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WO2023227070A1 - Acide ribonucléique double brin pour l'inhibition de l'expression du gène c3 et modificateur, conjugué et son utilisation - Google Patents

Acide ribonucléique double brin pour l'inhibition de l'expression du gène c3 et modificateur, conjugué et son utilisation Download PDF

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Publication number
WO2023227070A1
WO2023227070A1 PCT/CN2023/096337 CN2023096337W WO2023227070A1 WO 2023227070 A1 WO2023227070 A1 WO 2023227070A1 CN 2023096337 W CN2023096337 W CN 2023096337W WO 2023227070 A1 WO2023227070 A1 WO 2023227070A1
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seq
nucleotide sequence
sequence shown
strand includes
antisense strand
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Chinese (zh)
Inventor
王书成
黄河
刘薇
王岩
林国良
汪小君
荣梅
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Beijing Foyou Pharmaceutical Co Ltd
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Beijing Winsunny Pharmaceutical Co Ltd
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    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
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    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
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    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/10—Type of nucleic acid
    • C12N2310/14—Type of nucleic acid interfering nucleic acids [NA]
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    • C12N2310/00—Structure or type of the nucleic acid
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    • C12N2310/32—Chemical structure of the sugar
    • C12N2310/321—2'-O-R Modification
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    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/32—Chemical structure of the sugar
    • C12N2310/322—2'-R Modification

Definitions

  • the present disclosure belongs to the field of biomedicine. Specifically, the present disclosure relates to a double-stranded ribonucleic acid, a double-stranded ribonucleic acid modification, a double-stranded ribonucleic acid conjugate, a pharmaceutical composition and uses for inhibiting C3 gene expression, and Methods for inhibiting intracellular C3 gene expression.
  • Complement is a group of heat-labile proteins that exist in the serum and tissue fluid of humans and animals, have enzymatic activity after activation, and can mediate immune responses and inflammatory responses. After the complement system is activated, it mediates a series of cellular reactions, such as cell lysis, opsonophagocytosis (antigen-antibody binding), inflammatory response, clearance of immune complexes, etc.
  • the complement system is mainly composed of more than 30 types of glycoproteins such as intrinsic components, regulatory proteins and receptors. These proteins exist as soluble proteins in the blood or as membrane-associated proteins.
  • complement activation pathway Activation of complement causes a sequential cascade of enzymatic reactions (called the complement activation pathway), leading to the formation of the potent anaphylatoxins C3a and C5a, which induce a variety of physiological responses ranging from chemical attraction to apoptosis .
  • Complement activation is known to occur through three different pathways: the alternative pathway, the classical pathway, and the lectin pathway, involving proteins that exist primarily as inactive zymogens, which are then sequentially cleaved and activated.
  • the three pathways have different starting materials, but they intersect with each other and have a common terminal pathway.
  • the activation of the classical pathway begins with the binding of C1q to the Fc segment of the immune complex and relies on the production of specific antibodies, so it plays a role in the late infection or recovery period.
  • the alternative pathway directly provides a reaction surface for spontaneously produced C3b to initiate activation when infected cells by bacteria, fungi or viruses do not require the presence of antibodies, so it plays a role in the early stages of infection or the first infection before antibodies are produced.
  • the lectin pathway can also activate complement without the involvement of antibodies. Its activation substances are very wide, mainly MBL or fibrillar collagen that directly recognize N-galactosamine or mannose on the surface of pathogenic microorganisms. In addition to the recognition mechanism being different from the classic pathway, its subsequent The activation pathways are basically the same, with cross-promoting effects on the classical and alternative pathways.
  • the three complement activation pathways merge into a common terminal pathway at the C3 link to form C5 convertase, which activates C5 to cleave into C5a and C5b.
  • C5b binds to the cell surface and sequentially combines with C6, C7, C8 and 12 to 15 C9 molecules to form C5b6789n, the membrane attack complex (MAC), which mediates the cell lysis effect.
  • MAC membrane attack complex
  • Inappropriate activation of the complement system is responsible for proliferation and/or initiating pathology in many diseases, including, for example, paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, rheumatoid arthritis inflammation, chronic kidney disease, ischemia-reperfusion injury, and neurodegenerative diseases.
  • C3 complement inhibitors are a promising treatment method.
  • the US FDA approved Apellis Pharmaceuticals' Empaveli a synthetic cyclic peptide for the treatment of newly treated paroxysmal nocturnal hemoglobinuria (PNH).
  • PNH paroxysmal nocturnal hemoglobinuria
  • the present disclosure aims to provide a series of double-stranded ribonucleic acid, double-stranded ribonucleic acid modifications, double-stranded ribonucleic acid conjugates and pharmaceutical compositions for inhibiting complement C3 gene expression, which can inhibit C3 gene expression and be used in clinical disease treatment. It has important application prospects.
  • a double-stranded ribonucleic acid the double-stranded ribonucleic acid includes a sense strand and an antisense strand, the sense strand is complementary and/or substantially reverse complementary to the antisense strand to form the double-stranded ribonucleic acid
  • the sense strand includes a sequence A that differs from at least 15 consecutive nucleotides in the target sequence by no more than 3 nucleotides
  • the antisense strand includes a sequence A that differs from at least 15 consecutive nucleotides in the target sequence.
  • Sequence B that differs from the complementary sequence by no more than 3 nucleotides;
  • the target sequence is selected from the nucleotide sequence shown in any one of SEQ ID NO: 1-7.
  • a reverse complementary and/or substantially reverse complementary sequence B consisting of at least 15 consecutive nucleotides in the nucleotide sequence shown in any one of SEQ ID NO:364.
  • nucleotide sequence of the sense strand is the nucleotide sequence shown in any one of SEQ ID NO: 8-34 and SEQ ID NO: 364 Sequence A consisting of 15-28 consecutive nucleotides in the sequence is preferably 19-25 consecutive nucleotides, more preferably 19-23 consecutive nucleotides, and more preferably 19, 21 or 23 nucleotides.
  • [5] The double-stranded ribonucleic acid according to any one of [1]-[4], wherein the antisense strand consists of 15-28 nucleotides, preferably 19-25 nucleotides, more Preferred are 19-23 nucleotides, more preferably 19, 21 or 23 nucleotides.
  • the double-stranded ribonucleic acid according to any one of [1]-[6], wherein the length of the double-stranded region is 15-25 nucleotides, preferably 19-23 nucleotides, More preferably 19-21 nucleotides, more preferably 19, 21 or 23 nucleotides.
  • the sense strand and the antisense strand are complementary to form the double-stranded region, and the 3' end of the sense strand has 1-2 protruding nucleotides extending out of the double-stranded region, and the antisense strand is complementary to the double-stranded region.
  • the 3' end of the chain forms a blunt end; or,
  • the sense strand and the antisense strand are complementary to form the double-stranded region, and the 3' end of the antisense strand has 1-2 protruding nucleotides extending out of the double-stranded region, and the sense strand The 3' end of the chain forms a blunt end; or,
  • the sense strand and the antisense strand are complementary to form the double-stranded region, and the 3' ends of the sense strand and the antisense strand each have 1-2 protruding cores extending out of the double-stranded region. glycoside; or,
  • the sense strand and the antisense strand are complementary to form the double-stranded region, and the 3' ends of the sense strand and the antisense strand both form blunt ends.
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:35, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:131;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:36, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:132;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:37, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:133;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:38, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:134;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:39, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:135;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:40, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:136;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:41, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:137;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:42, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:138;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:43, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:139;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:44, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:140;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:45, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:141;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:46, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:142;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:47, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:143;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:48, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:144;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:49, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:145;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:50, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:146;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:51, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:147;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:52, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:148;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:53, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:149;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:54, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:150;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:55, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:151;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:56, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:152;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:57, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:153;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:58, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:154;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:59, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:155;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:60, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:156;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:61, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:157;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:62, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:158;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:63
  • the antisense strand includes the nucleotide sequence shown in SEQ ID NO:63
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:64, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:160;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:65, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:161;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:66, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:162;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO: 67, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO: 163;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:68, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:164;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:69, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:165;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:70, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:166;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:71, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:167;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:72, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:168;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:73, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:169;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:74, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:170;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:75, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:171;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:76, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:172;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:77, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:173;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:78, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:174;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:79, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:175;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:80, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:176;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:81, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:177;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:82, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:178;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:83, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:179;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:84, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:180;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:85, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:181;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:86, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:182;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:87, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:183;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:88, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:184;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:89, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:185;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:90, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:186;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:91, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:187;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:92, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:188;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:93, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:189;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:94, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:190;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:95, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:191;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:96, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:192;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:97, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:193;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:98, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:194;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:99, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:195;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:100, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:196;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:101, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:197;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:102, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:198;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:103, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:199;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:104, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:200;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:105, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:201;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:106, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:202;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:107, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:203;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:108, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO.
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:109, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:205;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:110, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:206;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:111, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:207;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:112, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:208;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:113, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:209;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:114, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:210;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:115, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:211;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:116, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:212;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:117, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:213;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:118, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:214;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:119, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:215;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:120, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:216;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:121, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:217;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:122, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:218;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:123, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:219;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:124, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:220;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:125, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:221;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:126, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:222;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:127, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:223;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:128, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:224;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:129, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:225;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:328, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:346;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:329, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:347;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:330, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:348;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:331, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:349;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:332, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:350;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:333, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:351;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:334, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:352;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:335, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:353;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:336, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:354;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:337, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:355;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:338, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:356;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:339, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:357;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:340, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:358;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:341, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:359;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:342, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:360;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:343, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:361;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:344, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:362;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:345, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:363.
  • each nucleotide in the sense strand is independently a modified nucleotide or an unmodified nucleoside. acid, and/or, each nucleotide in the antisense strand is independently a modified nucleotide or an unmodified nucleotide.
  • a double-stranded ribonucleic acid modification which is a double-stranded ribonucleic acid modification as described in any one of [1]-[14], and the double-stranded ribonucleic acid modification includes at least one of the following Chemical modification:
  • sequence A in the sense strand of the double-stranded ribonucleic acid is connected to sequence D consisting of 1-2 nucleotides, preferably a sequence consisting of 1-2 thymidine deoxyribonucleotides D; and/or, the 3' end of sequence B in the antisense strand of the double-stranded ribonucleic acid is connected to sequence E consisting of 1-2 nucleotides, preferably 1-2 thymidine deoxyribonucleotides Sequence E consisting of; and/or sequence A' is formed after excluding 1-2 nucleotides from the 3' end of sequence A in the sense strand of the double-stranded ribonucleic acid;
  • the sense strand and antisense strand of the double-stranded ribonucleic acid modification are selected from the following sequence combinations:
  • nucleotide sequence of the sense strand is the sequence shown in sequence A, and the nucleotide sequence of the antisense strand is the sequence shown in sequence B;
  • nucleotide sequence of the sense strand is the sequence shown in sequence A
  • nucleotide sequence of the antisense strand is the sequence shown in sequence B connected to sequence E;
  • nucleotide sequence of the sense strand is the sequence shown in sequence A connected to sequence D, and the nucleotide sequence of the antisense strand is the sequence shown in sequence B;
  • nucleotide sequence of the sense strand is the sequence shown in sequence A connected to sequence D
  • nucleotide sequence of the antisense strand is the sequence shown in sequence B connected to sequence E;
  • nucleotide sequence of the sense strand is the sequence shown in sequence A'
  • nucleotide sequence of the antisense strand is the sequence shown in sequence B;
  • nucleotide sequence of the sense strand is the sequence represented by sequence A'
  • nucleotide sequence of the antisense strand is the sequence represented by sequence B connected to sequence E.
  • nucleotide derivative in the nucleotide derivative modification is selected from the group consisting of isonucleotides, LNA, ENA, cET, UNA or GNA.
