21 nucleotides; Preferably, the positive strand has a nucleotide sequence or fragment thereof as shown in any one of SEQ ID NO:1-173, SEQ ID NO:697-705. The double-stranded oligonucleotide according to any one of claims 1-6, wherein, The sense and antisense strands of the double-stranded oligonucleotide are each selected from any of the following combinations: (1) A sense chain having the sequence shown in SEQ ID NO:31, and an antisense chain having the sequence shown in SEQ ID NO:205; (2) A sense chain having the sequence shown in SEQ ID NO:82, and an antisense chain having the sequence shown in SEQ ID NO:256; (3) A sense chain having the sequence shown in SEQ ID NO:104, and an antisense chain having the sequence shown in SEQ ID NO:278; (4) A sense chain having the sequence shown in SEQ ID NO:90, and an antisense chain having the sequence shown in SEQ ID NO:264; (5) A sense chain having the sequence shown in SEQ ID NO:47, and an antisense chain having the sequence shown in SEQ ID NO:221; (6) A sense chain having the sequence shown in SEQ ID NO:2 and an antisense chain having the sequence shown in SEQ ID NO:176; (7) A sense chain having the sequence shown in SEQ ID NO:698, and an antisense chain having the sequence shown in SEQ ID NO:707; (8) A sense chain having the sequence shown in SEQ ID NO:701, and an antisense chain having the sequence shown in SEQ ID NO:710; (9) A sense chain having the sequence shown in SEQ ID NO:22, and an antisense chain having the sequence shown in SEQ ID NO:196; (10) A sense chain having the sequence shown in SEQ ID NO:25, and an antisense chain having the sequence shown in SEQ ID NO:199; (11) A sense chain having the sequence shown in SEQ ID NO:48, and an antisense chain having the sequence shown in SEQ ID NO:222; (12) A sense chain having the sequence shown in SEQ ID NO:102, and an antisense chain having the sequence shown in SEQ ID NO:276; (13) A sense chain having the sequence shown in SEQ ID NO:91, and an antisense chain having the sequence shown in SEQ ID NO:265; (14) A sense chain having the sequence shown in SEQ ID NO:92, and an antisense chain having the sequence shown in SEQ ID NO:266; (15) A sense chain having the sequence shown in SEQ ID NO:3 and an antisense chain having the sequence shown in SEQ ID NO:177; (16) A sense chain having the sequence shown in SEQ ID NO:5 and an antisense chain having the sequence shown in SEQ ID NO:179; (17) A sense chain having the sequence shown in SEQ ID NO:6 and an antisense chain having the sequence shown in SEQ ID NO:180; (18) A sense chain having the sequence shown in SEQ ID NO:88, and an antisense chain having the sequence shown in SEQ ID NO:262; (19) A sense chain having the sequence shown in SEQ ID NO:94, and an antisense chain having the sequence shown in SEQ ID NO:268; (20) A sense chain having the sequence shown in SEQ ID NO:140, and an antisense chain having the sequence shown in SEQ ID NO:314; (21) A sense chain having the sequence shown in SEQ ID NO:144, and an antisense chain having the sequence shown in SEQ ID NO:318; (22) A sense chain having the sequence shown in SEQ ID NO:697, and an antisense chain having the sequence shown in SEQ ID NO:706; (23) A sense chain having the sequence shown in SEQ ID NO:699, and an antisense chain having the sequence shown in SEQ ID NO:708; (24) A sense chain having the sequence shown in SEQ ID NO:700, and an antisense chain having the sequence shown in SEQ ID NO:709; (25) A sense chain having the sequence shown in SEQ ID NO:702, and an antisense chain having the sequence shown in SEQ ID NO:711; (26) A sense chain having the sequence shown in SEQ ID NO:703, and an antisense chain having the sequence shown in SEQ ID NO:712; (27) A sense chain having the sequence shown in SEQ ID NO:704, and an antisense chain having the sequence shown in SEQ ID NO:713; (28) A sense chain having the sequence shown in SEQ ID NO:705, and an antisense chain having the sequence shown in SEQ ID NO:714; (29) A sense chain having the sequence shown in SEQ ID NO:1 and an antisense chain having the sequence shown in SEQ ID NO:175; (30) A sense chain having the sequence shown in SEQ ID NO:4 and an antisense chain having the sequence shown in SEQ ID NO:178; (31) A sense chain having the sequence shown in SEQ ID NO:7 and an antisense chain having the sequence shown in SEQ ID NO:181; (32) A sense chain having the sequence shown in SEQ ID NO:8 and an antisense chain having the sequence shown in SEQ ID NO:182; (33) A sense chain having the sequence shown in SEQ ID NO:9 and an antisense chain having the sequence shown in SEQ ID NO:183; (34) A sense chain having the sequence shown in SEQ ID NO:10, and an antisense chain having the sequence shown in SEQ ID NO:184; (35) A sense chain having the sequence shown in SEQ ID NO:11, and an antisense chain having the sequence shown in SEQ ID NO:185; (36) A sense chain having the sequence shown in SEQ ID NO:12, and an antisense chain having the sequence shown in SEQ ID NO:186; (37) A sense chain having the sequence shown in SEQ ID NO:13, and an antisense chain having the sequence shown in SEQ ID NO:187; (38) A sense chain having the sequence shown in SEQ ID NO:14, and an antisense chain having the sequence shown in SEQ ID NO:188; (39) A sense chain having the sequence shown in SEQ ID NO:15, and an antisense chain having the sequence shown in SEQ ID NO:189; (40) A sense chain having the sequence shown in SEQ ID NO:16, and an antisense chain having the sequence shown in SEQ ID NO:190; (41) A sense chain having the sequence shown in SEQ ID NO:17, and an antisense chain having the sequence shown in SEQ ID NO:191; (42) A sense chain having the sequence shown in SEQ ID NO:18, and an antisense chain having the sequence shown in SEQ ID NO:192; (43) A sense chain having the sequence shown in SEQ ID NO:19, and an antisense chain having the sequence shown in SEQ ID NO:193; (44) A sense chain having the sequence shown in SEQ ID NO:20, and an antisense chain having the sequence shown in SEQ ID NO:194; (45) A sense chain having the sequence shown in SEQ ID NO:21, and an antisense chain having the sequence shown in SEQ ID NO:195; (46) A sense chain having the sequence shown in SEQ ID NO:23, and an antisense chain having the sequence shown in SEQ ID NO:197; (47) A sense chain having the sequence shown in SEQ ID NO:24, and an antisense chain having the sequence shown in SEQ ID NO:198; (48) A sense chain having the sequence shown in SEQ ID NO:26, and an antisense chain having the sequence shown in SEQ ID NO:200; (49) A sense chain having the sequence shown in SEQ ID NO:27, and an antisense chain having the sequence shown in SEQ ID NO:201; (50) A sense chain having the sequence shown in SEQ ID NO:28, and an antisense chain having the sequence shown in SEQ ID NO:202; (51) A sense chain having the sequence shown in SEQ ID NO:29, and an antisense chain having the sequence shown in SEQ ID NO:203; (52) A sense chain having the sequence shown in SEQ ID NO:30, and an antisense chain having the sequence shown in SEQ ID NO:204; (53) A sense chain having the sequence shown in SEQ ID NO:32, and an antisense chain having the sequence shown in SEQ ID NO:206; (54) A sense chain having the sequence shown in SEQ ID NO:33, and an antisense chain having the sequence shown in SEQ ID NO:207; (55) A sense chain having the sequence shown in SEQ ID NO:34, and an antisense chain having the sequence shown in SEQ ID NO:208; (56) A sense chain having the sequence shown in SEQ ID NO:35, and an antisense chain having the sequence shown in SEQ ID NO:209; (57) A sense chain having the sequence shown in SEQ ID NO:36, and an antisense chain having the sequence shown in SEQ ID NO:210; (58) A sense chain having the sequence shown in SEQ ID NO:37, and an antisense chain having the sequence shown in SEQ ID NO:211; (59) A sense chain having the sequence shown in SEQ ID NO:38, and an antisense chain having the sequence shown in SEQ ID NO:212; (60) A sense chain having the sequence shown in SEQ ID NO:39, and an antisense chain having the sequence shown in SEQ ID NO:213; (61) A sense chain having the sequence shown in SEQ ID NO:40, and an antisense chain having the sequence shown in SEQ ID NO:214; (62) A sense chain having the sequence shown in SEQ ID NO:41, and an antisense chain having the sequence shown in SEQ ID NO:215; (63) A sense chain having the sequence shown in SEQ ID NO:42, and an antisense chain having the sequence shown in SEQ ID NO:216; (64) A sense chain having the sequence shown in SEQ ID NO:43, and an antisense chain having the sequence shown in SEQ ID NO:217; (65) A sense chain having the sequence shown in SEQ ID NO:44, and an antisense chain having the sequence shown in SEQ ID NO:218; (66) A sense chain having the sequence shown in SEQ ID NO:45, and an antisense chain having the sequence shown in SEQ ID NO:219; (67) A sense chain having the sequence shown in SEQ ID NO:46, and an antisense chain having the sequence shown in SEQ ID NO:220; (68) A sense chain having the sequence shown in SEQ ID NO:49, and an antisense chain having the sequence shown in SEQ ID NO:223; (69) A sense chain having the sequence shown in SEQ ID NO:50, and an antisense chain having the sequence shown in SEQ ID NO:224; (70) A sense chain having the sequence shown in SEQ ID NO:51, and an antisense chain having the sequence shown in SEQ ID NO:225; (71) A sense chain having the sequence shown in SEQ ID NO:52, and an antisense chain having the sequence shown in SEQ ID NO:226; (72) A