Serpinc1-targeting double-stranded ribonucleic acid

Abstract

Provided are a SERPINC1-targeting double-stranded ribonucleic acid, a pharmaceutically acceptable salt thereof or a ligand conjugate thereof. Further provided are a pharmaceutical composition comprising the double-stranded ribonucleic acid, the pharmaceutically acceptable salt thereof or the ligand conjugate thereof, and the therapeutic use of the double-stranded ribonucleic acid, the pharmaceutically acceptable salt thereof or the ligand conjugate thereof.

Description

Double-stranded RNA targeting SERPINC1

[0001] Citation of relevant applications

[0002] This application claims priority and benefits to Chinese Patent Application No. 202410925799.9, filed with the State Intellectual Property Office of the People's Republic of China on July 10, 2024, and Chinese Patent Application No. 202510887556.5, filed with the State Intellectual Property Office of the People's Republic of China on June 27, 2025, the entire contents of which are hereby incorporated herein by reference. Technical Field

[0003] This application belongs to the field of biomedicine and relates to a double-stranded ribonucleic acid (dsRNA) that targets SERPINC1 mRNA, its pharmaceutically acceptable salt, its ligand conjugate, or a pharmaceutical composition thereof, which can be used to inhibit the expression of SERPINC1. Background Technology

[0004] The SERPINC1 gene produces antithrombin III or AT-III (AT3), a protein that plays an important role in human blood. It belongs to the serine protease inhibitor superfamily and its main function is to inhibit thrombin and other activating serine proteases in the coagulation system, and to regulate the blood coagulation cascade.

[0005] Small interfering RNA (siRNA) can inhibit the expression of target genes by inhibiting or blocking the translation or transcription of target genes in a sequence-specific manner based on the RNA interference (RNAi) mechanism, thereby exerting an inhibitory effect at the mRNA level and achieving the purpose of treating diseases.

[0006] Invention Overview

[0007] On the one hand, this application provides a double-stranded ribonucleic acid (dsRNA), a pharmaceutically acceptable salt thereof, or a ligand conjugate thereof that targets SERPINC1 mRNA, wherein the dsRNA comprises a sense strand and an antisense strand, the sense strand being no more than 21 nucleotides in length and the antisense strand being no more than 23 nucleotides in length, and either the sense strand or the antisense strand optionally being modified.

[0008] On the other hand, this application provides a pharmaceutical composition comprising the dsRNA of this application, a pharmaceutically acceptable salt thereof or a ligand conjugate thereof, and a pharmaceutically acceptable carrier or excipient.

[0009] On the other hand, this application provides a kit for treating and / or preventing SERPINC1-mediated diseases, comprising the dsRNA of this application, a pharmaceutically acceptable salt thereof, a ligand conjugate thereof, or a pharmaceutical composition thereof; and optionally including instructions for use thereof.

[0010] On the other hand, this application provides a method for treating and / or preventing SERPINC1-mediated diseases, comprising administering to a subject (hereinafter also referred to as a subject) the dsRNA of this application, a pharmaceutically acceptable salt thereof, a ligand conjugate thereof, or a pharmaceutical composition thereof. In one embodiment, the method for treating and / or preventing SERPINC1-mediated diseases comprises administering to a subject (hereinafter also referred to as a subject) an effective amount of the dsRNA of this application, a pharmaceutically acceptable salt thereof, a ligand conjugate thereof, or a pharmaceutical composition thereof. In one embodiment, the method for treating and / or preventing SERPINC1-mediated diseases comprises administering to a subject a therapeutically and / or preventively effective amount of the dsRNA of this application, a pharmaceutically acceptable salt thereof, a ligand conjugate thereof, or a pharmaceutical composition thereof.

[0011] On the other hand, this application provides the use of the dsRNA described herein, its pharmaceutically acceptable salts, its ligand conjugates, or pharmaceutical compositions thereof in the preparation of medicaments for treating and / or preventing SERPINC1-mediated diseases.

[0012] On the other hand, this application provides the use of the dsRNA of this application, its pharmaceutically acceptable salt, its ligand conjugate, or its pharmaceutical composition thereof in the treatment and / or prevention of SERPINC1-mediated diseases.

[0013] On the other hand, this application provides the dsRNA of this application, its pharmaceutically acceptable salt, its ligand conjugate, or a pharmaceutical composition thereof for the treatment and / or prevention of SERPINC1-mediated diseases.

[0014] In some implementations, the SERPINC1-mediated diseases include bleeding disorders (such as hemophilia).

[0015] In some embodiments, the dsRNA of this application, its pharmaceutically acceptable salt, its ligand conjugate, or pharmaceutical composition thereof are used as a single therapeutic agent for treating and / or preventing SERPINC1-mediated diseases.

[0016] In some embodiments, the dsRNA of this application, its pharmaceutically acceptable salt, its ligand conjugate, or a pharmaceutical composition thereof may be used in combination with other therapeutic agents for the treatment and / or prevention of SERPINC1-mediated diseases.

[0017] Invention Details

[0018] The following will describe exemplary embodiments of this application. However, those skilled in the art will understand that the scope of protection of this application is not limited thereto. Various modifications, alterations or changes can be made based on the spirit and concept of this application, and the modified or altered content still falls within the scope of this application.

[0019] This application provides a double-stranded ribonucleic acid (dsRNA), a pharmaceutically acceptable salt thereof, or a ligand conjugate thereof, which targets SERPINC1 mRNA. The dsRNA comprises a sense strand and an antisense strand, wherein the length of the sense strand does not exceed 21 nucleotides, and the length of the antisense strand does not exceed 23 nucleotides. Optionally, either nucleotide of the sense strand or the antisense strand is modified. From the perspective of the sense strand or the antisense strand, any modification of either nucleotide of the sense strand or the antisense strand is considered part of the modification of the sense strand or the antisense strand.

[0020] This application provides a double-stranded ribonucleic acid (dsRNA), a pharmaceutically acceptable salt thereof, or a ligand conjugate thereof, wherein the dsRNA comprises a sense strand and an antisense strand, the sense strand containing, for example, SEQ ID NO.1, SEQ ID NO.7, SEQ ID NO.13, SEQ ID NO.19, SEQ ID NO.25, SEQ ID NO.31, SEQ ID NO.37, SEQ ID NO.43, SEQ ID NO.49, SEQ ID NO.55, SEQ ID NO.61, SEQ ID NO.67, SEQ ID NO.73, SEQ ID NO.79, SEQ ID NO.85, SEQ ID NO.91, SEQ ID NO.97, SEQ ID NO.103, SEQ ID NO.109, SEQ ID NO.115, SEQ ID NO.121, SEQ ID NO.127, SEQ ID NO.133, SEQ ID NO.139, SEQ ID NO.145, SEQ ID NO.151, SEQ ID NO.157, SEQ ID NO. The nucleotide sequence NO.163, SEQ ID NO.169, SEQ ID NO.175, SEQ ID NO.181, SEQ ID NO.187, SEQ ID NO.193, SEQ ID NO.199, SEQ ID NO.205, SEQ ID NO.211, SEQ ID NO.217, SEQ ID NO.223, SEQ ID NO.229, SEQ ID NO.235, SEQ ID NO.241, SEQ ID NO.247, SEQ ID NO.253, SEQ ID NO.259, SEQ ID NO.265, SEQ ID NO.271, SEQ ID NO.277, SEQ ID NO.283, SEQ ID NO.289, SEQ ID NO.295, SEQ ID NO.301, or SEQ ID NO.307 contains at least 15 consecutive nucleotides, and the length of the sense strand does not exceed 21 nucleotides, wherein the antisense strand contains nucleotide sequences such as SEQ ID NO.2, SEQ ID NO.8, SEQ ID NO.14, SEQ ID NO.307. NO.20, SEQ ID NO.26, SEQ ID NO.32, SEQ ID NO.38, SEQ ID NO.44, SEQ ID NO.50, SEQ ID NO.56, SEQ ID NO.62, SEQ ID NO.68, SEQ ID NO.74, SEQ ID NO.80. SEQ ID NO.86, SEQ ID NO.92, SEQ ID NO.98, SEQ ID NO.104, SEQ ID NO.110, SEQ ID NO.116, SEQ ID NO.122, SEQ ID NO.128, SEQ ID NO.134, SEQ ID NO.140, SEQ ID NO.146, SEQ ID NO.152, SEQ ID NO.158, SEQ ID NO.164, SEQ ID NO.170, SEQ ID NO.176, SEQ ID NO.182, SEQ ID NO.188, SEQ ID NO.194, SEQ ID NO.200, SEQ ID NO.206, SEQ ID NO.212, SEQ ID NO.218, SEQ ID NO.224, SEQ ID NO.230, SEQ ID NO.236, SEQ ID NO.242, SEQ ID NO.248, SEQ ID NO.254, SEQ ID NO.260, SEQ ID The nucleotide sequence shown in SEQ ID NO.266, SEQ ID NO.272, SEQ ID NO.278, SEQ ID NO.284, SEQ ID NO.290, SEQ ID NO.296, SEQ ID NO.302, or SEQ ID NO.308 contains at least 15 consecutive nucleotides and the antisense strand is no more than 23 nucleotides in length.

[0021] Chain of Justice: 5'-AACUGAACUGCCGACUCUA-3' (SEQ ID NO.1)

[0022] Antonym: 5'-UAGAGUCGGCAGUUCAGUUUG-3' (SEQ ID NO.2);

[0023] Chain of Justice: 5'-AACUGCCGACUCUAUCGAA-3' (SEQ ID NO.7)

[0024] Antonym: 5'-UUCGAUAGAGUCGGCAGUUCA-3' (SEQ ID NO.8);

[0025] Chain of Justice: 5'-ACUGAACUGCCGACUCUAU-3' (SEQ ID NO.13)

[0026] Antisense chain: 5'-AUAGAGUCGGCAGUUCAGUUU-3' (SEQ ID NO.14);

[0027] Chain of Justice: 5'-ACUGCCGACUCUAUCGAAA-3' (SEQ ID NO.19)

[0028] Antisense chain: 5'-UUUCGAUAGAGUCGGCAGUUC-3' (SEQ ID NO.20);

[0029] Chain of Justice: 5'-CCGACUCUAUCGAAAAGCA-3' (SEQ ID NO.25)

[0030] Antonym: 5'-UGCUUUUCGAUAGAGUCGGCA-3' (SEQ ID NO.26);

[0031] Chain of Justice: 5'-CUGAACUGCCGACUCUAUA-3' (SEQ ID NO.31)

[0032] Antisense chain: 5'-UAUAGAGUCGGCAGUUCAGUU-3' (SEQ ID NO.32);

[0033] Chain of Justice: 5'-CUGCCGACUCUAUCGAAAA-3' (SEQ ID NO.37)

[0034] Antisense chain: 5'-UUUUCGAUAGAGUCGGCAGUU-3' (SEQ ID NO.38);

[0035] Chain of Justice: 5'-GCCAAACUGAACUGCCGAA-3' (SEQ ID NO.43)

[0036] Antisense chain: 5'-UUCGGCAGUUCAGUUUGGCAA-3' (SEQ ID NO.44);

[0037] Chain of Justice: 5'-GCCGACUCUAUCGAAAAGA-3' (SEQ ID NO.49)

[0038] Antisense chain: 5'-UCUUUUCGAUAGAGUCGGCAG-3' (SEQ ID NO.50);

[0039] Chain of Justice: 5'-UGCCAAACUGAACUGCCGA-3' (SEQ ID NO.55)

[0040] Antisense chain: 5'-UCGGCAGUUCAGUUUGGCAAA-3' (SEQ ID NO.56);

[0041] Chain of Justice: 5'-UUGCCAAACUGAACUGCCA-3' (SEQ ID NO.61)

[0042] Antisense chain: 5'-UGGCAGUUCAGUUUGGCAAAG-3' (SEQ ID NO.62);

[0043] Chain of Justice: 5'-AAACUGAACUGCCGACUCU-3' (SEQ ID NO. 67)

[0044] Antisense chain: 5'-AGAGUCGGCAGUUCAGUUUGG-3' (SEQ ID NO.68);

[0045] Chain of Justice: 5'-AACUGUCCAAGGCCAAUUA-3' (SEQ ID NO.73)

[0046] Antisense chain: 5'-UAAUUGGCCUUGGACAGUUCC-3' (SEQ ID NO.74);

[0047] Chain of Justice: 5'-ACCAUUUACUUCAAGGGCA-3' (SEQ ID NO.79)

[0048] Antonym: 5'-UGCCCUUGAAGUAAAUGGUGU-3' (SEQ ID NO.80);

[0049] Chain of Justice: 5'-ACUCUAUCGAAAAGCCAAA-3' (SEQ ID NO.85)

[0050] Antonym: 5'-UUUGGCUUUUCGAUAGAGUCG-3' (SEQ ID NO.86);

[0051] Chain of Justice: 5'-CGACUCUAUCGAAAAGCCA-3' (SEQ ID NO.91)

[0052] Antonym: 5'-UGGCUUUUCGAUAGAGUCGGC-3' (SEQ ID NO.92);

[0053] Chain of Justice: 5'-CUAUGACCAAGCUGGGUGA-3' (SEQ ID NO.97)

[0054] Antisense chain: 5'-UCACCCAGCUUGGUCAUAGCA-3' (SEQ ID NO.98);

[0055] Chain of Justice: 5'-CUCUAUCGAAAAGCCAACA-3' (SEQ ID NO.103)

[0056] Antonym: 5'-UGUUGGCUUUUCGAUAGAGUC-3' (SEQ ID NO.104);

[0057] Chain of Justice: 5'-CUUCUUUGCCAAACUGAAA-3' (SEQ ID NO.109)

[0058] Antisense chain: 5'-UUUCAGUUUGGCAAAGAAGAA-3' (SEQ ID NO.110);

[0059] Chain of Justice: 5'-GACCAAGCUGGGUGCCUGU-3' (SEQ ID NO.115)

[0060] Antisense chain: 5'-ACAGGCACCCAGCUUGGUCAU-3' (SEQ ID NO.116);

[0061] Chain of Justice: 5'-GCUUUUGCUAUGACCAAGA-3' (SEQ ID NO.121)

[0062] Antisense chain: 5'-UCUUGGUCAUAGCAAAAGCCG-3' (SEQ ID NO.122);

[0063] Chain of Justice: 5'-GGUUAACACCAUUUACUUA-3' (SEQ ID NO.127)

[0064] Antisense chain: 5'-UAAGUAAAUGGUGUUAACCAG-3' (SEQ ID NO.128);

[0065] Chain of Justice: 5'-GUUAACACCAUUUACUUCA-3' (SEQ ID NO.133)

[0066] Antisense chain: 5'-UGAAGUAAAUGGUGUUAACCA-3' (SEQ ID NO.134);

[0067] Chain of Justice: 5'-UAUGACCAAGCUGGGUGCA-3' (SEQ ID NO.139)

[0068] Antonym: 5'-UGCACCCAGCUUGGUCAUAGC-3' (SEQ ID NO.140);

[0069] Chain of Justice: 5'-UCUAUCGAAAAGCCAACAA-3' (SEQ ID NO.145)

[0070] Antisense chain: 5'-UUGUUGGCUUUUCGAUAGAGU-3' (SEQ ID NO.146);

[0071] Chain of Justice: 5'-UGAACUGCCGACUCUAUCA-3' (SEQ ID NO.151)

[0072] Antisense chain: 5'-UGAUAGAGUCGGCAGUUCAGU-3' (SEQ ID NO.152);

[0073] Chain of Justice: 5'-UGAUGUACCAGGAAGGCAA-3' (SEQ ID NO.157)

[0074] Antisense chain: 5'-UUGCCUUCCUGGUACAUCAUA-3' (SEQ ID NO.158);

[0075] Chain of Justice: 5'-UGUGCAUUUACCGCUCCCA-3' (SEQ ID NO.163)

[0076] Antonym: 5'-UGGGAGCGGUAAAUGCACAUG-3' (SEQ ID NO.164);

[0077] Chain of Justice: 5'-UUGCUAUGACCAAGCUGGA-3' (SEQ ID NO.169)

[0078] Antisense chain: 5'-UCCAGCUUGGUCAUAGCAAAA-3' (SEQ ID NO.170);

[0079] Chain of Justice: 5'-UUUGCCAAACUGAACUGCA-3' (SEQ ID NO.175)

[0080] Antisense chain: 5'-UGCAGUUCAGUUUGGCAAAGA-3' (SEQ ID NO.176);

[0081] Chain of Justice: 5'-AACACCAUUUACUUCAAGA-3' (SEQ ID NO.181)

[0082] Antisense chain: 5'-UCUUGAAGUAAAUGGUGUUAA-3' (SEQ ID NO.182);

[0083] Chain of Justice: 5'-ACACCAUUUACUUCAAGGA-3' (SEQ ID NO.187)

[0084] Antisense chain: 5'-UCCUUGAAGUAAAUGGUGUUA-3' (SEQ ID NO.188);

[0085] Chain of Justice: 5'-AGGAGCAGCUGCAAGACAU-3' (SEQ ID NO.193)

[0086] Antisense chain: 5'-AUGUCUUGCAGCUGCUCCUUC-3' (SEQ ID NO.194);

[0087] Chain of Justice: 5'-CAAGGGCCUGUGGAAGUCA-3' (SEQ ID NO.199)

[0088] Antisense chain: 5'-UGACUUCCACAGGCCCUUGAA-3' (SEQ ID NO.200);

[0089] Chain of Justice: 5'-CAGCUGCAAGACAUGGGCA-3' (SEQ ID NO.205)

[0090] Antonym: 5'-UGCCCAUGUCUUGCAGCUGCU-3' (SEQ ID NO.206);

[0091] Chain of Justice: 5'-CCUUUUUGGAGACAAAUCA-3' (SEQ ID NO.211)

[0092] Antonym: 5'-UGAUUUGUCUCCAAAAAGGCG-3' (SEQ ID NO.212);

[0093] Chain of Justice: 5'-CUAUGAUGUACCAGGAAGA-3' (SEQ ID NO.217)

[0094] Antisense chain: 5'-UCUUCCUGGUACAUCAUAGAU-3' (SEQ ID NO.218);

[0095] Justice Chain: 5'-GAAGGAGCAGCUGCAAGAA-3' (SEQ ID NO.223)

[0096] Antisense chain: 5'-UUCUUGCAGCUGCUCCUUCAA-3' (SEQ ID NO.224);

[0097] Chain of Justice: 5'-GAGCCAAGCUCCAGCCCCU-3' (SEQ ID NO.229)

[0098] Antisense chain: 5'-AGGGGCUGGAGCUUGGCUCCA-3' (SEQ ID NO.230);

[0099] Chain of Justice: 5'-GCAGCUGCAAGACAUGGGA-3' (SEQ ID NO.235)

[0100] Antisense chain: 5'-UCCCAUGUCUUGCAGCUGCUC-3' (SEQ ID NO.236);

[0101] Chain of Justice: 5'-GCAUUUCUUGAGGUAAAUA-3' (SEQ ID NO.241)

[0102] Antisense chain: 5'-UAUUUACCUCAAGAAAUGCCU-3' (SEQ ID NO.242);

[0103] Justice Chain: 5'-GCCUGUGGAAGUCAAAGUU-3' (SEQ ID NO.247)

[0104] Antisense chain: 5'-AACUUUGACUUCCACAGGCCC-3' (SEQ ID NO.248);

[0105] Justice Chain: 5'-GCCUUUUUGGAGACAAAUA-3' (SEQ ID NO.253)

[0106] Antisense chain: 5'-UAUUUGUCUCCAAAAAGGCGA-3' (SEQ ID NO.254);

[0107] Chain of Justice: 5'-GGGCCUGUGGAAGUCAAAA-3' (SEQ ID NO.259)

[0108] Antisense chain: 5'-UUUUGACUUCCACAGGCCCUU-3' (SEQ ID NO.260);

[0109] Chain of Justice: 5'-UAACACCAUUUACUUCAAA-3' (SEQ ID NO.265)

[0110] Antisense chain: 5'-UUUGAAGUAAAUGGUGUUAAC-3' (SEQ ID NO.266);

[0111] Chain of Justice: 5'-UACUUCAAGGGCCUGUGGA-3' (SEQ ID NO.271)

[0112] Antisense chain: 5'-UCCACAGGCCCUUGAAGUAAA-3' (SEQ ID NO.272);

[0113] Chain of Justice: 5'-UUAACACCAUUUACUUCAA-3' (SEQ ID NO.277)

[0114] Antisense chain: 5'-UUGAAGUAAAUGGUGUUAACC-3' (SEQ ID NO.278);

[0115] Chain of Justice: 5'-UUACUUCAAGGGCCUGUGA-3' (SEQ ID NO.283)

[0116] Antisense chain: 5'-UCACAGGCCCUUGAAGUAAAU-3' (SEQ ID NO.284);

[0117] Justice Chain: 5'-UUCAAGGGCCUGUGGAAGU-3' (SEQ ID NO.289)

[0118] Antisense chain: 5'-ACUUCCACAGGCCCUUGAAGU-3' (SEQ ID NO.290);

[0119] Chain of Justice: 5'-UUCUUCUUUGCCAAACUGA-3' (SEQ ID NO.295)

[0120] Antisense chain: 5'-UCAGUUUGGCAAAGAAGAAGU-3' (SEQ ID NO.296);

[0121] Chain of Justice: 5'-UUUUGCUAUGACCAAGCUA-3' (SEQ ID NO.301)

[0122] Antisense chain: 5'-UAGCUUGGUCAUAGCAAAAGC-3' (SEQ ID NO.302);

[0123] Chain of Justice: 5'-UUUUUGGAGACAAAUCCCU-3' (SEQ ID NO.307)

[0124] Antisense chain: 5'-AGGGAUUUGUCUCCAAAAAGG-3' (SEQ ID NO.308);

[0125] Either nucleotide of the sense or antisense strand is optionally modified.