  • the sense strand contains phosphorothioate diester bonds at the positions shown below:
  • the ribonucleotides at positions 2, 6, 14 and 16 in the antisense strand are 2'-F modified ribonucleotides,
  • the remaining ribonucleotides in the antisense strand are 2'-O-CH 3 modified ribonucleotides;
  • the ribonucleotides at positions 2, 6, 8, 9, 14 and 16 in the antisense strand are 2'- F-modified ribonucleotides, the remaining ribonucleotides in the antisense strand are 2'-O-CH 3 modified ribonucleotides;
  • the ribonucleotides at positions 2, 14 and 16 in the antisense strand are 2'-F modified ribonucleotides, and the antisense strand
  • the ribonucleotide at position 6 in the chain is a ribonucleotide modified by the nucleotide derivative GNA, and the ribonucleotides at the remaining positions in the antisense chain are ribonucleotides modified by 2'-O-CH 3 acid;
  • the ribonucleotides at positions 2, 6, 14 and 16 in the antisense strand are 2'-F modified ribonucleotides
  • the ribonucleotide at position 7 in the antisense strand is a ribonucleotide modified by the nucleotide derivative GNA, and the ribonucleotides at the remaining positions in the antisense strand are modified with 2'-O-CH 3 of ribonucleotides.
  • N 1 -N 23 are independently selected from ribonucleotides whose bases are A, U, C or G,
  • T stands for deoxyribonucleotide whose base is thymine.
  • the lowercase letter m indicates that the ribonucleotide adjacent to the right side of the letter m is a 2'-O-CH 3 modified ribonucleotide.
  • the lowercase letter f indicates that the ribonucleotide adjacent to the left side of the letter f is a 2’-F modified ribonucleotide.
  • -(s)- indicates that two adjacent nucleotides are connected by a phosphorothioate diester bond.
  • N 1 -N 23 are independently selected from ribonucleotides whose bases are A, U, C or G,
  • T stands for deoxyribonucleotide whose base is thymine.
  • the lowercase letter m indicates that the ribonucleotide adjacent to the right side of the letter m is a 2'-O-CH 3 modified ribonucleotide.
  • the lowercase letter f indicates that the ribonucleotide adjacent to the left side of the letter f is a 2’-F modified ribonucleotide.
  • P1 indicates that the nucleotide adjacent to the right side of the letter is a 5’-phosphate nucleotide
  • -(s)- means that two adjacent nucleotides are connected by a phosphorothioate diester bond
  • GNA indicates that the ribonucleotide adjacent to the right side is a ribonucleotide modified with GNA.
  • the double-stranded ribonucleic acid modified product according to any one of [15] to [25], wherein the double-stranded ribonucleic acid modified product is an siRNA modified product.
  • the double-stranded ribonucleic acid modification according to any one of [15] to [26], wherein the double-stranded ribonucleic acid modification is an siRNA modification for inhibiting C3 gene expression.
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:227, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:242;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:228, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:243;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:229, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:244;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:230, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:245;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:231, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:246;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:232, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:247;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:233, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:248;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:234, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:249;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:235, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:250;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:236, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:251;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:237, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:252;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:238, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:253;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:239, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:254;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:240, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:255;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:241, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:256;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:263, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:260;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:264, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:261;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:265, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:262;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:266, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:283;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:263, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:283;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:266, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:284;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:266, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:285;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:266, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:286;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:236, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:287;
  • the sense strand comprises the nucleotide sequence shown in SEQ ID NO:267
  • the antisense strand comprises the nucleotide sequence shown in SEQ ID NO:267
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:236, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:288;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:236, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:289;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:236, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:290;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:228, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:291;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:264, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:291;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:228, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:292;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:228, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:293;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:228, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:294;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:238, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:295;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:265, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:295;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:238, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:296;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:238, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:297;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:238, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:298;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:268, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:299;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:269, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:299;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:268, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:300;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:268, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:301;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:268, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:302;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:270, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:303;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:271, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:303;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:270, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:304;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:270, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:305;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:270, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:306;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:272, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:307;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:273, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:307;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:272, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:308;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:272, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:309;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:272, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:310;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:274, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:311;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:267, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:311;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:274, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:312;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:274, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:313;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:274, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:314;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:275, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:315;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:276, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:316;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:277, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:317;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:278, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:318;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:279, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:319;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:280, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:320;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:281, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:321;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:282, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:322.
  • a double-stranded ribonucleic acid conjugate wherein the double-stranded ribonucleic acid conjugate includes the double-stranded ribonucleic acid as described in any one of [1]-[14], or as [15] - The double-stranded ribonucleic acid modification according to any one of [28]; and, a conjugation group connected to the double-stranded ribonucleic acid or the double-stranded ribonucleic acid modification.
  • the sense strand and the antisense strand of the double-stranded ribonucleic acid conjugate are complementary to form a double-stranded region of the double-stranded ribonucleic acid conjugate, and the 3' end of the sense strand forms a blunt end, and the The 3' end of the antisense strand has 1-2 protruding nucleotides extending out of the double-stranded region;
  • the sense strand and the antisense strand of the double-stranded ribonucleic acid conjugate are complementary to form the double-stranded region of the double-stranded ribonucleic acid conjugate, and the 3' end of the sense strand forms a blunt end, and the antisense strand The 3' end forms a blunt end.
  • the double helix structure is double-stranded ribonucleic acid or double-stranded ribonucleic acid modification.
  • the double-stranded ribonucleic acid conjugate according to any one of [29] to [34], wherein the double-stranded ribonucleic acid conjugate is an siRNA conjugate for inhibiting C3 gene expression.
  • the double-stranded ribonucleic acid conjugate according to any one of [29] to [35], wherein the double-stranded ribonucleic acid conjugate is composed of any siRNA shown in Table 1 conjugated to The double-stranded ribonucleic acid conjugate is formed by connecting any siRNA modification shown in Table 2 with a conjugating group;
  • the sense strand and antisense strand of the double-stranded ribonucleic acid are selected from the following combinations:
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:35, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:131;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:36, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:132;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:37
  • the antisense strand includes the nucleotide sequence shown in SEQ ID NO:37
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:38, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:134;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:39, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:135;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:40, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:136;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:41, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:137;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:42, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:138;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:43, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:139;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:44, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:140;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:45, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:141;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:46, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:142;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:47, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:143;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:48, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:144;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:49, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:145;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:50, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:146;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:51, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:147;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:52, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:148;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:53, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:149;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:54, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:150;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:55, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:151;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:56, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:152;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:57, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:153;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:58, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:154;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:59, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:155;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:60, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:156;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:61, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:157;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:62, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:158;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:63, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:159;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:64, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:160;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:65, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:161;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:66, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:162;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO: 67, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO: 163;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:68, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:164;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:69, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:165;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:70, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:166;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:71, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:167;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:72, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:168;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:73, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:169;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:74, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:170;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:75, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:171;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:76, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:172;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:77, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:173;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:78, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:174;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:79, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:175;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:80, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:176;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:81, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:177;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:82, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:82 The nucleotide sequence shown in NO:178;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:83, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:179;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:84, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:180;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:85, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:181;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:86, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:182;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:87, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:183;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:88, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:184;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:89, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:185;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:90, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:186;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:91, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:187;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:92, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:188;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:93, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:189;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:94, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:190;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:95, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:191;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:96, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:192;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:97, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:193;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:98, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:194;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:99, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:195;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:100, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:196;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:101, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:197;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:102, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:198;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:103, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:199;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:104, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:200;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:105, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:201;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:106, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:202;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:107, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:203;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:108, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:204;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:109, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:205;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:110, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:206;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:111, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:207;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:112, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:208;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:113, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:209;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:114, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:210;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:115, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:211;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:116, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:212;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:117, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:213;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:118, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:214;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:119, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:215;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:120, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:216;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:121, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:217;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:122, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:218;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:123, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:219;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:124, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:220;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:125, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:221;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:126, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:222;
  • the sense strand comprises the nucleotide sequence shown in SEQ ID NO:127
  • the antisense strand comprises the nucleotide sequence shown in SEQ ID NO:127