sense chain having the sequence shown in SEQ ID NO:53, and an antisense chain having the sequence shown in SEQ ID NO:227; (73) A sense chain having the sequence shown in SEQ ID NO:54, and an antisense chain having the sequence shown in SEQ ID NO:228; (74) A sense chain having the sequence shown in SEQ ID NO:55, and an antisense chain having the sequence shown in SEQ ID NO:229; (75) A sense chain having the sequence shown in SEQ ID NO:56, and an antisense chain having the sequence shown in SEQ ID NO:230; (76) A sense chain having the sequence shown in SEQ ID NO:57, and an antisense chain having the sequence shown in SEQ ID NO:231; (77) A sense chain having the sequence shown in SEQ ID NO:58, and an antisense chain having the sequence shown in SEQ ID NO:232; (78) A sense chain having the sequence shown in SEQ ID NO:59, and an antisense chain having the sequence shown in SEQ ID NO:233; (79) A sense chain having the sequence shown in SEQ ID NO:60, and an antisense chain having the sequence shown in SEQ ID NO:234; (80) A sense chain having the sequence shown in SEQ ID NO:61, and an antisense chain having the sequence shown in SEQ ID NO:235; (81) A sense chain having the sequence shown in SEQ ID NO:62, and an antisense chain having the sequence shown in SEQ ID NO:236; (82) A sense chain having the sequence shown in SEQ ID NO:63, and an antisense chain having the sequence shown in SEQ ID NO:237; (83) A sense chain having the sequence shown in SEQ ID NO:64, and an antisense chain having the sequence shown in SEQ ID NO:238; (84) A sense chain having the sequence shown in SEQ ID NO:65, and an antisense chain having the sequence shown in SEQ ID NO:239; (85) A sense chain having the sequence shown in SEQ ID NO:66, and an antisense chain having the sequence shown in SEQ ID NO:240; (86) A sense chain having the sequence shown in SEQ ID NO:67, and an antisense chain having the sequence shown in SEQ ID NO:241; (87) A sense chain having the sequence shown in SEQ ID NO:68, and an antisense chain having the sequence shown in SEQ ID NO:242; (88) A sense chain having the sequence shown in SEQ ID NO:69, and an antisense chain having the sequence shown in SEQ ID NO:243; (89) A sense chain having the sequence shown in SEQ ID NO:70, and an antisense chain having the sequence shown in SEQ ID NO:244; (90) A sense chain having the sequence shown in SEQ ID NO:71, and an antisense chain having the sequence shown in SEQ ID NO:245; (91) A sense chain having the sequence shown in SEQ ID NO:72, and an antisense chain having the sequence shown in SEQ ID NO:246; (92) A sense chain having the sequence shown in SEQ ID NO:73, and an antisense chain having the sequence shown in SEQ ID NO:247; (93) A sense chain having the sequence shown in SEQ ID NO:74, and an antisense chain having the sequence shown in SEQ ID NO:248; (94) A sense chain having the sequence shown in SEQ ID NO:75, and an antisense chain having the sequence shown in SEQ ID NO:249; (95) A sense chain having the sequence shown in SEQ ID NO:76, and an antisense chain having the sequence shown in SEQ ID NO:250; (96) A sense chain having the sequence shown in SEQ ID NO:77, and an antisense chain having the sequence shown in SEQ ID NO:251; (97) A sense chain having the sequence shown in SEQ ID NO:78, and an antisense chain having the sequence shown in SEQ ID NO:252; (98) A sense chain having the sequence shown in SEQ ID NO:79, and an antisense chain having the sequence shown in SEQ ID NO:253; (99) A sense chain having the sequence shown in SEQ ID NO:80, and an antisense chain having the sequence shown in SEQ ID NO:254; (100) A sense chain having the sequence shown in SEQ ID NO:81, and an antisense chain having the sequence shown in SEQ ID NO:255; (101) A sense chain having the sequence shown in SEQ ID NO:83, and an antisense chain having the sequence shown in SEQ ID NO:257; (102) A sense chain having the sequence shown in SEQ ID NO:84, and an antisense chain having the sequence shown in SEQ ID NO:258; (103) A sense chain having the sequence shown in SEQ ID NO:85, and an antisense chain having the sequence shown in SEQ ID NO:259; (104) A sense chain having the sequence shown in SEQ ID NO:86, and an antisense chain having the sequence shown in SEQ ID NO:260; (105) A sense chain having the sequence shown in SEQ ID NO:87, and an antisense chain having the sequence shown in SEQ ID NO:261; (106) A sense chain having the sequence shown in SEQ ID NO:89, and an antisense chain having the sequence shown in SEQ ID NO:263; (107) A sense chain having the sequence shown in SEQ ID NO:93, and an antisense chain having the sequence shown in SEQ ID NO:267; (108) A sense chain having the sequence shown in SEQ ID NO:95, and an antisense chain having the sequence shown in SEQ ID NO:269; (109) A sense chain having the sequence shown in SEQ ID NO:96, and an antisense chain having the sequence shown in SEQ ID NO:270; (110) A sense chain having the sequence shown in SEQ ID NO:97, and an antisense chain having the sequence shown in SEQ ID NO:271; (111) A sense chain having the sequence shown in SEQ ID NO:98, and an antisense chain having the sequence shown in SEQ ID NO:272; (112) A sense chain having the sequence shown in SEQ ID NO:99, and an antisense chain having the sequence shown in SEQ ID NO:273; (113) A sense chain having the sequence shown in SEQ ID NO:100, and an antisense chain having the sequence shown in SEQ ID NO:274; (114) A sense chain having the sequence shown in SEQ ID NO:101, and an antisense chain having the sequence shown in SEQ ID NO:275; (115) A sense chain having the sequence shown in SEQ ID NO:103, and an antisense chain having the sequence shown in SEQ ID NO:277; (116) A sense chain having the sequence shown in SEQ ID NO:105, and an antisense chain having the sequence shown in SEQ ID NO:279; (117) A sense chain having the sequence shown in SEQ ID NO:106, and an antisense chain having the sequence shown in SEQ ID NO:280; (118) A sense chain having the sequence shown in SEQ ID NO:107, and an antisense chain having the sequence shown in SEQ ID NO:281; (119) A sense chain having the sequence shown in SEQ ID NO:108, and an antisense chain having the sequence shown in SEQ ID NO:282; (120) A sense chain having the sequence shown in SEQ ID NO:109, and an antisense chain having the sequence shown in SEQ ID NO:283; (121) A sense chain having the sequence shown in SEQ ID NO:110, and an antisense chain having the sequence shown in SEQ ID NO:284; (122) A sense chain having the sequence shown in SEQ ID NO:111, and an antisense chain having the sequence shown in SEQ ID NO:285; (123) A sense chain having the sequence shown in SEQ ID NO:112, and an antisense chain having the sequence shown in SEQ ID NO:286; (124) A sense chain having the sequence shown in SEQ ID NO:113, and an antisense chain having the sequence shown in SEQ ID NO:287; (125) A sense chain having the sequence shown in SEQ ID NO:114, and an antisense chain having the sequence shown in SEQ ID NO:288; (126) A sense chain having the sequence shown in SEQ ID NO:115, and an antisense chain having the sequence shown in SEQ ID NO:289; (127) A sense chain having the sequence shown in SEQ ID NO:116, and an antisense chain having the sequence shown in SEQ ID NO:290; (128) A sense chain having the sequence shown in SEQ ID NO:117, and an antisense chain having the sequence shown in SEQ ID NO:291; (129) A sense chain having the sequence shown in SEQ ID NO:118, and an antisense chain having the sequence shown in SEQ ID NO:292; (130) A sense chain having the sequence shown in SEQ ID NO:119, and an antisense chain having the sequence shown in SEQ ID NO:293; (131) A sense chain having the sequence shown in SEQ ID NO:120, and an antisense chain having the sequence shown in SEQ ID NO:294; (132) A sense chain having the sequence shown in SEQ ID NO:121, and an antisense chain having the sequence shown in SEQ ID NO:295; (133) A sense chain having the sequence shown in SEQ ID NO:122, and an antisense chain having the sequence shown in SEQ ID NO:296; (134) A sense chain having the sequence shown in SEQ ID NO:123, and an antisense chain having the sequence shown in SEQ ID NO:297; (135) A sense chain having the sequence shown in SEQ ID NO:124, and an antisense chain having the sequence shown in SEQ ID NO:298; (136) A sense chain having the sequence shown in SEQ ID NO:125, and an antisense chain having the sequence shown in SEQ ID NO:299; (137) A sense chain having the sequence shown in SEQ ID NO:126, and an antisense chain having the sequence shown in SEQ ID NO:300; (138) A sense chain having the sequence shown in SEQ ID NO:127, and an antisense chain having the sequence shown in SEQ ID NO:301; (139) A sense chain having the sequence shown in SEQ ID NO:128, and an antisense chain having the sequence shown in SEQ ID NO:302; (140) A sense chain having the sequence shown in SEQ ID NO:129, and an antisense chain having the sequence shown in SEQ ID NO:303; (141) A sense chain having the sequence shown in SEQ ID NO:130, and an antisense chain having the sequence shown in SEQ ID NO:304; (142) A sense chain having the sequence shown in SEQ ID NO:131, and an antisense chain having the sequence shown in SEQ ID NO:305; (143) A sense chain having the sequence shown in SEQ ID NO:132, and an antisense chain having the sequence shown in SEQ ID NO:306; (144) A sense chain having the sequence shown in SEQ ID NO:133, and an antisense chain having the sequence shown in SEQ ID NO:307; (145) A sense chain having