[0126] In some embodiments, the justice chain includes, for example, SEQ ID NO.1, SEQ ID NO.7, SEQ ID NO.13, SEQ ID NO.19, SEQ ID NO.25, SEQ ID NO.31, SEQ ID NO.37, SEQ ID NO.43, SEQ ID NO.49, SEQ ID NO.55, SEQ ID NO.61, SEQ ID NO.67, SEQ ID NO.73, SEQ ID NO.79, SEQ ID NO.85, SEQ ID NO.91, SEQ ID NO.97, SEQ ID NO.103, SEQ ID NO.109, SEQ ID NO.115, SEQ ID NO.121, SEQ ID NO.127, SEQ ID NO.133, SEQ ID NO.139, SEQ ID NO.145, SEQ ID NO.151, SEQ ID NO.157, SEQ ID NO.163, SEQ ID NO.169, SEQ ID NO.175, SEQ ID NO.181, SEQ ID NO. The nucleotide sequence shown in SEQ ID NO.187, SEQ ID NO.193, SEQ ID NO.199, SEQ ID NO.205, SEQ ID NO.211, SEQ ID NO.217, SEQ ID NO.223, SEQ ID NO.229, SEQ ID NO.235, SEQ ID NO.241, SEQ ID NO.247, SEQ ID NO.253, SEQ ID NO.259, SEQ ID NO.265, SEQ ID NO.271, SEQ ID NO.277, SEQ ID NO.283, SEQ ID NO.289, SEQ ID NO.295, SEQ ID NO.301, or SEQ ID NO.307 contains at least 15 consecutive nucleotides and the length of the positive strand does not exceed 21 nucleotides, wherein the at least 15 consecutive nucleotides may be selected from 15, 16, 17, 18, 19, 20, or 21 consecutive nucleotides.

[0127] In some embodiments, the antisense chain contains, for example, SEQ ID NO.2, SEQ ID NO.8, SEQ ID NO.14, SEQ ID NO.20, SEQ ID NO.26, SEQ ID NO.32, SEQ ID NO.38, SEQ ID NO.44, SEQ ID NO.50, SEQ ID NO.56, SEQ ID NO.62, SEQ ID NO.68, SEQ ID NO.74, SEQ ID NO.80, SEQ ID NO.86, SEQ ID NO.92, SEQ ID NO.98, SEQ ID NO.104, SEQ ID NO.110, SEQ ID NO.116, SEQ ID NO.122, SEQ ID NO.128, SEQ ID NO.134, SEQ ID NO.140, SEQ ID NO.146, SEQ ID NO.152, SEQ ID NO.158, SEQ ID NO.164, SEQ ID NO.170, SEQ ID NO.176, SEQ ID NO.182, SEQ ID NO. The nucleotide sequence shown in SEQ ID NO.188, SEQ ID NO.194, SEQ ID NO.200, SEQ ID NO.206, SEQ ID NO.212, SEQ ID NO.218, SEQ ID NO.224, SEQ ID NO.230, SEQ ID NO.236, SEQ ID NO.242, SEQ ID NO.248, SEQ ID NO.254, SEQ ID NO.260, SEQ ID NO.266, SEQ ID NO.272, SEQ ID NO.278, SEQ ID NO.284, SEQ ID NO.290, SEQ ID NO.296, SEQ ID NO.302, or SEQ ID NO.308 contains at least 15 consecutive nucleotides and the antisense strand is no more than 23 nucleotides in length, wherein the at least 15 consecutive nucleotides may be selected from 15, 16, 17, 18, 19, 20, 21, 22, or 23 consecutive nucleotides.

[0128] In some embodiments, this application provides a double-stranded ribonucleic acid (dsRNA), a pharmaceutically acceptable salt thereof, or a ligand conjugate thereof, wherein the dsRNA comprises a sense strand and an antisense strand, the sense strand containing, for example, SEQ ID NO.1, SEQ ID NO.7, SEQ ID NO.13, SEQ ID NO.19, SEQ ID NO.25, SEQ ID NO.31, SEQ ID NO.37, SEQ ID NO.43, SEQ ID NO.49, SEQ ID NO.55, SEQ ID NO.61, SEQ ID NO.67, SEQ ID NO.73, SEQ ID NO.79, SEQ ID NO.85, SEQ ID NO.91, SEQ ID NO.97, SEQ ID NO.103, SEQ ID NO.109, SEQ ID NO.115, SEQ ID NO.121, SEQ ID NO.127, SEQ ID NO.133, SEQ ID NO.139, SEQ ID NO.145, SEQ ID NO.151, SEQ ID NO.157, SEQ ID NO. The nucleotide sequences shown in SEQ ID NO.163, SEQ ID NO.169, SEQ ID NO.175, SEQ ID NO.181, SEQ ID NO.187, SEQ ID NO.193, SEQ ID NO.199, SEQ ID NO.205, SEQ ID NO.211, SEQ ID NO.217, SEQ ID NO.223, SEQ ID NO.229, SEQ ID NO.235, SEQ ID NO.241, SEQ ID NO.247, SEQ ID NO.253, SEQ ID NO.259, SEQ ID NO.265, SEQ ID NO.271, SEQ ID NO.277, SEQ ID NO.283, SEQ ID NO.289, SEQ ID NO.295, SEQ ID NO.301, or SEQ ID NO.307, wherein the length of the sense strand does not exceed 21 nucleotides, and the antisense strand contains nucleotide sequences such as SEQ ID NO.2, SEQ ID NO.8, SEQ ID NO.14, SEQ ID NO.20, SEQ ID NO.301, or SEQ ID NO.307. NO.26, SEQ ID NO.32, SEQ ID NO.38, SEQ ID NO.44, SEQ ID NO.50, SEQ ID NO.56, SEQ ID NO.62, SEQ ID NO.68, SEQ ID NO.74, SEQ ID NO.80. SEQ ID NO.86, SEQ ID NO.92, SEQ ID NO.98, SEQ ID NO.104, SEQ ID NO.110, SEQ ID NO.116, SEQ ID NO.122, SEQ ID NO.128, SEQ ID NO.134, SEQ ID NO.140, SEQ ID NO.146, SEQ ID NO.152, SEQ ID NO.158, SEQ ID NO.164, SEQ ID NO.170, SEQ ID NO.176, SEQ ID NO.182, SEQ ID NO.188, SEQ ID NO.194, SEQ ID NO.200, SEQ ID NO.206, SEQ ID NO.212, SEQ ID NO.218, SEQ ID NO.224, SEQ ID NO.230, SEQ ID NO.236, SEQ ID NO.242, SEQ ID NO.248, SEQ ID NO.254, SEQ ID NO.260, SEQ ID The nucleotide sequence is specified in SEQ ID NO. 266, SEQ ID NO. 272, SEQ ID NO. 278, SEQ ID NO. 284, SEQ ID NO. 290, SEQ ID NO. 296, SEQ ID NO. 302, or SEQ ID NO. 308, and the antisense strand is no more than 23 nucleotides in length; either nucleotide in the sense or antisense strand is optionally modified.

[0129] In some embodiments, this application provides a double-stranded ribonucleic acid (dsRNA), a pharmaceutically acceptable salt thereof, or a ligand conjugate thereof, wherein the dsRNA comprises a sense strand and an antisense strand, and the nucleotide sequence of the sense strand is as follows: SEQ ID NO.1, SEQ ID NO.7, SEQ ID NO.13, SEQ ID NO.19, SEQ ID NO.25, SEQ ID NO.31, SEQ ID NO.37, SEQ ID NO.43, SEQ ID NO.49, SEQ ID NO.55, SEQ ID NO.61, SEQ ID NO.67, SEQ ID NO.73, SEQ ID NO.79, SEQ ID NO.85, SEQ ID NO.91, SEQ ID NO.97, SEQ ID NO.103, SEQ ID NO.109, SEQ ID NO.115, SEQ ID NO.121, SEQ ID NO.127, SEQ ID NO.133, SEQ ID NO.139, SEQ ID NO.145, SEQ ID NO.151, SEQ ID NO. The nucleotide sequences shown in SEQ ID NO.157, SEQ ID NO.163, SEQ ID NO.169, SEQ ID NO.175, SEQ ID NO.181, SEQ ID NO.187, SEQ ID NO.193, SEQ ID NO.199, SEQ ID NO.105, SEQ ID NO.211, SEQ ID NO.217, SEQ ID NO.223, SEQ ID NO.229, SEQ ID NO.235, SEQ ID NO.241, SEQ ID NO.247, SEQ ID NO.253, SEQ ID NO.259, SEQ ID NO.265, SEQ ID NO.271, SEQ ID NO.277, SEQ ID NO.283, SEQ ID NO.289, SEQ ID NO.295, SEQ ID NO.301, or SEQ ID NO.307, wherein the nucleotide sequence of the antisense strand is as shown in SEQ ID NO.2, SEQ ID NO.8, SEQ ID NO.14, SEQ ID NO.20, SEQ ID NO.301, or SEQ ID NO.307. NO.26, SEQ ID NO.32, SEQ ID NO.38, SEQ ID NO.44, SEQ ID NO.50, SEQ ID NO.56, SEQ ID NO.62, SEQ ID NO.68, SEQ ID NO.74, SEQ ID NO.80, SEQ ID NO.86. SEQ ID NO.92, SEQ ID NO.98, SEQ ID NO.104, SEQ ID NO.110, SEQ ID NO.116, SEQ ID NO.122, SEQ ID NO.128, SEQ ID NO.134, SEQ ID NO.140, SEQ ID NO.146, SEQ ID NO.152, SEQ ID NO.158, SEQ ID NO.164, SEQ ID NO.170, SEQ ID NO.176, SEQ ID NO.182, SEQ ID NO.188, SEQ ID NO.194, SEQ ID NO.200, SEQ ID NO.206, SEQ ID NO.212, SEQ ID NO.218, SEQ ID NO.224, SEQ ID NO.230, SEQ ID NO.236, SEQ ID NO.242, SEQ ID NO.248, SEQ ID NO.254, SEQ ID NO.260, SEQ ID NO.266, SEQ ID The nucleotide sequences shown in SEQ ID NO. 272, SEQ ID NO. 278, SEQ ID NO. 284, SEQ ID NO. 290, SEQ ID NO. 296, SEQ ID NO. 302, or SEQ ID NO. 308; any nucleotide in the sense or antisense strand is optionally modified.

[0130] In some embodiments, this application also provides a dsRNA, a pharmaceutically acceptable salt thereof, or a ligand conjugate thereof, said dsRNA comprising a sense strand and an antisense strand, said sense strand and antisense strand having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with the full length of the nucleotide sequences of said sense strand and antisense strand, respectively.

[0131] In some embodiments, the dsRNA of this application, its pharmaceutically acceptable salt, or its ligand conjugate are RNAi drugs.

[0132] In some embodiments, the dsRNA, its pharmaceutically acceptable salt, or its ligand conjugate of this application is siRNA.

[0133] In a specific embodiment, the dsRNA, its pharmaceutically acceptable salt, or its ligand conjugate has a double-stranded region composed of complementary sense and antisense strands, and optionally, protrusions at the 5' and / or 3' ends of the sense and / or antisense strands. In a preferred embodiment, the dsRNA, its pharmaceutically acceptable salt, or its ligand conjugate has a double-stranded region composed of complementary sense and antisense strands, and optionally, protrusions at the 5' and / or 3' ends of the sense and / or antisense strands. In a preferred embodiment, the dsRNA, its pharmaceutically acceptable salt, or its ligand conjugate has a double-stranded region composed of complementary sense and antisense strands, and a protrusion at the 3' end of the antisense strand. In a preferred embodiment, the dsRNA, its pharmaceutically acceptable salt, or its ligand conjugate has a double-stranded region composed of complementary sense and antisense strands, and a protrusion at the 3' end of the sense strand.

[0134] Dual-chain region

[0135] In some embodiments, the double-stranded region of the dsRNA has a length of 19-23 pairs of nucleotides, for example, the double-stranded region of the dsRNA has a length of 19, 20, 21, 22 or 23 pairs of nucleotides.

[0136] Protruding end

[0137] In some embodiments, the justice chain or antisense chain optionally includes a protruding end located at the 5' end and / or the 3' end.

[0138] In some embodiments, the protrusion contains 1, 2, 3, 4, or 5 nucleotides. In some embodiments, the protrusion contains 1 or 2 nucleotides.

[0139] In some embodiments, the positive strand optionally includes a 5' end and / or a 3' end. In some embodiments, the positive strand optionally includes a 1, 2, 3, 4, or 5 nucleotide apex located at the 5' end and / or the 3' end. In some embodiments, the positive strand optionally includes a 1 or 2 nucleotide apex located at the 5' end and / or the 3' end.

[0140] In some embodiments, the antisense strand optionally includes a 5' end and / or a 3' end. In some embodiments, the antisense strand optionally includes a 1, 2, 3, 4, or 5 nucleotide apex located at the 5' end and / or the 3' end. In some embodiments, the antisense strand optionally includes a 1 or 2 nucleotide apex located at the 5' end and / or the 3' end.

[0141] In some embodiments, the protruding end is selected from unmodified or modified A, G, C, U or T.

[0142] In a specific embodiment, the overhang may be 1, 2, 3, 4, or 5 nucleotides at the 5' and / or 3' ends of the sense or antisense strand, preferably 1 or 2 nucleotides. In a specific embodiment, the dsRNA, or its pharmaceutically acceptable salt, or its ligand conjugate, contains an additional sequence as the overhang, which may contain 1, 2, 3, 4, or 5 nucleotides, preferably 1 or 2 nucleotides, attached to the 5' and / or 3' ends of the sense or antisense strand.

[0143] As an example, when the ribonucleotides at the 5' and / or 3' ends of the sense or antisense strands are overhangs, if the sense strand has 21 nucleotides and the antisense strand has 23 nucleotides, and positions 1-21 of the sense strand are complementary to positions 1-21 of the antisense strand, then positions 22-23 of the antisense strand constitute an overhang at the 3' end of the antisense strand; that is, the 5' end of the sense strand is blunt or blunt. When the sense strand has 21 nucleotides and the antisense strand has 21 nucleotides... When the first 20 positions of the sense strand are complementary to the first 20 positions of the antisense strand, the nucleotides at positions 21 of the sense strand and antisense strand respectively form the 3' ends of the sense strand and antisense strand. When the sense strand is 21 nucleotides and the antisense strand is 23 nucleotides, and the first 21 positions of the sense strand are complementary to the third 23 positions of the antisense strand, the nucleotides at positions 1-2 of the antisense strand form the 5' end of the antisense strand. That is, the 5' end of the sense strand is a blunt or blunt end.

[0144] In some embodiments, where the nucleotides at the 5' and / or 3' ends of the sense or antisense strand serve as overhangs, the antisense strand optionally includes an overhang located at the 5' and / or 3' end, the overhang being selected from unmodified or modified ribonucleotide sequences GA, CA, AC, CG, UG, GG, UA, AU, AA, UU, or UC. In some embodiments, the antisense strand optionally includes an overhang located at the 3' end, the overhang being selected from unmodified or modified ribonucleotide sequences UU, GG, AU, CG, UC, AA, or UA.

[0145] In a specific embodiment, the dsRNA, its modifications or pharmaceutically acceptable salts or its ligand conjugates include an additional sequence as a protrusion at the 5' and / or 3' end of the antisense or sense strand, the additional sequence comprising 1, 2, 3, 4 or 5 nucleotides, preferably 1 or 2 nucleotides, at the 5' and / or 3' end.

[0146] In some embodiments, the protrusion is an additional sequence optionally located at the 5' end and / or 3' end of the antisense chain, the protrusion being selected from unmodified or modified GA, CA, AC, CG, UG, GG, UA, AU, AA, UU, or UC. In some embodiments, the protrusion is an additional sequence located at the 3' end of the antisense chain, the protrusion being selected from unmodified or modified UU, GG, AU, CG, UC, AA, or UA.

[0147] In some implementations, the additional sequence serving as the protruding end comprises a selection from unmodified or modified U or T.

[0148] In some embodiments, when the additional sequence serving as the overhang is one nucleotide, the overhang is selected from unmodified or modified U or T. In some embodiments, when the additional sequence serving as the overhang is one nucleotide, the overhang is selected from 2'-O-methyl modified U (hereinafter also referred to as u) or deoxythymidine nucleotide (hereinafter also referred to as dT).

[0149] In some embodiments, when the additional sequence serving as the overhang is two nucleotides, the overhang is selected from unmodified or modified UU or TT. In some embodiments, when the additional sequence serving as the overhang is two nucleotides, the overhang is selected from uu or dTdT.

[0150] In some implementations, the protruding ends are optional additional sequences located at the 5' and / or 3' ends of the justice chain, and the protruding ends are selected from uu or dTdT.

[0151] In some embodiments, the protrusion is an additional sequence optionally located at the 5' end and / or 3' end of the antisense chain, and the protrusion is selected from uu or dTdT.

[0152] In some embodiments, the protruding end is connected to its adjacent nucleotide via a phosphate ester group or a thiophosphate ester group.

[0153] In some embodiments, one or more nucleotides in the protruding ends are linked by phosphate ester groups or thiophosphate ester groups.

[0154] In some embodiments, one or more nucleotides in the overhang are connected to each other or to the overhang and its adjacent nucleotides by phosphate ester bonds or thiophosphate ester bonds.

[0155] Modification

[0156] In some implementations, the justice chain or antisense chain is optionally modified.

[0157] In some embodiments, one or more nucleotides of the sense or antisense strand are modified.

[0158] In some embodiments, each nucleotide may be modified with the same or different modifications, which may include one or more changes to one or two of the non-linked phosphoester oxygens and / or one or more of the linked phosphoester oxygens; changes to the components of the ribose (e.g., the 2' hydroxyl group on the ribose); complete replacement of the phosphoester portion with a "dephosphorylated" linker; modification of naturally occurring bases; and modification of the ribose-phosphoester backbone.

[0159] In some embodiments, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23 nucleotides of the positive chain are modified; or nucleotides within the range of any of the aforementioned values ​​are modified, for example, 1-23, 1-22, 1-21, 1-20, 1-19, 1-18, 1-17, 1-16, 1-15, 1-14, 1-13, 1-12, 1-11, or 1-10 nucleotides are modified.

[0160] In some embodiments, one or more, two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, ten or more, eleven or more, twelve or more, thirteen or more, fourteen or more, fifteen or more, sixteen or more, seventeen or more, eighteen or more, nineteen or more, twenty or more, twenty or more, twenty or more, twenty or more, or twenty or more, nucleotides of the positive strand are modified; typically, ten or more, eleven or more, twelve or more, thirteen or more, fourteen or more, fifteen or more, sixteen or more, seventeen or more, eighteen or more, nineteen or more, twenty or more, or twenty or more, nucleotides of the positive strand are modified.

[0161] In some embodiments, all nucleotides of the positive strand are modified.

[0162] In some embodiments, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 nucleotides of the antisense strand are modified; or nucleotides within the range of any of the aforementioned values ​​are modified, for example, 1-25, 1-24, 1-23, 1-22, 1-21, 1-20, 1-19, 1-18, 1-17, 1-16, 1-15, 1-14, 1-13, 1-12, 1-11, or 1-10 nucleotides of the antisense strand are modified.

[0163] In some embodiments, one or more, two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, ten or more, eleven or more, twelve or more, thirteen or more, fourteen or more, fifteen or more, sixteen or more, seventeen or more, eighteen or more, nineteen or more, twenty or more, twenty or more, twelve or more, thirteen or more, twenty or more, thirteen or more, twenty or more, 24 or more, or twenty or more, nucleotides of the antisense strand are modified; typically, ten or more, eleven or more, twelve or more, thirteen or more, fourteen or more, fifteen or more, sixteen or more, seventeen or more, eighteen or more, nineteen or more, twenty or more, twenty or more, 21 or more, twenty or more, thirteen or more, 22 or more, thirteen or more, nucleotides of the antisense strand are modified.

[0164] In some embodiments, all nucleotides of the antisense strand are modified.

[0165] In some embodiments, all nucleotides of the sense strand and all nucleotides of the antisense strand are modified.

[0166] In some embodiments, the modification is selected from glycosyl modifications of nucleotides, base modifications, internucleotide linker bond modifications, or terminal modifications.

[0167] In some embodiments, the glycosylation of the nucleotide is selected from dehydroxylation, fluorination, amination, alkylation, hydroxyalkylation, or hydroxyalkenylation.

[0168] In some embodiments, the glycosyl modification of the nucleotide occurs at the 2' position of the glycosyl group.

[0169] In some embodiments, the glycosyl modification is selected from 2'-dehydroxylated, 2'-fluorinated, 2'-amino, 2'-alkyl, 2'-O-alkyl, 2'-O-ether, and 2'-O-alkenyl. In some embodiments, the glycosyl modification is selected from 2'-dehydroxylated, 2'-fluorinated, 2'-amino, 2'-methyl, 2'-ethyl, 2'-methyl-O-methyl, 2'-ethyl-O-methyl, 2'-O-methyl, 2'-O-ethyl, 2'-O-ethyl-O-methyl, or 2'-O-allyl.