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:128, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:224;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:129, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:225;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:328, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:346;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:329, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:347;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:330, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:348;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:331, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:349;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:332, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:350;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:333, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:351;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:334, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:352;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:335, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:353;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:336, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:354;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:337, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:355;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:338, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:356;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:339, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:357;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:340, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:358;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:341, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:359;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:342, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:360;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:343, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:361;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:344, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:362;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:345, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:363;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:227, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:242;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:228, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:243;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:229, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:244;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:230, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:245;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:231, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:246;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:232, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:247;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:233, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:248;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:234, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:249;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:235, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:250;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:236, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:251;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:237, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:252;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:238, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:253;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:239, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:254;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:240, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:255;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:241, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:256;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:263, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:260;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:264, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:261;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:265, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:262;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:266, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:283;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:263, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:283;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:266, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:284;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:266, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:285;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:266, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:286;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:236, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:287;
  • the sense strand comprises the nucleotide sequence shown in SEQ ID NO:267
  • the antisense strand comprises the nucleotide sequence shown in SEQ ID NO:267
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:236, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:288;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:236, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:289;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:236, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:290;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:228, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:291;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:264, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:291;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:228, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:292;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:228, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:293;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:228, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:294;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:238, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:295;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:265, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:295;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:238, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:296;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:238, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:297;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:238, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:298;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:268, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:299;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:269, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:299;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:268, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:300;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:268, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:301;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:268, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:302;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:270, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:303;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:271, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:303;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:270, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:304;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:270, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:305;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:270, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:306;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:272, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:307;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:273, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:307;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:272, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:308;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:272, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:309;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:272, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:310;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:274, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:311;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:267, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:311;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:274, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:312;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:274, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:313;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:274, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:314;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:275, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:315;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:276, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:316;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:277, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:317;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:278, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:318;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:279, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:319;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:280, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:320;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:281, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:321;
  • the sense strand includes the nucleotide sequence shown in SEQ ID NO:282, and the antisense strand includes the nucleotide sequence shown in SEQ ID NO:322;
  • the sense strand connecting the conjugate group includes the sequence shown in SEQ ID NO:257
  • the antisense strand includes the sequence shown in SEQ ID NO:260 nucleotide sequence
  • the sense strand connecting the conjugate group includes the sequence shown in SEQ ID NO:258, and the antisense strand includes the core shown in SEQ ID NO:261 nucleotide sequence;
  • the sense strand connecting the conjugate group includes the sequence shown in SEQ ID NO:259, and the antisense strand includes the core shown in SEQ ID NO:262 nucleotide sequence;
  • the sense strand connecting the conjugate group includes SEQ ID NO: 257
  • the sequence shown, the antisense strand includes the nucleotide sequence shown in SEQ ID NO:283;
  • the sense strand connecting the conjugate group includes the sequence shown in SEQ ID NO:257, and the antisense strand includes the core shown in SEQ ID NO:284 nucleotide sequence;
  • the sense strand connecting the conjugate group includes the sequence shown in SEQ ID NO:257, and the antisense strand includes the core shown in SEQ ID NO:285 nucleotide sequence;
  • the sense strand connecting the conjugate group includes the sequence shown in SEQ ID NO:257, and the antisense strand includes the core shown in SEQ ID NO:286 nucleotide sequence;
  • the sense strand connecting the conjugate group includes the sequence shown in SEQ ID NO:323, and the antisense strand includes the core shown in SEQ ID NO:251 nucleotide sequence;
  • the sense strand connecting the conjugate group includes the sequence shown in SEQ ID NO:323, and the antisense strand includes the core shown in SEQ ID NO:287 nucleotide sequence;
  • the sense strand connecting the conjugate group includes the sequence shown in SEQ ID NO: 323, and the antisense strand includes the core shown in SEQ ID NO: 288 nucleotide sequence;
  • the sense strand connecting the conjugate group includes the sequence shown in SEQ ID NO:323, and the antisense strand includes the core shown in SEQ ID NO:289 nucleotide sequence;
  • the sense strand connecting the conjugate group includes the sequence shown in SEQ ID NO:323, and the antisense strand includes the core shown in SEQ ID NO:290 nucleotide sequence;
  • the sense strand connecting the conjugate group includes the sequence shown in SEQ ID NO:258, and the antisense strand includes the core shown in SEQ ID NO:291 nucleotide sequence;
  • the sense strand connecting the conjugate group includes the sequence shown in SEQ ID NO:258, and the antisense strand includes the core shown in SEQ ID NO:292 nucleotide sequence;
  • the sense strand connecting the conjugate group includes the sequence shown in SEQ ID NO:258, and the antisense strand includes the core shown in SEQ ID NO:293 nucleotide sequence;
  • the sense strand connecting the conjugate group includes the sequence shown in SEQ ID NO:258, and the antisense strand includes the core shown in SEQ ID NO:294 nucleotide sequence;
  • the sense strand connecting the conjugate group includes the sequence shown in SEQ ID NO:259, and the antisense strand includes the core shown in SEQ ID NO:295 nucleotide sequence;
  • the sense strand connecting the conjugate group includes the sequence shown in SEQ ID NO:259, and the antisense strand includes the core shown in SEQ ID NO:296 nucleotide sequence;
  • the sense strand connecting the conjugate group includes the sequence shown in SEQ ID NO:259, and the antisense strand includes the core shown in SEQ ID NO:297 nucleotide sequence;
  • the sense strand connecting the conjugate group includes the sequence shown in SEQ ID NO:259, and the antisense strand includes the core shown in SEQ ID NO:298 nucleotide sequence;
  • the sense strand connecting the conjugate group includes the sequence shown in SEQ ID NO:324, and the antisense strand includes the core shown in SEQ ID NO:299 nucleotide sequence;
  • the sense strand connecting the conjugate group includes the sequence shown in SEQ ID NO:324, and the antisense strand includes the core shown in SEQ ID NO:300 nucleotide sequence;
  • the sense strand connecting the conjugate group includes the sequence shown in SEQ ID NO:324, and the antisense strand includes the core shown in SEQ ID NO:301 nucleotide sequence;
  • the sense strand connecting the conjugate group includes the sequence shown in SEQ ID NO:324, and the antisense strand includes the core shown in SEQ ID NO:302 nucleotide sequence;
  • the sense strand connecting the conjugate group includes the sequence shown in SEQ ID NO:325, and the antisense strand includes the core shown in SEQ ID NO:303 nucleotide sequence;
  • the sense strand connecting the conjugate group includes the sequence shown in SEQ ID NO:325, and the antisense strand includes the core shown in SEQ ID NO:304. nucleotide sequence;
  • the sense strand connecting the conjugate group includes the sequence shown in SEQ ID NO:325, and the antisense strand includes the core shown in SEQ ID NO:305 nucleotide sequence;
  • the sense strand connecting the conjugate group includes the sequence shown in SEQ ID NO:325, and the antisense strand includes the core shown in SEQ ID NO:306 nucleotide sequence;
  • the sense strand connecting the conjugate group includes the sequence shown in SEQ ID NO:326, and the antisense strand includes the core shown in SEQ ID NO:307 nucleotide sequence;
  • the sense strand connecting the conjugate group includes the sequence shown in SEQ ID NO:326, and the antisense strand includes the core shown in SEQ ID NO:308 nucleotide sequence;
  • the sense strand connecting the conjugate group includes the sequence shown in SEQ ID NO:326, and the antisense strand includes the core shown in SEQ ID NO:309 nucleotide sequence;
  • the sense strand connecting the conjugate group includes the sequence shown in SEQ ID NO:326, and the antisense strand includes the core shown in SEQ ID NO:310 nucleotide sequence;
  • the sense strand connecting the conjugate group includes the sequence shown in SEQ ID NO:327, and the antisense strand includes the core shown in SEQ ID NO:311 nucleotide sequence;
  • the sense strand connecting the conjugate group includes the sequence shown in SEQ ID NO:327, and the antisense strand includes the core shown in SEQ ID NO:312 nucleotide sequence;
  • the sense strand connecting the conjugate group includes the sequence shown in SEQ ID NO:327, and the antisense strand includes the core shown in SEQ ID NO:313 nucleotide sequence;
  • the sense strand connecting the conjugate group includes the sequence shown in SEQ ID NO:327
  • the antisense strand includes the core shown in SEQ ID NO:314. nucleotide sequence.
  • a pharmaceutical composition wherein the pharmaceutical composition includes at least one of the following: double-stranded ribonucleic acid as described in any one of [1]-[14], such as [15]-[28]
  • the double-stranded ribonucleic acid modification described in any one of [29] to [36] is the double-stranded ribonucleic acid conjugate described in any one of [29] to [36].
  • composition according to [38] The pharmaceutical composition according to [37], wherein the pharmaceutical composition further includes one or more pharmaceutically acceptable carriers.
  • Paroxysmal nocturnal hemoglobinuria atypical hemolytic uremic syndrome, rheumatoid arthritis, chronic kidney disease, ischemia-reperfusion injury, neurodegenerative diseases, asthma, systemic lupus erythematosus, glomerulonephritis, Psoriasis, dermatomyositis bullous pemphigoid, Shiga toxin E.
  • coli-related hemolytic uremic syndrome myasthenia gravis, neuromyelitis optica, dense deposit disease, C3 neurological disease, age-related macular degeneration, cold agglutinin disease, antineutrophil cytoplasmic antibody-associated vasculitis, humoral and vascular graft rejection, graft dysfunction, myocardial infarction, sensitized recipients of grafts, and sepsis.
  • a method for inhibiting intracellular C3 gene expression includes combining the cell with the double-stranded ribonucleic acid according to any one of [1]-[14], according to [15 ]-[28] The double-stranded ribonucleic acid modification according to any one of [29]-[36], or the double-stranded ribonucleic acid conjugate according to any one of [29]-[36], or according to any one of [37]-[38] Contact with the pharmaceutical composition described in one item.
  • the double-stranded ribonucleic acid provided by the present disclosure can combine in cells to form an RNA-induced silencing complex (RISC), cleave the mRNA transcribed by the complement C3 gene, and efficiently and specifically inhibit the expression of the complement C3 gene.
  • RISC RNA-induced silencing complex
  • the double-stranded ribonucleic acid is siRNA.
  • siRNA targets and degrades the transcript product of the C3 gene, mRNA, and exerts the effect of RNA interference to inhibit the protein expression of the C3 gene. It is a method with high inhibition rate and good specificity.
  • C3 complement inhibitor C3 complement inhibitor.
  • the present disclosure modifies double-stranded ribonucleic acid to obtain a double-stranded ribonucleic acid modified product.
  • the double-stranded ribonucleic acid modified product has high stability and is suitable for use in in vivo disease treatment.
  • the double-stranded ribonucleic acid modification is a siRNA modification, which has high stability and good inhibitory activity.
  • the present disclosure connects a conjugation group to double-stranded ribonucleic acid or double-stranded ribonucleic acid modifications to obtain a conjugate of double-stranded ribonucleic acid or double-stranded ribonucleic acid modifications, which can be used to deliver tissues and cells.
  • Medium and high-efficiency targeted delivery reduces the impact of double-stranded ribonucleic acid or double-stranded ribonucleic acid modifications on non-targeted normal tissues and cells, and improves its safety in clinical disease treatment.
  • the double-stranded ribonucleic acid conjugate is an siRNA conjugate. While maintaining the inhibitory activity and stability of siRNA, it also has organ or tissue targeting, which can reduce the impact on other tissues or organs and reduce the use of siRNA molecules. quantity, can achieve the purpose of reducing toxicity and reducing costs.
  • the conjugation group in the present disclosure is a group (GalNAc) with the structure shown in Formula I.
  • GalNAc can be used for targeted delivery to liver cells and tissues, and can be used to effectively inhibit the expression of the C3 gene in the liver.
  • C3 refers to well-known genes and polypeptides also known in the art as: ARMD9, C3a anaphylatoxin, ASP, complement component C3a, C3a, complement component C3b, C3b, prepro-C3, acylation stimulating protein cleavage product, CPAMD1, complement C3, C3 and PZP-like ⁇ -2-macroglobulin domain containing protein 1, complement C3 and AHUS5.
  • GenBank GenBank
  • database UniProt
  • OMIM Online Mendelian Inheritance in Man
  • C3 gene can be a wild-type C3 gene or a C3 gene mutant with sequence variation. Many sequence variations in the C3 gene have been identified and can be found, for example, in NCBIdbSNP and UniProt (see, eg, ncbi.nlm.nih.gov/snp).
  • polypeptide and protein interchangeably refer to a sequence of at least two amino acid residues linked to each other by covalent bonds (eg, peptide bonds), and may be recombinant polypeptides, natural polypeptides, or synthetic polypeptides.
  • a polypeptide can be linear or branched, it can contain modified amino acids, and it can be interrupted by non-amino acids.
  • the term also includes amino acid polymers that have been modified (eg, disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation, such as conjugation with a labeling component).
  • target sequence refers to the contiguous portion of the nucleotide sequence of the mRNA molecule formed during the transcription of the target gene, including the mRNA as a product of RNA processing of the primary transcript.
  • the target sequence is no less than 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 50, 80, 100, 150, A nucleotide sequence consisting of 200, 300, 400, 500, 600 or 700 consecutively linked nucleosides.
  • the target sequence is 19, 20, 22, 23, 24, 25, 27, 28, 34, 35, 38, 50, 57, 58, 61, 106, 340, 385, 441, 548, 584 or 633 A sequence of nucleotides consisting of consecutively linked nucleosides.
  • another shorter target sequence may be included in the target sequence.
  • one or more shorter target sequences may be included in the target sequence. It should be considered that two or more shorter target sequences included in the same target sequence have the same characteristics.
  • the target gene is the C3 gene.
  • the target portion of the sequence will be at least long enough to serve as a substrate for iRNA-directed cleavage at or near the nucleotide sequence portion of the mRNA molecule formed during transcription of the C3 gene.
  • G", “C”, “A”, “T” and “U” usually represent the bases of guanine, cytosine, adenine, thymine and uracil respectively, but in this field It is also commonly known that “G”, “C”, “A”, “T” and “U” each also generally represent nucleosides containing guanine, cytosine, adenine, thymine and uracil as bases respectively acid, which is a common way of expressing deoxyribonucleic acid sequences and/or ribonucleic acid sequences, so in the context of this disclosure, “G”, “C”, “A”, “T”, “U” The meaning includes various possible situations mentioned above.
  • ribonucleotide or “nucleotide” may also refer to a modified nucleotide (as described in further detail below) or an alternative replacement moiety.
  • guanine, cytosine, adenine, and uracil can be substituted by other moieties without substantially changing the base of an oligonucleotide, including a nucleotide having such a substituted moiety.
  • Base pairing properties For example, without limitation, a nucleotide including inosine as its base may be base-paired with a nucleotide including adenine, cytosine, or uracil.
  • uracil, guanine or adenine containing nucleotides may be replaced by eg inosine containing nucleotides in the nucleotide sequence of the dsRNA characterized in the present invention.
  • adenine and cytosine anywhere in the oligonucleotide can be replaced with guanine and uracil, respectively, to form G-U wobble base pairing with the target mRNA. Sequences containing such substituted moieties are suitable for use in the compositions and methods characterized herein.
  • RNAi agent RNAi agent
  • RNA interference agent RNA interference agent
  • siRNA siRNA and mediate silencing induced by RNA.
  • RISC RISC complex
  • iRNA directs the sequence-specific degradation of mRNA through a process known as RNA interference (RNAi).
  • RNAi RNA interference
  • An iRNA modulates, eg, inhibits, the expression of a target gene in a cell, such as a cell of a subject (eg, a mammalian subject).
  • double-stranded ribonucleic acid double-stranded RNA (dsRNA) molecule
  • dsRNA double-stranded RNA
  • dsRNA double-stranded RNA
  • double-stranded ribonucleic acid triggers the degradation of target RNA, such as mRNA, through a post-transcriptional gene silencing mechanism (referred to herein as RNA interference or RNAi).