the sequence shown in SEQ ID NO:134, and an antisense chain having the sequence shown in SEQ ID NO:308; (146) A sense chain having the sequence shown in SEQ ID NO:135, and an antisense chain having the sequence shown in SEQ ID NO:309; (147) A sense chain having the sequence shown in SEQ ID NO:136, and an antisense chain having the sequence shown in SEQ ID NO:310; (148) A sense chain having the sequence shown in SEQ ID NO:137, and an antisense chain having the sequence shown in SEQ ID NO:311; (149) A sense chain having the sequence shown in SEQ ID NO:138, and an antisense chain having the sequence shown in SEQ ID NO:312; (150) A sense chain having the sequence shown in SEQ ID NO:139, and an antisense chain having the sequence shown in SEQ ID NO:313; (151) A sense chain having the sequence shown in SEQ ID NO:141, and an antisense chain having the sequence shown in SEQ ID NO:315; (152) A sense chain having the sequence shown in SEQ ID NO:142, and an antisense chain having the sequence shown in SEQ ID NO:316; (153) A sense chain having the sequence shown in SEQ ID NO:143, and an antisense chain having the sequence shown in SEQ ID NO:317; (154) A sense chain having the sequence shown in SEQ ID NO:145, and an antisense chain having the sequence shown in SEQ ID NO:319; (155) A sense chain having the sequence shown in SEQ ID NO:146, and an antisense chain having the sequence shown in SEQ ID NO:320; (156) A sense chain having the sequence shown in SEQ ID NO:147, and an antisense chain having the sequence shown in SEQ ID NO:321; (157) A sense chain having the sequence shown in SEQ ID NO:148, and an antisense chain having the sequence shown in SEQ ID NO:322; (158) A sense chain having the sequence shown in SEQ ID NO:149, and an antisense chain having the sequence shown in SEQ ID NO:323; (159) A sense chain having the sequence shown in SEQ ID NO:150, and an antisense chain having the sequence shown in SEQ ID NO:324; (160) A sense chain having the sequence shown in SEQ ID NO:151, and an antisense chain having the sequence shown in SEQ ID NO:325; (161) A sense chain having the sequence shown in SEQ ID NO:152, and an antisense chain having the sequence shown in SEQ ID NO:326; (162) A sense chain having the sequence shown in SEQ ID NO:153, and an antisense chain having the sequence shown in SEQ ID NO:327; (163) A sense chain having the sequence shown in SEQ ID NO:154, and an antisense chain having the sequence shown in SEQ ID NO:328; (164) A sense chain having the sequence shown in SEQ ID NO:155, and an antisense chain having the sequence shown in SEQ ID NO:329; (165) A sense chain having the sequence shown in SEQ ID NO:156, and an antisense chain having the sequence shown in SEQ ID NO:330; (166) A sense chain having the sequence shown in SEQ ID NO:157, and an antisense chain having the sequence shown in SEQ ID NO:331; (167) A sense chain having the sequence shown in SEQ ID NO:158, and an antisense chain having the sequence shown in SEQ ID NO:332; (168) A sense chain having the sequence shown in SEQ ID NO:159, and an antisense chain having the sequence shown in SEQ ID NO:333; (169) A sense chain having the sequence shown in SEQ ID NO:160, and an antisense chain having the sequence shown in SEQ ID NO:334; (170) A sense chain having the sequence shown in SEQ ID NO:161, and an antisense chain having the sequence shown in SEQ ID NO:335; (171) A sense chain having the sequence shown in SEQ ID NO:162, and an antisense chain having the sequence shown in SEQ ID NO:336; (172) A sense chain having the sequence shown in SEQ ID NO:163, and an antisense chain having the sequence shown in SEQ ID NO:337; (173) A sense chain having the sequence shown in SEQ ID NO:164, and an antisense chain having the sequence shown in SEQ ID NO:338; (174) A sense chain having the sequence shown in SEQ ID NO:165, and an antisense chain having the sequence shown in SEQ ID NO:339; (175) A sense chain having the sequence shown in SEQ ID NO:166, and an antisense chain having the sequence shown in SEQ ID NO:340; (176) A sense chain having the sequence shown in SEQ ID NO:167, and an antisense chain having the sequence shown in SEQ ID NO:341; (177) A sense chain having the sequence shown in SEQ ID NO:168, and an antisense chain having the sequence shown in SEQ ID NO:342; (178) A sense chain having the sequence shown in SEQ ID NO:169, and an antisense chain having the sequence shown in SEQ ID NO:343; (179) A sense chain having the sequence shown in SEQ ID NO:170, and an antisense chain having the sequence shown in SEQ ID NO:344; (180) A sense chain having the sequence shown in SEQ ID NO:171, and an antisense chain having the sequence shown in SEQ ID NO:345; (181) A positive chain having the sequence shown in SEQ ID NO:172, and an antisense chain having the sequence shown in SEQ ID NO:346; or (182) A sense chain having the sequence shown in SEQ ID NO:173, and an antisense chain having the sequence shown in SEQ ID NO:347; The antisense strand has a length of 21, 22, or 23 nucleotides, and the sense strand has a length of 19, 20, or 21 nucleotides. According to claim 7, the double-stranded oligonucleotide, wherein, The sense and antisense strands of the double-stranded oligonucleotide are each selected from any of the following combinations: (1) A sense chain having the sequence shown in SEQ ID NO:31, and an antisense chain having the sequence shown in SEQ ID NO:205; (2) A sense chain having the sequence shown in SEQ ID NO:82, and an antisense chain having the sequence shown in SEQ ID NO:256; (3) A sense chain having the sequence shown in SEQ ID NO:104, and an antisense chain having the sequence shown in SEQ ID NO:278; (4) A sense chain having the sequence shown in SEQ ID NO:90, and an antisense chain having the sequence shown in SEQ ID NO:264; (5) A sense chain having the sequence shown in SEQ ID NO:47, and an antisense chain having the sequence shown in SEQ ID NO:221; (6) A sense chain having the sequence shown in SEQ ID NO:2 and an antisense chain having the sequence shown in SEQ ID NO:176; (7) A sense chain having the sequence shown in SEQ ID NO:22, and an antisense chain having the sequence shown in SEQ ID NO:196; (8) A sense chain having the sequence shown in SEQ ID NO:25, and an antisense chain having the sequence shown in SEQ ID NO:199; (9) A sense chain having the sequence shown in SEQ ID NO:48, and an antisense chain having the sequence shown in SEQ ID NO:222; (10) A sense chain having the sequence shown in SEQ ID NO:102, and an antisense chain having the sequence shown in SEQ ID NO:276; (11) A sense chain having the sequence shown in SEQ ID NO:3 and an antisense chain having the sequence shown in SEQ ID NO:177; (12) A sense chain having the sequence shown in SEQ ID NO:5 and an antisense chain having the sequence shown in SEQ ID NO:179; (13) A sense chain having the sequence shown in SEQ ID NO:6 and an antisense chain having the sequence shown in SEQ ID NO:180; (14) A sense chain having the sequence shown in SEQ ID NO:88, and an antisense chain having the sequence shown in SEQ ID NO:262; (15) A sense chain having the sequence shown in SEQ ID NO:94, and an antisense chain having the sequence shown in SEQ ID NO:268; (16) A positive chain having the sequence shown in SEQ ID NO:140, and an antisense chain having the sequence shown in SEQ ID NO:314; or (17) A sense chain having the sequence shown in SEQ ID NO:144, and an antisense chain having the sequence shown in SEQ ID NO:

318. According to claim 7, the double-stranded oligonucleotide, wherein, The sense and antisense strands of the double-stranded oligonucleotide are each selected from any of the following combinations: (1) A sense chain having the sequence shown in SEQ ID NO:698, and an antisense chain having the sequence shown in SEQ ID NO:707; (2) A sense chain having the sequence shown in SEQ ID NO:701, and an antisense chain having the sequence shown in SEQ ID NO:710; (3) A sense chain having the sequence shown in SEQ ID NO:91, and an antisense chain having the sequence shown in SEQ ID NO:265; (4) A sense chain having the sequence shown in SEQ ID NO:92, and an antisense chain having the sequence shown in SEQ ID NO:266; (5) A sense chain having the sequence shown in SEQ ID NO:697, and an antisense chain having the sequence shown in SEQ ID NO:706; (6) A sense chain having the sequence shown in SEQ ID NO:699, and an antisense chain having the sequence shown in SEQ ID NO:708; (7) A sense chain having the sequence shown in SEQ ID NO:700, and an antisense chain having the sequence shown in SEQ ID NO:709; (8) A sense chain having the sequence shown in SEQ ID NO:702, and an antisense chain having the sequence shown in SEQ ID NO:711; (9) A sense chain having the sequence shown in SEQ ID NO:703, and an antisense chain having the sequence shown in SEQ ID NO:712; (10) A positive chain having the sequence shown in SEQ ID NO:704, and an antisense chain having the sequence shown in SEQ ID NO:713; or (11) A sense chain having the sequence shown in SEQ ID NO:705, and an antisense chain having the sequence shown in SEQ ID NO:714; The antisense strand has a length of 21, 22, or 23 nucleotides, and the sense strand has a length of 19, 20, or 21 nucleotides. The double-stranded oligonucleotide according to any one of claims 7-9, wherein, The sense and antisense strands of the double-stranded oligonucleotide are each selected from any of the following combinations: (1) A sense chain having the sequence shown in SEQ ID NO:31, and an antisense chain