[0170] In some embodiments, the linker bond modification between the nucleotides is selected from phosphate thioesters (PS), dithiophosphates (PS2), methylphosphates (MP), methoxypropyl phosphates (MOP), or aminophosphates. In some embodiments, the linker bond modification between the nucleotides is selected from phosphate thioesters (PS). In some embodiments, the nucleotides are linked by phosphate thioester bonds.

[0171] In some embodiments, the terminal modification is selected from modifications on the terminal phosphate or hydroxyl groups. In some embodiments, the terminal modification is selected from 5'-terminal modifications or 3'-terminal modifications. In some embodiments, the terminal modification is selected from 5'-phosphate, 3'-phosphate, 5'-methylphosphate (5'-MP), 5'-thiophosphate (5'-PS), 3'-(E)-vinylphosphate, or 5'-(E)-vinylphosphate (5'-(E)-VP) on the ribosome of the terminal nucleotide. In some embodiments, the terminal modification is selected from 5'-phosphate, 5'-methylphosphate (5'-MP), 5'-thiophosphate (5'-PS), or 5'-(E)-vinylphosphate (5'-(E)-VP) on the ribosome of the terminal nucleotide. In some embodiments, the terminal modification is selected from 5'-phosphate or 5'-(E)-vinylphosphate on the ribosome of the terminal nucleotide.

[0172] In some embodiments, the modification is selected from 2'-dehydroxylation, 2'-fluorination, 2'-amino, 2'-methyl, 2'-ethyl, 2'-methyl-O-methyl, 2'-ethyl-O-methyl, 2'-O-methyl, 2'-O-ethyl, 2'-O-allyl, thiophosphate, methylphosphate, aminophosphate, 5'-phosphate, 3'-phosphate, 5'-(E)-vinyl phosphate, or 3'-(E)-vinyl phosphate.

[0173] In some embodiments, the modification is selected from 2'-dehydroxylation, 2'-fluorination, 2'-O-methyl, 2'-O-ethyl, 2'-O-ethyl-O-methyl, 2'-O-allyl, thiophosphate, or 5'-(E)-vinyl phosphate.

[0174] In some embodiments, the modification is selected from 2'-fluoro, 2'-O-methyl, thiophosphate, or 5'-(E)-vinyl phosphate.

[0175] As will be detailed below, when referring to the nth nucleotide of the sense and antisense strands, the counting begins from the 5' end unless otherwise specified.

[0176] In some embodiments, a thiophosphate group is used to modify the first two nucleotides and / or the first three nucleotides of one or both ends of the two nucleic acid strands of the dsRNA, its pharmaceutically acceptable salt, or its ligand conjugate. For example, taking the positive strand as an example, the thiophosphate group is used to modify the first and second nucleotides and / or the second and third nucleotides and / or the first and second nucleotides and the second and third nucleotides of the positive strand.

[0177] In some embodiments, for cases where there is no additional sequence as a protrusion, the nucleotides at positions 1 and 2 of the positive strand and / or at positions 2 and 3 of the positive strand are modified with thiophosphate groups.

[0178] In some embodiments, for cases where there is no additional sequence as a protrusion, the antisense strand is modified with a thiophosphate group between the 1st and 2nd nucleotides, between the 2nd and 3rd nucleotides, between the 19th and 20th nucleotides, and / or between the 20th and 21st nucleotides.

[0179] In some embodiments, when there is an additional sequence as an overhang, the thiophosphate group modification may be located between nucleotides in the additional sequence.

[0180] In some embodiments, the 5'-terminus of the antisense chain is modified with 5'-(E)-vinyl phosphate.

[0181] In some embodiments, the positive strand has 2, 3, 4, or 5 nucleotides modified with 2'-fluorination. In some embodiments, the positive strand has 14, 15, 16, 17, 18, or 19 nucleotides modified with 2'-O-methylation. In some embodiments, the positive strand has 3 or 4 nucleotides modified with 2'-fluorination. In some embodiments, the positive strand has 15, 16, 17, or 18 nucleotides modified with 2'-O-methylation. In some embodiments, the positive strand has 3 or 4 nucleotides modified with 2'-fluorination. In some embodiments, the positive strand has 15 or 16 nucleotides modified with 2'-O-methylation.

[0182] In some embodiments, 0, 1, or 2 nucleotides at positions 1 to 6 of the positive strand are modified with 2'-fluorine.

[0183] In some embodiments, four, five, or six nucleotides at positions 1 to 6 of the positive strand are modified with 2'-O-methyl.

[0184] In some embodiments, two or three nucleotides at positions 7 to 9 of the positive strand are modified with 2'-fluorination.

[0185] In some embodiments, one or more nucleotides at positions 7 to 9 of the positive strand are modified with 2'-O-methyl.

[0186] In some embodiments, one or two nucleotides at positions 10 to 19 of the positive strand are modified with 2'-fluorination.

[0187] In some embodiments, eight, nine, or ten nucleotides at positions 10 to 19 of the positive strand are modified with 2'-O-methyl.

[0188] In some embodiments, the 7th, 8th, and 9th nucleotides of the positive strand are 2'-fluorinated, and 0, 1, or 2 nucleotides of the 1st to 6th and / or 10th to 19th nucleotides of the positive strand are also 2'-fluorinated. In some embodiments, the 7th, 8th, and 9th nucleotides of the positive strand are 2'-fluorinated, and 0, 1, or 2 nucleotides of the 1st to 6th and 10th to 19th nucleotides of the positive strand are also 2'-fluorinated. In some embodiments, the 7th, 8th, and 9th nucleotides of the positive strand are 2'-fluorinated, and 0 or 1 nucleotides of the 1st to 6th and 10th to 19th nucleotides of the positive strand are 2'-fluorinated. In some embodiments, the 7th, 8th, and 9th nucleotides of the positive strand are 2'-fluorinated, and the 5th nucleotide of the positive strand is 2'-fluorinated.

[0189] In some embodiments, the antisense strand has 2, 3, 4, 5, 6 or 7 nucleotides modified with 2'-fluorination.

[0190] In some embodiments, 14, 15, 16, 17, 18, 19, 20, or 21 nucleotides of the antisense strand are modified with 2'-O-methyl. In some embodiments, 3, 4, 5, or 6 nucleotides at positions 2, 6, 8, 9, 14, and 16 of the antisense strand are modified with 2'-fluorine. In some embodiments, 3 or 4 nucleotides at positions 2, 6, 14, and 16 of the antisense strand are modified with 2'-fluorine. In some embodiments, 4 nucleotides at positions 2, 6, 14, and 16 of the antisense strand are modified with 2'-fluorine. In some embodiments, 6 nucleotides at positions 2, 6, 8, 9, 14, and 16 of the antisense strand are modified with 2'-fluorine.

[0191] In some embodiments, the nucleotides at positions 2, 6, 14, and 16 of the antisense strand are 2'-fluorinated, and any one or two of the nucleotides at positions 1, 3 to 5, 7 to 13, 15, and / or 17 to 21, and / or 17 to 23 of the antisense strand are also 2'-fluorinated.

[0192] In some embodiments, 14, 15, 16, 17, 18, or 19 nucleotides at positions 1, 3 to 5, 7, 10 to 13, 15, and / or 17 to 21 of the antisense strand are modified with 2'-O-methyl.

[0193] In one specific embodiment, the 7th, 8th, and 9th nucleotides of the sense strand are 2'-fluorinated, the 5th nucleotide of the sense strand is 2'-fluorinated or 2'-O-methylinated, and the other nucleotides of the sense strand are 2'-O-methylinated; and the 2nd, 6th, 14th, and 16th nucleotides of the antisense strand are 2'-fluorinated, the 8th and 9th nucleotides of the antisense strand are 2'-fluorinated or 2'-O-methylinated, and the other nucleotides of the antisense strand are 2'-O-methylinated.

[0194] In one specific embodiment, the 5th, 7th, 8th, and 9th nucleotides of the sense strand are 2'-fluorinated, the other nucleotides of the sense strand are 2'-O-methylinated, the 2nd, 6th, 14th, and 16th nucleotides of the antisense strand are 2'-fluorinated, the 8th and 9th nucleotides of the antisense strand are 2'-fluorinated or 2'-O-methylinated, and the other nucleotides of the antisense strand are 2'-O-methylinated.

[0195] In one specific embodiment, the 5th, 7th, 8th, and 9th nucleotides of the sense strand are 2'-fluorinated, the other nucleotides of the sense strand are 2'-O-methylinated, and the 2nd, 6th, 8th, 9th, 14th, and 16th nucleotides of the antisense strand are 2'-fluorinated, the other nucleotides of the antisense strand are 2'-O-methylinated.

[0196] In one specific embodiment, the nucleotides at positions 5, 7, 8, and 9 of the sense strand are 2'-fluorinated, the other nucleotides of the sense strand are 2'-O-methylinated, and the nucleotides at positions 2, 6, 14, and 16 of the antisense strand are 2'-fluorinated, the other nucleotides of the antisense strand are 2'-O-methylinated.

[0197] In one specific embodiment, the 7th, 8th, and 9th nucleotides of the sense strand are 2'-fluorinated, the other nucleotides of the sense strand are 2'-O-methylinated, the 2nd, 6th, 14th, and 16th nucleotides of the antisense strand are 2'-fluorinated, the 8th and 9th nucleotides of the antisense strand are 2'-fluorinated or 2'-O-methylinated, and the other nucleotides of the antisense strand are 2'-O-methylinated.

[0198] In one specific embodiment, the 7th, 8th, and 9th nucleotides of the sense strand are 2'-fluorinated, the other nucleotides of the sense strand are 2'-O-methylinated, and the 2nd, 6th, 8th, 9th, 14th, and 16th nucleotides of the antisense strand are 2'-fluorinated, the other nucleotides of the antisense strand are 2'-O-methylinated.

[0199] In one specific embodiment, the 7th, 8th, and 9th nucleotides of the sense strand are 2'-fluorinated, the other nucleotides of the sense strand are 2'-O-methylinated, and the 2nd, 6th, 14th, and 16th nucleotides of the antisense strand are 2'-fluorinated, the other nucleotides of the antisense strand are 2'-O-methylinated.

[0200] In one specific embodiment, the 7th, 8th, and 9th nucleotides of the sense strand are 2'-fluorinated, the 5th nucleotide of the sense strand is 2'-fluorinated or 2'-O-methylinated, and the other nucleotides of the sense strand are 2'-O-methylinated; and the 2nd, 6th, 14th, and 16th nucleotides of the antisense strand are 2'-fluorinated, the 8th and 9th nucleotides of the antisense strand are 2'-fluorinated or 2'-O-methylinated, and the other nucleotides of the antisense strand are 2'-O-methylinated; furthermore, thiophosphate groups are used between the 1st and 2nd nucleotides of the sense strand, between the 2nd and 3rd nucleotides of the sense strand, between the 1st and 2nd nucleotides of the antisense strand, between the 2nd and 3rd nucleotides of the antisense strand, between the 1st and 2nd nucleotides at the 3' end of the antisense strand, and / or between the 2nd and 3rd nucleotides at the 3' end of the antisense strand. Optionally, the 5' end of the antisense strand is modified with 5'-(E)-vinyl phosphate.

[0201] In one specific embodiment, the 7th, 8th, and 9th nucleotides of the sense strand are 2'-fluorinated, the 5th nucleotide of the sense strand is 2'-fluorinated or 2'-O-methylinated, and the other nucleotides of the sense strand are 2'-O-methylinated; and the 2nd, 6th, 14th, and 16th nucleotides of the antisense strand are 2'-fluorinated, the 8th and 9th nucleotides of the antisense strand are 2'-fluorinated or 2'-O-methylinated, and the other nucleotides of the antisense strand are 2'-O-methylinated; furthermore, thiophosphate groups are used between the 1st and 2nd nucleotides of the sense strand, between the 2nd and 3rd nucleotides of the sense strand, between the 1st and 2nd nucleotides of the antisense strand, between the 2nd and 3rd nucleotides of the antisense strand, between the 19th and 20th nucleotides of the antisense strand, and / or between the 20th and 21st nucleotides of the antisense strand. Optionally, the 5'-terminus of the antisense strand is modified with 5'-(E)-vinyl phosphate.

[0202] In one specific embodiment, the 5th, 7th, 8th, and 9th nucleotides of the sense strand are 2'-fluorinated, the other nucleotides of the sense strand are 2'-O-methylated, and the 2nd, 6th, 8th, 9th, 14th, and 16th nucleotides of the antisense strand are 2'-fluorinated, the other nucleotides of the antisense strand are 2'-O-methylated. Furthermore, thiophosphate groups are used between the 1st and 2nd nucleotides of the sense strand, between the 2nd and 3rd nucleotides of the sense strand, between the 1st and 2nd nucleotides of the antisense strand, between the 2nd and 3rd nucleotides of the antisense strand, between the 19th and 20th nucleotides of the antisense strand, and / or between the 20th and 21st nucleotides of the antisense strand. Optionally, the 5'-terminus of the antisense strand is modified with 5'-(E)-vinyl phosphate.

[0203] In one specific embodiment, the 5th, 7th, 8th, and 9th nucleotides of the sense strand are 2'-fluorinated, the other nucleotides of the sense strand are 2'-O-methylated, and the 2nd, 6th, 14th, and 16th nucleotides of the antisense strand are 2'-fluorinated, the other nucleotides of the antisense strand are 2'-O-methylated. Furthermore, thiophosphate groups are used between the 1st and 2nd nucleotides of the sense strand, between the 2nd and 3rd nucleotides of the sense strand, between the 1st and 2nd nucleotides of the antisense strand, between the 2nd and 3rd nucleotides of the antisense strand, between the 19th and 20th nucleotides of the antisense strand, and / or between the 20th and 21st nucleotides of the antisense strand. Optionally, the 5'-terminus of the antisense strand is modified with 5'-(E)-vinyl phosphate.

[0204] In one specific embodiment, the 7th, 8th, and 9th nucleotides of the sense strand are 2'-fluorinated, the other nucleotides of the sense strand are 2'-O-methylated, the 2nd, 6th, 14th, and 16th nucleotides of the antisense strand are 2'-fluorinated, the other nucleotides of the antisense strand are 2'-O-methylated, and thiophosphate groups are used between the 1st and 2nd nucleotides of the sense strand, between the 2nd and 3rd nucleotides of the sense strand, between the 1st and 2nd nucleotides of the antisense strand, between the 2nd and 3rd nucleotides of the antisense strand, between the 19th and 20th nucleotides of the antisense strand, and / or between the 20th and 21st nucleotides of the antisense strand. Optionally, the 5'-terminus of the antisense strand is modified with 5'-(E)-vinyl phosphate.

[0205] In one specific embodiment, the 7th, 8th, and 9th nucleotides of the sense strand are 2'-fluorinated, the other nucleotides of the sense strand are 2'-O-methylated, the 2nd, 6th, 8th, 9th, 14th, and 16th nucleotides of the antisense strand are 2'-fluorinated, the other nucleotides of the antisense strand are 2'-O-methylated, and thiophosphate groups are used between the 1st and 2nd nucleotides of the sense strand, between the 2nd and 3rd nucleotides of the sense strand, between the 1st and 2nd nucleotides of the antisense strand, between the 2nd and 3rd nucleotides of the antisense strand, between the 19th and 20th nucleotides of the antisense strand, and / or between the 20th and 21st nucleotides of the antisense strand. Optionally, the 5'-terminus of the antisense strand is modified with 5'-(E)-vinyl phosphate.

[0206] ligands

[0207] In some embodiments, the ligand includes a branching group and a linking group.

[0208] In some embodiments, the ligand is linked to the dsRNA via a linker group. Hereinafter, the dsRNA with the ligand linked is referred to as a dsRNA-ligand conjugate.

[0209] In some embodiments, the ligand is linked to one or more target groups via a branching group. In some embodiments, the branching group comprises a target group.

[0210] In some embodiments, the ligand contains at least one targeting group. In some embodiments, the ligand contains one, two, three, four, or five targeting groups. In some embodiments, the ligand contains two, three, or four targeting groups. In some embodiments, the ligand contains three targeting groups.

[0211] In some embodiments, the targeting group is selected from the GalNAc group.

[0212] In some embodiments, the ligand contains one, two, three, four, or five GalNAc groups. In some embodiments, the ligand contains two, three, or four GalNAc groups. In some embodiments, the ligand contains three GalNAc groups.

[0213] In some embodiments, the branching groups are selected from:

[0214] In some embodiments, the linking group is selected from:

[0215] In some embodiments, the ligand is selected from:

[0216] In some embodiments, the ligand is attached to either the sense or antisense strand. In some embodiments, the ligand is attached to the 5' or 3' end of either the sense or antisense strand. In some embodiments, the ligand is attached to the 5' or 3' end of the sense strand. In some embodiments, the ligand is attached to the 3' end of the sense strand.

[0217] In some embodiments, the ligand is linked to the sense or antisense strand of the dsRNA via a phosphate ester or thiophosphate group. In some embodiments, the ligand is linked to the sense strand via a phosphate ester or thiophosphate group. In some embodiments, the ligand is linked to the 3' end of the sense strand via a phosphate ester or thiophosphate group.

[0218] In some embodiments, the dsRNA ligand conjugate is shown below:

[0219] In some embodiments, the dsRNA ligand conjugate is selected from:

[0220] In some embodiments, the dsRNA ligand conjugate is selected from:

[0221] In some embodiments, the unmodified sense strand of the dsRNA is selected from:

[0222] Table 1. Unmodified Chain of Justice

[0223] In some embodiments, the unmodified antisense strand of the dsRNA is selected from:

[0224] Table 2. Unmodified antisense chains

[0225] In some embodiments, the modified sense strand of the dsRNA is selected from:

[0226] Table 3. Modified Chain of Justice

[0227] In some embodiments, the modified antisense strand of the dsRNA is selected from:

[0228] Table 4. Modified antisense chains

[0229] The dsRNA of this application can be formed by including any of the above-described sense strands and any of the above-described antisense strands.