  • target RNA such as mRNA
  • RNA interference post-transcriptional gene silencing mechanism
  • each strand of a dsRNA molecule typically, the majority of the nucleotides of each strand of a dsRNA molecule are ribonucleotides, but as detailed herein, each or both strands may also include one or more non-ribonucleotides Acids, for example, deoxyribonucleotides and/or modified nucleotides. Additionally, as used in this disclosure, "double-stranded ribonucleic acid" may include ribonucleotides with chemical modifications, phosphate backbones, and the like. These modifications may include all types of modifications disclosed herein or known in the art.
  • nucleotide refers to compounds in which the position of the base in the ribose ring is changed in the nucleotide, for example, the base is not attached to the 1'-position of the ribose ring, but is A compound formed by linking to the 2'-position or 3'-position of the ribose ring.
  • the double-stranded ribonucleic acid of the present disclosure is an siRNA that interacts with the mRNA sequence transcribed by the target gene (eg, the mRNA sequence transcribed by the C gene) to direct cleavage of the target RNA.
  • the target gene eg, the mRNA sequence transcribed by the C gene
  • Dicer ribonuclease III-like enzyme
  • processes dsRNA into 19-23 base pair short interfering RNA with a characteristic two-base 3' overhang (Bernstein et al.
  • siRNAs are subsequently incorporated into the RNA-induced silencing complex (RISC), where one or more helicases unwind the siRNA duplex, making it possible for the complementary antisense strand to guide target recognition (Nykanen et al., (2001) Cell 107:309).
  • RISC RNA-induced silencing complex
  • one or more endonucleases within the RISC cleave the target to induce silencing (Elbashir et al., (2001) Genes Dev. 15: 188).
  • overhanging nucleotide refers to a protruding or Multiple unpaired nucleotides, or vice versa.
  • “Blunt end” or “blunt end” means that there are no unpaired nucleotides, ie, no nucleotide overhangs, at that end of the double-stranded ribonucleic acid.
  • a "blunt-ended" double-stranded RNA is a dsRNA that is double-stranded throughout its length, ie, it has no nucleotide overhangs at either end of the molecule.
  • antisense strand refers to the strand of a region of double-stranded RNA that is substantially complementary to a target sequence (eg, derived from human C3 mRNA).
  • target sequence eg, derived from human C3 mRNA.
  • mismatches are most tolerated in the terminal region, and if mismatches occur, they are usually in one or more regions at the terminal end, such as the 5' and/or Within 5, 4, 3, 2 or 1 nucleotide of the 3 end.
  • sense strand refers to a double-stranded nucleic acid strand containing a region that is substantially complementary to a region of the antisense strand.
  • the terms “complementary” or “reverse complementary” are used interchangeably and have the meaning well known to those skilled in the art, that is, in a double-stranded nucleic acid molecule, the bases on one strand are connected to the bases on the other strand. Paired in complementary ways.
  • the purine base adenine (A) always pairs with the pyrimidine base thymine (T) (or uracil (U) in RNA);
  • the purine base guanine (C) always pairs with the pyrimidine base Pairs with cytosine (G).
  • Each base pair consists of a purine and a pyrimidine.
  • mismatch in this field means that in double-stranded nucleic acids, the bases at corresponding positions do not pair in a complementary manner.
  • substantially reverse complementary means that there are no more than 3 base mismatches between the two nucleotide sequences involved, that is, there are 1, 2, and 2 base mismatches between the two nucleotide sequences involved. or 3 base mismatches; “complete complementarity” means that there are no base mismatches between the two nucleotide sequences.
  • suppression may be used interchangeably with “reduction,””silencing,””downregulation,””suppression” and other similar terms and includes any level of suppression.
  • the term "inhibiting the expression of a C3 gene” includes inhibiting any C3 gene (such as, for example, a mouse C3 gene, a rat C3 gene, a monkey C3 gene, or a human C3 gene) as well as variants (eg, naturally occurring variants) of the C3 gene, or Expression of mutants.
  • the C3 gene may be a wild-type C3 gene, a mutant C3 gene, or in the case of a genetically manipulated cell, cell population or organism, a transgenic C3 gene.
  • “Inhibition of C3 gene expression” includes any level of inhibition of the C3 gene, such as at least partial inhibition of the expression of the C3 gene, such as inhibition of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%.
  • each independently means that at least two groups (or ring systems) present in the structure with the same or similar value ranges can have the same or different meanings under specific circumstances.
  • substituent X and substituent Y are each independently hydrogen, hydroxyl, alkyl or aryl, then when substituent X is hydrogen, substituent Y can be either hydrogen, hydroxyl, alkyl or aryl. ;Similarly, when the substituent Y is hydrogen, the substituent X can be either hydrogen, hydroxyl, alkyl or aryl.
  • alkyl includes straight-chain, branched or cyclic saturated alkyl groups.
  • alkyl groups include, but are not limited to, methyl, ethyl, propyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, n-pentyl, cyclohexyl, and the like. group.
  • the "C 1-6 " in "C 1-6 alkyl” refers to a linear, branched or cyclic arrangement containing 1, 2, 3, 4, 5 or 6 carbon atoms. group.
  • alkoxy refers to an alkyl group attached to the remainder of the molecule through an oxygen atom (-O-alkyl), wherein said alkyl group is as defined herein.
  • alkoxy include methoxy, ethoxy, trifluoromethoxy, difluoromethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, n- Pentyloxy etc.
  • treatment refers to exposing a subject to (e.g., administering) a double-stranded ribonucleic acid, a double-stranded ribonucleic acid modification, a double-stranded ribonucleic acid conjugate, or a pharmaceutical composition after suffering from a disease, so that the subject is not exposed to the disease. Reducing the symptoms of the disease does not necessarily mean that they must be completely suppressed. Suffering from a disease means that the body has symptoms of the disease.
  • prevention refers to: by exposing a subject to (e.g., administering) the double-stranded ribonucleic acid, double-stranded ribonucleic acid modification, double-stranded ribonucleic acid conjugate, pharmaceutical composition of the present disclosure before suffering from the disease, Thus, reducing the symptoms of a disease compared with no exposure does not necessarily mean that the disease must be completely suppressed.
  • an effective amount refers to an amount or dosage of the double-stranded ribonucleic acid, double-stranded ribonucleic acid modification, double-stranded ribonucleic acid conjugate or pharmaceutical composition of the present invention, which after administration to a patient in single or multiple doses, Produce the desired effect in patients in need of treatment or prophylaxis.
  • the effective amount can be readily determined by the attending physician, who is one of skill in the art, by considering various factors such as: the species of the mammal; its size, age and general health; the specific disease involved; the extent or severity of the disease; The individual patient's response; the specific antibody administered; the mode of administration; the bioavailability characteristics of the administered formulation; the dosage regimen selected; and the use of any concomitant therapy.
  • disease associated with abnormal expression of the C3 gene is a disease or disorder caused by or associated with complement activation.
  • disease associated with abnormal expression of the C3 gene includes diseases, disorders or conditions that would benefit from reduced expression of C3 (i.e., "C3-related diseases”). Such diseases are typically associated with inflammation and/or immune system activation, such as membrane attack complex-mediated lysis, allergic reactions, and/or hemolysis.
  • Non-limiting examples of complement component-related diseases include paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), asthma, rheumatoid arthritis (RA); antiphospholipid antibody syndrome Symptoms; lupus nephritis; ischemia-reperfusion injury; classic or invasive hemolytic uremic syndrome (tHUS); dense deposit disease (DDD); neuromyelitis optica (NMO); multifocal motor neuropathy ( MMN); multiple sclerosis (MS); macular degeneration (e.g., age-related macular degeneration (AMD)); hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome; thrombotic thrombocytopenic purpura (TTP) ; Spontaneous abortion; Pauciimmune vasculitis; Epidermolysis bullosa; Recurrent abortion; Preeclampsia, traumatic brain injury, myasthenia gravis, cold agglutin
  • coli related hemolytic uremia syndrome C3 neuropathy, antineutrophil cytoplasmic antibody-associated vasculitis, humoral and vascular graft rejection, graft dysfunction, myocardial infarction, allogeneic transplantation, sepsis, coronary artery disease, dermatomyositis , Graves' disease, atherosclerosis, Alzheimer's disease, systemic inflammatory response, sepsis, septic shock, spinal cord injury, glomerulonephritis, Hashimoto's thyroiditis, type I diabetes, Psoriasis, pemphigus, autoimmune hemolytic anemia (AIHA), ITP, pulmonary hemorrhage nephritis syndrome, Degos disease, antiphospholipid syndrome (APS), catastrophic APS (CAPS), cardiovascular disorders, myocarditis, Cerebrovascular disorders, peripheral (e.g., musculoskeletal) vascular disorders, renovascular disorders, mesenteric/intestinal vascular disorders, vasculitis,
  • pharmaceutically acceptable excipients or “pharmaceutically acceptable carriers” refers to auxiliary materials widely used in the field of pharmaceutical production.
  • the main purpose of using excipients is to provide a pharmaceutical composition that is safe to use, stable in nature and/or has specific functionality, and also to provide a method so that after the drug is administered to the subject, the active ingredient can be used in the desired manner. rate dissolution, or promote effective absorption of the active ingredient in the subject to whom it is administered.
  • Pharmaceutically acceptable excipients may be inert fillers or functional ingredients that provide a certain function for the pharmaceutical composition (such as stabilizing the overall pH value of the composition or preventing the degradation of the active ingredients in the composition).
  • Non-limiting examples of pharmaceutically acceptable excipients include, but are not limited to, binders, suspending agents, emulsifiers, diluents (or fillers), granulating agents, adhesives, disintegrants, lubricants, and anti-adhesive agents. , glidants, wetting agents, gelling agents, absorption delaying agents, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavoring agents, sweeteners, etc.
  • compositions of the present disclosure may be prepared using any method known to those skilled in the art. For example, conventional mixing, dissolving, granulating, emulsifying, grinding, encapsulating, embedding and/or lyophilizing processes.
  • the methods of administration can be varied or adapted in any applicable manner to meet the needs of the nature of the drug, convenience of the patient and medical staff, and other relevant factors.
  • mammals include, but are not limited to, domestic animals (e.g., cattle, sheep, cats, dogs, and horses), primates (e.g., humans and non-human primates such as monkeys), rabbits, and rodents (e.g., , mice and rats).
  • domestic animals e.g., cattle, sheep, cats, dogs, and horses
  • primates e.g., humans and non-human primates such as monkeys
  • rabbits e.g., mice and rats.
  • a first aspect of the present disclosure provides a double-stranded ribonucleic acid (dsRNA) for inhibiting the expression of the complement C3 gene.
  • dsRNA double-stranded ribonucleic acid
  • One strand of the double-stranded ribonucleic acid is the antisense strand.
  • the antisense strand is complementary to the mRNA sequence formed during the expression process of the target gene (i.e., the C3 gene) and is used to guide the transcript of the target mRNA (i.e., the C3 gene). ) cutting.
  • the other sense strand in the double-stranded RNA includes a double-stranded region that is partially complementary and fully complementary to the antisense strand to form a double-stranded RNA.
  • double-stranded ribonucleic acid serves as a substrate for endonuclease (Dicer) and is cleaved into small fragments of dsRNA, that is, siRNA.
  • the double-stranded ribonucleic acid is siRNA.
  • siRNA assembles to form the RNA-induced silencing complex (RISC) RISC complex, which cleaves the target mRNA and inhibits the expression of the complement C3 gene.
  • RISC RNA-induced silencing complex
  • siRNA that binds to the target mRNA is designed.
  • the target sequence is selected from the nucleotide sequences set forth in any one of SEQ ID NOs: 1-7. In some more specific embodiments, the target sequence is selected from the nucleotide sequence shown in any one of SEQ ID NO:8-34 and SEQ ID NO:364.