having the sequence shown in SEQ ID NO:205; (2) A sense chain having the sequence shown in SEQ ID NO:82, and an antisense chain having the sequence shown in SEQ ID NO:256; (3) A sense chain having the sequence shown in SEQ ID NO:104, and an antisense chain having the sequence shown in SEQ ID NO:278; (4) A sense chain having the sequence shown in SEQ ID NO:90, and an antisense chain having the sequence shown in SEQ ID NO:264; (5) A sense chain having the sequence shown in SEQ ID NO:47, and an antisense chain having the sequence shown in SEQ ID NO:221; (6) A sense chain having the sequence shown in SEQ ID NO:2 and an antisense chain having the sequence shown in SEQ ID NO:176; (7) A sense chain having the sequence shown in SEQ ID NO:22, and an antisense chain having the sequence shown in SEQ ID NO:196; (8) A sense chain having the sequence shown in SEQ ID NO:25, and an antisense chain having the sequence shown in SEQ ID NO:199; (9) A sense chain having the sequence shown in SEQ ID NO:48, and an antisense chain having the sequence shown in SEQ ID NO:222; (10) A sense chain having the sequence shown in SEQ ID NO:91, and an antisense chain having the sequence shown in SEQ ID NO:265; (11) A sense chain having the sequence shown in SEQ ID NO:92, and an antisense chain having the sequence shown in SEQ ID NO:266; or (12) A sense chain having the sequence shown in SEQ ID NO:102, and an antisense chain having the sequence shown in SEQ ID NO:276; The antisense strand has a length of 21, 22, or 23 nucleotides, and the sense strand has a length of 19, 20, or 21 nucleotides. The double-stranded oligonucleotide according to any one of claims 7-10, wherein, The sense and antisense strands of the double-stranded oligonucleotide are each selected from any of the following combinations: (1) A sense chain having the sequence shown in SEQ ID NO:31, and an antisense chain having the sequence shown in SEQ ID NO:205; (2) A sense chain having the sequence shown in SEQ ID NO:82, and an antisense chain having the sequence shown in SEQ ID NO:256; (3) A sense chain having the sequence shown in SEQ ID NO:104, and an antisense chain having the sequence shown in SEQ ID NO:278; (4) A sense chain having the sequence shown in SEQ ID NO:90, and an antisense chain having the sequence shown in SEQ ID NO:264; (5) A sense chain having the sequence shown in SEQ ID NO:47, and an antisense chain having the sequence shown in SEQ ID NO:221; (6) A sense chain having the sequence shown in SEQ ID NO:2 and an antisense chain having the sequence shown in SEQ ID NO:176; (7) A positive chain having the sequence shown in SEQ ID NO:698, and an antisense chain having the sequence shown in SEQ ID NO:707; or (8) A sense chain having the sequence shown in SEQ ID NO:701, and an antisense chain having the sequence shown in SEQ ID NO:710; The antisense strand has a length of 21, 22, or 23 nucleotides, and the sense strand has a length of 19, 20, or 21 nucleotides. The double-stranded oligonucleotide according to any one of claims 1-11, wherein, The double-stranded oligonucleotide contains modified nucleotides. The double-stranded oligonucleotide according to any one of claims 1-12, wherein, In the double-stranded oligonucleotide, at least a portion of the nucleotides in the sense strand and the antisense strand are modified nucleotides. Preferably, each nucleotide of the sense or antisense strand is a modified nucleotide. The double-stranded oligonucleotide according to any one of claims 1-13, wherein, The modified nucleotides are selected from 2'-methoxy-modified nucleotides, 2'-fluorine-modified nucleotides, 2'-deoxynucleotides, inosine or hypoxanthine nucleotides, 5'-phosphate nucleotides, 2',3'-seco nucleotide mimics, locked nucleotides (LNA), unlocked nucleic acid nucleotides (UNA), glycol nucleic acid nucleotides (GNA), bicyclic nucleic acids (BNA), 2'-F-arabinonucleotides, 2'-methoxyethyl nucleotides, abase-free nucleotides, ribitol, reverse nucleotides, reverse abase-free nucleotides (Invab), reverse 2'-OMe nucleotides, reverse 2'-deoxynucleotides, 2'-amino-modified nucleotides, 2'-alkyl-modified nucleotides, morpholinonucleotides, 3'-OMe nucleotides, phosphate ester-modified nucleotides, terminal nucleotides linked to cholesterol derivatives or dodecanoic acid bis(decylamide) groups, 2'-amino-modified nucleotides, aminophosphates, nucleotides containing non-natural bases or 5'-phosphate ester mimics modified with nucleotides; Preferably, the sense strand and the antisense strand each independently contain at least one nucleotide internucleotide bond; Preferably, the internucleotide bond is a phosphate thioester bond; Preferably, the 5'-phosphate analogue is selected from 5'-oxymethylphosphonate, 5'-vinylphosphonate, 5'-vinylphosphate analogue, 5'-vinylphosphonate-2'-N-acetyl or 5'-malonylphosphonate. The double-stranded oligonucleotide according to any one of claims 1-14, wherein, The nucleotides at positions 7, 8, and 9 starting from the 5' end of the positive strand are 2'-fluorinated nucleotides, and there is exactly one nucleotide at position 5, 11, or 12 that is a 2'-fluorinated nucleotide. Preferably, the nucleotides at positions 2, 6, 7, 14, and 16 starting from the 5' end of the antisense strand are 2'-fluorinated nucleotides, and there is only one nucleotide at position 4 or 5 that is a 2'-fluorinated nucleotide; Preferably, a phosphate thioester bond exists between the first and second nucleotides, and between the second and third nucleotides, starting from the 5' end of the positive strand; Preferably, a phosphate thioester bond exists between the first and second nucleotides, the second and third nucleotides, the 19th and 20th nucleotides, and the 20th and 21st nucleotides starting from the 5' end of the antisense strand; Preferably, the modification type of the double-stranded oligonucleotide is selected from any one of the following combinations: (1) The nucleotides at positions 5, 7, 8, and 9 starting from the 5' end of the sense strand are 2'-fluorinated nucleotides, and the remaining nucleotides are 2'-methoxyinated nucleotides. Furthermore, there are thiophosphate bonds between the first and second nucleotides and between the second and third nucleotides starting from the 5' end of the sense strand. The nucleotides at positions 2, 4, 6, 7, 10, 12, 14, and 16 starting from the 5' end of the antisense strand are 2'-fluorinated nucleotides, and the remaining nucleotides are 2'-methoxyinated nucleotides. Furthermore, there are thiophosphate bonds between the first and second nucleotides, between the second and third nucleotides, between the 19th and 20th nucleotides, and between the 20th and 21st nucleotides starting from the 5' end of the antisense strand. (2) The nucleotides at positions 7, 8, 9, and 12 starting from the 5' end of the sense strand are 2'-fluorinated nucleotides, and the remaining nucleotides are 2'-methoxyinated nucleotides. A thiophosphate bond exists between the first and second nucleotides, and between the second and third nucleotides, starting from the 5' end of the sense strand. The nucleotides at positions 2, 4, 6, 7, 10, 12, 14, and 16 starting from the 5' end of the antisense strand are 2'-fluorinated nucleotides, and the remaining nucleotides are 2'-methoxyinated nucleotides. A thiophosphate bond exists between the first and second nucleotides, between the second and third nucleotides, between the 19th and 20th nucleotides, and between the 20th and 21st nucleotides, starting from the 5' end of the antisense strand. (3) The nucleotides at positions 7, 8, 9, and 11 starting from the 5' end of the sense strand are 2'-fluorinated nucleotides, and the remaining nucleotides are 2'-methoxyinated nucleotides. Furthermore, there are thiophosphate bonds between the first and second nucleotides and between the second and third nucleotides starting from the 5' end of the sense strand. The nucleotides at positions 2, 5, 6, 7, 14, and 16 starting from the 5' end of the antisense strand are 2'-fluorinated nucleotides, and the remaining nucleotides are 2'-methoxyinated nucleotides. Furthermore, there are thiophosphate bonds between the first and second nucleotides, between the second and third nucleotides, between the 19th and 20th nucleotides, and between the 20th and 21st nucleotides starting from the 5' end of the antisense strand. According to claim 15, the double-stranded oligonucleotide, wherein, The nucleotides at positions 7, 8, 9, and 12, starting from the 5' end of the sense strand, are 2'-fluorinated nucleotides, and the remaining nucleotides are 2'-methoxyinated nucleotides. Furthermore, thiophosphate bonds exist between the first and second nucleotides, and between the second and third nucleotides, starting from the 5' end of the sense strand. Similarly, the nucleotides at positions 2, 4, 6, 7, 10, 12, 14, and 16, starting from the 5' end of the antisense strand, are 2'-fluorinated nucleotides, and the remaining nucleotides are 2'-methoxyinated nucleotides. Furthermore, thiophosphate bonds exist between the first and second nucleotides, between the second and third nucleotides, between the 19th and 20th nucleotides, and between the 20th and 21st nucleotides, starting from the 5' end of the antisense strand. The double-stranded oligonucleotide according to any one of claims 1-16, wherein, The sense and antisense strands of the double-stranded oligonucleotide are each selected from any of the following combinations; or the sense and antisense strands