[0230] For example, the dsRNA comprises any one of the following sense strands: SEQ ID NO:1, SEQ ID NO:3, SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:11, SEQ ID NO:13, SEQ ID NO:15, SEQ ID NO:17, SEQ ID NO:19, SEQ ID NO:21, SEQ ID NO:23, SEQ ID NO:25, SEQ ID NO:27, SEQ ID NO:29, SEQ ID NO:31, SEQ ID NO:33, SEQ ID NO:35, SEQ ID NO:37, SEQ ID NO:39, SEQ ID NO:41, SEQ ID NO:43, SEQ ID NO:45, SEQ ID NO:47, SEQ ID NO:49, SEQ ID NO:51, SEQ ID NO:53, SEQ ID NO:55, SEQ ID NO:57, SEQ ID NO:59, SEQ ID NO:61, SEQ ID NO:63, SEQ ID NO:65, SEQ ID NO:67, SEQ ID NO:69, SEQ ID NO:71, SEQ ID NO:73, SEQ ID NO:75, SEQ ID NO:77, SEQ ID NO:79, SEQ ID NO:81, SEQ ID NO:83, SEQ ID NO:85, SEQ ID NO:87, SEQ ID NO:89, SEQ ID NO:91, SEQ ID NO:93, SEQ ID NO:95, SEQ ID NO:97, SEQ ID NO:99, SEQ ID NO:101, SEQ ID NO:103, SEQ ID NO:105, SEQ ID NO:107, SEQ ID NO:109, SEQ ID NO:111, SEQ ID NO:113, SEQ ID NO:115, SEQ ID NO:117, SEQ ID NO:119, SEQ ID NO:121, SEQ ID NO:123, SEQ ID NO:125, SEQ ID NO:127, SEQ ID NO:129, SEQ ID NO:131, SEQ ID NO:133, SEQ ID NO:135, SEQ ID NO:137, SEQ ID NO:139, SEQ ID NO:141, SEQ ID NO:143, SEQ ID NO:145, SEQ IDNO:147、SEQ ID NO:149、SEQ ID NO:151、SEQ ID NO:153、SEQ ID NO:155、SEQ ID NO:157、SEQ ID NO:159、SEQ ID NO:161、SEQ ID NO:163、SEQ ID NO:165、SEQ ID NO:167、SEQ ID NO:169、SEQ ID NO:171、SEQ ID NO:173、SEQ ID NO:175、SEQ ID NO:177、SEQ ID NO:179、SEQ ID NO:181、SEQ ID NO:183、SEQ ID NO:185、SEQ ID NO:187、SEQ ID NO:189、SEQ ID NO:191、SEQ ID NO:193、SEQ ID NO:195、SEQ ID NO:197、SEQ ID NO:199、SEQ ID NO:201、SEQ ID NO:203、SEQ ID NO:205、SEQ ID NO:207、SEQ ID NO:209、SEQ ID NO:211、SEQ ID NO:213、SEQ ID NO:215、SEQ ID NO:217、SEQ ID NO:219、SEQ ID NO:221、SEQ ID NO:223、SEQ ID NO:225、SEQ ID NO:227、SEQ ID NO:229、SEQ ID NO:231、SEQ ID NO:233、SEQ ID NO:235、SEQ ID NO:237、SEQ ID NO:239、SEQ ID NO:241、SEQ ID NO:243、SEQ ID NO:245、SEQ ID NO:247、SEQ ID NO:249、SEQ ID NO:251、SEQ ID NO:253、SEQ ID NO:255、SEQ ID NO:257、SEQ ID NO:259、SEQ ID NO:261、SEQ ID NO:263、SEQ ID NO:265、SEQ ID NO:267、SEQ ID NO:269、SEQ ID NO:271、SEQ ID NO:273、SEQ ID NO:275、SEQ ID NO:277、SEQ ID NO:279、SEQ ID NO:281、SEQ ID NO:283、SEQ ID NO:285、SEQ ID NO:287、SEQ IDNO: 289, SEQ ID NO: 291, SEQ ID NO: 293, SEQ ID NO: 295, SEQ ID NO: 297, SEQ ID NO: 299, SEQ ID NO: 301, SEQ ID NO: 303, SEQ ID NO: 305, SEQ ID NO: 307, SEQ ID NO: 309 or SEQ ID NO: 311; and the dsRNA comprises any one of the following antisense strands: SEQ ID NO: 2, SEQ ID NO: 4, SEQ ID NO: 6, SEQ ID NO: 8, SEQ ID NO: 10, SEQ ID NO: 12, SEQ ID NO: 14, SEQ ID NO: 16, SEQ ID NO: 18, SEQ ID NO: 20, SEQ ID NO: 22, SEQ ID NO: 24, SEQ ID NO: 26, SEQ ID NO: 28, SEQ ID NO: 30, SEQ ID NO: 32, SEQ ID NO: 34, SEQ ID NO: 36, SEQ ID NO: 38, SEQ ID NO: 40, SEQ ID NO: 42, SEQ ID NO: 44, SEQ ID NO: 46, SEQ ID NO: 48, SEQ ID NO: 50, SEQ ID NO: 52, SEQ ID NO: 54, SEQ ID NO: 56, SEQ ID NO: 58, SEQ ID NO: 60, SEQ ID NO: 62, SEQ ID NO: 64, SEQ ID NO: 66, SEQ ID NO: 68, SEQ ID NO: 70, SEQ ID NO: 72, SEQ ID NO: 74, SEQ ID NO: 76, SEQ ID NO: 78, SEQ ID NO: 80, SEQ ID NO: 82, SEQ ID NO: 84, SEQ ID NO: 86, SEQ ID NO: 88, SEQ ID NO: 90, SEQ ID NO: 92, SEQ ID NO: 94, SEQ ID NO: 96, SEQ ID NO: 98, SEQ ID NO: 100, SEQ ID NO: 102, SEQ ID NO: 104, SEQ ID NO: 106, SEQ ID NO: 108, SEQ ID NO: 110, SEQ ID NO: 112, SEQ ID NO: 114, SEQ ID NO: 116, SEQ ID NO: 118, SEQ ID NO: 120, SEQ ID NO: 122, SEQ IDNO:124、SEQ ID NO:126、SEQ ID NO:128、SEQ ID NO:130、SEQ ID NO:132、SEQ ID NO:134、SEQ ID NO:136、SEQ ID NO:138、SEQ ID NO:140、SEQ ID NO:142、SEQ ID NO:144、SEQ ID NO:146、SEQ ID NO:148、SEQ ID NO:150、SEQ ID NO:152、SEQ ID NO:154、SEQ ID NO:156、SEQ ID NO:158、SEQ ID NO:160、SEQ ID NO:162、SEQ ID NO:164、SEQ ID NO:166、SEQ ID NO:168、SEQ ID NO:170、SEQ ID NO:172、SEQ ID NO:174、SEQ ID NO:176、SEQ ID NO:178、SEQ ID NO:180、SEQ ID NO:182、SEQ ID NO:184、SEQ ID NO:186、SEQ ID NO:188、SEQ ID NO:190、SEQ ID NO:192、SEQ ID NO:194、SEQ ID NO:196、SEQ ID NO:198、SEQ ID NO:200、SEQ ID NO:202、SEQ ID NO:204、SEQ ID NO:206、SEQ ID NO:208、SEQ ID NO:210、SEQ ID NO:212、SEQ ID NO:214、SEQ ID NO:216、SEQ ID NO:218、SEQ ID NO:220、SEQ ID NO:222、SEQ ID NO:224、SEQ ID NO:226、SEQ ID NO:228、SEQ ID NO:230、SEQ ID NO:232、SEQ ID NO:234、SEQ ID NO:236、SEQ ID NO:238、SEQ ID NO:240、SEQ ID NO:242、SEQ ID NO:244、SEQ ID NO:246、SEQ ID NO:248、SEQ ID NO:250、SEQ ID NO:252、SEQ ID NO:254、SEQ ID NO:256、SEQ ID NO:258、SEQ ID NO:260、SEQ ID NO:262、SEQ ID NO:264、SEQ IDNO:266, SEQ ID NO:268, SEQ ID NO:270, SEQ ID NO:272, SEQ ID NO:274, SEQ ID NO:276, SEQ ID NO:278, SEQ ID NO:280, SEQ ID NO:282, SEQ ID NO:284, SEQ ID NO:286, SEQ ID NO:288, SEQ ID NO:290, SEQ ID NO:292, SEQ ID NO:294, SEQ ID NO:296, SEQ ID NO:298, SEQ ID NO:300, SEQ ID NO:302, SEQ ID NO:304, SEQ ID NO:306, SEQ ID NO:308, SEQ ID NO:310, or SEQ ID NO:312.

[0231] In some embodiments, the dsRNA (e.g., siRNA, unmodified) is selected from:

[0232] Table 5. siRNA (unmodified)

[0233] In some embodiments, the dsRNA (modified) is selected from:

[0234] Table 6. dsRNA (modified)

[0235] In some embodiments, the ligand conjugate of the dsRNA (e.g., siRNA, including modified or unmodified) is selected from:

[0236] Table 7. dsRNA ligand conjugates

[0237] Wherein, L represents a ligand, which is as described above; in some embodiments, the ligand is selected from L01 ligand or L02 ligand. The sequence ID number of the positive strand refers to the sequence ID number of the nucleic acid sequence in the positive strand. The L at the 3' end of the positive strand sequence of the dsRNA ligand conjugate indicates that a ligand is attached at the 3' end of the positive strand sequence in this dsRNA ligand conjugate.

[0238] In Tables 1-7 above, the uppercase letters G, C, A, or U typically represent nucleotides containing guanine, cytosine, adenine, or uracil as bases, respectively; the lowercase letters g, c, a, and u represent nucleotides whose ribosomes are modified with 2'-methoxy groups, i.e., g, c, a, and u represent 2'-O-methyl G, 2'-O-methyl C, 2'-O-methyl A, and 2'-O-methyl U, respectively; the uppercase letters plus their... The lowercase letter f on the right indicates that the ribosyl group of the corresponding uppercase letter is modified by 2'-fluorine, that is, Gf, Cf, Af, and Uf represent 2'-fluorine G, 2'-fluorine C, 2'-fluorine A, and 2'-fluorine U, respectively; the lowercase letter s indicates that the two nucleotide residues adjacent to s are linked by a thiophosphate group, for example, "csu" indicates that the c and u residues are linked by a thiophosphate group; L indicates a ligand, such as L01 ligand and L02 ligand.

[0239] Pharmaceutically acceptable salts

[0240] In some embodiments, the salts described above are selected from alkali addition salts, acid addition salts, and combinations thereof.

[0241] In some embodiments, the base addition salt is selected from sodium, potassium, calcium, ammonium, organic amine, magnesium salts and combinations thereof, and the acid addition salt is selected from inorganic acid salts, organic acid salts and combinations thereof.

[0242] In some embodiments, the inorganic acid is selected from hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, and combinations thereof, and the organic acid is selected from acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, octanoic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, and combinations thereof. Beneficial effects

[0243] The double-stranded ribonucleic acid (SSRNA), its pharmaceutically acceptable salt, or its ligand conjugates disclosed in this application exhibit good inhibitory activity against SERPINC1, and can inhibit or reduce SERPINC1 mRNA expression in cells. The SSRNA, its pharmaceutically acceptable salt, or its ligand conjugates disclosed in this application demonstrate good stability and can exert efficient and sustained effects in vivo. Furthermore, the SSRNA, its pharmaceutically acceptable salt, or its ligand conjugates disclosed in this application exhibit low off-target effects, minimal toxicity, and high safety. Therefore, they have promising prospects for drug development.

[0244] Definitions and Explanations

[0245] Unless otherwise stated, the following terms and phrases as used herein are intended to have the following meanings. A particular term or phrase should not be considered uncertain or unclear unless specifically defined, but should be understood in accordance with the meaning as understood by one of ordinary skill in the art. When trade names appear herein, they are intended to refer to the corresponding product or its active ingredient.

[0246] In this application, unless otherwise stated, the terms "comprising, including, and containing" or equivalents are open-ended expressions, meaning that in addition to the listed elements, components, or steps, other unspecified elements, components, or steps may be covered.

[0247] When any variable appears more than once in a compound, nucleotide, single-stranded, or double-stranded structure, its definition is independent in each case. For example, the modifications described in this application occur independently; that is, unless otherwise specified, a modification of the sense strand does not affect a modification of the antisense strand, a modification of one nucleotide does not affect a modification of another nucleotide, and a modification of the sugar group of one nucleotide does not affect a modification of another sugar group of the same nucleotide. The effect includes whether a modification occurs and the type of modification used.

[0248] SERPINC1 (Serpin Family C Member 1) is a gene located on human chromosome 1 (1q23-25), approximately 13.5-15 kb in length, containing 7 exons and 6 introns. Antithrombin III (AT-III) is the expression product of the SERPINC1 gene. In this application, SERPINC1 mRNA, AT3 mRNA, or AT-III mRNA have the same meaning, referring to the mRNA transcribed from the SERPINC1 gene.

[0249] The SERPINC1 gene sequence used in this application can be obtained from publicly available databases, such as GenBank. siRNA was designed using the human SERPINC1 transcript NM_000488.4, the macaque SERPINC1 transcript NM_001104583.1, and the mouse NM_080844.5 as target genes. All siRNA sequences showed 100% identity with the human, macaque, and mouse transcripts, or contained one mismatch.

[0250] As is known in the art, the terms "interfering RNA" or "RNAi" or "interfering RNA sequence" refer to single-stranded RNA (e.g., mature miRNA) or double-stranded RNA (e.g., double-stranded RNA such as siRNA, aiRNA, or pre-miRNA) that, when in the same cell as a target gene or sequence, are capable of reducing or inhibiting the expression of that target gene or sequence (e.g., by mediating the degradation of mRNA complementary to the interfering RNA sequence or inhibiting the translation or transcription of mRNA complementary to the interfering RNA sequence). The interfering RNA may have substantially or completely identical identity to the target gene or sequence, or may include mismatched regions (i.e., mismatched sequences).

[0251] The double-stranded RNA of this application functions as interfering RNA. In the following text, the double-stranded RNA of this application will sometimes be referred to as siRNA.

[0252] As is known in the art, the term "mismatch region" or "mismatch sequence" refers to a portion of an interfering RNA (e.g., siRNA, aiRNA, miRNA) sequence that is not 100% complementary to its target sequence. Interfering RNA (e.g., siRNA, aiRNA, miRNA) may have at least 1, 2, 3, 4, 5, 6, or more mismatch regions. Mismatch regions may be continuous or separated by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more nucleotides. A mismatch region may comprise a single nucleotide or may comprise 2, 3, 4, 5, 6, or more nucleotides.

[0253] The term "identity" refers to the similarity between two nucleotide sequences or two amino acid sequences. Sequence identity preferably involves the percentage of nucleotides or amino acids in a sequence that occupy the same position in two or more sequences of the same length. Specifically, the "% identity" of two amino acid sequences or two nucleotide sequences can be determined by aligning the sequences for optimal comparison (e.g., introducing vacancies in either sequence to achieve optimal alignment with the other) and comparing the amino acids or nucleotides at the corresponding positions. Vacancies are generally considered dissimilar positions, regardless of their actual position in the alignment. An "optimal alignment" is generally the alignment of the two sequences that results in the highest percentage of identity. The percentage of identity is determined by the number of identical nucleotides in the compared sequences (i.e., % identity = number of identical positions / total number of positions × 100). The sequence identity of this application is at least 80%, 85%, 90%, or 95%, preferably at least 90%. Non-limiting examples include: 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, and 100%. The percentage of identity between two sequences can be determined using mathematical algorithms known to those skilled in the art.

[0254] As is known in the art, interfering RNA includes "small interfering RNA (siRNA)" with lengths, for example, about 15-60, 15-50, 15-40, 15-30, 15-25, 19-25, 19-23, or 19-21 nucleotides. The double-stranded ribonucleic acid of this application can function as such siRNA and can have the corresponding length.

[0255] As used in this application, the nucleotide positions of the sense or antisense strand are counted starting from the 5' end. For dsRNAs with a sense strand of 19 nucleotides and an antisense strand of 21 nucleotides, for example, in 5'-AACUGAACUGCCGACUCUA-3' (SEQ ID NO:1), the first position is A and the 19th position is A; in 5'-UAGAGUCGGCAGUUCAGUUUG-3' (SEQ ID NO:2), the first position is U and the 21st position is G. For dsRNAs with a sense strand of more than 19 nucleotides and an antisense strand of more than 21 nucleotides, for example, if the sense strand has several nucleotides added to the end of SEQ ID NO:1 and the antisense strand has several nucleotides added to the end of SEQ ID NO:2, the method of counting the nucleotide positions of the sense or antisense strand will not change, that is, the first position of the sense strand is still the first position of SEQ ID NO:1, and the first position of the antisense strand is still the first position of SEQ ID NO:2.

[0256] As is known in the art, and unless otherwise stated, when the term "complementary" is used to describe the relationship between a first nucleic acid sequence and a second nucleic acid sequence, it refers to the ability of an oligonucleotide or polynucleotide containing the first nucleic acid sequence to hybridize with an oligonucleotide or polynucleotide containing the second nucleic acid sequence under specific conditions and form a double-stranded structure. As described in this application, a "complementary" sequence may also include a double-stranded structure formed by base pairs consisting of non-Watson-Crick base pairs and / or non-natural or modified nucleotides, or it may be a double-stranded structure formed entirely by base pairs consisting of non-Watson-Crick base pairs and / or non-natural or modified nucleotides, provided that the above requirements regarding their hybridization ability are met.

[0257] As is known in the art, a “fully complementary” sequence comprises an oligonucleotide or polynucleotide containing a first nucleic acid sequence and an oligonucleotide or polynucleotide containing a second nucleic acid sequence, with base pairing along the full length of both the first and second nucleic acid sequences.

[0258] As is known in the art, “basically complementary” means that two nucleic acid sequences are completely complementary or that at least 85% (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) of their overlapping nucleotides are complementary.

[0259] The terms “complementary,” “fully complementary,” and “fundamentally complementary” used in this application may be used based on the base pairing between the sense and antisense strands of the dsRNA, or between the antisense strand of the dsRNA and the target sequence, as can be understood from the content in which they are used.

[0260] In this art, “G,” “C,” “A,” “T,” and “U” typically represent the bases of guanine, cytosine, adenine, thymine, and uracil, respectively. However, it is also generally known in the art that each of “G,” “C,” “A,” “T,” and “U” typically also represents a nucleotide containing guanine, cytosine, adenine, thymine, and uracil as a base, respectively. This is a common practice in representing deoxyribonucleic acid (DNA) sequences and / or ribonucleic acid (RNA) sequences. Therefore, in the context of this disclosure, the meanings of “G,” “C,” “A,” “T,” and “U” include all of the above-mentioned possible scenarios. However, it should be understood that the term “ribonucleotide” or “nucleotide” can also refer to a modified nucleotide (as further detailed elsewhere herein) or one having an alternative substitution. Those skilled in the art will recognize that guanine, cytosine, adenine, and uracil can be substituted with other parts without substantially altering the base-pairing properties of an oligonucleotide (including a nucleotide having such a substitution). For example, without limitation, nucleotides containing inosine as their base can be base-paired with nucleotides containing adenine, cytosine, or uracil. Therefore, nucleotides containing uracil, guanine, or adenine can be replaced in the nucleotide sequence of the dsRNA characterized in this application by nucleotides containing, for example, inosine.

[0261] As is known in the art, the terms "double-stranded ribonucleic acid," "double-stranded RNA," or "dsRNA" are used interchangeably. The term "dsRNA" comprises two antiparallel and complementary nucleic acid strands with a "sense" or "antisense" orientation relative to the target RNA (e.g., the SERPINC1 gene). In embodiments of this application, dsRNA can degrade the target RNA (e.g., mRNA) via an RNA interference (RNAi) mechanism.

[0262] The double-stranded RNA of this application contains a sense strand and an antisense strand. The term "sense strand" or "sensory strand" refers to a single strand in the dsRNA double helix that is substantially complementary to a region of the antisense strand. The term "antisense strand" refers to a single strand in the dsRNA double helix that is substantially complementary to a region of the target sequence. If the sense strand is not perfectly complementary to the antisense strand, mismatches may occur within the molecule or in the terminal regions. Typically, the most tolerable mismatches are in the terminal regions.

[0263] As is known in the art, the double strands of dsRNA can have the same or different numbers of nucleotides. The length of the double-stranded region formed by complementarity can be any length that allows for the degradation of the target RNA, and the possible lengths are in the range of about 9 to 36 pairs of nucleotides, such as 15 to 30 pairs, 16 to 28 pairs, 19 to 21 pairs, etc.

[0264] As is known in the art, outside the double-stranded region, dsRNA may include one or more nucleotide overhangs, which refer to at least one unpaired nucleotide / nucleoside analogue. For example, an overhang exists when the 3' end of one strand of the dsRNA extends beyond the 5' end of the other strand (or vice versa). The nucleotides at the "overhang" may include 0-5 nucleotides, where "0" indicates no "overhang" and "5" indicates 5 additional nucleotides (i.e., not paired with the other single strand) on a single strand of the dsRNA double strand. These optional "overhangs" may be located at the 5' and / or 3' ends of any single strand of the two strands of the dsRNA. In some embodiments, the "overhang" comprises 0-5 nucleotides. In some embodiments, the "overhang" comprises 0-2 nucleotides. In some embodiments, the "overhang" at the 3' and / or 5' ends of the sense strand of the dsRNA has 0-2 nucleotides. In some embodiments, the "overhang" at the 3' and / or 5' ends of the antisense strand of the dsRNA has 0-2 nucleotides. The nucleotide forming the "protrusion" can be A, G, C, U, or T, or a modified structure thereof. The nucleotide forming the "protrusion" can be U, T, or dT, or a modified structure thereof. In some embodiments, the "protrusion" includes, but is not limited to, "TT," "dTdT," "UU," or their corresponding modified structures, such as UU modified with a 2' methoxy group, i.e., uu. In some embodiments, the "protrusion" at the 3' and / or 5' ends of the antisense strand of the dsRNA is substantially complementary to the target RNA. In some embodiments, the "protrusion" at the 3' and / or 5' ends of the antisense strand of the dsRNA is completely complementary to the target RNA. In some embodiments, the "protrusion" at the 3' end of the antisense strand of the dsRNA is completely complementary to the target RNA. The terms "blunt," "obtuse," or "dull" refer to the absence of unpaired nucleotides at the ends of the dsRNA, i.e., the absence of nucleotide protrusions. A dsRNA with both ends being "blunt" or "dull" is a dsRNA that is a double-stranded region throughout its entire length, meaning there are no nucleotide protrusions at either end of the molecule.

[0265] In this application, the dsRNA or any single strand thereof is optionally modified, and both unmodified and modified ribonucleic acid are within the scope of protection of this application. The modification will not result in a significant weakening or loss of the dsRNA's function in inhibiting SERPINC1 gene expression. The modification of the dsRNA or any single strand thereof may be located at the 5' and / or 3' ends, at nucleotides, or at internucleotide links. It can be synthesized or modified using methods known in the art.

[0266] In this application, the types of nucleotide modifications include, but are not limited to, modifications occurring at the bases, (ribo)glycosyl groups, or linkages between nucleotides (phosphate backbone modifications). The modifications described in this application occur independently; that is, unless otherwise specified, modifications to the sense strand do not affect modifications to the antisense strand, modifications to one nucleotide do not affect modifications to another nucleotide, and the type of modification to one nucleotide does not affect other types of modifications (e.g., modifications to glycosyl groups do not affect other modifications to the same nucleotide, such as modifications to another glycosyl group of the same nucleotide, base modifications of the same nucleotide, or phosphate backbone modifications of the same nucleotide). The influence includes whether modification occurs and the type of modification used. From the perspective of the sense strand or antisense strand, any modification to any nucleotide of the sense strand or antisense strand is part of the sense strand or antisense strand modification.

[0267] In this application, a nucleotide may contain one or more types of modifications, such as only one of base modification, (ribo)syl modification, or phosphate backbone modification; or simultaneously containing two or more of base modification, (ribo)syl modification, or phosphate backbone modification. Unless otherwise indicated, a description or limitation of a certain type of modification contained in a nucleotide does not preclude the denial that the nucleotide may also contain other types of modifications. For example, "when describing a modified nucleotide, the modification contains 2'-OMe or 2'-F modification" means that the nucleotide contains a 2'-OMe or 2'-F modification of the (ribo)syl group, and optionally also contains other types of modifications (such as base modification or phosphate backbone modification).