  • the nucleotide sequence shown in SEQ ID NO:1 includes SEQ ID NO:8 ⁇ 9, The nucleotide sequence shown in SEQ ID NO:364.
  • the nucleotide sequence shown in SEQ ID NO:2 includes the nucleotide sequence shown in SEQ ID NO:10-13.
  • the nucleotide sequence shown in SEQ ID NO:3 includes the nucleotide sequence shown in SEQ ID NO:14-16.
  • the nucleotide sequence shown in SEQ ID NO:4 includes the nucleotide sequence shown in SEQ ID NO:17 ⁇ 20.
  • the nucleotide sequence shown in SEQ ID NO:5 includes the nucleotide sequence shown in SEQ ID NO:21 ⁇ 24.
  • the nucleotide sequence shown in SEQ ID NO: 6 includes the nucleotide sequence shown in SEQ ID NO: 25-30.
  • the nucleotide sequence shown in SEQ ID NO:7 includes the nucleotide sequence shown in SEQ ID NO:31 ⁇ 34.
  • the antisense strand comprises sequence B that differs by no more than 3 nucleotides from the reverse complement of at least 15 contiguous nucleotides in the target sequence. Specifically, the starting nucleotide is selected in the target sequence in the direction from the 5' end to the 3' end, and at least 15 nucleotides extending in the 3' direction including the starting nucleotide are used as the siRNA. Combined area.
  • the antisense strand contains the reverse complement of the nucleotide sequence corresponding to the binding region.
  • the starting nucleotide can be a nucleotide at any position of the target sequence, as long as at least 15 consecutive nucleotides (including the starting nucleotide) can be obtained based on the starting nucleotide extending in the 3' direction of the target sequence. nucleotide at the starting position).
  • the nucleotide sequence of the antisense strand may be completely complementary or substantially complementary to the target sequence.
  • the nucleotide sequence of the antisense strand contains no more than 3 mismatched bases with the target sequence. For example, there are 1, 2, or 3 mismatched bases.
  • the nucleotide sequence of the antisense strand is completely complementary to the target sequence, there are no mismatched bases between the nucleotide sequence of the antisense strand and the target sequence.
  • the antisense strand consists of at least 15 nucleotides. In some embodiments, the antisense strand consists of 15-28 nucleotides. For example, the antisense strand is 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, or 28 nucleotides in length.
  • the antisense strand consists of 19-25 nucleotides, more preferably 19-23 nucleotides, and most preferably 19, 21 or 23 nucleotides.
  • the sense strand comprises sequence A that differs by no more than 3 nucleotides from at least 15 consecutive nucleotides in the target sequence.
  • the sense strand includes a region complementary to the antisense strand, and the nucleotide sequence of the sense strand is identical or substantially identical to the sequence of the binding region of the antisense strand on the target sequence. Therefore, the nucleotide sequence of the sense strand is at least 15 consecutive nucleotides in the target sequence that binds the antisense strand; alternatively, the nucleotide sequence of the sense strand is the same as at least 15 consecutive nucleotides in the target sequence that binds the antisense strand.
  • the sense strand consists of at least 15 nucleotides. In some embodiments, the sense strand consists of 15-28 nucleotides. For example, the sense strand is 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, or 28 nucleotides in length.
  • the sense strand consists of 19-25 nucleotides, more preferably 19-23 nucleotides, and most preferably 19, 21 or 23 nucleotides.
  • the length of the sense strand and the length of the antisense strand may be the same or different.
  • the sense strand and the antisense strand have the same length.
  • the length ratio of the sense strand/antisense strand is 15/15, 16/16, 17/17, 18/18, 19/19, 20 /20, 21/21, 22/22, 23/23, 24/24, 25/25, 26/26, 27/27 or 28/28.
  • the length ratio of sense strand/antisense strand is 19/19, 20/20, 21/21, 22/22, 23/23, 24/24 or 25/25, more preferably 19/19, 20/20 , 21/21, 22/22 or 23/23, most preferably 19/19, 21/21 or 23/23.
  • the sense and antisense strands are different lengths.
  • the length ratio of sense strand/antisense strand is 19/20, 19/21, 19/22, 19/23, 19/24, 19/25, 19/26, 20/19, 20/21, 20/ 22, 20/23, 20/24, 20/25, 20/26, 21/19, 21/20, 21/22, 21/23, 21/24, 21/25, 21/26, 22/19, 22/20, 22/21, 22/ 23, 22/24, 22/25, 22/26, 23/19, 23/20, 23/21, 23/22, 23/24, 23/25 or 23/26, etc.; in some preferred embodiments In , the length ratio of sense strand/antisense strand is 19/21 or 21/23.
  • the sense strand and the antisense strand may be completely complementary or substantially complementary. When the two are substantially complementary, there will be no more than 3 mismatched bases in the double-stranded region formed by the sense strand and the antisense strand.
  • the sense strand, the antisense strand, or a combination thereof has overhanging nucleotides extending out of the double-stranded region.
  • the number of overhanging nucleotides may be 1 or more, for example, 1 or 2.
  • the protruding 1-2 nucleotides can be located at the 5' end, 3' end or both ends of any antisense strand or sense strand, and each protruding nucleotide can be any type of nucleotide.
  • the sense strand is complementary to the antisense strand to form the double-stranded region, and the 3' end of the sense strand has 1-2 protruding nucleosides extending out of the double-stranded region. acid, the 3' end of the antisense strand forms a blunt end.
  • the sense strand and the antisense strand are complementary to form the double-stranded region, and the 3' end of the antisense strand has 1-2 protruding cores extending out of the double-stranded region. The 3' end of the sense strand forms a blunt end.
  • the sense strand and the antisense strand are complementary to form the double-stranded region, and the 3' ends of the sense strand and the antisense strand each have 1-2 strands extending out of the double-stranded region. Overhanging nucleotides in the chain region.
  • the sense strand and the antisense strand are complementary to form the double-stranded region, and the 3' ends of the sense strand and the antisense strand both form blunt ends.
  • the nucleotide sequence of the antisense strand and the target sequence may be completely complementary or substantially complementary; the sense strand and the antisense strand may be completely complementary or substantially complementary. Therefore, the following description of the target sequences SEQ ID NO:8 ⁇ SEQ ID NO:34, SEQ ID NO:364 and siRNA that can be complementary to these target sequences, for each siRNA's antisense strand, includes its complementary target
  • the sequence (for example, any one of SEQ ID NO: 8 ⁇ SEQ ID NO: 34, SEQ ID NO: 364) is basically complementary, that is, the nucleotide sequence of the antisense strand of each siRNA can There is a base mismatch with the corresponding target sequence; for each sense strand of siRNA, it includes the target sequence that is complementary to it (for example, SEQ ID NO:8 ⁇ SEQ ID NO:34, SEQ ID NO:364 (any of) are substantially complementary, that is, the nucleotide sequence of the sense strand of
  • the nucleotide sequence of the sense strand is sequence A consisting of 19 consecutive nucleotides in the sequence shown in SEQ ID NO:8, and the nucleotide sequence of the antisense strand is SEQ ID NO:8
  • the reverse complementary sequence B consisting of 19 consecutive nucleotides in the sequence shown.
  • the 3' ends of the sense strand and the antisense strand both form blunt ends.
  • the double-stranded ribonucleic acid is siRNA1 shown in Table 1.
  • the nucleotide sequence of the sense strand is sequence A consisting of 19 consecutive nucleotides in the sequence shown in SEQ ID NO:9
  • the nucleotide sequence of the antisense strand is SEQ ID NO:9
  • the reverse complementary sequence B consisting of 19 consecutive nucleotides in the sequence shown.
  • the 3' ends of the sense strand and the antisense strand both form blunt ends.
  • the nucleotide sequence of the sense strand is sequence A consisting of 21 consecutive nucleotides in the sequence shown in SEQ ID NO:9
  • the nucleotide sequence of the antisense strand is SEQ ID NO:9
  • the reverse complementary sequence B consisting of 21 consecutive nucleotides in the sequence shown.
  • the 3' ends of both the sense strand and the antisense strand have two protruding nucleotides extending out of the double-stranded region.
  • the nucleotide sequence of the sense strand is sequence A consisting of 23 consecutive nucleotides in the sequence shown in SEQ ID NO:9
  • the nucleotide sequence of the antisense strand is SEQ ID NO:9
  • the reverse complementary sequence B consisting of 23 consecutive nucleotides in the sequence shown.
  • the 3' ends of both the sense strand and the antisense strand have two protruding nucleotides extending out of the double-stranded region.
  • the double-stranded ribonucleic acid is any siRNA among siRNA2 to siRNA10, siRNA118 to siRNA128, siRNA130 to siRNA132, siRNA134, and siRNA135 shown in Table 1.
  • the nucleotide sequence of the sense strand is sequence A consisting of 21 consecutive nucleotides in the sequence shown in SEQ ID NO:10
  • the nucleotide sequence of the antisense strand is SEQ ID NO:10
  • the reverse complementary sequence B consisting of 21 consecutive nucleotides in the sequence shown.
  • the 3' ends of both the sense strand and the antisense strand have two protruding nucleotides extending out of the double-stranded region.
  • the nucleotide sequence of the sense strand is sequence A consisting of 19 consecutive nucleotides in the sequence shown in SEQ ID NO:10
  • the nucleotide sequence of the antisense strand is SEQ ID NO:10
  • the reverse complementary sequence B consisting of 19 consecutive nucleotides in the sequence shown.
  • the 3' ends of the sense strand and the antisense strand both form blunt ends.
  • the double-stranded ribonucleic acid is any one of siRNA11 to siRNA13 shown in Table 1.
  • the nucleotide sequence of the sense strand is sequence A consisting of 19 consecutive nucleotides in the sequence shown in SEQ ID NO:11
  • the nucleotide sequence of the antisense strand is SEQ ID NO:11
  • the reverse complementary sequence B consisting of 19 consecutive nucleotides in the sequence shown.
  • the 3' ends of the sense strand and the antisense strand both form blunt ends.
  • the double-stranded ribonucleic acid is siRNA14 shown in Table 1.
  • the nucleotide sequence of the sense strand is sequence A consisting of 23 consecutive nucleotides in the sequence shown in SEQ ID NO:12
  • the nucleotide sequence of the antisense strand is SEQ ID NO:12
  • the reverse complementary sequence B consisting of 23 consecutive nucleotides in the sequence shown.
  • the 3' ends of both the sense strand and the antisense strand have two protruding nucleotides extending out of the double-stranded region.
  • the nucleotide sequence of the sense strand is sequence A consisting of 21 consecutive nucleotides in the sequence shown in SEQ ID NO:12
  • the nucleotide sequence of the antisense strand is SEQ ID NO:12
  • the reverse complementary sequence B consisting of 21 consecutive nucleotides in the sequence shown.
  • the 3' ends of both the sense strand and the antisense strand have two protruding nucleotides extending out of the double-stranded region.
  • the nucleotide sequence of the sense strand is sequence A consisting of 19 consecutive nucleotides in the sequence shown in SEQ ID NO:12
  • the nucleotide sequence of the antisense strand is SEQ ID NO:12
  • the reverse complementary sequence B consisting of 19 consecutive nucleotides in the sequence shown.
  • the 3' ends of the sense strand and the antisense strand both form blunt ends.
  • the double-stranded ribonucleic acid is any siRNA among siRNA15 to siRNA21 shown in Table 1.
  • the nucleotide sequence of the sense strand is sequence A consisting of 19 consecutive nucleotides in the sequence shown in SEQ ID NO:13
  • the nucleotide sequence of the antisense strand is SEQ ID NO:13
  • the reverse complementary sequence B consisting of 19 consecutive nucleotides in the sequence shown.
  • the 3' ends of the sense strand and the antisense strand both form blunt ends.
  • the double-stranded ribonucleic acid is any one of siRNA22 to siRNA23 shown in Table 1.
  • the nucleotide sequence of the sense strand is sequence A consisting of 19 consecutive nucleotides in the sequence shown in SEQ ID NO:14
  • the nucleotide sequence of the antisense strand is SEQ ID NO:14
  • the reverse complementary sequence B consisting of 19 consecutive nucleotides in the sequence shown.
  • the 3' ends of the sense strand and the antisense strand both form blunt ends.
  • the double-stranded ribonucleic acid is any siRNA among siRNA24 to siRNA26 shown in Table 1.
  • the nucleotide sequence of the sense strand is sequence A consisting of 19 consecutive nucleotides in the sequence shown in SEQ ID NO:15
  • the nucleotide sequence of the antisense strand is SEQ ID NO:15
  • the reverse complementary sequence B consisting of 19 consecutive nucleotides in the sequence shown.
  • the 3' ends of the sense strand and the antisense strand both form blunt ends.
  • the double-stranded ribonucleic acid is any siRNA among siRNA27 to siRNA29 shown in Table 1.
  • the nucleotide sequence of the sense strand is sequence A consisting of 19 consecutive nucleotides in the sequence shown in SEQ ID NO:16
  • the nucleotide sequence of the antisense strand is SEQ ID NO:16
  • the reverse complementary sequence B consisting of 19 consecutive nucleotides in the sequence shown.
  • the 3' ends of the sense strand and the antisense strand both form blunt ends.
  • the double-stranded ribonucleic acid is siRNA30 shown in Table 1.
  • the nucleotide sequence of the sense strand is sequence A consisting of 19 consecutive nucleotides in the sequence shown in SEQ ID NO:17
  • the nucleotide sequence of the antisense strand is SEQ ID NO:17
  • the reverse complementary sequence B consisting of 19 consecutive nucleotides in the sequence shown.
  • the 3' ends of the sense strand and the antisense strand both form blunt ends.
  • the double-stranded ribonucleic acid is any siRNA among siRNA31 to siRNA32 shown in Table 1.
  • the nucleotide sequence of the sense strand is sequence A consisting of 19 consecutive nucleotides in the sequence shown in SEQ ID NO:18
  • the nucleotide sequence of the antisense strand is SEQ ID NO:18
  • the reverse complementary sequence B consisting of 19 consecutive nucleotides in the sequence shown.
  • the 3' ends of the sense strand and the antisense strand both form blunt ends.
  • the nucleotide sequence of the sense strand is sequence A consisting of 21 consecutive nucleotides in the sequence shown in SEQ ID NO:18
  • the nucleotide sequence of the antisense strand is SEQ ID NO:18
  • the reverse complementary sequence B consisting of 21 consecutive nucleotides in the sequence shown.
  • the 3' ends of both the sense strand and the antisense strand have two protruding nucleotides extending out of the double-stranded region.
  • the nucleotide sequence of the sense strand is sequence A consisting of 23 consecutive nucleotides in the sequence shown in SEQ ID NO:18
  • the nucleotide sequence of the antisense strand is SEQ ID NO:18
  • the reverse complementary sequence B consisting of 23 consecutive nucleotides in the sequence shown.
  • the 3' ends of both the sense strand and the antisense strand have two protruding nucleotides extending out of the double-stranded region.
  • the double-stranded ribonucleic acid is any one of siRNA33 to siRNA41 shown in Table 1.
  • the nucleotide sequence of the sense strand is sequence A consisting of 19 consecutive nucleotides in the sequence shown in SEQ ID NO:19
  • the nucleotide sequence of the antisense strand is SEQ ID NO:19
  • the reverse complementary sequence B consisting of 19 consecutive nucleotides in the sequence shown.
  • the 3' ends of the sense strand and the antisense strand both form blunt ends.
  • the double-stranded ribonucleic acid is siRNA42 shown in Table 1.
  • the nucleotide sequence of the sense strand is sequence A consisting of 19 consecutive nucleotides in the sequence shown in SEQ ID NO:20
  • the nucleotide sequence of the antisense strand is SEQ ID NO:20
  • the reverse complementary sequence B consisting of 19 consecutive nucleotides in the sequence shown.
  • the 3' ends of the sense strand and the antisense strand both form blunt ends.
  • the double-stranded ribonucleic acid is any one of siRNA43 to siRNA44 shown in Table 1.
  • the nucleotide sequence of the sense strand is sequence A consisting of 19 consecutive nucleotides in the sequence shown in SEQ ID NO:21
  • the nucleotide sequence of the antisense strand is SEQ ID NO:21
  • the reverse complementary sequence B consisting of 19 consecutive nucleotides in the sequence shown.
  • the 3' ends of the sense strand and the antisense strand both form blunt ends.
  • the double-stranded ribonucleic acid is any siRNA among siRNA45 to siRNA46 shown in Table 1.
  • the nucleotide sequence of the sense strand is sequence A consisting of 19 consecutive nucleotides in the sequence shown in SEQ ID NO:22
  • the nucleotide sequence of the antisense strand is SEQ ID NO:22
  • the reverse complementary sequence B consisting of 19 consecutive nucleotides in the sequence shown.
  • the 3' ends of the sense strand and the antisense strand both form blunt ends.
  • the nucleotide sequence of the sense strand is sequence A consisting of 21 consecutive nucleotides in the sequence shown in SEQ ID NO:22
  • the nucleotide sequence of the antisense strand is SEQ ID NO:22
  • the reverse complementary sequence B consisting of 21 consecutive nucleotides in the sequence shown.
  • the 3' ends of both the sense strand and the antisense strand have two protruding nucleotides extending out of the double-stranded region.
  • the double-stranded ribonucleic acid is any siRNA among siRNA47 to siRNA50 shown in Table 1.
  • the nucleotide sequence of the sense strand is the 19 consecutive nucleotides in the sequence shown in SEQ ID NO:23.
  • the nucleotide sequence of the antisense strand is sequence A, which is composed of continuation nucleotides.
  • the nucleotide sequence of the antisense strand is sequence B, which is the reverse complement of the sequence B composed of 19 consecutive nucleotides in the sequence shown in SEQ ID NO:23.
  • the 3' ends of the sense strand and the antisense strand both form blunt ends.
  • the double-stranded ribonucleic acid is any siRNA among siRNA51 to siRNA53 shown in Table 1.
  • the nucleotide sequence of the sense strand is sequence A consisting of 19 consecutive nucleotides in the sequence shown in SEQ ID NO:24
  • the nucleotide sequence of the antisense strand is SEQ ID NO:24
  • the reverse complementary sequence B consisting of 19 consecutive nucleotides in the sequence shown.
  • the 3' ends of the sense strand and the antisense strand both form blunt ends.
  • the double-stranded ribonucleic acid is any siRNA among siRNA54 to siRNA55 shown in Table 1.
  • the nucleotide sequence of the sense strand is sequence A consisting of 19 consecutive nucleotides in the sequence shown in SEQ ID NO:25
  • the nucleotide sequence of the antisense strand is SEQ ID NO:25
  • the reverse complementary sequence B consisting of 19 consecutive nucleotides in the sequence shown.
  • the 3' ends of the sense strand and the antisense strand both form blunt ends.
  • the nucleotide sequence of the sense strand is sequence A consisting of 21 consecutive nucleotides in the sequence shown in SEQ ID NO:25
  • the nucleotide sequence of the antisense strand is SEQ ID NO:25
  • the reverse complementary sequence B consisting of 21 consecutive nucleotides in the sequence shown.
  • the 3' ends of both the sense strand and the antisense strand have two protruding nucleotides extending out of the double-stranded region.
  • the double-stranded ribonucleic acid is any siRNA among siRNA56 to siRNA58 shown in Table 1.
  • the nucleotide sequence of the sense strand is sequence A consisting of 19 consecutive nucleotides in the sequence shown in SEQ ID NO:26
  • the nucleotide sequence of the antisense strand is SEQ ID NO:26
  • the reverse complementary sequence B consisting of 19 consecutive nucleotides in the sequence shown.
  • the 3' ends of the sense strand and the antisense strand both form blunt ends.
  • the double-stranded ribonucleic acid is any siRNA among siRNA59 to siRNA60 shown in Table 1.
  • the nucleotide sequence of the sense strand is sequence A consisting of 19 consecutive nucleotides in the sequence shown in SEQ ID NO:27
  • the nucleotide sequence of the antisense strand is SEQ ID NO:27
  • the reverse complementary sequence B consisting of 19 consecutive nucleotides in the sequence shown.
  • the 3' ends of the sense strand and the antisense strand both form blunt ends.
  • the double-stranded ribonucleic acid is siRNA61 shown in Table 1.
  • the nucleotide sequence of the sense strand is sequence A consisting of 19 consecutive nucleotides in the sequence shown in SEQ ID NO:28
  • the nucleotide sequence of the antisense strand is SEQ ID NO:28
  • the reverse complementary sequence B consisting of 19 consecutive nucleotides in the sequence shown.
  • the 3' ends of the sense strand and the antisense strand both form blunt ends.
  • the double-stranded ribonucleic acid is any siRNA among siRNA62 to siRNA63 shown in Table 1.
  • the nucleotide sequence of the sense strand is sequence A consisting of 19 consecutive nucleotides in the sequence shown in SEQ ID NO:29
  • the nucleotide sequence of the antisense strand is SEQ ID NO:29
  • the reverse complementary sequence B consisting of 19 consecutive nucleotides in the sequence shown.
  • the 3' ends of the sense strand and the antisense strand both form blunt ends.
  • the double-stranded ribonucleic acid is any siRNA among siRNA64 to siRNA65 shown in Table 1.
  • the nucleotide sequence of the sense strand is sequence A consisting of 19 consecutive nucleotides in the sequence shown in SEQ ID NO:30
  • the nucleotide sequence of the antisense strand is SEQ ID NO:30
  • the reverse complementary sequence B consisting of 19 consecutive nucleotides in the sequence shown.
  • the 3' ends of the sense strand and the antisense strand both form blunt ends.
  • the nucleotide sequence of the sense strand is sequence A consisting of 21 consecutive nucleotides in the sequence shown in SEQ ID NO:30
  • the nucleotide sequence of the antisense strand is SEQ ID NO:30
  • the reverse complementary sequence B consisting of 21 consecutive nucleotides in the sequence shown.
  • the 3' ends of both the sense strand and the antisense strand have two protruding nucleotides extending out of the double-stranded region.
  • the nucleotide sequence of the sense strand is sequence A consisting of 23 consecutive nucleotides in the sequence shown in SEQ ID NO:30
  • the nucleotide sequence of the antisense strand is SEQ ID NO:30
  • the reverse complementary sequence B consisting of 23 consecutive nucleotides in the sequence shown.
  • the 3' ends of both the sense strand and the antisense strand have two protruding nucleotides extending out of the double-stranded region.
  • the double-stranded ribonucleic acid is any siRNA among siRNA66 to siRNA86 shown in Table 1.
  • the nucleotide sequence of the sense strand is sequence A consisting of 19 consecutive nucleotides in the sequence shown in SEQ ID NO:31
  • the nucleotide sequence of the antisense strand is SEQ ID NO:31
  • the reverse complementary sequence B consisting of 19 consecutive nucleotides in the sequence shown.
  • the 3' ends of the sense strand and the antisense strand both form blunt ends.
  • the double-stranded ribonucleic acid is siRNA87 shown in Table 1.
  • the nucleotide sequence of the sense strand is sequence A consisting of 19 consecutive nucleotides in the sequence shown in SEQ ID NO:32
  • the nucleotide sequence of the antisense strand is SEQ ID NO:32
  • the reverse complementary sequence B consisting of 19 consecutive nucleotides in the sequence shown.
  • the 3' ends of the sense strand and the antisense strand both form blunt ends.
  • the double-stranded ribonucleic acid is any siRNA among siRNA88 to siRNA89 shown in Table 1.
  • the nucleotide sequence of the sense strand is sequence A consisting of 19 consecutive nucleotides in the sequence shown in SEQ ID NO:33
  • the nucleotide sequence of the antisense strand is SEQ ID NO:33
  • the reverse complementary sequence B consisting of 19 consecutive nucleotides in the sequence shown.