of the double-stranded oligonucleotide comprise at least 17 consecutive nucleotide sequences that differ from the nucleotide sequences shown in any of the following combinations by no more than 4, 3, 2, or 1 nucleotides: (1) A sense chain having the sequence shown in SEQ ID NO:379, and an antisense chain having the sequence shown in SEQ ID NO:553; (2) A sense chain having the sequence shown in SEQ ID NO:430, and an antisense chain having the sequence shown in SEQ ID NO:604; (3) A sense chain having the sequence shown in SEQ ID NO:452, and an antisense chain having the sequence shown in SEQ ID NO:626; (4) A sense chain having the sequence shown in SEQ ID NO:438, and an antisense chain having the sequence shown in SEQ ID NO:612; (5) A sense chain having the sequence shown in SEQ ID NO:395, and an antisense chain having the sequence shown in SEQ ID NO:569; (6) A sense chain having the sequence shown in SEQ ID NO:350, and an antisense chain having the sequence shown in SEQ ID NO:524; (7) A sense chain having the sequence shown in SEQ ID NO:716, and an antisense chain having the sequence shown in SEQ ID NO:725; (8) A sense chain having the sequence shown in SEQ ID NO:719, and an antisense chain having the sequence shown in SEQ ID NO:728; (9) A sense chain having the sequence shown in SEQ ID NO:370, and an antisense chain having the sequence shown in SEQ ID NO:544; (10) A sense chain having the sequence shown in SEQ ID NO:373, and an antisense chain having the sequence shown in SEQ ID NO:547; (11) A sense chain having the sequence shown in SEQ ID NO:396, and an antisense chain having the sequence shown in SEQ ID NO:570; (12) A sense chain having the sequence shown in SEQ ID NO:450, and an antisense chain having the sequence shown in SEQ ID NO:624; (13) A sense chain having the sequence shown in SEQ ID NO:439, and an antisense chain having the sequence shown in SEQ ID NO:613; (14) A sense chain having the sequence shown in SEQ ID NO:440, and an antisense chain having the sequence shown in SEQ ID NO:614; (15) A sense chain having the sequence shown in SEQ ID NO:351, and an antisense chain having the sequence shown in SEQ ID NO:525; (16) A sense chain having the sequence shown in SEQ ID NO:353, and an antisense chain having the sequence shown in SEQ ID NO:527; (17) A sense chain having the sequence shown in SEQ ID NO:354, and an antisense chain having the sequence shown in SEQ ID NO:528; (18) A sense chain having the sequence shown in SEQ ID NO:436, and an antisense chain having the sequence shown in SEQ ID NO:610; (19) A sense chain having the sequence shown in SEQ ID NO:442, and an antisense chain having the sequence shown in SEQ ID NO:616; (20) A sense chain having the sequence shown in SEQ ID NO:488, and an antisense chain having the sequence shown in SEQ ID NO:662; (21) A sense chain having the sequence shown in SEQ ID NO:492, and an antisense chain having the sequence shown in SEQ ID NO:666; (22) A sense chain having the sequence shown in SEQ ID NO:715, and an antisense chain having the sequence shown in SEQ ID NO:724; (23) A sense chain having the sequence shown in SEQ ID NO:717, and an antisense chain having the sequence shown in SEQ ID NO:726; (24) A sense chain having the sequence shown in SEQ ID NO:718, and an antisense chain having the sequence shown in SEQ ID NO:727; (25) A sense chain having the sequence shown in SEQ ID NO:720, and an antisense chain having the sequence shown in SEQ ID NO:729; (26) A sense chain having the sequence shown in SEQ ID NO:721, and an antisense chain having the sequence shown in SEQ ID NO:730; (27) A sense chain having the sequence shown in SEQ ID NO:722, and an antisense chain having the sequence shown in SEQ ID NO:731; (28) A sense chain having the sequence shown in SEQ ID NO:723, and an antisense chain having the sequence shown in SEQ ID NO:732; (29) A sense chain having the sequence shown in SEQ ID NO:349, and an antisense chain having the sequence shown in SEQ ID NO:523; (30) A sense chain having the sequence shown in SEQ ID NO:352, and an antisense chain having the sequence shown in SEQ ID NO:526; (31) A sense chain having the sequence shown in SEQ ID NO:355, and an antisense chain having the sequence shown in SEQ ID NO:529; (32) A sense chain having the sequence shown in SEQ ID NO:356, and an antisense chain having the sequence shown in SEQ ID NO:530; (33) A sense chain having the sequence shown in SEQ ID NO:357, and an antisense chain having the sequence shown in SEQ ID NO:531; (34) A sense chain having the sequence shown in SEQ ID NO:358, and an antisense chain having the sequence shown in SEQ ID NO:532; (35) A sense chain having the sequence shown in SEQ ID NO:359, and an antisense chain having the sequence shown in SEQ ID NO:533; (36) A sense chain having the sequence shown in SEQ ID NO:360, and an antisense chain having the sequence shown in SEQ ID NO:534; (37) A sense chain having the sequence shown in SEQ ID NO:361, and an antisense chain having the sequence shown in SEQ ID NO:535; (38) A sense chain having the sequence shown in SEQ ID NO:362, and an antisense chain having the sequence shown in SEQ ID NO:536; (39) A sense chain having the sequence shown in SEQ ID NO:363, and an antisense chain having the sequence shown in SEQ ID NO:537; (40) A sense chain having the sequence shown in SEQ ID NO:364, and an antisense chain having the sequence shown in SEQ ID NO:538; (41) A sense chain having the sequence shown in SEQ ID NO:365, and an antisense chain having the sequence shown in SEQ ID NO:539; (42) A sense chain having the sequence shown in SEQ ID NO:366, and an antisense chain having the sequence shown in SEQ ID NO:540; (43) A sense chain having the sequence shown in SEQ ID NO:367, and an antisense chain having the sequence shown in SEQ ID NO:541; (44) A sense chain having the sequence shown in SEQ ID NO:368, and an antisense chain having the sequence shown in SEQ ID NO:542; (45) A sense chain having the sequence shown in SEQ ID NO:369, and an antisense chain having the sequence shown in SEQ ID NO:543; (46) A sense chain having the sequence shown in SEQ ID NO:371, and an antisense chain having the sequence shown in SEQ ID NO:545; (47) A sense chain having the sequence shown in SEQ ID NO:372, and an antisense chain having the sequence shown in SEQ ID NO:546; (48) A sense chain having the sequence shown in SEQ ID NO:374, and an antisense chain having the sequence shown in SEQ ID NO:548; (49) A sense chain having the sequence shown in SEQ ID NO:375, and an antisense chain having the sequence shown in SEQ ID NO:549; (50) A sense chain having the sequence shown in SEQ ID NO:376, and an antisense chain having the sequence shown in SEQ ID NO:550; (51) A sense chain having the sequence shown in SEQ ID NO:377, and an antisense chain having the sequence shown in SEQ ID NO:551; (52) A sense chain having the sequence shown in SEQ ID NO:378, and an antisense chain having the sequence shown in SEQ ID NO:552; (53) A sense chain having the sequence shown in SEQ ID NO:380, and an antisense chain having the sequence shown in SEQ ID NO:554; (54) A sense chain having the sequence shown in SEQ ID NO:381, and an antisense chain having the sequence shown in SEQ ID NO:555; (55) A sense chain having the sequence shown in SEQ ID NO:382, and an antisense chain having the sequence shown in SEQ ID NO:556; (56) A sense chain having the sequence shown in SEQ ID NO:383, and an antisense chain having the sequence shown in SEQ ID NO:557; (57) A sense chain having the sequence shown in SEQ ID NO:384, and an antisense chain having the sequence shown in SEQ ID NO:558; (58) A sense chain having the sequence shown in SEQ ID NO:385, and an antisense chain having the sequence shown in SEQ ID NO:559; (59) A sense chain having the sequence shown in SEQ ID NO:386, and an antisense chain having the sequence shown in SEQ ID NO:560; (60) A sense chain having the sequence shown in SEQ ID NO:387, and an antisense chain having the sequence shown in SEQ ID NO:561; (61) A sense chain having the sequence shown in SEQ ID NO:388, and an antisense chain having the sequence shown in SEQ ID NO:562; (62) A sense chain having the sequence shown in SEQ ID NO:389, and an antisense chain having the sequence shown in SEQ ID NO:563; (63) A sense chain having the sequence shown in SEQ ID NO:390, and an antisense chain having the sequence shown in SEQ ID NO:564; (64) A sense chain having the sequence shown in SEQ ID NO:391, and an antisense chain having the sequence shown in SEQ ID NO:565; (65) A sense chain having the sequence shown in SEQ ID NO:392, and an antisense chain having the sequence shown in SEQ ID NO:566; (66) A sense chain having the sequence shown in SEQ ID NO:393, and an antisense chain having the sequence shown in SEQ ID NO:567; (67) A sense chain having the sequence shown in SEQ ID NO:394, and an antisense chain having the sequence shown in SEQ ID NO:568; (68) A sense chain having the sequence shown in SEQ ID NO:397, and an antisense chain having the sequence shown in SEQ ID NO:571; (69) A sense chain having the sequence shown in SEQ ID NO:398, and an antisense chain having the sequence shown in SEQ ID NO:572; (70) A sense chain having the sequence shown in SEQ ID NO:399, and an antisense chain having the sequence shown in SEQ ID NO:573; (71) A sense chain having the sequence shown in SEQ ID NO:400, and an antisense chain having the sequence shown in SEQ ID NO:574; (72) A sense chain having the sequence shown in SEQ ID NO:401, and an