[0268] In this application, the modified bases or base modifications include the removal of bases from natural bases A, U, C, G, and T (i.e., obtaining base-free nucleotides) or the alteration of their chemical structure to obtain non-natural bases (the chemical structure alterations include, but are not limited to, alterations to atoms, functional groups, or functional groups using methods such as substitution, addition, exclusion, cyclization, and cyclization). The modified bases or base modifications are within the scope of this application. It will be understood in the art that modified bases may result in mismatches, which may affect the pairing properties of the sense and antisense strands of dsRNA or the pairing properties of the antisense strand with the target mRNA, thereby potentially having a beneficial effect on the function and role of dsRNA.

[0269] In this application, the modification of the nucleotide includes, but is not limited to, occurring on the glycosyl group of the nucleotide, including one or more substituted or de-substituted glycosyl moieties, such as the removal of a hydroxyl group from the carbonyl group, or fluorination, amination, alkylation, hydroxyalkylation, or hydroxyalkenylation. The modification on the glycosyl group can occur at various positions on the sugar ring. Exemplarily, the modification on the glycosyl group of the nucleotide includes, but is not limited to, 2'-dehydroxylation, 2'-fluorination, 2'-amino, 2'-methyl, 2'-ethyl, 2'-methyl-O-methyl, 2'-ethyl-O-methyl, 2'-O-methyl, 2'-O-ethyl, 2'-O-ethyl-O-methyl, or 2'-O-allyl, and the modified nucleoside structure can be as follows:

[0270] Base represents a base.

[0271] In this application, the modification of the linking bonds between the nucleotides includes substitution or replacement of atoms or functional groups of the phosphate ester group, such as thiophosphate (PS), dithiophosphate (PS2), methyl phosphate (MP), methoxypropyl phosphate (MOP), or aminophosphate.

[0272] In this application, the uppercase letters G, C, A, U, or T typically represent nucleotides containing guanine, cytosine, adenine, uracil, or thymine as bases, respectively. The letter combination dT represents a deoxyribonucleotide with thymine as the base. The lowercase letters g, c, a, and u represent nucleotides whose ribose group is modified with a 2'-methoxy group, i.e., g, c, a, and u represent 2'-O-methyl G, 2'-O-methyl C, 2'-O-methyl A, and 2'-O-methyl U, respectively. An uppercase letter followed by a lowercase f to its right indicates that the nucleotide is modified with a 2'-fluorine group, i.e., Gf, Cf, Af, and Uf represent 2'-fluoro G, 2'-fluoro C, 2'-fluoro A, and 2'-fluoro U, respectively. The lowercase letter 's' indicates that the two nucleotide residues adjacent to 's' are linked by a thiophosphate group. For example, "csu" indicates that the 'c' and 'u' residues are linked by a thiophosphate group. 'VP-' indicates that the nucleotide to the right of the hyphen is a (E)-vinyl phosphate modified nucleotide. For example, "VP-u" indicates a (E)-vinyl phosphate modified 2'-O-methyl U.

[0273] In this application, the 5' and / or 3' end modifications refer to modifications occurring at the 5' and / or 3' ends of dsRNA or any single strand thereof, such as phosphorylation, conjugation, or reverse bonding. Taking the 5' end as an example, modifications include, but are not limited to, 5'-phosphate, 5'-methylphosphate (5'-MP), 5'-thiophosphate (5'-PS), or 5'-(E)-vinylphosphate (5'-(E)-VP), and the structure of the modified nucleotide can be as follows:

[0274] Where Base represents a base, and X is selected from hydroxyl groups or 2' modifications on sugar groups.

[0275] In this application, the ligand is a group linked to dsRNA, comprising a branched group and a linker, wherein the dsRNA, linker, and branched group are sequentially linked (e.g., as shown in Formula 104). The branched group contains at least one (e.g., one, two, three, four, or five) targeting group that is pharmaceutically acceptable, targeting the dsRNA to a specific tissue or enhancing cellular uptake. The targeting group is, for example, but not limited to, a GalNAc (N-acetylgalactosamine, e.g., as shown in Formula 105) group. Multiple targeting groups are linked in series or parallel via the branched group. The GalNAc group can be monovalent, divalent, trivalent, or tetravalent. The terms monovalent, divalent, trivalent, and tetravalent, as used herein, refer to the molar ratio of dsRNA molecules to GalNAc molecules in a dsRNA-ligand conjugate formed by the dsRNA molecule and a ligand containing GalNAc as a targeting group, respectively, being 1:1, 1:2, 1:3, and 1:4. In some embodiments, when the dsRNA of this application is conjugated with a ligand containing GalNAc, the GalNAc molecule is trivalent or tetravalent. In some embodiments, when the dsRNA of this application is conjugated with a ligand containing GalNAc, the GalNAc molecule is trivalent.

[0276] In this application, the ligand can be attached to the phosphate group, 2'-hydroxyl group, 3'-hydroxyl group, or base of the nucleotide. The ligand can be attached to any nucleotide of the dsRNA, including but not limited to the 5' or 3' terminal nucleotide of the sense or antisense strand, or a non-terminal intermediate nucleotide. When the ligand is attached to the end of the dsRNA strand, it can be attached to the phosphate group of the nucleotide; when the ligand is attached to an intermediate nucleotide of the dsRNA, it can be attached to the sugar ring or base of the nucleotide.

[0277] In this application, the types of ligands or their preparation methods may refer to methods known in the art, including but not limited to the ligands and their preparation methods described in WO2009082607, WO2014025805, WO2015006740, and WO2021249484, the entire disclosure of which is incorporated herein by reference. Exemplary ligands include, but are not limited to, L01 or L02 as described above.

[0278] In this application, unless otherwise stated, "conjugation" refers to the connection between two or more chemical parts, each having a specific function, in a non-covalent or covalent manner; correspondingly, "conjugated compound" refers to a compound formed by the non-covalent or covalent connection between the respective chemical parts. In this application, conjugated compounds connected to each other in a covalent manner are preferred.

[0279] In this application, the ligand is attached to the 5' or 3' end of the sense or antisense strand. Preferably, the ligand is attached to the 5' or 3' end of the sense strand. More preferably, the ligand is attached to the 3' end of the sense strand. Exemplarily, the dsRNA-ligand conjugate formed by the attachment of the dsRNA to the ligand is shown in Formula 102 or Formula 103 below:

[0280] The compounds of this application (e.g., the double-stranded ribonucleic acid of this application, its pharmaceutically acceptable salts, and its ligand conjugates) may exist in specific geometric or stereoisomeric forms, all of which are within the scope of this application. This application envisions all such compounds, including (R)- and (S)-enantiomers, diastereomers, racemic mixtures, and other mixtures, such as mixtures enriched with enantiomers or diastereomers, all of which are within the scope of this application. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of this application.

[0281] Unless otherwise stated, the terms "enantiomer" or "optical isomer" refer to stereoisomers that are mirror images of each other.

[0282] Unless otherwise stated, the term "diastereomer" refers to a stereoisomer of a molecule having two or more chiral centers and being in a non-mirror relationship with each other.

[0283] Unless otherwise specified, use wedge-shaped solid line keys. and wedge-shaped dashed key The absolute configuration of the center of a solid is represented by a straight solid line key. and straight dashed key The relative configuration of the center of a solid is indicated by a wavy line. Indicates wedge-shaped solid line key or wedge-shaped dashed key Or use wavy lines Indicates a straight solid line key and / or straight dashed key

[0284] Unless otherwise stated, the terms "rich in one isomer," "isomer enrichment," "rich in one enantiomer," or "enantiomer enrichment" mean that the content of one isomer or enantiomer is less than 100%, and the content of the isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.

[0285] Unless otherwise stated, the terms "isomer excess" or "enantiomer excess" refer to the difference between the relative percentages of two isomers or two enantiomers. For example, if one isomer or enantiomer is 90% and the other isomer or enantiomer is 10%, then the isomer or enantiomer excess (ee value) is 80%.

[0286] Optically active (R)- and (S)- isomers, as well as D- and L- isomers, can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. To obtain an enantiomer of a compound of this application, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide a pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a salt of the diastereomeric isomer is formed with a suitable optically active acid or base, followed by diastereomeric resolution using conventional methods known in the art, and then the pure enantiomer is recovered. Furthermore, the separation of enantiomers and diastereomeric isomers is typically accomplished by using chromatography employing a chiral stationary phase and optionally combined with chemical derivatization (e.g., from amines to carbamates). The compounds of this application may contain atomic isotopes in non-natural proportions on one or more atoms constituting the compound. For example, compounds can be labeled with radioactive isotopes, such as tritium ( 3 H), Iodine-125 ( 125 I) or C-14 14C). For example, deuterium can be used to replace hydrogen to form deuterated drugs. The bond between deuterium and carbon is stronger than that between ordinary hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs have advantages such as reduced toxicity, increased drug stability, enhanced efficacy, and prolonged drug biological half-life. All isotopic variations of the compounds in this application, regardless of whether they are radioactive, are included within the scope of this application.

[0287] The term “treatment” means administering the compound or preparation described in this application (e.g., the double-stranded ribonucleic acid of this application, its pharmaceutically acceptable salt, its ligand conjugate, or pharmaceutical composition) to improve or eliminate a disease or one or more symptoms associated with said disease, and includes: (i) suppressing the disease or disease state, i.e., curbing its development; (ii) alleviating the disease or disease state, even if the disease or disease state subsides.

[0288] The term “prevention” means administering the compound or preparation described in this application (e.g., the double-stranded RNA of this application, its pharmaceutically acceptable salt, its ligand conjugate, or pharmaceutical composition) to prevent a disease or one or more symptoms associated with said disease, and includes: preventing the occurrence of the disease or disease state in a subject, particularly when such subjects are susceptible to the disease state but have not yet been diagnosed with the disease state.

[0289] The terms “subject,” “patient,” or “object” are used interchangeably herein and refer to an animal that has become a subject of treatment, observation, or experimentation. In some embodiments, the subject is a mammal, preferably a primate, and more preferably a human.

[0290] The term "therapeutic effective amount" refers to the amount of the compound of this application (e.g., the double-stranded RNA of this application, its pharmaceutically acceptable salt, or its ligand conjugate) used to treat or prevent a particular disease, condition, or disorder; (ii) reduce, improve, or eliminate one or more symptoms of a particular disease, condition, or disorder; or (iii) prevent or delay the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The amount of the compound of this application constituting a "therapeutic effective amount" varies depending on the compound, the disease state and its severity, the route of administration, and the age of the subject to be treated, but may routinely be determined by a person skilled in the art based on their own knowledge and the content of this application.

[0291] The therapeutic dose of the compound in this application may be determined based on factors such as the specific purpose of treatment, the method of administration, the patient's health and condition, and the prescribing physician's judgment. The proportion or concentration of the compound in the pharmaceutical composition may not be fixed and depends on various factors, including dosage, chemical properties (e.g., hydrophobicity), and route of administration. For example, the compound may be provided as a physiologically buffered saline solution containing about 0.1–10% w / v of the compound for parenteral administration. Some typical dosage ranges are from about 1 μg / kg to about 1 g / kg body weight / day. In some embodiments, the dosage range is from about 0.01 mg / kg to about 100 mg / kg body weight / day. The dosage is likely to depend on variables such as the type and severity of the disease or condition, the general health status of the specific patient, the relative biological potency of the selected compound, the excipient formulation, and the route of administration. The effective dose can be obtained by extrapolation from dose-response curves derived from in vitro or animal model testing systems.

[0292] The term "pharmaceutically acceptable" refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and other animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0293] As pharmaceutically acceptable salts, for example, metal salts, ammonium salts, salts formed with organic bases, salts formed with inorganic acids, salts formed with organic acids, and salts formed with basic or acidic amino acids may be mentioned.

[0294] The term "pharmaceutical composition" refers to a mixture of one or more compounds of this application (e.g., the double-stranded ribonucleic acid of this application, its pharmaceutically acceptable salt, or its ligand conjugate) with a pharmaceutically acceptable carrier, excipient, or excipient. The purpose of a pharmaceutical composition is to facilitate the administration of the compound of this application to an organism. In this document, the terms "pharmaceutical composition" and "formulation" have the same meaning and are used interchangeably. Carriers, excipients, or excipients as used herein include any and all solvents, diluents or other liquid excipients, dispersants or suspending agents, surfactants, isotonic agents, thickeners or emulsifiers, preservatives, solid binders, lubricants, etc., suitable for the desired particular dosage form. Various carriers, excipients, or excipients used to formulate pharmaceutically acceptable compositions and methods for their preparation may be employed using known techniques. The use of any conventional carrier media, except those incompatible with the compounds of this application (e.g., producing any adverse biological effects or otherwise interacting harmfully with any other component of the pharmaceutically acceptable composition), is covered within the scope of this application. In some specific embodiments, the carriers, excipients or excipients used herein are those commonly used in the field of dsRNA drug delivery.

[0295] The pharmaceutical compositions of this application can be prepared by combining the compounds of this application with suitable pharmaceutically acceptable carriers, excipients or excipients, for example, formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalers, gels, microspheres and aerosols, etc.

[0296] Typical routes of administration for the compounds of this application or their pharmaceutical compositions include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, vaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.

[0297] The pharmaceutical composition of this application can be manufactured using methods well known in the art, such as conventional mixing, dissolving, granulation, sugar-coated pill making, grinding, emulsification, freeze drying, etc.

[0298] The kit of this application includes the double-stranded ribonucleic acid of this application, its pharmaceutically acceptable salt, its ligand conjugate, or pharmaceutical composition; and optionally, instructions for use of the double-stranded ribonucleic acid of this application, its pharmaceutically acceptable salt, its ligand conjugate, or pharmaceutical composition for the treatment and / or prevention of PNPLA3-mediated diseases.

[0299] The solvents used in this application are commercially available.

[0300] Unless otherwise specified, the solvent ratios used in column chromatography and preparative thin-layer silica gel chromatography in this application are all volume ratios.

[0301] It is known in the art that modified nucleotide groups can be introduced into the dsRNA described in this application using nucleoside monomers with corresponding modifications. Those skilled in the art can learn from the prior art about methods for preparing the corresponding modified nucleoside monomers and methods for introducing the modified nucleotide groups into dsRNA. All modified nucleoside monomers can be obtained commercially or prepared using known methods.

[0302] As is known in the art, the desired ribonucleic acid can be obtained through conventional ribonucleic acid preparation methods (e.g., solid-phase synthesis and liquid-phase synthesis), for example, through phosphoramide solid-phase synthesis technology. The preparation method of the double-stranded ribonucleic acid, its pharmaceutically acceptable salt, or its ligand conjugates of this application comprises the following steps: sequentially linking nucleotide monomers in a 3' to 5' orientation according to the nucleotide type or sequence of the sense or antisense strand of the double-stranded ribonucleic acid to synthesize the sense and antisense strands. The linking of each nucleotide monomer includes four steps: deprotection, coupling, capping, oxidation, or sulfidation. Those skilled in the art can use conventional reaction conditions, reagent types and amounts, or adjust them according to experimental conditions to achieve the deprotection, coupling, capping, oxidation, or sulfidation reactions.

[0303] In some embodiments, for the synthesis of ribonucleic acid containing ligands, the ligand can be linked to the ribonucleic acid through a coupling reaction during or after the synthesis of oligonucleotides. Alternatively, the ligand can be linked to a solid support first, and then the nucleoside monomer can be sequentially linked to the ligand-solid support in a 3' to 5' direction.

[0304] Methods for purification and desalting are well known to those skilled in the art. For example, ribonucleic acid (RNA) can be purified by preparative ion chromatography. Alternatively, RNA can be desalted by reversed-phase chromatography or ultrafiltration centrifugation.

[0305] Annealing methods are well known to those skilled in the art. For example, the sense and antisense chains can be mixed in a 1:1 molar ratio, heated to 70-95°C, and then cooled to room temperature to form a double-chain structure.

[0306] During the synthesis process, the concentration of ribonucleic acid can be detected by, for example, ion exchange chromatography, or the molecular weight can be determined by liquid chromatography-mass spectrometry, or the concentration can be determined by micro spectrophotometer to control the synthesis quality. Such detection methods are well known to those skilled in the art.

[0307] Unless otherwise specified, singular terms encompass plural terms, and plural terms encompass singular terms. Unless otherwise specified, the words "a" or "an" mean "at least one" or "at least one". Unless otherwise specified, the use of "or" means "and / or".

[0308] For purposes of description and disclosure, all patents, patent applications, and other identified publications are expressly incorporated herein by reference. These publications are provided solely because their publication predates the filing date of this application. All statements regarding the dates of these documents or representations of their contents are based on information available to the applicant and do not constitute any acknowledgment of the accuracy of the dates or contents of these documents. Furthermore, in any country, any reference to these publications herein does not constitute an endorsement that such publication is part of the general knowledge in the art. Detailed Implementation

[0309] The present application is described in detail below through examples, but this does not imply any adverse limitation thereof. The compounds of this application can be prepared by various synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments of this application. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of this application without departing from the spirit and scope of this application.

[0310] The prepared double-stranded ribonucleic acid, its pharmaceutically acceptable salt, or its ligand conjugate can be confirmed as the target product by detection methods such as mass spectrometry.

[0311] Reagents and Materials

[0312] Commercially available monomers used in the synthesis

[0313] reagents used in synthesis

[0314] This application uses the following abbreviations:

[0315] DCM stands for dichloromethane; ACN stands for acetonitrile; DIC stands for diisopropylcarbodiimide; DMAP stands for dimethylaminopyridine; DMT stands for di-p-methoxytriphenylmethyl; NEAA stands for non-essential amino acid; MEM stands for 2-methoxyethoxymethyl.

[0316] Example 1: siRNA sequence design and specificity analysis

[0317] siRNA was designed using the human SERPINC1 gene transcript NM_000488.4, the macaque SERPINC1 gene transcript NM_001104583.1, and the mouse NM_080844.5 as target genes.

[0318] To predict the off-target potential of these siRNAs, we divided the entire siRNA sequence into three parts: the seed region, the cleavage site, and other locations, assigning different weights to base mismatches in these three parts based on their importance. Based on this information, we developed an off-target prediction scoring program. Using our program, we can calculate the degree of matching between these siRNA sequences and the human transcriptome, thus obtaining an off-target score for each siRNA sequence-reference transcript pair. Based on these off-target scores, the specificity of these sequences can be categorized into different levels: high specificity, medium specificity, and low specificity.

[0319] Preparation Example 1: GalNAc ligands (ligands containing GalNAc groups as targeting groups) were attached to a solid support.

[0320] Weigh 1.0 g of amino-CPG (amino loading: 30-40 μmol / g), add 5 mL of decapping agent DBK, react for 1 min, drain the reagent, and repeat the above operation 4 times. Based on a loading of 35 μmol, add 2 eq of GalNAc ligand / acetonitrile solution, then add a condensation reagent consisting of 2.5 eq DIC and 2.5 eq DMAP. React at 25-30℃ for 24 h. After the reaction, filter off the solvent, wash with anhydrous acetonitrile, and then add GalNAc ligand and condensation reagent according to the above dosage, reacting for another 24 h. After the reaction, wash the solid support with anhydrous acetonitrile, add 4 mL of a 1:1 mixture of Capping A and Capping B, react for 2 min, drain, add another 4 mL of the above mixture, react for 2 min, drain, wash with anhydrous acetonitrile, and vacuum dry at 30℃ for 1 h for later use. In this example, the GalNAc ligand can be either L01 or L02 ligand.

[0321] Preparation Example 2: Preparation of Double-Stranded Ribonucleic Acid

[0322] 2.1.1 Synthesis of GalNAc ligand-ssRNA (sense strand)

[0323] On a K&A nucleic acid synthesizer, the aforementioned GalNAc ligand-solid support was placed in a synthesis column, and ssRNA was synthesized using the standard phosphoramide technique. Specific steps included:

[0324] 1) DMT removal (deoxidation): First, wash the resin twice with acetonitrile, then remove the DMT on the resin with 3% trichloroacetic acid / DCM, and wash with acetonitrile 4 to 5 times.

[0325] 2) Condensation (coupling): Add monomers to the synthesis column, add condensation reagents (2.5 eq DIC, 2.5 eq DMAP), and condense at room temperature for 10 minutes. Wash 4-5 times with acetonitrile.

[0326] 3) Capping: First use Capping A, then use Capping B to cap the unreacted hydroxyl groups. Wash with acetonitrile 4-5 times.

[0327] 4) Oxidation: Add oxidizing agent, oxidize for 2 minutes, then wash with acetonitrile 4 to 5 times.

[0328] Repeat steps 1) to 4) until all sequences are synthesized. Finally, remove DMT with the decapping agent DBK and wash with acetonitrile 4 to 5 times.

[0329] Formation of thiophosphate bonds: Replace the oxidizing agent with a thioating agent and set the thioating time to 10 minutes to complete the formation of thiophosphate bonds.

[0330] 2.1.2 Synthesis of ssRNA (ligandless sense strand)

[0331] On a K&A nucleic acid synthesizer, a universal CPG solid-phase carrier is placed in a synthesis column, and ssRNA is synthesized according to the standard phosphoramide technique. Specific steps include:

[0332] 1) DMT removal (deoxidation): The resin is first washed twice with acetonitrile, and then DMT on the resin is removed with 3% trichloroacetic acid / DCM. The resin is washed 4 to 5 times with acetonitrile.

[0333] 2) Condensation (coupling): Add monomer and condensation reagent to the synthesis column and condense at room temperature for 10 minutes. Wash with acetonitrile 4-5 times.

[0334] 3) Capping: First use Capping A, then use Capping B to cap the unreacted hydroxyl groups. Wash with acetonitrile 4-5 times.