  • the 3' ends of the sense strand and the antisense strand both form blunt ends.
  • the double-stranded ribonucleic acid is any one of siRNA90 to siRNA94 shown in Table 1.
  • the nucleotide sequence of the sense strand is sequence A consisting of 19 consecutive nucleotides in the sequence shown in SEQ ID NO:34
  • the nucleotide sequence of the antisense strand is SEQ ID NO:34
  • the reverse complementary sequence B consisting of 19 consecutive nucleotides in the sequence shown.
  • the 3' ends of the sense strand and the antisense strand both form blunt ends.
  • the double-stranded ribonucleic acid is siRNA95 shown in Table 1.
  • the nucleotide sequence of the sense strand is sequence A consisting of 21 consecutive nucleotides in the sequence shown in SEQ ID NO:364, and the nucleotide sequence of the antisense strand is SEQ ID NO:364
  • the reverse complementary sequence B consisting of 21 consecutive nucleotides in the sequence shown.
  • the 3' ends of both the sense strand and the antisense strand have two protruding nucleotides extending out of the double-stranded region.
  • the nucleotide sequence of the sense strand is sequence A consisting of 23 consecutive nucleotides in the sequence shown in SEQ ID NO:364, and the nucleotide sequence of the antisense strand is SEQ ID NO:364
  • the reverse complementary sequence B consisting of 23 consecutive nucleotides in the sequence shown.
  • the 3' ends of both the sense strand and the antisense strand have two protruding nucleotides extending out of the double-stranded region.
  • the double-stranded ribonucleic acid is any one of siRNA129 and siRNA133 shown in Table 1.
  • the sense strand includes the nucleotide sequence shown in any one of SEQ ID NO:35-129 and SEQ ID NO:328-345
  • the antisense strand includes the nucleotide sequence shown in any one of SEQ ID NO:35-129 and SEQ ID NO:328-345. :131-225, the nucleotide sequence shown in any one of SEQ ID NO:346 ⁇ 363.
  • the double-stranded ribonucleic acid is selected from any of the siRNAs shown in Table 1.
  • the siRNA provided by the present disclosure has high binding specificity to the target mRNA (C3 mRNA), has good silencing activity of the target mRNA, can significantly inhibit complement C3 gene expression, and is used to treat inappropriate activation of the complement system. disease.
  • the present disclosure provides an siRNA composition comprising any one or a combination of two or more of the siRNAs shown in Table 1.
  • each nucleotide of the sense strand is independently a modified nucleotide or an unmodified core. glycosides. In some embodiments, each nucleotide of the antisense strand is independently a modified nucleotide or an unmodified nucleotide.
  • any two adjacent nucleotides in the sense strand are connected by a phosphodiester bond or a phosphorothioate diester bond. In some embodiments, any two adjacent nucleotides in the antisense strand are connected by a phosphodiester bond or a phosphorothioate diester bond.
  • the 5' terminal nucleotide of the sense strand is linked to a 5' phosphate group or a 5' phosphate derivative group. In some embodiments, the 5' terminal nucleotide of the antisense strand is linked to a 5' phosphate group or a 5' phosphate derivative group.
  • the structure of the 5' phosphate group is:
  • the structures of the 5' phosphate derivative group include but are not limited to: wait.
  • Base represents a base, such as A, U, G, C or T.
  • R' is hydroxyl or substituted by various groups known to those skilled in the art, for example, 2'-fluoro (2'-F) modified nucleotides, 2'-alkoxy modified nucleotides , 2'-substituted alkoxy modified nucleotides, 2'-alkyl modified nucleotides, 2'-substituted alkyl modified nucleotides, 2'-deoxyribonucleotides.
  • 2'-fluoro (2'-F) modified nucleotides 2'-alkoxy modified nucleotides
  • 2'-substituted alkoxy modified nucleotides 2'-alkyl modified nucleotides
  • 2'-substituted alkyl modified nucleotides 2'-deoxyribonucleotides.
  • a second aspect of the present disclosure provides a double-stranded ribonucleic acid modification.
  • the double-stranded ribonucleic acid modification is an siRNA modification.
  • siRNA modifications can improve the stability of siRNA while maintaining high C3 mRNA inhibitory activity.
  • double-stranded ribonucleic acid modifications comprise modification of at least one nucleotide.
  • the modification of the nucleotide is at least one selected from the group consisting of modification of the ribose group and modification of the base.
  • “modification of nucleotides” refers to nucleotides or nucleotide derivatives formed by replacing the 2' hydroxyl group of the ribose group of the nucleotide with other groups, or a base on the nucleotide. A nucleotide whose base is a modified base. The modification of the nucleotide will not cause the siRNA's function of inhibiting gene expression to be significantly weakened or lost.
  • modified nucleotides disclosed in J.K. Watts, G.F. Deleavey, and M.J. Damha, Chemically modified siRNA: tools and applications. Dr ug Discov Today, 2008, 13 (19-20): 842-55, can be selected.
  • the stability of siRNA can be improved through nucleotide modification and its high inhibition efficiency of C3 gene can be maintained.
  • the modified nucleotide has the following structure:
  • Base represents a base, such as A, U, G, C or T.
  • the hydroxyl group at the 2' position of the ribose group is substituted with R.
  • the hydroxyl groups at the 2' position of these ribosyl groups can be substituted with various groups known to those skilled in the art, for example, 2'-fluoro (2'-F) modified nucleotides, 2'-alkoxy modified nucleotides nucleotides, 2'-substituted alkoxy modified nucleotides, 2'-alkyl modified nucleotides, 2'-substituted alkyl modified nucleotides, 2'-deoxyribonucleosides acid.
  • 2'-fluoro (2'-F) modified nucleotides 2'-alkoxy modified nucleotides nucleotides, 2'-substituted alkoxy modified nucleotides, 2'-alkyl modified nucleotides, 2'-sub
  • the 2'-alkoxy modified nucleotide is a 2'-methoxy (2'-OMe, 2'-O- CH3 ) modified nucleotide, and the like.
  • the modification of the nucleotide is a modification of a base.
  • the modification of the base may be various types of modifications known to those skilled in the art. Exemplary base modifications include but are not limited to m 6 A, ⁇ , m 1 A, m 5 A, ms 2 i 6 A, i 6 A, m 3 C, m 5 C, ac 4 C, m 7 G, m 2,2 G, m 2 G, m 1 G, Q, m 5 U, mcm 5 U, ncm 5 U, ncm 5 Um, D, mcm 5 s 2 U, Inosine(I), hm 5 C , s 4 U, s 2 U, azobenzene, Cm, Um, Gm, t 6 A, yW, ms 2 t 6 A or its derivatives.
  • a nucleotide derivative refers to a nucleotide that can replace a nucleotide in a nucleic acid, but is structurally different from adenine ribonucleotide, guanine ribonucleotide, cytosine ribonucleotide, uracil ribose Nucleotides or thymine deoxyribonucleotide compounds.
  • the nucleotide derivative may be an isonucleotide, a bridged nucleic acid (BNA), or acyclic nucleotide.
  • BNA refers to constrained or inaccessible nucleotides.
  • BNA may contain a five-membered ring, a six-membered ring, or a seven-membered ring bridged structure with a "fixed" C3'-endoglycocondensation.
  • the bridge is usually incorporated into the 2'-, 4'-position of the ribose to provide a 2', 4'-BNA nucleotide, such as LNA, ENA, cET, etc.
  • LNA is shown in formula (1)
  • ENA is shown in formula (2)
  • cET is shown in formula (3):
  • Acyclic nucleotides are a type of nucleotide formed by opening the sugar ring of a nucleotide, such as unlocked nucleic acid (UNA) or glycerol nucleic acid (GNA).
  • UNA is represented by formula (4)
  • GNA is represented by formula (4). 5
  • R is selected from H, OH or alkoxy (O-alkyl).
  • nucleotide derivative modification refers to a nucleotide in a nucleic acid being replaced with a nucleotide derivative.
  • the nucleotide derivative is selected from isonucleotides, LNA, ENA, cET, UNA or GNA.
  • nucleotides in the nucleic acid are replaced with isonucleotides, also referred to as isonucleoside modifications in the context of this disclosure.
  • isonucleoside modification includes incorporation of isonucleoside at one or more sites of the sense strand and/or antisense strand of the siRNA to be modified, to replace the natural nucleoside for coupling at the corresponding position.
  • the isonucleoside modification employs D-isonucleoside modification. In other embodiments, the isonucleoside modification employs L-isonucleoside modification. In yet other embodiments, the isonucleoside modification employs D-isonucleoside modification and L-isonucleoside modification.
  • the double-stranded ribonucleic acid modification comprises modification of a phosphodiester bond at at least one position.
  • the modification of the phosphodiester bond means that at least one oxygen atom in the phosphodiester bond is replaced by a sulfur atom to form a phosphorothioate diester bond.
  • the phosphorothioate diester bond can stabilize the double-stranded structure of siRNA and maintain the specificity of base pairing.
  • An exemplary phosphorothioate diester bond structure is as follows:
  • the double-stranded ribonucleic acid modification comprises a chemical modification of at least one of the following:
  • the double-stranded ribonucleic acid modification is an siRNA modification comprising at least one chemical modification among (1)-(4).
  • sequence A in the sense strand and sequence B in the antisense strand are complementary to form a double-stranded region
  • sequence A and sequence B can be any of the following:
  • sequence A and sequence B both form blunt ends
  • sequence A has 1-2 protruding nucleotides extending out of the double-stranded region, and the 3’ end of sequence B forms a blunt end;
  • sequence B has 1-2 protruding nucleotides extending out of the double-stranded region, and the 3’ end of sequence A forms a blunt end;
  • sequence A has 1-2 protruding nucleotides extending out of the double-stranded region
  • sequence B has 1-2 protruding nucleotides extending out of the double-stranded region. Nucleotides.
  • nucleotide sequence of the sense strand is the sequence shown in Sequence A
  • nucleotide sequence of the antisense strand is the sequence shown in Sequence B.
  • the sense strand and the antisense strand are complementary to form a double-stranded region, and there are no overhanging nucleotides at the 3' ends of the sense strand and the antisense strand
  • the sense strand and the antisense strand are Add 1-2 nucleotides to the 3' end of at least one of the strands as overhanging nucleotides.
  • 1-2 nucleotides connected to the 3' end of the sense strand constitute sequence D
  • 1-2 nucleotides connected to the 3' end of the antisense strand constitute sequence E.
  • nucleotide sequence of the sense strand is the sequence shown in sequence A connected to sequence D
  • nucleotide sequence of the antisense strand is the sequence shown in sequence B connected to sequence E
  • nucleotide sequence of the sense strand is the sequence represented by sequence A
  • nucleotide sequence of the antisense strand is the sequence represented by sequence B connected to sequence E
  • nucleotide sequence of the sense strand is the sequence represented by sequence A connected to sequence D
  • nucleotide sequence of the antisense strand is the sequence represented by sequence represented by sequence B.
  • TT deoxyribonucleotides
  • TT deoxyribonucleotides
  • nucleotide sequences of the sense strand and the antisense strand are complementary to form a double-stranded region, and there is no overhanging nucleotide at the 3' end of the sense strand, 1 is added at the 3' end of the sense strand.
  • -Sequence D consisting of 2 nucleotides as the overhanging nucleotide. Then, when the nucleotide sequence formed by connecting sequence A to sequence D is chemically modified, sequence D consisting of 1-2 nucleotides is excluded.
  • the nucleotide sequence of the sense strand is the sequence shown in sequence A
  • the nucleotide sequence of the antisense strand is the sequence shown in sequence B.
  • the nucleotide sequence of the sense strand is the sequence represented by sequence A
  • the nucleotide sequence of the antisense strand is the sequence represented by sequence B connected to sequence E.