antisense chain having the sequence shown in SEQ ID NO:575; (73) A sense chain having the sequence shown in SEQ ID NO:402, and an antisense chain having the sequence shown in SEQ ID NO:576; (74) A sense chain having the sequence shown in SEQ ID NO:403, and an antisense chain having the sequence shown in SEQ ID NO:577; (75) A sense chain having the sequence shown in SEQ ID NO:404, and an antisense chain having the sequence shown in SEQ ID NO:578; (76) A sense chain having the sequence shown in SEQ ID NO:405, and an antisense chain having the sequence shown in SEQ ID NO:579; (77) A sense chain having the sequence shown in SEQ ID NO:406, and an antisense chain having the sequence shown in SEQ ID NO:580; (78) A sense chain having the sequence shown in SEQ ID NO:407, and an antisense chain having the sequence shown in SEQ ID NO:581; (79) A sense chain having the sequence shown in SEQ ID NO:408, and an antisense chain having the sequence shown in SEQ ID NO:582; (80) A sense chain having the sequence shown in SEQ ID NO:409, and an antisense chain having the sequence shown in SEQ ID NO:583; (81) A sense chain having the sequence shown in SEQ ID NO:410, and an antisense chain having the sequence shown in SEQ ID NO:584; (82) A sense chain having the sequence shown in SEQ ID NO:411, and an antisense chain having the sequence shown in SEQ ID NO:585; (83) A sense chain having the sequence shown in SEQ ID NO:412, and an antisense chain having the sequence shown in SEQ ID NO:586; (84) A sense chain having the sequence shown in SEQ ID NO:413, and an antisense chain having the sequence shown in SEQ ID NO:587; (85) A sense chain having the sequence shown in SEQ ID NO:414, and an antisense chain having the sequence shown in SEQ ID NO:588; (86) A sense chain having the sequence shown in SEQ ID NO:415, and an antisense chain having the sequence shown in SEQ ID NO:589; (87) A sense chain having the sequence shown in SEQ ID NO:416, and an antisense chain having the sequence shown in SEQ ID NO:590; (88) A sense chain having the sequence shown in SEQ ID NO:417, and an antisense chain having the sequence shown in SEQ ID NO:591; (89) A sense chain having the sequence shown in SEQ ID NO:418, and an antisense chain having the sequence shown in SEQ ID NO:592; (90) A sense chain having the sequence shown in SEQ ID NO:419, and an antisense chain having the sequence shown in SEQ ID NO:593; (91) A sense chain having the sequence shown in SEQ ID NO:420, and an antisense chain having the sequence shown in SEQ ID NO:594; (92) A sense chain having the sequence shown in SEQ ID NO:421, and an antisense chain having the sequence shown in SEQ ID NO:595; (93) A sense chain having the sequence shown in SEQ ID NO:422, and an antisense chain having the sequence shown in SEQ ID NO:596; (94) A sense chain having the sequence shown in SEQ ID NO:423, and an antisense chain having the sequence shown in SEQ ID NO:597; (95) A sense chain having the sequence shown in SEQ ID NO:424, and an antisense chain having the sequence shown in SEQ ID NO:598; (96) A sense chain having the sequence shown in SEQ ID NO:425, and an antisense chain having the sequence shown in SEQ ID NO:599; (97) A sense chain having the sequence shown in SEQ ID NO:426, and an antisense chain having the sequence shown in SEQ ID NO:600; (98) A sense chain having the sequence shown in SEQ ID NO:427, and an antisense chain having the sequence shown in SEQ ID NO:601; (99) A sense chain having the sequence shown in SEQ ID NO:428, and an antisense chain having the sequence shown in SEQ ID NO:602; (100) A sense chain having the sequence shown in SEQ ID NO:429, and an antisense chain having the sequence shown in SEQ ID NO:603; (101) A sense chain having the sequence shown in SEQ ID NO:431, and an antisense chain having the sequence shown in SEQ ID NO:605; (102) A sense chain having the sequence shown in SEQ ID NO:432, and an antisense chain having the sequence shown in SEQ ID NO:606; (103) A sense chain having the sequence shown in SEQ ID NO:433, and an antisense chain having the sequence shown in SEQ ID NO:607; (104) A sense chain having the sequence shown in SEQ ID NO:434, and an antisense chain having the sequence shown in SEQ ID NO:608; (105) A sense chain having the sequence shown in SEQ ID NO:435, and an antisense chain having the sequence shown in SEQ ID NO:609; (106) A sense chain having the sequence shown in SEQ ID NO:437, and an antisense chain having the sequence shown in SEQ ID NO:611; (107) A sense chain having the sequence shown in SEQ ID NO:441, and an antisense chain having the sequence shown in SEQ ID NO:615; (108) A sense chain having the sequence shown in SEQ ID NO:443, and an antisense chain having the sequence shown in SEQ ID NO:617; (109) A sense chain having the sequence shown in SEQ ID NO:444, and an antisense chain having the sequence shown in SEQ ID NO:618; (110) A sense chain having the sequence shown in SEQ ID NO:445, and an antisense chain having the sequence shown in SEQ ID NO:619; (111) A sense chain having the sequence shown in SEQ ID NO:446, and an antisense chain having the sequence shown in SEQ ID NO:620; (112) A sense chain having the sequence shown in SEQ ID NO:447, and an antisense chain having the sequence shown in SEQ ID NO:621; (113) A sense chain having the sequence shown in SEQ ID NO:448, and an antisense chain having the sequence shown in SEQ ID NO:622; (114) A sense chain having the sequence shown in SEQ ID NO:449, and an antisense chain having the sequence shown in SEQ ID NO:623; (115) A sense chain having the sequence shown in SEQ ID NO:451, and an antisense chain having the sequence shown in SEQ ID NO:625; (116) A sense chain having the sequence shown in SEQ ID NO:453, and an antisense chain having the sequence shown in SEQ ID NO:627; (117) A sense chain having the sequence shown in SEQ ID NO:454, and an antisense chain having the sequence shown in SEQ ID NO:628; (118) A sense chain having the sequence shown in SEQ ID NO:455, and an antisense chain having the sequence shown in SEQ ID NO:629; (119) A sense chain having the sequence shown in SEQ ID NO:456, and an antisense chain having the sequence shown in SEQ ID NO:630; (120) A sense chain having the sequence shown in SEQ ID NO:457, and an antisense chain having the sequence shown in SEQ ID NO:631; (121) A sense chain having the sequence shown in SEQ ID NO:458, and an antisense chain having the sequence shown in SEQ ID NO:632; (122) A sense chain having the sequence shown in SEQ ID NO:459, and an antisense chain having the sequence shown in SEQ ID NO:633; (123) A sense chain having the sequence shown in SEQ ID NO:460, and an antisense chain having the sequence shown in SEQ ID NO:634; (124) A sense chain having the sequence shown in SEQ ID NO:461, and an antisense chain having the sequence shown in SEQ ID NO:635; (125) A sense chain having the sequence shown in SEQ ID NO:462, and an antisense chain having the sequence shown in SEQ ID NO:636; (126) A sense chain having the sequence shown in SEQ ID NO:463, and an antisense chain having the sequence shown in SEQ ID NO:637; (127) A sense chain having the sequence shown in SEQ ID NO:464, and an antisense chain having the sequence shown in SEQ ID NO:638; (128) A sense chain having the sequence shown in SEQ ID NO:465, and an antisense chain having the sequence shown in SEQ ID NO:639; (129) A sense chain having the sequence shown in SEQ ID NO:466, and an antisense chain having the sequence shown in SEQ ID NO:640; (130) A sense chain having the sequence shown in SEQ ID NO:467, and an antisense chain having the sequence shown in SEQ ID NO:641; (131) A sense chain having the sequence shown in SEQ ID NO:468, and an antisense chain having the sequence shown in SEQ ID NO:642; (132) A sense chain having the sequence shown in SEQ ID NO:469, and an antisense chain having the sequence shown in SEQ ID NO:643; (133) A sense chain having the sequence shown in SEQ ID NO:470, and an antisense chain having the sequence shown in SEQ ID NO:644; (134) A sense chain having the sequence shown in SEQ ID NO:471, and an antisense chain having the sequence shown in SEQ ID NO:645; (135) A sense chain having the sequence shown in SEQ ID NO:472, and an antisense chain having the sequence shown in SEQ ID NO:646; (136) A sense chain having the sequence shown in SEQ ID NO:473, and an antisense chain having the sequence shown in SEQ ID NO:647; (137) A sense chain having the sequence shown in SEQ ID NO:474, and an antisense chain having the sequence shown in SEQ ID NO:648; (138) A sense chain having the sequence shown in SEQ ID NO:475, and an antisense chain having the sequence shown in SEQ ID NO:649; (139) A sense chain having the sequence shown in SEQ ID NO:476, and an antisense chain having the sequence shown in SEQ ID NO:650; (140) A sense chain having the sequence shown in SEQ ID NO:477, and an antisense chain having the sequence shown in SEQ ID NO:651; (141) A sense chain having the sequence shown in SEQ ID NO:478, and an antisense chain having the sequence shown in SEQ ID NO:652; (142) A sense chain having the sequence shown in SEQ ID NO:479, and an antisense chain having the sequence shown in SEQ ID NO:653; (143) A sense chain having the sequence shown in SEQ ID NO:480, and an antisense chain having the sequence shown in SEQ ID NO:654; (144) A sense chain having the sequence shown in SEQ ID NO:481, and an antisense chain having the sequence shown in SEQ ID NO:655; (145) A sense chain having the sequence shown in SEQ ID NO:482, and an antisense chain having the sequence shown in SEQ ID NO:656; (146) A sense chain having the sequence shown in SEQ ID NO:483, and an antisense chain having the sequence shown in SEQ ID NO:657; (147) A sense chain having the sequence shown in SEQ ID NO:484, and an antisense chain having the sequence shown in SEQ ID NO:658; (148) A sense chain having the sequence shown in SEQ ID NO:485, and an antisense chain having the sequence shown in SEQ ID NO:659; (149) A sense chain having the sequence shown in SEQ ID NO:486, and an antisense chain having the sequence shown in SEQ ID NO:660; (150) A sense chain having the sequence shown in SEQ ID NO:487, and an antisense chain having the sequence shown in SEQ ID NO:661; (151) A sense chain having the sequence shown in SEQ ID NO:489, and an antisense chain having the sequence shown in SEQ ID NO:663; (152) A sense chain having the sequence shown in SEQ ID NO:490, and an antisense chain having the sequence shown in SEQ ID NO:664; (153) A sense chain having the sequence shown in SEQ ID NO:491, and an antisense chain having the sequence shown in SEQ ID NO:665; (154) A sense chain having the sequence shown in SEQ ID NO:493, and an antisense chain having the sequence shown in SEQ ID NO:667; (155) A sense chain having the sequence shown in SEQ ID NO:494, and an antisense chain having the sequence shown in SEQ ID NO:668; (156) A sense chain having the sequence shown in SEQ ID NO:495, and an antisense chain having the sequence shown in SEQ ID NO:669; (157) A sense chain having the sequence shown in SEQ ID NO:496, and an antisense chain having the sequence shown in SEQ ID NO:670; (158) A sense chain having the sequence shown in SEQ ID NO:497, and an antisense chain having the sequence shown in SEQ ID NO:671; (159) A sense chain having the sequence shown in SEQ ID NO:498, and an antisense chain having the sequence shown in SEQ ID NO:672; (160) A sense chain having the sequence shown in SEQ ID NO:499, and an antisense chain having the sequence shown in SEQ ID NO:673; (161) A sense chain having the sequence shown in SEQ ID NO:500, and an antisense chain having the sequence shown in SEQ ID NO:674; (162) A sense chain having the sequence shown in SEQ ID NO:501, and an antisense chain having the sequence shown in SEQ ID NO:675; (163) A sense chain having the sequence shown in SEQ ID NO:502, and an antisense chain having the sequence shown in SEQ ID NO:676; (164) A sense chain having the sequence shown in SEQ ID NO:503, and an antisense chain having the sequence shown in SEQ ID NO:677; (165) A sense chain having the sequence shown in SEQ ID NO:504, and an antisense chain having the sequence shown in SEQ ID NO:678; (166) A sense chain having the sequence shown in SEQ ID NO:505, and an antisense chain having the sequence shown in SEQ ID NO:679; (167) A sense chain having the sequence shown in SEQ ID NO:506, and an antisense chain having the sequence shown in SEQ ID NO:680; (168) A sense chain having the sequence shown in SEQ ID NO:507, and an antisense chain having the sequence shown in SEQ ID NO:681; (169) A sense chain having the sequence shown in SEQ ID NO:508, and an antisense chain having the sequence shown in SEQ ID NO:682; (170) A sense chain having the sequence shown in SEQ ID NO:509, and an antisense chain having the sequence shown in SEQ ID NO:683; (171) A sense chain having the sequence shown in SEQ ID NO:510, and an antisense chain having the sequence shown in SEQ ID NO:684; (172) A sense chain having the sequence shown in SEQ ID NO:511, and an antisense chain having the sequence shown in SEQ ID NO:685; (173) A sense chain having the sequence shown in SEQ ID NO:512, and an antisense chain having the sequence shown in SEQ ID NO:686; (174) A sense chain having the sequence shown in SEQ ID NO:513, and an antisense chain having the sequence shown in SEQ ID NO:687; (175) A sense chain having the sequence shown in SEQ ID NO:514, and an antisense chain having the sequence shown in SEQ ID NO:688; (176) A sense chain having the sequence shown in SEQ ID NO:515, and an antisense chain having the sequence shown in SEQ ID NO:689; (177) A sense chain having the sequence shown in SEQ ID NO:516, and an antisense chain having the sequence shown in SEQ ID NO:690; (178) A sense chain having the sequence shown in SEQ ID NO:517, and an antisense chain having the sequence shown in SEQ ID NO:691; (179) A sense chain having the sequence shown in SEQ ID NO:518, and an antisense chain having the sequence shown in SEQ ID NO:692; (180) A sense chain having the sequence shown in SEQ ID NO:519, and an antisense chain having the sequence shown in SEQ ID NO:693; (181) A sense chain having the sequence shown in SEQ ID NO:520, and an antisense chain having the sequence shown in SEQ ID NO:694; or (182) A sense chain having the sequence shown in SEQ ID NO:521, and an antisense chain having the sequence shown in SEQ ID NO:

695. According to claim 17, the double-stranded oligonucleotide, wherein, The sense and antisense strands of the double-stranded oligonucleotide are each selected from any of the following combinations; or the sense and antisense strands of the double-stranded oligonucleotide comprise at least 17 consecutive nucleotide sequences that differ from the nucleotide sequences shown in any of the following combinations by no more than 4, 3, 2, or 1 nucleotides: (1) A sense chain having the sequence shown in SEQ ID NO:379, and an antisense chain having the sequence shown in SEQ ID NO:553; (2) A sense chain having the sequence shown in SEQ ID NO:430, and an antisense chain having the sequence shown in SEQ ID NO:604; (3) A sense chain having the sequence shown in SEQ ID NO:452, and an antisense chain having the sequence shown in SEQ ID NO:626; (4) A sense chain having the sequence shown in SEQ ID NO:438, and an antisense chain having the sequence shown in SEQ ID NO:612; (5) A sense chain having the sequence shown in SEQ ID NO:395, and an antisense chain having the sequence shown in SEQ ID NO:569; (6) A sense chain having the sequence shown in SEQ ID NO:350, and an antisense chain having the sequence shown in SEQ ID NO:524; (7) A sense chain having the sequence shown in SEQ ID NO:370, and an antisense chain having the sequence shown in SEQ ID NO:544; (8) A sense chain having the sequence shown in SEQ ID NO:373, and an antisense chain having the sequence shown in SEQ ID NO:547; (9) A sense chain having the sequence shown in SEQ ID NO:396, and an antisense chain having the sequence shown in SEQ ID NO:570; (10) A sense chain having the sequence shown in SEQ ID NO:450, and an antisense chain having the sequence shown in SEQ ID NO:624; (11) A sense chain having the sequence shown in SEQ ID NO:351, and an antisense chain having the sequence shown in SEQ ID NO:525; (12) A sense chain having the sequence shown in SEQ ID NO:353, and an antisense chain having the sequence shown in SEQ ID NO:527; (13) A sense chain having the sequence shown in SEQ ID NO:354, and an antisense chain having the sequence shown in SEQ ID NO:528; (14) A sense chain having the sequence shown in SEQ ID NO:436, and an antisense chain having the sequence shown in SEQ ID NO:610; (15) A sense chain having the sequence shown in SEQ ID NO:442, and an antisense chain having the sequence shown in SEQ ID NO:616; (16) A positive chain having the sequence shown in SEQ ID NO:488, and an antisense chain having the sequence shown in SEQ ID NO:662; or (17) A sense chain having the sequence shown in SEQ ID NO:492, and an antisense chain having the sequence shown in SEQ ID NO:

666. According to claim 17, the double-stranded oligonucleotide, wherein, The sense and antisense strands of the double-stranded oligonucleotide are each selected from any of the following combinations; or the sense and antisense strands of the double-stranded oligonucleotide comprise at least 17 consecutive nucleotide sequences that differ from the nucleotide sequences shown in any of the following combinations by no more than 4, 3, 2, or 1 nucleotides: (1) A sense chain having the sequence shown in SEQ ID NO:716, and an antisense chain having the sequence shown in SEQ ID NO:725; (2) A sense chain having the sequence shown in SEQ ID NO:719, and an antisense chain having the sequence shown in SEQ ID NO:728; (3) A sense chain having the sequence shown in SEQ ID NO:439, and an antisense chain having the sequence shown in SEQ ID NO:613; (4) A sense chain having the sequence shown in SEQ ID NO:440, and an antisense chain having the sequence shown in SEQ ID NO:614; (5) A sense chain having the sequence shown in SEQ ID NO:715, and an antisense chain having the sequence shown in SEQ ID NO:724; (6) A sense chain having the sequence shown in SEQ ID NO:717, and an antisense chain having the sequence shown in SEQ ID NO:726; (7) A sense chain having the sequence shown in SEQ ID NO:718, and an antisense chain having the sequence shown in SEQ ID NO:727; (8) A sense chain having the sequence shown in SEQ ID NO:720, and an antisense chain having the sequence shown in SEQ ID NO:729; (9) A sense chain having the sequence shown in SEQ ID NO:721, and an antisense chain having the sequence shown in SEQ ID NO:730; (10) A positive chain having the sequence shown in SEQ ID NO:722, and an antisense chain having the sequence shown in SEQ ID NO:731; or (11) A sense chain having the sequence shown in SEQ ID NO:723, and an antisense chain having the sequence shown in SEQ ID NO:

732. The double-stranded oligonucleotide according to any one of claims 17-19, wherein, The sense and antisense strands of the double-stranded oligonucleotide are each selected from any of the following combinations; or the sense and antisense strands of the double-stranded oligonucleotide comprise at least 17 consecutive nucleotide sequences that differ from the nucleotide sequences shown in any of the following combinations by no more than 4, 3, 2, or 1 nucleotides: (1) A sense chain having the sequence shown in SEQ ID NO:379, and an antisense chain having the sequence shown in SEQ ID NO:553; (2) A sense chain having the sequence shown in SEQ ID NO:430, and an antisense chain having the sequence shown in SEQ ID NO:604; (3) A sense chain having the sequence shown in SEQ ID NO:452, and an antisense chain having the sequence shown in SEQ ID NO:626; (4) A sense chain having the sequence shown in SEQ ID NO:395, and an antisense chain having the sequence shown in SEQ ID NO:569; (5) A sense chain having the sequence shown in SEQ ID NO:438, and an antisense chain having the sequence shown in SEQ ID NO:612; (6) A sense chain having the sequence shown in SEQ ID NO:350, and an antisense chain having the sequence shown in SEQ ID NO:524; (7) A sense chain having the sequence shown in SEQ ID NO:370, and an antisense chain having the sequence shown in SEQ ID NO:544; (8) A sense chain having the sequence shown in SEQ ID NO:373, and an antisense chain having the sequence shown in SEQ ID NO:547; (9) A sense chain having the sequence shown in SEQ ID NO:396, and an antisense chain having the sequence shown in SEQ ID NO:570; (10) A sense chain having the sequence shown in SEQ ID NO:439, and an antisense chain having the sequence shown in SEQ ID NO:613; (11) A positive chain having the sequence shown in SEQ ID NO:440, and an antisense chain having the sequence shown in SEQ ID NO:614; or (12) A sense chain having the sequence shown in SEQ ID NO:450, and an antisense chain having the sequence shown in SEQ ID NO:

624. The double-stranded oligonucleotide according to any one of claims 17-20, wherein, The sense and antisense strands of the double-stranded oligonucleotide are each selected from any of the following combinations; or the sense and antisense strands of the double-stranded oligonucleotide comprise at least 17 consecutive nucleotide sequences that differ from the nucleotide sequences shown in any of the following combinations by no more than 4, 3, 2, or 1 nucleotides: (1) A sense chain having the sequence shown in SEQ ID NO:379, and an antisense chain having the sequence shown in SEQ ID NO:553; (2) A sense chain having the sequence shown in SEQ ID NO:430, and an antisense chain having the sequence shown in SEQ ID NO:604; (3) A sense chain having the sequence shown in SEQ ID NO:452, and an antisense chain having the sequence shown in SEQ ID NO:626; (4) A sense chain having the sequence shown in SEQ ID NO:395, and an antisense chain having the sequence shown in SEQ ID NO:569; (5) A sense chain having the sequence shown in SEQ ID NO:438, and an antisense chain having the sequence shown in SEQ ID NO:612; (6) A sense chain having the sequence shown in SEQ ID NO:350, and an antisense chain having the sequence shown in SEQ ID NO:524; (7) A positive chain having the sequence shown in SEQ ID NO:716, and an antisense chain having the sequence shown in SEQ ID NO:725; or (8) A sense chain having the sequence shown in SEQ ID NO:719 and an antisense chain having the sequence shown in SEQ ID NO:

728. The double-stranded oligonucleotide according to any one of claims 1-21, wherein, At least one nucleotide of the double-stranded oligonucleotide is conjugated to one or more target ligands; Preferably, the targeting ligand is conjugated to the sense strand of the oligonucleotide; Preferably, the targeting ligand is conjugated to any nucleotide position on the sense strand of the oligonucleotide; Preferably, the targeting ligand is conjugated to the 5' end of the sense strand of the oligonucleotide; Preferably, the targeting ligand is conjugated to the sense strand of the double-stranded oligonucleotide at the 3'-end; Preferably, the targeting ligand comprises an N-acetylgalactosamine (GalNAc) moiety; Preferably, the GalNac portion is a monovalent GalNAc portion, a divalent GalNAc portion, a trivalent GalNAc portion, or a tetravalent GalNAc portion; Preferably, the targeting ligand has the following structure: Preferably, the targeting ligand has the following structure: The double-stranded oligonucleotide according to any one of claims 1-22, wherein, The 3' end of the sense strand of the double-stranded oligonucleotide is conjugated to a targeting ligand with the following structure: Preferably, the sense and antisense strands of the double-stranded oligonucleotide are each selected from any of the following combinations; or the sense and antisense strands of the double-stranded oligonucleotide comprise at least 17 consecutive nucleotide sequences that differ from the nucleotide sequences shown in any of the following combinations by no more than 4, 3, 2, or 1 nucleotides: (1) A sense chain having the sequence shown in SEQ ID NO:379, and an antisense chain having the sequence shown in SEQ ID NO:553; (2) A sense chain having the sequence shown in SEQ ID NO:430, and an antisense chain having the sequence shown in SEQ ID NO:604; (3) A sense chain having the sequence shown in SEQ ID NO:452, and an antisense chain having the sequence shown in SEQ ID NO:626; (4) A sense chain having the sequence shown in SEQ ID NO:395, and an antisense chain having the sequence shown in SEQ ID NO:569; (5) A sense chain having the sequence shown in SEQ ID NO:438, and an antisense chain having the sequence shown in SEQ ID NO:612; (6) A sense chain having the sequence shown in SEQ ID NO:350, and an antisense chain having the sequence shown in SEQ ID NO:524; (7) A positive chain having the sequence shown in SEQ ID NO:716, and an antisense chain having the sequence shown in SEQ ID NO:725; or (8) A sense chain having the sequence shown in SEQ ID NO:719 and an antisense chain having the sequence shown in SEQ ID NO:

728. A composition comprising the double-stranded oligonucleotide of any one of claims 1-23 or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier. The composition according to claim 24 further comprises one or more additional therapeutic components. The composition according to claim 24, wherein, The composition is packaged in a box, container, packaging, dispenser, pre-filled syringe, or vial. The composition according to claim 24, wherein, The composition is formulated for administration via ocular, vaginal, rectal, nasal, transdermal, subcutaneous, intravenous, intra-arterial, intralymphatic, intrabronchial, intrapleural, intraperitoneal, cerebrospinal, or intramuscular injection, or for administration to the lungs, intrathecal, or intracardiac organs. A cell comprising the double-stranded oligonucleotide as described in any one of claims 1-23. A method for inhibiting coagulation factor XI gene expression in vitro, the method comprising contacting cells with an effective amount of the double-stranded oligonucleotide of any one of claims 1-23 and / or the composition of any one of claims 24-27. A reagent kit, wherein, The kit contains the double-stranded oligonucleotide of any one of claims 1-23 and / or the composition of any one of claims 24-27. Use of the double-stranded oligonucleotide according to any one of claims 1-23 and / or the composition according to any one of claims 24-27 in the preparation of a medicament for the prevention or treatment of disease. The use according to claim 31, wherein, The disease in question is either a thromboembolic disease or an ischemic stroke. According to the use of claim 32, the thromboembolic disease includes one or more of the following: deep vein thrombosis, venous or arterial thrombosis, pulmonary embolism, myocardial infarction, stroke, thrombosis caused by atrial fibrillation, thrombosis after cardiovascular bypass surgery, thrombosis after knee and hip replacement surgery, and thrombosis associated with chronic kidney disease or end-stage renal disease. The use according to claim 33, wherein, Thrombosis associated with chronic kidney disease or end-stage renal disease includes thrombosis associated with dialysis or other procoagulant states. A method for treating or preventing a disease or ailment in a subject, wherein, The method comprises administering to the subject an amount of oligonucleotide as described in any one of claims 1-23 and / or a composition as described in any one of claims 24-27 sufficient to inhibit the expression of the coagulation factor XI gene in the subject. The method according to claim 35, wherein, The disease or condition mentioned is a thromboembolic disease or ischemic stroke. The method of claim 36, wherein the thromboembolic disease comprises one or more of the following: deep vein thrombosis, venous or arterial thrombosis, pulmonary embolism, myocardial infarction, stroke, thrombosis caused by atrial fibrillation, thrombosis after cardiovascular bypass surgery, thrombosis after knee and hip replacement surgery, and thrombosis associated with chronic kidney disease or end-stage renal disease. The method according to claim 37, wherein, Thrombosis associated with chronic kidney disease or end-stage renal disease includes thrombosis associated with dialysis or other procoagulant states.

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