[0335] 4) Oxidation: Add oxidizing agent, oxidize for 2 minutes, then wash with acetonitrile 4 to 5 times.

[0336] Repeat steps 1) to 4) until all sequences are synthesized. Finally, remove DMT with the decapping agent DBK and wash with acetonitrile 4 to 5 times.

[0337] Formation of thiophosphate bonds: Replace the oxidizing agent with a thioating agent and set the thioating time to 10 minutes to complete the formation of thiophosphate bonds.

[0338] 2.2 Synthesis of asRNA (ligandless antisense strand)

[0339] On a K&A nucleic acid synthesizer, the above-mentioned CPG solid-phase carrier was placed into a synthesis column and synthesized according to the method described in 2.1.1 or 2.1.2.

[0340] 2.3 Separation of GalNAc ligand-ssRNA / ssRNA or asRNA from solid-phase carrier

[0341] The lysis reagent was ammonia:ethanol = 3:1 (v:v, where the ammonia concentration was 25-28%). 5 mL of the lysis reagent was added per 100 mg of solid support, and the reaction was stirred at 65-70 °C for 3 h. After the reaction was complete, the mixture was allowed to cool to room temperature and precipitated with ice-cold n-butanol, then placed in a -20 °C freezer for 30 min. The precipitate was obtained by centrifugation, followed by washing with n-butanol, repeated twice. Finally, the precipitate was washed with acetone, centrifuged, and vacuum dried to obtain the crude product, which was then analyzed by mass spectrometry.

[0342] The LC-MS (negative ion mode) conditions are as follows:

[0343] Chromatographic column: HILIC chromatographic column

[0344] Mobile phase A: 20 mm ammonium formate, pH 6.2

[0345] Mobile phase B: 20 ​​mmol ammonium formate + 95% ACN

[0346] Column temperature: 45℃

[0347] Flow rate: 1 mL / min.

[0348] 2.4 Annealing to form siRNA (dsRNA)

[0349] Dissolve the crude single-stranded RNA in water and remove the vector by membrane filtration. Determine the concentrations of the sense and antisense strands using a micro spectrophotometer, add the sense and antisense strands (to a molar ratio of 1:1), mix, denature at 94°C for 4 min, and anneal at room temperature.

[0350] 2.5 Purification of siRNA (dsRNA)

[0351] Purification was performed using a DNAPac RP 10*150mm 4μm column. Mobile phase A was 0.1mol / L triethylamine, pH 8.0, and mobile phase B was 0.1mol / L triethylamine, pH 8.0 + 50% ACN. Detection wavelengths were 215nm and 260nm. The main peak was collected, and rotary evaporation was used to remove most of the solvent to obtain the target product.

[0352] 2.6 Desalination and content calibration

[0353] Using 3K ultrafiltration centrifuge tubes, centrifuge at 12000×g for 12min to concentrate and desalinate the liquid; after the concentrated liquid is ready, water is added to replace it, and this process is repeated more than 5 times.

[0354] Concentration determination: The concentration of the concentrated sample was determined using a micro spectrophotometer.

[0355] The prepared double-stranded ribonucleic acid or its ligand conjugates are shown in Table 8:

[0356] Table 8. Double-stranded ribonucleic acid or its ligand conjugates

[0357] In this context, the uppercase letters G, C, A, or U typically represent nucleotides containing guanine, cytosine, adenine, or uracil as bases, respectively. The lowercase letters g, c, a, and u indicate that the ribosyl group of the corresponding uppercase nucleotide is modified with a 2'-methoxy group, i.e., g, c, a, and u represent 2'-O-methyl G, 2'-O-methyl C, 2'-O-methyl A, and 2'-O-methyl U, respectively. An uppercase letter followed by a lowercase f to its right indicates that the ribosyl group of the corresponding uppercase nucleotide is modified with a 2'-fluorine group, i.e., Gf, Cf, Af, and Uf represent 2'-fluoro G, 2'-fluoro C, 2'-fluoro A, and 2'-fluoro U, respectively. The lowercase letter s indicates that the two adjacent nucleotide residues are linked by a thiophosphate group; for example, "csu" indicates that the c and u residues are linked by a thiophosphate group. L represents a ligand; for example, the structures of ligands L01 and L02 are shown below.

[0358] The aforementioned double-stranded ribonucleic acid, its pharmaceutically acceptable salt, or its ligand conjugate (the ligand L is selected from L01 ligand or L02 ligand) can be prepared according to the method described in this application or methods known in the art.

[0359] The mass spectrometry data of the double-stranded ribonucleic acid, its pharmaceutically acceptable salt, or its ligand conjugates obtained in this application are as expected, confirming that the target product has been obtained.

[0360] Example 3 In vitro test

[0361] Cell culture and transfection

[0362] HepG2 cells were completely cultured in MEM (Gibco, catalog number 11095-080) containing 10% fetal bovine serum (Gibco, catalog number 10099-141), 1% sodium pyruvate (Gibco, catalog number 11360-070), and 1% NEAA at 37°C in an incubator containing 5% CO2 / 95% air (purchased from Shanghai Institute of Cell Biology). When the cells reached near confluence, they were treated with trypsin and released from the culture flasks. HepG2 cells were then sputtered at a rate of 5 × 10⁶ cells / year. 4 Cells were seeded in 48-well plates and cultured overnight. siRNA was diluted to 0.2 μM and 0.02 μM with enzyme-free water. For siRNA transfection, 0.75 μL of Lipofectamine RNAiMAX transfection reagent (Invitrogen, catalog number 13778150) was added to 25 μL of OPTI-MEM medium and mixed thoroughly. Then, 1.25 μL of siRNA was added to the OPTI-MEM medium containing the transfection reagent, mixed thoroughly, and incubated at room temperature for 5 minutes. 225 μL of complete MEM medium was added to each well, and the complex was added to the culture wells. The cells were cultured for another 24 hours. Two concentrations of each siRNA were prepared.

[0363] Single-dose experiments were conducted at final dsRNA concentrations of 1 nM and 0.1 nM.

[0364] Detection

[0365] Discard the cell supernatant and extract total intracellular RNA using an RNA extraction kit (Takara, catalog number 9767). Take an appropriate amount of total RNA and reverse transcribe it to obtain cDNA according to the instructions of a reverse transcription kit (Takara, catalog number RR036A). The 480SYBR Green I Master (Roche, catalog number 04887352001-1) kit is used to detect the relative expression level of AT3 mRNA using cDNA as a template and following the instructions with specific primer sequences.

[0366] The relative quantification of the target gene was performed using the Ct(△△Ct) comparison method.

[0367] AT3 mRNA inhibition rate (%) = (1-2) -△△Ct )*100%

[0368] △Ct(test group) = Ct(target gene in test group) - Ct(internal reference gene in test group)

[0369] △Ct(control group) = Ct(target gene in control group) - Ct(internal reference gene in control group)

[0370] △△Ct(test group) = △Ct(test group) - △Ct(control group average)

[0371] △△Ct(control group) = △Ct(control group) - △Ct(control group average)

[0372] The results are shown in Table 9 below.

[0373] Table 9 Results of in vitro tests

[0374] Example 4 HepG2 cell viability assay A

[0375] Cell culture and transfection

[0376] HepG2 cells were completely cultured in MEM (Gibco, catalog number 11095-080) containing 10% fetal bovine serum (Gibco, catalog number 10099-141), 1% sodium pyruvate (Gibco, catalog number 11360-070), and 1% NEAA at 37°C in an incubator containing 5% CO2 / 95% air (purchased from Shanghai Institute of Cell Biology). When the cells reached near confluence, they were treated with trypsin and released from the culture flasks. HepG2 cells were then sputtered at a rate of 5 × 10⁶ cells / year. 4 Cells were seeded in 48-well plates and cultured overnight. siRNA was diluted to 2 μM and 0.02 μM with enzyme-free water. For siRNA transfection, 0.75 μL of Lipofectamine RNAiMAX transfection reagent (Invitrogen, catalog number 13778150) was added to 25 μL of OPTI-MEM medium and mixed thoroughly. Then, 1.25 μL of siRNA was added to the OPTI-MEM medium containing the transfection reagent, mixed thoroughly, and incubated at room temperature for 5 minutes. 225 μL of complete MEM medium was added to each well, and the complex was added to the culture wells. The cells were cultured for another 24 hours. Two concentrations of each siRNA were prepared.

[0377] Single-dose experiments were conducted at final dsRNA concentrations of 10 nM and 0.1 nM.

[0378] Detection

[0379] The cell supernatant was discarded, and total intracellular RNA was extracted using an RNA extraction kit (Takara, catalog number 9767). An appropriate amount of total RNA was then reverse transcribed into cDNA using a reverse transcription kit (Takara, catalog number RR036A). The relative expression level of AT3 mRNA was detected using the CharmQ SYBR qPCR Master Mix (Vazyme, catalog number Q311-02) kit, with the cDNA as a template, following the manufacturer's instructions and specific primer sequences.

[0380] Table 10 Primer Sequences

[0381] The relative quantification of the target gene was performed using the Ct(△△Ct) comparison method.

[0382] AT3 mRNA inhibition rate (%) = (1-2) -△△Ct )*100%

[0383] The results are shown in Table 11.

[0384] Table 11 Results of HepG2 cell viability assay (A)

[0385] Example 5 Hep3B cell viability assay B

[0386] Cell culture and transfection

[0387] Hep3B cells (purchased from Nanjing Kebai) were completely cultured in MEM (Gibco, catalog number 11095-080) containing 10% fetal bovine serum (Gibco, catalog number 10099-141), 1% sodium pyruvate (Gibco, catalog number 11360-070), and 1% NEAA at 37°C in an incubator containing 5% CO2 / 95% air. When the cells reached near confluence, they were treated with trypsin and released from the culture flask. Hep3B cells were then cultured at a rate of 2 × 10⁶ cells / year. 4Cells were seeded in 96-well plates and cultured overnight. siRNA was diluted 5-fold with enzyme-free water to a concentration range of 2 μM–0.00064 μM. For siRNA transfection, 0.3 μL of Lipofectamine RNAiMAX transfection reagent (Invitrogen, catalog number 13778150) was added to 10 μL of OPTI-MEM medium and mixed thoroughly. Then, 0.5 μL of siRNA was added to the OPTI-MEM medium containing the transfection reagent, mixed thoroughly, and incubated at room temperature for 5 minutes. 90 μL of complete MEM medium was added to each well, and the complex was added to the culture wells. The cells were cultured for another 48 hours. Six concentrations were set for each siRNA, with the final drug concentration range being 10 nM–0.0032 nM.

[0388] Detection

[0389] Discard the culture medium, wash once with PBS, and perform cell lysis according to the detailed instructions of the QuantiGene Sample Processing Kit (Cultured Cells) (Invitrogen, catalog number QS0101); mix the cell lysis buffer and specific probe (Thermo, catalog number QGS-1000, AssyID: SA-3000229) according to the QuantiGene instructions. TM The Singleplex Assay (Invitrogen, catalog number QS0013) detailed instructions describe the specific capture of intracellular AT3 mRNA, with chemiluminescence (RLU) values ​​read using a Tecan multi-microplate reader. The siRNA silencing efficiency (%) is calculated as follows: (1 - (RLU sample group - RLU blank group) / (RLU control group - RLU blank group)) × 100%

[0390] The results are shown in Table 12 below.

[0391] Table 12 Results of Hep3B cell viability assay (B)

[0392] Example 6: Activity of primary mouse hepatocytes

[0393] Cell Culture and Free Adsorption

[0394] Primary hepatocytes were extracted from mice using a primary hepatocyte extraction kit (Livo Biotechnology, catalog number LV-PHIK001); the primary mouse hepatocytes were then processed at a concentration of 2 × 10⁻⁶. 4 Cells were seeded in 96-well plates, and 2 μL of enzyme-free water diluted with siRNA was added to each well. The cells were cultured for 48 hours. The drug concentration was 100 nM - 0.412 nM.

[0395] Detection

[0396] The cell supernatant was discarded, and total intracellular RNA was extracted using an RNA extraction kit (Auvi Biotech, catalog number RNC643-03H). An appropriate amount of total RNA was then reverse transcribed into cDNA using a reverse transcription kit (Takara, catalog number RR036A). The relative expression level of AT3 mRNA was detected using the CharmQ SYBR qPCR Master Mix (Vazyme, catalog number Q311-02) kit, with the cDNA as a template, following the manufacturer's instructions and specific primer sequences.

[0397] Table 13 Primer sequences

[0398] The relative quantification of the target gene was performed using the Ct(△△Ct) comparison method.

[0399] AT3 mRNA inhibition rate (%) = (1-2) -△△Ct )*100%

[0400] The results are shown in Table 13A below.

[0401] Table 13A shows the viability results of primary mouse hepatocytes.

[0402] Example 7: Inhibition of AT3 protein expression at different time points after drug administration in C57BL / 6 mice

[0403] This experiment used 4-6 week old male C57BL / 6 mice (Shanghai Silex Laboratory Animal Co., Ltd.), randomly divided into groups of 5 mice each. Each group was administered either the compound or a PBS control. The day of the first administration was designated as day 0 of the experiment. The corresponding compound solution was administered subcutaneously at a dose of 5 mg / kg based on the animal's body weight. PBS control mice were administered PBS at a volume of 10 mL / kg body weight per mouse. Blood samples were collected from the orbital sinus before administration and on days 3, 7, 14, 21, 28, 35, and 49 after administration. Plasma was separated, and the AT3 protein content in the plasma was measured at each time point using the Mouse Antithrombin III ELISA Kit (SERPINC1) (Abcam, catalog number Ab108800).

[0404] Table 14 In vivo experimental design table

[0405] The AT3 protein inhibition rate is calculated using the following equation:

[0406] AT3 protein inhibition rate = (1 - protein content in the test group / protein content in the control group) × 100%.

[0407] The results are shown in Table 15.

[0408] Table 15 Results of the inhibition of AT3 protein expression in mouse plasma

[0409] The results confirmed that after a single dose, the siRNAs of this application all showed excellent inhibition of mouse AT3 protein expression. In particular, TD19M02L01, TD41M02L01, and TD47M02L01 all showed the highest AT3 protein inhibition rate of about 90%, resulting in 50% inhibition maintained for 49 days.

[0410] Example 8: Inhibition of AT3 protein expression at different time points after drug administration in AAV-AT3 mice

[0411] In this experiment, 4-6 week old male C57BL / 6 mice (Shanghai Slack Laboratory Animal Co., Ltd.) were used. Each mouse was injected with 200 μL (virus titer 5 × 10⁻⁶) via the tail vein. 11 AAV-CTM-AT3 (prepared by Shandong Weizhen Biotechnology Co., Ltd.) was administered at a concentration of vg / ml. On day 28 post-viral injection, blood was collected from the orbital cavity of all mice to collect serum for AT3 protein level detection. AAV-AT3 mice were grouped according to their AT3 protein levels, with three mice in each group. Each group received either the compound or a PBS control. The day of the first administration was designated as day 0 of the experiment. The corresponding compound solution was administered subcutaneously at a dose of 5 mg / kg, based on the animal's body weight. PBS control mice received 10 mL / kg body weight of PBS per mouse. Blood was collected from the orbital cavity before administration and on days 7, 14, and 28 post-administration. Serum was separated, and the AT3 protein content in the serum at each time point was measured using the Antithrombin III Human ELISA Kit (Abcam, catalog number Ab108801).

[0412] Table 16 In vivo experimental design table

[0413] The AT3 protein inhibition rate is calculated using the following equation:

[0414] AT3 protein inhibition rate = (1 - protein content in the test group / protein content in the control group) × 100%.

[0415] The results are shown in Table 17.

[0416] Table 17 Results of the inhibition of AT3 protein expression in mouse serum

[0417] The results confirmed that after a single dose, the siRNAs in this application effectively knocked down the AT3 protein level, with a maximum knockdown level of 90%.

Claims

1. A double-stranded ribonucleic acid (dsRNA), a pharmaceutically acceptable salt thereof, or a ligand conjugate thereof, targeting SERPINC1 mRNA, said dsRNA comprising a sense strand and an antisense strand, said sense strand being no more than 21 nucleotides in length and said antisense strand being no more than 23 nucleotides in length, said sense strand or antisense strand optionally being modified.

2. A double-stranded ribonucleic acid (dsRNA), a pharmaceutically acceptable salt thereof, or a ligand conjugate thereof, said dsRNA comprising a sense strand and an antisense strand, said sense strand containing, for example, SEQ ID NO.1, SEQ ID NO.7, SEQ ID NO.13, SEQ ID NO.19, SEQ ID NO.25, SEQ ID NO.31, SEQ ID NO.37, SEQ ID NO.43, SEQ ID NO.49, SEQ ID NO.55, SEQ ID NO.61, SEQ ID NO.67, SEQ ID NO.73, SEQ ID NO.79, SEQ ID NO.85, SEQ ID NO.91, SEQ ID NO.97, SEQ ID NO.103, SEQ ID NO.109, SEQ ID NO.115, SEQ ID NO.121, SEQ ID NO.127, SEQ ID NO.133, SEQ ID NO.139, SEQ ID NO.145, SEQ ID NO.151, SEQ ID NO.157, SEQ ID NO. The nucleotide sequence NO.163, SEQ ID NO.169, SEQ ID NO.175, SEQ ID NO.181, SEQ ID NO.187, SEQ ID NO.193, SEQ ID NO.199, SEQ ID NO.205, SEQ ID NO.211, SEQ ID NO.217, SEQ ID NO.223, SEQ ID NO.229, SEQ ID NO.235, SEQ ID NO.241, SEQ ID NO.247, SEQ ID NO.253, SEQ ID NO.259, SEQ ID NO.265, SEQ ID NO.271, SEQ ID NO.277, SEQ ID NO.283, SEQ ID NO.289, SEQ ID NO.295, SEQ ID NO.301, or SEQ ID NO.307 contains at least 15 consecutive nucleotides, and the length of the sense strand does not exceed 21 nucleotides, wherein the antisense strand contains nucleotide sequences such as SEQ ID NO.2, SEQ ID NO.8, SEQ ID NO.14, SEQ ID NO.

307. NO.20, SEQ ID NO.26, SEQ ID NO.32, SEQ ID NO.38, SEQ ID NO.44, SEQ ID NO.50, SEQ ID NO.56, SEQ ID NO.62, SEQ ID NO.68, SEQ ID NO.74, SEQ ID NO.

80. SEQ ID NO.86, SEQ ID NO.92, SEQ ID NO.98, SEQ ID NO.104, SEQ ID NO.110, SEQ ID NO.116, SEQ ID NO.122, SEQ ID NO.128, SEQ ID NO.134, SEQ ID NO.140, SEQ ID NO.146, SEQ ID NO.152, SEQ ID NO.158, SEQ ID NO.164, SEQ ID NO.170, SEQ ID NO.176, SEQ ID NO.182, SEQ ID NO.188, SEQ ID NO.194, SEQ ID NO.200, SEQ ID NO.206, SEQ ID NO.212, SEQ ID NO.218, SEQ ID NO.224, SEQ ID NO.230, SEQ ID NO.236, SEQ ID NO.242, SEQ ID NO.248, SEQ ID NO.254, SEQ ID NO.260, SEQ ID The nucleotide sequence shown in SEQ ID NO.266, SEQ ID NO.272, SEQ ID NO.278, SEQ ID NO.284, SEQ ID NO.290, SEQ ID NO.296, SEQ ID NO.302, or SEQ ID NO.308 contains at least 15 consecutive nucleotides and the antisense strand is no more than 23 nucleotides in length. Chain of Justice: 5'-AACUGAACUGCCGACUCUA-3' (SEQ ID NO.1) Antonym: 5'-UAGAGUCGGCAGUUCAGUUUG-3' (SEQ ID NO.2); Chain of Justice: 5'-AACUGCCGACUCUAUCGAA-3' (SEQ ID NO.7) Antisense chain: 5'-UUCGAUAGAGUCGGCAGUUCA-3' (SEQ ID NO.8); Chain of Justice: 5'-ACUGAACUGCCGACUCUAU-3' (SEQ ID NO.13) Antisense chain: 5'-AUAGAGUCGGCAGUUCAGUUU-3' (SEQ ID NO.14); Chain of Justice: 5'-ACUGCCGACUCUAUCGAAA-3' (SEQ ID NO.19) Antonym: 5'-UUUCGAUAGAGUCGGCAGUUC-3' (SEQ ID NO.20); Chain of Justice: 5'-CCGACUCUAUCGAAAAGCA-3' (SEQ ID NO.25) Antonym: 5'-UGCUUUUCGAUAGAGUCGGCA-3' (SEQ ID NO.26); Chain of Justice: 5'-CUGAACUGCCGACUCUAUA-3' (SEQ ID NO.31) Antisense chain: 5'-UAUAGAGUCGGCAGUUCAGUU-3' (SEQ ID NO.32); Chain of Justice: 5'-CUGCCGACUCUAUCGAAAA-3' (SEQ ID NO.37) Antisense chain: 5'-UUUUCGAUAGAGUCGGCAGUU-3' (SEQ ID NO.38); Chain of Justice: 5'-GCCAAACUGAACUGCCGAA-3' (SEQ ID NO.43) Antisense chain: 5'-UUCGGCAGUUCAGUUUGGCAA-3' (SEQ ID NO.44); Chain of Justice: 5'-GCCGACUCUAUCGAAAAGA-3' (SEQ ID NO.49) Antisense chain: 5'-UCUUUUCGAUAGAGUCGGCAG-3' (SEQ ID NO.50); Chain of Justice: 5'-UGCCAAACUGAACUGCCGA-3' (SEQ ID NO.55) Antisense chain: 5'-UCGGCAGUUCAGUUUGGCAAA-3' (SEQ ID NO.56); Chain of Justice: 5'-UUGCCAAACUGAACUGCCA-3' (SEQ ID NO.61) Antisense chain: 5'-UGGCAGUUCAGUUUGGCAAAG-3' (SEQ ID NO.62); Chain of Justice: 5'-AAACUGAACUGCCGACUCU-3' (SEQ ID NO. 67) Antisense chain: 5'-AGAGUCGGCAGUUCAGUUUGG-3' (SEQ ID NO.68); Chain of Justice: 5'-AACUGUCCAAGGCCAAUUA-3' (SEQ ID NO.73) Antisense chain: 5'-UAAUUGGCCUUGGACAGUUCC-3' (SEQ ID NO.74); Chain of Justice: 5'-ACCAUUUACUUCAAGGGCA-3' (SEQ ID NO.79) Antonym: 5'-UGCCCUUGAAGUAAAUGGUGU-3' (SEQ ID NO.80); Chain of Justice: 5'-ACUCUAUCGAAAAGCCAAA-3' (SEQ ID NO.85) Antonym: 5'-UUUGGCUUUUCGAUAGAGUCG-3' (SEQ ID NO.86); Chain of Justice: 5'-CGACUCUAUCGAAAAGCCA-3' (SEQ ID NO.91) Antonym: 5'-UGGCUUUUCGAUAGAGUCGGC-3' (SEQ ID NO.92); Chain of Justice: 5'-CUAUGACCAAGCUGGGUGA-3' (SEQ ID NO.97) Antisense chain: 5'-UCACCCAGCUUGGUCAUAGCA-3' (SEQ ID NO.98); Chain of Justice: 5'-CUCUAUCGAAAAGCCAACA-3' (SEQ ID NO.103) Antonym: 5'-UGUUGGCUUUUCGAUAGAGUC-3' (SEQ ID NO.104); Chain of Justice: 5'-CUUCUUUGCCAAACUGAAA-3' (SEQ ID NO.109) Antisense chain: 5'-UUUCAGUUUGGCAAAGAAGAA-3' (SEQ ID NO.110); Chain of Justice: 5'-GACCAAGCUGGGUGCCUGU-3' (SEQ ID NO.115) Antisense chain: 5'-ACAGGCACCCAGCUUGGUCAU-3' (SEQ ID NO.116); Chain of Justice: 5'-GCUUUUGCUAUGACCAAGA-3' (SEQ ID NO.121) Antisense chain: 5'-UCUUGGUCAUAGCAAAAGCCG-3' (SEQ ID NO.122); Chain of Justice: 5'-GGUUAACACCAUUUACUUA-3' (SEQ ID NO.127) Antisense chain: 5'-UAAGUAAAUGGUGUUAACCAG-3' (SEQ ID NO.128); Chain of Justice: 5'-GUUAACACCAUUUACUUCA-3' (SEQ ID NO.133) Antisense chain: 5'-UGAAGUAAAUGGUGUUAACCA-3' (SEQ ID NO.134); Chain of Justice: 5'-UAUGACCAAGCUGGGUGCA-3' (SEQ ID NO.139) Antonym: 5'-UGCACCCAGCUUGGUCAUAGC-3' (SEQ ID NO.140); Chain of Justice: 5'-UCUAUCGAAAAGCCAACAA-3' (SEQ ID NO.145) Antisense chain: 5'-UUGUUGGCUUUUCGAUAGAGU-3' (SEQ ID NO.146); Chain of Justice: 5'-UGAACUGCCGACUCUAUCA-3' (SEQ ID NO.151) Antisense chain: 5'-UGAUAGAGUCGGCAGUUCAGU-3' (SEQ ID NO.152); Chain of Justice: 5'-UGAUGUACCAGGAAGGCAA-3' (SEQ ID NO.157) Antisense chain: 5'-UUGCCUUCCUGGUACAUCAUA-3' (SEQ ID NO.158); Chain of Justice: 5'-UGUGCAUUUACCGCUCCCA-3' (SEQ ID NO.163) Antonym: 5'-UGGGAGCGGUAAAUGCACAUG-3' (SEQ ID NO.164); Chain of Justice: 5'-UUGCUAUGACCAAGCUGGA-3' (SEQ ID NO.169) Antisense chain: 5'-UCCAGCUUGGUCAUAGCAAAA-3' (SEQ ID NO.170); Chain of Justice: 5'-UUUGCCAAACUGAACUGCA-3' (SEQ ID NO.175) Antisense chain: 5'-UGCAGUUCAGUUUGGCAAAGA-3' (SEQ ID NO.176); Chain of Justice: 5'-AACACCAUUUACUUCAAGA-3' (SEQ ID NO.181) Antisense chain: 5'-UCUUGAAGUAAAUGGUGUUAA-3' (SEQ ID NO.182); Chain of Justice: 5'-ACACCAUUUACUUCAAGGA-3' (SEQ ID NO.187) Antisense chain: 5'-UCCUUGAAGUAAAUGGUGUUA-3' (SEQ ID NO.188); Chain of Justice: 5'-AGGAGCAGCUGCAAGACAU-3' (SEQ ID NO.193) Antisense chain: 5'-AUGUCUUGCAGCUGCUCCUUC-3' (SEQ ID NO.194); Chain of Justice: 5'-CAAGGGCCUGUGGAAGUCA-3' (SEQ ID NO.199) Antisense chain: 5'-UGACUUCCACAGGCCCUUGAA-3' (SEQ ID NO.200); Chain of Justice: 5'-CAGCUGCAAGACAUGGGCA-3' (SEQ ID NO.205) Antonym: 5'-UGCCCAUGUCUUGCAGCUGCU-3' (SEQ ID NO.206); Chain of Justice: 5'-CCUUUUUGGAGACAAAUCA-3' (SEQ ID NO.211) Antonym: 5'-UGAUUUGUCUCCAAAAAGGCG-3' (SEQ ID NO.212); Chain of Justice: 5'-CUAUGAUGUACCAGGAAGA-3' (SEQ ID NO.217) Antisense chain: 5'-UCUUCCUGGUACAUCAUAGAU-3' (SEQ ID NO.218); Justice Chain: 5'-GAAGGAGCAGCUGCAAGAA-3' (SEQ ID NO.223) Antisense chain: 5'-UUCUUGCAGCUGCUCCUUCAA-3' (SEQ ID NO.224); Chain of Justice: 5'-GAGCCAAGCUCCAGCCCCU-3' (SEQ ID NO.229) Antisense chain: 5'-AGGGGCUGGAGCUUGGCUCCA-3' (SEQ ID NO.230); Chain of Justice: 5'-GCAGCUGCAAGACAUGGGA-3' (SEQ ID NO.235) Antisense chain: 5'-UCCCAUGUCUUGCAGCUGCUC-3' (SEQ ID NO.236); Chain of Justice: 5'-GCAUUUCUUGAGGUAAAUA-3' (SEQ ID NO.241) Antisense chain: 5'-UAUUUACCUCAAGAAAUGCCU-3' (SEQ ID NO.242); Justice Chain: 5'-GCCUGUGGAAGUCAAAGUU-3' (SEQ ID NO.247) Antisense chain: 5'-AACUUUGACUUCCACAGGCCC-3' (SEQ ID NO.248); Justice Chain: 5'-GCCUUUUUGGAGACAAAUA-3' (SEQ ID NO.253) Antisense chain: 5'-UAUUUGUCUCCAAAAAGGCGA-3' (SEQ ID NO.254); Chain of Justice: 5'-GGGCCUGUGGAAGUCAAAA-3' (SEQ ID NO.259) Antisense chain: 5'-UUUUGACUUCCACAGGCCCUU-3' (SEQ ID NO.260); Chain of Justice: 5'-UAACACCAUUUACUUCAAA-3' (SEQ ID NO.265) Antisense chain: 5'-UUUGAAGUAAAUGGUGUUAAC-3' (SEQ ID NO.266); Chain of Justice: 5'-UACUUCAAGGGCCUGUGGA-3' (SEQ ID NO.271) Antisense chain: 5'-UCCACAGGCCCUUGAAGUAAA-3' (SEQ ID NO.272); Chain of Justice: 5'-UUAACACCAUUUACUUCAA-3' (SEQ ID NO.277) Antisense chain: 5'-UUGAAGUAAAUGGUGUUAACC-3' (SEQ ID NO.278); Chain of Justice: 5'-UUACUUCAAGGGCCUGUGA-3' (SEQ ID NO.283) Antisense chain: 5'-UCACAGGCCCUUGAAGUAAAU-3' (SEQ ID NO.284); Justice Chain: 5'-UUCAAGGGCCUGUGGAAGU-3' (SEQ ID NO.289) Antisense chain: 5'-ACUUCCACAGGCCCUUGAAGU-3' (SEQ ID NO.290); Chain of Justice: 5'-UUCUUCUUUGCCAAACUGA-3' (SEQ ID NO.295) Antisense chain: 5'-UCAGUUUGGCAAAGAAGAAGU-3' (SEQ ID NO.296); Chain of Justice: 5'-UUUUGCUAUGACCAAGCUA-3' (SEQ ID NO.301) Antisense chain: 5'-UAGCUUGGUCAUAGCAAAAGC-3' (SEQ ID NO.302); Chain of Justice: 5'-UUUUUGGAGACAAAUCCCU-3' (SEQ ID NO.307) Antisense chain: 5'-AGGGAUUUGUCUCCAAAAAGG-3' (SEQ ID NO.308); The justice chain or antisense chain is optionally modified.

3. The double-stranded ribonucleic acid, its pharmaceutically acceptable salt, or its ligand conjugate according to claim 1 or 2, wherein, The sense strand contains SEQ ID NO.1, SEQ ID NO.7, SEQ ID NO.13, SEQ ID NO.19, SEQ ID NO.25, SEQ ID NO.31, SEQ ID NO.37, SEQ ID NO.43, SEQ ID NO.49, SEQ ID NO.55, SEQ ID NO.61, SEQ ID NO.67, SEQ ID NO.73, SEQ ID NO.79, SEQ ID NO.85, SEQ ID NO.91, SEQ ID NO.97, SEQ ID NO.103, SEQ ID NO.109, SEQ ID NO.115, SEQ ID NO.121, SEQ ID NO.127, SEQ ID NO.133, SEQ ID NO.139, SEQ ID NO.145, SEQ ID NO.151, SEQ ID NO.157, SEQ ID NO.163, SEQ ID NO.169, SEQ ID NO.175, SEQ ID NO.181, SEQ ID NO.187, SEQ ID The nucleotide sequences shown in SEQ ID NO.193, SEQ ID NO.199, SEQ ID NO.205, SEQ ID NO.211, SEQ ID NO.217, SEQ ID NO.223, SEQ ID NO.229, SEQ ID NO.235, SEQ ID NO.241, SEQ ID NO.247, SEQ ID NO.253, SEQ ID NO.259, SEQ ID NO.265, SEQ ID NO.271, SEQ ID NO.277, SEQ ID NO.283, SEQ ID NO.289, SEQ ID NO.295, SEQ ID NO.301, or SEQ ID NO.307, with the sense strand being no more than 21 nucleotides in length, and the antisense strand containing nucleotide sequences such as SEQ ID NO.2, SEQ ID NO.8, SEQ ID NO.14, SEQ ID NO.20, SEQ ID NO.26, SEQ ID NO.32, SEQ ID NO.38, SEQ ID NO.44, SEQ ID NO.50, SEQ ID NO.56, or SEQ ID NO.

307. NO.62, SEQ ID NO.68, SEQ ID NO.74, SEQ ID NO.80, SEQ ID NO.86, SEQ ID NO.92, SEQ ID NO.98, SEQ ID NO.104, SEQ ID NO.

110. SEQ ID NO.116, SEQ ID NO.122, SEQ ID NO.128, SEQ ID NO.134, SEQ ID NO.140, SEQ ID NO.146, SEQ ID NO.152, SEQ ID NO.158, SEQ ID NO.164, SEQ ID NO.170, SEQ ID NO.176, SEQ ID NO.182, SEQ ID NO.188, SEQ ID NO.194, SEQ ID NO.200, SEQ ID NO.206, SEQ ID NO.212, SEQ ID NO.218, SEQ ID NO.224, SEQ ID NO.230, SEQ ID NO.236, SEQ ID NO.242, SEQ ID NO.248, SEQ ID NO.254, SEQ ID NO.260, SEQ ID NO.266, SEQ ID NO.272, SEQ ID NO.278, SEQ ID NO.284, SEQ ID NO.290, SEQ The nucleotide sequence must be as shown in SEQ ID NO. 296, SEQ ID NO. 302, or SEQ ID NO. 308, and the antisense strand must be no longer than 23 nucleotides.

4. The double-stranded ribonucleic acid, its pharmaceutically acceptable salt, or its ligand conjugate according to any one of claims 1-3, wherein, The nucleotide sequence of the sense strand is as follows: SEQ ID NO.1, SEQ ID NO.7, SEQ ID NO.13, SEQ ID NO.19, SEQ ID NO.25, SEQ ID NO.31, SEQ ID NO.37, SEQ ID NO.43, SEQ ID NO.49, SEQ ID NO.55, SEQ ID NO.61, SEQ ID NO.67, SEQ ID NO.73, SEQ ID NO.79, SEQ ID NO.85, SEQ ID NO.91, SEQ ID NO.97, SEQ ID NO.103, SEQ ID NO.109, SEQ ID NO.115, SEQ ID NO.121, SEQ ID NO.127, SEQ ID NO.133, SEQ ID NO.139, SEQ ID NO.145, SEQ ID NO.151, SEQ ID NO.157, SEQ ID NO.163, SEQ ID NO.169, SEQ ID NO.175, SEQ ID NO.181, SEQ ID NO.187, SEQ The nucleotide sequences are SEQ ID NO.193, SEQ ID NO.199, SEQ ID NO.205, SEQ ID NO.211, SEQ ID NO.217, SEQ ID NO.223, SEQ ID NO.229, SEQ ID NO.235, SEQ ID NO.241, SEQ ID NO.247, SEQ ID NO.253, SEQ ID NO.259, SEQ ID NO.265, SEQ ID NO.271, SEQ ID NO.277, SEQ ID NO.283, SEQ ID NO.289, SEQ ID NO.295, SEQ ID NO.301, or SEQ ID NO.307, wherein the nucleotide sequence of the antisense strand is as shown in SEQ ID NO.2, SEQ ID NO.8, SEQ ID NO.14, SEQ ID NO.20, SEQ ID NO.26, SEQ ID NO.32, SEQ ID NO.38, SEQ ID NO.44, SEQ ID NO.50, SEQ ID NO.56, or SEQ ID NO.

307. NO.62, SEQ ID NO.68, SEQ ID NO.74, SEQ ID NO.80, SEQ ID NO.86, SEQ ID NO.92, SEQ ID NO.98, SEQ ID NO.104, SEQ ID NO.110, SEQ ID NO.The nucleotide sequence shown in SEQ ID NO.116, SEQ ID NO.122, SEQ ID NO.128, SEQ ID NO.134, SEQ ID NO.140, SEQ ID NO.146, SEQ ID NO.152, SEQ ID NO.158, SEQ ID NO.164, SEQ ID NO.170, SEQ ID NO.176, SEQ ID NO.182, SEQ ID NO.188, SEQ ID NO.194, SEQ ID NO.200, SEQ ID NO.206, SEQ ID NO.212, SEQ ID NO.218, SEQ ID NO.224, SEQ ID NO.230, SEQ ID NO.236, SEQ ID NO.242, SEQ ID NO.248, SEQ ID NO.254, SEQ ID NO.260, SEQ ID NO.266, SEQ ID NO.272, SEQ ID NO.278, SEQ ID NO.284, SEQ ID NO.290, SEQ ID NO.296, SEQ ID NO.302 or SEQ ID NO.

308.

5. The double-stranded ribonucleic acid, its pharmaceutically acceptable salt, or its ligand conjugate according to any one of claims 1-3, wherein, The sense or antisense strand optionally includes a protrusion at the 5' end and / or the 3' end; or, the protrusion is 1, 2, 3, 4, or 5 nucleotides at the 5' end and / or the 3' end of the sense or antisense strand; or, the dsRNA, its pharmaceutically acceptable salt, or its ligand conjugate contains an additional sequence as the protrusion.

6. The double-stranded ribonucleic acid, its pharmaceutically acceptable salt, or its ligand conjugate according to claim 5, wherein, The protrusion contains 1, 2, 3, 4 or 5 nucleotides; or, the protrusion contains 1 or 2 nucleotides.

7. The double-stranded ribonucleic acid, its pharmaceutically acceptable salt, or its ligand conjugate according to claim 5 or 6, wherein the overhang is selected from unmodified or modified A, G, C, U, or T; or selected from unmodified or modified U or T; Alternatively, when the additional sequence serving as the overhang is 1 nucleotide, the overhang is selected from u or dT; or when the additional sequence serving as the overhang is 2 nucleotides, the overhang is selected from uu or dTdT.

8. The double-stranded ribonucleic acid, its pharmaceutically acceptable salt, or its ligand conjugate according to any one of claims 5-7, wherein, The additional sequence serving as the protrusion is connected to its adjacent nucleotides via a phosphate ester group or a thiophosphate ester group; or, one or more nucleotides in the additional sequence serving as the protrusion are connected to each other via a phosphate ester group or a thiophosphate ester group.

9. The double-stranded ribonucleic acid, its pharmaceutically acceptable salt, or its ligand conjugate according to any one of claims 1-8, wherein, One, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, or twenty-one nucleotides of the positive strand are modified, or nucleotides within any of the aforementioned values ​​are modified; or one or more, two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, ten or more, eleven or more, twelve or more, thirteen or more, fourteen or more, fifteen or more, sixteen or more, seventeen or more, eighteen or more, nineteen or more, twenty or more, or twenty or more nucleotides of the positive strand are modified; or all nucleotides of the positive strand are modified; and / or One, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twelve, twenty-one, twenty-two, or twenty-three nucleotides of the antisense strand are modified, or nucleotides within any of the aforementioned values ​​are modified; or one or more, two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, ten or more, eleven or more, twelve or more, thirteen or more, fourteen or more, fifteen or more, sixteen or more, seventeen or more, eighteen or more, nineteen or more, twenty or more, twenty or more, twenty or more, twenty or more, twenty or more, twenty-two or more, or twenty-three nucleotides of the antisense strand are modified; or all nucleotides of the antisense strand are modified.

10. The double-stranded ribonucleic acid, its pharmaceutically acceptable salt, or its ligand conjugate according to any one of claims 1-9, wherein, The modification is selected from glycosyl modifications of nucleotides, linkage modifications between nucleotides, or terminal modifications.

11. The double-stranded ribonucleic acid, its pharmaceutically acceptable salt, or its ligand conjugate according to any one of claims 1-10, wherein, The glycosyl modification of the nucleotide is selected from 2'-dehydroxylation, 2'-fluorination, 2'-amino, 2'-alkyl, 2'-O-alkyl, 2'-O-ether, and 2'-O-alkenyl; or, the glycosyl modification of the nucleotide is selected from 2'-dehydroxylation, 2'-fluorination, 2'-amino, 2'-methyl, 2'-ethyl, 2'-methyl-O-methyl, 2'-ethyl-O-methyl, 2'-O-methyl, 2'-O-ethyl, 2'-O-ethyl-O-methyl, or 2'-O-allyl; The linker modification between the nucleotides is selected from phosphate thioesters (PS), dithiophosphates (PS2), methylphosphates (MP), methoxypropyl phosphates (MOP), or aminophosphates; or, the linker modification between the nucleotides is selected from phosphate thioesters (PS); and / or The terminal modification is selected from 5'-terminal modification or 3'-terminal modification; or, the terminal modification is selected from 5'-phosphate, 5'-methylphosphate (5'-MP), 5'-thiophosphate (5'-PS) or 5'-(E)-vinylphosphate (5'-(E)-VP).

12. The double-stranded ribonucleic acid, its pharmaceutically acceptable salt, or its ligand conjugate according to any one of claims 1-11, wherein, The first and second nucleotides of the sense strand and / or the second and third nucleotides of the sense strand are modified with thiophosphate groups, and the first and second nucleotides of the antisense strand, the second and third nucleotides of the antisense strand, the 19th and 20th nucleotides of the antisense strand and / or the 20th and 21st nucleotides of the antisense strand are modified with thiophosphate groups.

13. The double-stranded ribonucleic acid, its pharmaceutically acceptable salt, or its ligand conjugate according to any one of claims 1-12, wherein, The positive strand has 2, 3, 4 or 5 nucleotides modified with 2'-fluorination, and the positive strand has 14, 15, 16, 17, 18 or 19 nucleotides modified with 2'-O-methyl; and / or; The antisense strand has 2, 3, 4, 5, 6 or 7 nucleotides modified with 2'-fluorination, and the antisense strand has 14, 15, 16, 17, 18, 19, 20 or 21 nucleotides modified with 2'-O-methyl.

14. The double-stranded ribonucleic acid, its pharmaceutically acceptable salt, or its ligand conjugate according to any one of claims 1-13, wherein, The positive strand contains 0, 1, or 2 nucleotides at positions 1 to 6 with 2'-fluorination; 4, 5, or 6 nucleotides at positions 1 to 6 with 2'-O-methylation; 2 or 3 nucleotides at positions 7 to 9 with 2'-fluorination; 0 or 1 nucleotide at positions 7 to 9 with 2'-O-methylation; 0 or 1 nucleotide at positions 10 to 19 or 10 to 21 with 2'-fluorination; or 8, 9, 10, 11, or 12 nucleotides at positions 10 to 19 or 10 to 21 with 2'-O-methylation; or The 7th, 8th, and 9th nucleotides of the positive strand are 2'-fluorinated, and 0, 1, or 2 nucleotides of the 1st to 6th and / or 10th to 19th or 10th to 21st nucleotides of the positive strand are also 2'-fluorinated; or The 7th, 8th and 9th nucleotides of the positive strand are 2'-fluorinated, and 0 or 1 nucleotides of the 1st to 6th and / or 10th to 19th or 10th to 21st nucleotides of the positive strand are also 2'-fluorinated.

15. The double-stranded ribonucleic acid, its pharmaceutically acceptable salt, or its ligand conjugate according to any one of claims 1-14, wherein, The antisense strand has three or four nucleotides at positions 2, 6, 14, and 16 modified with 2'-fluorination; or The antisense strand has 3, 4, 5, or 6 nucleotides at positions 2, 6, 8, 9, 14, and 16 that are 2'-fluorinated; or The nucleotides at positions 2, 6, 14, and 16 of the antisense strand are 2'-fluorinated, and any one or two of the nucleotides at positions 1, 3 to 5, 7 to 13, 15, and / or 17 to 21 and / or 17 to 23 of the antisense strand are also 2'-fluorinated; or The antisense strand has 14, 15, 16, 17, 18, or 19 nucleotides at positions 1, 3 to 5, 7, 10 to 13, 15, 17 to 21, and / or 17 to 23 modified with 2'-O-methyl.

16. The double-stranded ribonucleic acid, its pharmaceutically acceptable salt, or its ligand conjugate according to any one of claims 1-15, wherein, The ligand in the ligand conjugate contains at least one targeting group; or the ligand in the ligand conjugate contains one, two, three, four or five targeting groups.

17. The double-stranded ribonucleic acid, its pharmaceutically acceptable salt, or its ligand conjugate according to claim 16, wherein, The targeting group is the GalNAc group.

18. The double-stranded ribonucleic acid, its pharmaceutically acceptable salt, or its ligand conjugate according to any one of claims 1-17, wherein, The ligands in the ligand conjugate include the following branched groups:

19. The double-stranded ribonucleic acid, its pharmaceutically acceptable salt, or its ligand conjugate according to any one of claims 1-18, wherein, The ligands in the ligand conjugate are selected from:

20. The double-stranded ribonucleic acid, its pharmaceutically acceptable salt, or its ligand conjugate according to any one of claims 1-19, wherein, The ligand in the ligand conjugate is attached to the 5' or 3' end of the sense or antisense strand; or, the ligand in the ligand conjugate is attached to the 5' or 3' end of the sense strand; or, the ligand in the ligand conjugate is attached to the 3' end of the sense strand.

21. The double-stranded ribonucleic acid, its pharmaceutically acceptable salt, or its ligand conjugate according to any one of claims 1-20, wherein, The double-stranded ribonucleic acid comprises any one of the following sense strands: SEQ ID NO:1, SEQ ID NO:3, SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:11, SEQ ID NO:13, SEQ ID NO:15, SEQ ID NO:17, SEQ ID NO:19, SEQ ID NO:21, SEQ ID NO:23, SEQ ID NO:25, SEQ ID NO:27, SEQ ID NO:29, SEQ ID NO:31, SEQ ID NO:33, SEQ ID NO:35, SEQ ID NO:37, SEQ ID NO:39, SEQ ID NO:41, SEQ ID NO:43, SEQ ID NO:45, SEQ ID NO:47, SEQ ID NO:49, SEQ ID NO:51, SEQ ID NO:53, SEQ ID NO:55, SEQ ID NO:57, SEQ ID NO:59, SEQ ID NO:61, SEQ ID NO:63, SEQ ID NO:65, SEQ ID NO:67, SEQ ID NO:69, SEQ ID NO:71, SEQ ID NO:73, SEQ ID NO:75, SEQ ID NO:77, SEQ ID NO:79, SEQ ID NO:81, SEQ ID NO:83, SEQ ID NO:85, SEQ ID NO:87, SEQ ID NO:89, SEQ ID NO:91, SEQ ID NO:93, SEQ ID NO:95, SEQ ID NO:97, SEQ ID NO:99, SEQ ID NO:101, SEQ ID NO:103, SEQ ID NO:105, SEQ ID NO:107, SEQ ID NO:109, SEQ ID NO:111, SEQ ID NO:113, SEQ ID NO:115, SEQ ID NO:117, SEQ ID NO:119, SEQ ID NO:121, SEQ ID NO:123, SEQ ID NO:125, SEQ ID NO:127, SEQ ID NO:129, SEQ ID NO:131, SEQ ID NO:133, SEQ ID NO:135, SEQ ID NO:137, SEQ ID NO:139, SEQ ID NO:141, SEQ ID NO:143, SEQ ID NO:145, SEQ IDNO:147、SEQ ID NO:149、SEQ ID NO:151、SEQ ID NO:153、SEQ ID NO:155、SEQ ID NO:157、SEQ ID NO:159、SEQ ID NO:161、SEQ ID NO:163、SEQ ID NO:165、SEQ ID NO:167、SEQ ID NO:169、SEQ ID NO:171、SEQ ID NO:173、SEQ ID NO:175、SEQ ID NO:177、SEQ ID NO:179、SEQ ID NO:181、SEQ ID NO:183、SEQ ID NO:185、SEQ ID NO:187、SEQ ID NO:189、SEQ ID NO:191、SEQ ID NO:193、SEQ ID NO:195、SEQ ID NO:197、SEQ ID NO:199、SEQ ID NO:201、SEQ ID NO:203、SEQ ID NO:205、SEQ ID NO:207、SEQ ID NO:209、SEQ ID NO:211、SEQ ID NO:213、SEQ ID NO:215、SEQ ID NO:217、SEQ ID NO:219、SEQ ID NO:221、SEQ ID NO:223、SEQ ID NO:225、SEQ ID NO:227、SEQ ID NO:229、SEQ ID NO:231、SEQ ID NO:233、SEQ ID NO:235、SEQ ID NO:237、SEQ ID NO:239、SEQ ID NO:241、SEQ ID NO:243、SEQ ID NO:245、SEQ ID NO:247、SEQ ID NO:249、SEQ ID NO:251、SEQ ID NO:253、SEQ ID NO:255、SEQ ID NO:257、SEQ ID NO:259、SEQ ID NO:261、SEQ ID NO:263、SEQ ID NO:265、SEQ ID NO:267、SEQ ID NO:269、SEQ ID NO:271、SEQ ID NO:273、SEQ ID NO:275、SEQ ID NO:277、SEQ ID NO:279、SEQ ID NO:281、SEQ ID NO:283、SEQ ID NO:285、SEQ ID NO:287、SEQ IDNO: 289, SEQ ID NO: 291, SEQ ID NO: 293, SEQ ID NO: 295, SEQ ID NO: 297, SEQ ID NO: 299, SEQ ID NO: 301, SEQ ID NO: 303, SEQ ID NO: 305, SEQ ID NO: 307, SEQ ID NO: 309 or SEQ ID NO: 311; and The double-stranded ribonucleic acid comprises any one of the following antisense strands: SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, SEQ ID NO:18, SEQ ID NO:20, SEQ ID NO:22, SEQ ID NO:24, SEQ ID NO:26, SEQ ID NO:28, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:34, SEQ ID NO:36, SEQ ID NO:38, SEQ ID NO:40, SEQ ID NO:42, SEQ ID NO:44, SEQ ID NO:46, SEQ ID NO:48, SEQ ID NO:50, SEQ ID NO:52, SEQ ID NO:54, SEQ ID NO:56, SEQ ID NO:58, SEQ ID NO:60, SEQ ID NO:62, SEQ ID NO:64, SEQ ID NO:66, SEQ ID NO:68, SEQ ID NO:70, SEQ ID NO:72, SEQ ID NO:74, SEQ ID NO:76, SEQ ID NO:78, SEQ ID NO:80, SEQ ID NO:82, SEQ ID NO:84, SEQ ID NO:86, SEQ ID NO:88, SEQ ID NO:90, SEQ ID NO:92, SEQ ID NO:94, SEQ ID NO:96, SEQ ID NO:98, SEQ ID NO:100, SEQ ID NO:102, SEQ ID NO:104, SEQ ID NO:106, SEQ ID NO:108, SEQ ID NO:110, SEQ ID NO:112, SEQ ID NO:114, SEQ ID NO:116, SEQ ID NO:118, SEQ ID NO:120, SEQ ID NO:122, SEQ ID NO:124, SEQ ID NO:126, SEQ ID NO:128, SEQ ID NO:130, SEQ ID NO:132, SEQ ID NO:134, SEQ ID NO:136, SEQ ID NO:138, SEQ ID NO:140, SEQ ID NO:142, SEQ ID NO:144, SEQ ID NO:146, SEQ IDNO:148、SEQ ID NO:150、SEQ ID NO:152、SEQ ID NO:154、SEQ ID NO:156、SEQ ID NO:158、SEQ ID NO:160、SEQ ID NO:162、SEQ ID NO:164、SEQ ID NO:166、SEQ ID NO:168、SEQ ID NO:170、SEQ ID NO:172、SEQ ID NO:174、SEQ ID NO:176、SEQ ID NO:178、SEQ ID NO:180、SEQ ID NO:182、SEQ ID NO:184、SEQ ID NO:186、SEQ ID NO:188、SEQ ID NO:190、SEQ ID NO:192、SEQ ID NO:194、SEQ ID NO:196、SEQ ID NO:198、SEQ ID NO:200、SEQ ID NO:202、SEQ ID NO:204、SEQ ID NO:206、SEQ ID NO:208、SEQ ID NO:210、SEQ ID NO:212、SEQ ID NO:214、SEQ ID NO:216、SEQ ID NO:218、SEQ ID NO:220、SEQ ID NO:222、SEQ ID NO:224、SEQ ID NO:226、SEQ ID NO:228、SEQ ID NO:230、SEQ ID NO:232、SEQ ID NO:234、SEQ ID NO:236、SEQ ID NO:238、SEQ ID NO:240、SEQ ID NO:242、SEQ ID NO:244、SEQ ID NO:246、SEQ ID NO:248、SEQ ID NO:250、SEQ ID NO:252、SEQ ID NO:254、SEQ ID NO:256、SEQ ID NO:258、SEQ ID NO:260、SEQ ID NO:262、SEQ ID NO:264、SEQ ID NO:266、SEQ ID NO:268、SEQ ID NO:270、SEQ ID NO:272、SEQ ID NO:274、SEQ ID NO:276、SEQ ID NO:278、SEQ ID NO:280、SEQ ID NO:282、SEQ ID NO:284、SEQ ID NO:286、SEQ ID NO:288、SEQ IDNO: 290, SEQ ID NO: 292, SEQ ID NO: 294, SEQ ID NO: 296, SEQ ID NO: 298, SEQ ID NO: 300, SEQ ID NO: 302, SEQ ID NO: 304, SEQ ID NO: 306, SEQ ID NO: 308, SEQ ID NO: 310 or SEQ ID NO:

312.

22. The double-stranded ribonucleic acid, its pharmaceutically acceptable salt, or its ligand conjugate according to any one of claims 1-21, wherein, The double-stranded ribonucleic acid contains the following sequence pairs of sense strand and antisense strand: SEQ ID NO:1 / SEQ ID NO:2, SEQ ID NO:3 / SEQ ID NO:4, SEQ ID NO:5 / SEQ ID NO:6, SEQ ID NO:7 / SEQ ID NO:8, SEQ ID NO:9 / SEQ ID NO:10, SEQ ID NO:11 / SEQ ID NO:12, SEQ ID NO:13 / SEQ ID NO:14, SEQ ID NO:15 / SEQ ID NO:16, SEQ ID NO:17 / SEQ ID NO:18, SEQ ID NO:19 / SEQ ID NO:20, SEQ ID NO:21 / SEQ ID NO:22, SEQ ID NO:23 / SEQ ID NO:24, SEQ ID NO:25 / SEQ ID NO:26, SEQ ID NO:27 / SEQ ID NO:28, SEQ ID NO:29 / SEQ ID NO:30, SEQ ID NO:31 / SEQ ID NO:32, SEQ ID NO:33 / SEQ ID NO:34, SEQ ID NO:35 / SEQ ID NO:36, SEQ ID NO:37 / SEQ ID NO:38, SEQ ID NO:39 / SEQ ID NO:40, SEQ ID NO:41 / SEQ ID NO:42, SEQ ID NO:43 / SEQ ID NO:44, SEQ ID NO:45 / SEQ ID NO:46, SEQ ID NO:47 / SEQ ID NO:48, SEQ ID NO:49 / SEQ ID NO:50, SEQ ID NO:51 / SEQ ID NO:52, SEQ ID NO:53 / SEQ ID NO:54, SEQ ID NO:55 / SEQ ID NO:56, SEQ ID NO:57 / SEQ ID NO:58, SEQ ID NO:59 / SEQ ID NO:60, SEQ ID NO:61 / SEQ ID NO:62, SEQ ID NO:63 / SEQ ID NO:64, SEQ ID NO:65 / SEQ ID NO:66, SEQ ID NO:67 / SEQ ID NO:68, SEQ ID NO:69 / SEQ ID NO:7, SEQ ID NO:71 / SEQ ID NO:72, SEQ ID NO:73 / SEQ ID NO:74, SEQ ID NO:75 / SEQNO:76、SEQ ID NO:77 / SEQ ID NO:78、SEQ ID NO:79 / SEQ ID NO:80、SEQ ID NO:81 / SEQ ID NO:82、SEQ ID NO:83 / SEQ ID NO:84、SEQ ID NO:85 / SEQ ID NO:86、SEQ ID NO:87 / SEQ ID NO:88、SEQ ID NO:89 / SEQ ID NO:90、SEQ ID NO:91 / SEQ ID NO:92、SEQ ID NO:93 / SEQ ID NO:94、SEQ ID NO:95 / SEQ ID NO:96、SEQ ID NO:97 / SEQ ID NO:98、SEQ ID NO:99 / SEQ ID NO:100、SEQ ID NO:101 / SEQ ID NO:102、SEQ ID NO:103 / SEQ ID NO:104、SEQ ID NO:105 / SEQ ID NO:106、SEQ ID NO:107 / SEQ ID NO:108、SEQ ID NO:109 / SEQ ID NO:110、SEQ ID NO:111 / SEQ ID NO:112、SEQ ID NO:113 / SEQ ID NO:114、SEQ ID NO:115 / SEQ ID NO:116、SEQ ID NO:117 / SEQ ID NO:118、SEQ ID NO:119 / SEQ ID NO:120、SEQ ID NO:121 / SEQ ID NO:122、SEQ ID NO:123 / SEQ ID NO:124、SEQ ID NO:125 / SEQ ID NO:126、SEQ ID NO:127 / SEQ ID NO:128、SEQ ID NO:129 / SEQ ID NO:130、SEQ ID NO:131 / SEQ ID NO:132、SEQ ID NO:133 / SEQ ID NO:134、SEQ ID NO:135 / SEQ ID NO:136、SEQ ID NO:137 / SEQ ID NO:138、SEQ ID NO:139 / SEQ ID NO:140、SEQ ID NO:141 / SEQ ID NO:142、SEQ ID NO:143 / SEQ ID NO:144、SEQ ID NO:145 / SEQ ID NO:146、SEQ ID NO:147 / SEQ ID NO:148、SEQ IDNO:149 / SEQ ID NO:150、SEQ ID NO:151 / SEQ ID NO:152、SEQ ID NO:153 / SEQ ID NO:154、SEQ ID NO:155 / SEQ ID NO:156、SEQ ID NO:157 / SEQ ID NO:158、SEQ ID NO:159 / SEQ ID NO:160、SEQ ID NO:161 / SEQ ID NO:162、SEQ ID NO:163 / SEQ ID NO:164、SEQ ID NO:165 / SEQ ID NO:166、SEQ ID NO:167 / SEQ ID NO:168、SEQ ID NO:169 / SEQ ID NO:170、SEQ ID NO:171 / SEQ ID NO:172、SEQ ID NO:173 / SEQ ID NO:174、SEQ ID NO:175 / SEQ ID NO:176、SEQ ID NO:177 / SEQ ID NO:178、SEQ ID NO:179 / SEQ ID NO:180、SEQ ID NO:181 / SEQ ID NO:182、SEQ ID NO:183 / SEQ ID NO:184、SEQ ID NO:185 / SEQ ID NO:186、SEQ ID NO:187 / SEQ ID NO:188、SEQ ID NO:189 / SEQ ID NO:190、SEQ ID NO:191 / SEQ ID NO:192、SEQ ID NO:193 / SEQ ID NO:194、SEQ ID NO:195 / SEQ ID NO:196、SEQ ID NO:197 / SEQ ID NO:198、SEQ ID NO:199 / SEQ ID NO:200、SEQ ID NO:201 / SEQ ID NO:202、SEQ ID NO:203 / SEQ ID NO:204、SEQ ID NO:205 / SEQ ID NO:206、SEQ ID NO:207 / SEQ ID NO:208、SEQ ID NO:209 / SEQ ID NO:210、SEQ ID NO:211 / SEQ ID NO:212、SEQ ID NO:213 / SEQ ID NO:214、SEQ ID NO:215 / SEQ ID NO:216、SEQ ID NO:217 / SEQ ID NO:218、SEQ ID NO:219 / SEQ IDNO:220、SEQ ID NO:221 / SEQ ID NO:222、SEQ ID NO:223 / SEQ ID NO:224、SEQ ID NO:225 / SEQ ID NO:226、SEQ ID NO:227 / SEQ ID NO:228、SEQ ID NO:229 / SEQ ID NO:230、SEQ ID NO:231 / SEQ ID NO:232、SEQ ID NO:233 / SEQ ID NO:234、SEQ ID NO:235 / SEQ ID NO:236、SEQ ID NO:237 / SEQ ID NO:238、SEQ ID NO:239 / SEQ ID NO:240、SEQ ID NO:241 / SEQ ID NO:242、SEQ ID NO:243 / SEQ ID NO:244、SEQ ID NO:245 / SEQ ID NO:246、SEQ ID NO:247 / SEQ ID NO:248、SEQ ID NO:249 / SEQ ID NO:250、SEQ ID NO:251 / SEQ ID NO:252、SEQ ID NO:253 / SEQ ID NO:254、SEQ ID NO:255 / SEQ ID NO:256、SEQ ID NO:257 / SEQ ID NO:258、SEQ ID NO:259 / SEQ ID NO:260、SEQ ID NO:261 / SEQ ID NO:262、SEQ ID NO:263 / SEQ ID NO:264、SEQ ID NO:265 / SEQ ID NO:266、SEQ ID NO:267 / SEQ ID NO:268、SEQ ID NO:269 / SEQ ID NO:270、SEQ ID NO:271 / SEQ ID NO:272、SEQ ID NO:273 / SEQ ID NO:274、SEQ ID NO:275 / SEQ ID NO:276、SEQ ID NO:277 / SEQ ID NO:278、SEQ ID NO:279 / SEQ ID NO:280、SEQ ID NO:281 / SEQ ID NO:282、SEQ ID NO:283 / SEQ ID NO:284、SEQ ID NO:285 / SEQ ID NO:286、SEQ ID NO:287 / SEQ ID NO:288、SEQ ID NO:289 / SEQ ID NO:290、SEQ IDNO: 291 / SEQ ID NO: 292, SEQ ID NO: 293 / SEQ ID NO: 294, SEQ ID NO: 295 / SEQ ID NO: 296, SEQ ID NO: 297 / SEQ ID NO: 298, SEQ ID NO: 299 / SEQ ID NO: 300, SEQ ID NO: 301 / SEQ ID NO: 302, SEQ ID NO: 303 / SEQ ID NO: 304, SEQ ID NO: 305 / SEQ ID NO: 306, SEQ ID NO: 307 / SEQ ID NO: 308, SEQ ID NO: 309 / SEQ ID NO: 310 or SEQ ID NO: 311 / SEQ ID NO:

312.

23. The double-stranded ribonucleic acid according to any one of claims 1-22, its pharmaceutically acceptable salt, or its ligand conjugate, wherein the ribonucleic acid is selected from: in, The L represents a ligand, which is selected from L01 ligand or L02 ligand.

24. A pharmaceutical composition comprising a double-stranded ribonucleic acid according to any one of claims 1-23, a pharmaceutically acceptable salt thereof, or a ligand conjugate thereof, optionally comprising a pharmaceutically acceptable carrier or excipient.

25. Use of the double-stranded ribonucleic acid of any one of claims 1-23, a pharmaceutically acceptable salt thereof, or a ligand conjugate thereof, or the pharmaceutical composition of claim 24 in the preparation of a medicament for treating and / or preventing SERPINC1-mediated diseases; optionally, the SERPINC1-mediated diseases include bleeding disorders; optionally, the SERPINC1-mediated diseases are hemophilia.

26. The use according to claim 25, wherein, The double-stranded ribonucleic acid, its pharmaceutically acceptable salt or its ligand conjugate, or the pharmaceutical composition may be used in combination with other therapeutic agents.

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