  • sequence A when sequence A is complementary to sequence B to form a double-stranded region, the 3' end of sequence A has When there are 1-2 protruding nucleotides extending out of the double-stranded region, the protruding nucleotide at the 3' end of sequence A is excluded and the nucleotide sequence of the sense strand is used.
  • sequence A' The sequence excluding the overhanging nucleotide at the 3' end is called sequence A'.
  • nucleotide sequence of the sense strand of the double-stranded ribonucleic acid modified product is the sequence shown in sequence A'
  • nucleotide sequence of the antisense strand of the double-stranded ribonucleic acid modified product is the sequence shown in sequence B
  • nucleotide sequence of the sense strand of the double-stranded ribonucleic acid modification is the sequence shown in sequence A'
  • nucleotide sequence of the antisense strand of the double-stranded ribonucleic acid modification is the sequence shown in sequence B connecting sequence E. .
  • the sense strand of the siRNA modification includes the following modifications: the ribonucleotides at positions 7, 9, 10 and 11 in the sense strand are 2'-fluoro modified ribonucleotide; ribonucleotides at other positions in the sense strand are 2'-methoxy modified ribonucleotides.
  • the sense strand of the siRNA modification includes a phosphorothioate diester bond at the following position: the 1st nucleotide starting from the 5' end and the 1st nucleotide starting from the 5' end. Between 2 nucleotides, between the 2nd nucleotide starting from the 5' end and the 3rd nucleotide, between the 1st nucleotide starting from the 3' end and the 2nd nucleotide starting from the 3' end between the 2nd and 3rd nucleotides starting from the 3' end.
  • the sense strand of the siRNA modification includes a phosphorothioate diester bond at the following position: the 1st nucleotide starting from the 5' end and the 1st nucleotide starting from the 5' end. Between 2 nucleotides, between the 2nd and 3rd nucleotides starting from the 5' end.
  • the sense strand of the siRNA modification has a structure shown in any one of (a 1 )-(a 3 ):
  • N 1 to N 23 are independently selected from ribonucleotides whose bases are A, U, C or G.
  • the capital letter T represents deoxyribonucleotides whose base is thymine, and the lowercase letter m represents this letter.
  • the ribonucleotide adjacent to the right side of m is a 2'-O-CH 3 modified ribonucleotide.
  • the lowercase letter f indicates that the ribonucleotide adjacent to the left side of the letter f is 2'-F modified.
  • Ribonucleotide, -(s)- means that two adjacent nucleotides are connected by a phosphorothioate diester bond.
  • the sense strand of the siRNA modification has a structure shown in any one of (a 4 ) to (a 5 ):
  • N 1 to N 23 are independently selected from ribonucleotides whose bases are A, U, C or G.
  • the capital letter T represents deoxyribonucleotides whose base is thymine, and the lowercase letter m represents this letter.
  • the ribonucleotide adjacent to the right side of m is a 2'-O-CH 3 modified ribonucleotide.
  • the lowercase letter f indicates that the ribonucleotide adjacent to the left side of the letter f is 2'-F modified.
  • Ribonucleotide, -(s)- means that two adjacent nucleotides are connected by a phosphorothioate diester bond.
  • the antisense strand of the siRNA modification includes the following modifications: ribonucleotides at any odd-numbered positions in the antisense strand are 2'-methoxy modified The ribonucleotide at any even-numbered position in the antisense strand is a 2'-fluorinated modified ribonucleotide.
  • the antisense strand of the siRNA modification includes the following modifications: ribose at positions 2, 6, 14 and 16 in the antisense strand
  • the nucleotides are 2'-F modified ribonucleotides, and the remaining ribonucleotides in the antisense strand are 2'-O- CH modified ribonucleotides.
  • the antisense strand of the siRNA modification includes the following modifications: the 2nd, 6th, 8th, 9th, and 9th positions in the antisense strand.
  • the ribonucleotides at positions 14 and 16 are 2'-F modified Ribonucleotides, the remaining ribonucleotides in the antisense strand are 2'-O-CH 3 modified ribonucleotides.
  • the ribonucleotides at positions 2, 14 and 16 in the antisense strand are 2'-F modified ribonucleotides
  • the ribonucleotide at position 6 in the antisense strand is a ribonucleotide modified by the nucleotide derivative GNA, and the ribonucleotides at the remaining positions in the antisense strand are modified with 2'-O-CH 3 of ribonucleotides.
  • the antisense strand of the siRNA modification includes the following modifications: ribose at positions 2, 6, 14 and 16 in the antisense strand
  • the nucleotide is a 2'-F modified ribonucleotide
  • the ribonucleotide at position 7 in the antisense strand is a ribonucleotide modified by the nucleotide derivative GNA
  • the ribonucleotide at position is a 2'-O-CH 3 modified ribonucleotide.
  • the antisense strand of the siRNA modification includes a phosphorothioate diester bond at the following position: the 1st nucleotide starting from the 5' end and Between the 2nd nucleotide, between the 2nd nucleotide and the 3rd nucleotide starting from the 5' end, between the 1st nucleotide and the 2nd nucleotide starting from the 3' end between the 2nd and 3rd nucleotides starting from the 3' end.
  • a 5' phosphate group or a 5' phosphate derivative group is attached to the nucleotide at the 5' end of the antisense strand in the direction from the 5' end to the 3' end.
  • the structure of the 5' phosphate group is:
  • the structures of the 5' phosphate derivative group include but are not limited to: wait.
  • the siRNA modification antisense strand has the structure shown in any one of the following (b 1 )-(b 15 ):
  • N 1 to N 23 are independently selected from ribonucleotides whose bases are A, U, C or G.
  • the capital letter T represents deoxyribonucleotides whose base is thymine, and the lowercase letter m represents this letter.
  • the ribonucleotide adjacent to the right side of m is a 2'-O-CH 3 modified ribonucleotide.
  • the lowercase letter f indicates that the ribonucleotide adjacent to the left side of the letter f is 2'-F modified.
  • Ribonucleotide indicates that the adjacent nucleotide on the right side of the letter is a 5'-phosphate nucleotide, -(s)- indicates that the two adjacent nucleotides are connected by a phosphorothioate diester bond , (GNA) indicates that the ribonucleotide adjacent to the right side is a ribonucleotide modified by GNA.
  • the sense strand comprises a nucleotide sequence as shown in any one of SEQ ID NOs: 227-241, 263-265, 266-282
  • the antisense strand comprises a nucleotide sequence as shown in any one of SEQ ID NOs: 227-241, 263-265, 266-282 ID NO: 242-256, 260-262, 283-322 any one of the nucleotide sequences.
  • double-stranded ribonucleic acid modifications include, but are not limited to, siRNA modifications as shown in Table 2.
  • the third aspect of the present disclosure provides a double-stranded ribonucleic acid conjugate, which is obtained by conjugating the double-stranded ribonucleic acid provided by the first aspect of the present disclosure or the double-stranded ribonucleic acid modification provided by the second aspect and a conjugation group. .
  • the sense strand and the antisense strand of the double-stranded ribonucleic acid conjugate form a double-stranded region of the double-stranded ribonucleic acid conjugate, and are formed at the 3' end of the sense strand of the double-stranded ribonucleic acid conjugate.
  • Flat ends In some embodiments, the 3' end of the sense strand of the double-stranded ribonucleic acid conjugate forms a blunt end and the 3' end of the antisense strand of the double-stranded ribonucleic acid conjugate has 1-2 extensions out of the duplex. overhanging nucleotides in the region.
  • the 3' end of the sense strand of the double-stranded ribonucleic acid conjugate forms a blunt end
  • the 3' end of the antisense strand of the double-stranded ribonucleic acid conjugate forms a blunt end
  • the double-stranded ribonucleic acid conjugate is obtained by conjugating a double-stranded ribonucleic acid modification with a conjugating group.
  • the sense strand and the antisense strand of the double-stranded ribonucleic acid modification are complementary to form the double-stranded region of the double-stranded ribonucleic acid modification, and the 3' end of the sense strand of the double-stranded ribonucleic acid modification forms a blunt end, and the conjugation group The group is conjugated to the 3' end of the sense strand with a blunt end to form a double-stranded ribonucleic acid conjugate.
  • the sense strand of the double-stranded ribonucleic acid modification is the sequence shown in sequence A
  • the antisense strand is the sequence shown in sequence B connected to sequence E.
  • the 3' end of the sense strand of the double-stranded ribonucleic acid modified product is blunt-ended, and the 3' end of the sense strand of the double-stranded ribonucleic acid modified product is connected to a conjugation group to form a double-stranded ribonucleic acid conjugate.
  • the sense strand of the double-stranded ribonucleic acid modification is the sequence shown in sequence A
  • the antisense strand is the sequence shown in sequence B.
  • the 3' end of the sense strand of the double-stranded ribonucleic acid modified product forms a blunt end
  • a conjugation group is connected to the 3' end of the sense strand of the double-stranded ribonucleic acid modified product to form a double-stranded ribonucleic acid conjugate.
  • the sense strand of the double-stranded ribonucleic acid modification is the sequence shown in sequence A connected to sequence D
  • the antisense strand is the sequence shown in sequence B connected to sequence E.
  • the 3' end of the sense strand of the double-stranded ribonucleic acid modified product has a protruding sequence D consisting of 1-2 nucleotides. After excluding the sequence D at the 3' end of the sense strand of the double-stranded ribonucleic acid modified product, A conjugation group is connected to the 3' end of sequence A to form a double-stranded ribonucleic acid conjugate.
  • the sense strand of the double-stranded ribonucleic acid modification is the sequence shown in sequence A connected to sequence D
  • the antisense strand is The chain is the sequence shown in sequence B.
  • the 3' end of the sense strand of the double-stranded ribonucleic acid modified product has a protruding sequence D consisting of 1-2 nucleotides. After excluding the sequence D at the 3' end of the sense strand of the double-stranded ribonucleic acid modified product, A conjugation group is connected to the 3' end of sequence A to form a double-stranded ribonucleic acid conjugate.
  • the sense strand of the double-stranded ribonucleic acid modification is the sequence shown in sequence A
  • the antisense strand is the sequence shown in sequence B connected to sequence E.
  • the 3' end of sequence A has a protruding nucleotide extending out of the double-stranded region, and the sequence after excluding the protruding nucleotide located at the 3' end of sequence A (also called sequence A') is used.
  • sequence A' The nucleotide sequence to which the conjugation group is attached.
  • nucleotide sequence of the sense strand of the double-stranded ribonucleic acid conjugate is the sequence represented by sequence A'
  • nucleotide sequence of the antisense strand is the sequence represented by sequence B connected to sequence E.
  • the sense strand of the double-stranded ribonucleic acid modification is the sequence shown in Sequence A
  • the antisense strand is the sequence shown in Sequence B.
  • the 3' end of sequence A has a protruding nucleotide extending out of the double-stranded region, and the sequence after excluding the protruding nucleotide located at the 3' end of sequence A (also called sequence A') is used.
  • sequence A' The nucleotide sequence to which the conjugation group is attached. Therefore, the nucleotide sequence of the sense strand of the double-stranded ribonucleic acid conjugate is the sequence shown in sequence A', and the nucleotide sequence of the antisense strand is the sequence shown in sequence B.
  • the sense strand of the double-stranded ribonucleic acid conjugate has a structure shown in any one of (d 1 )-(d 2 ):
  • N 1 to N 23 are independently selected from ribonucleotides whose bases are A, U, C or G.
  • the capital letter T represents deoxyribonucleotides whose base is thymine, and the lowercase letter m represents this letter.
  • the ribonucleotide adjacent to the right side of m is a 2'-O-CH 3 modified ribonucleotide.
  • the lowercase letter f indicates that the ribonucleotide adjacent to the left side of the letter f is 2'-F modified.
  • Ribonucleotide, -(s)- means that two adjacent nucleotides are connected by a phosphorothioate diester bond.
  • L96 is also the conjugate group GalNAc shown in formula I.
  • the antisense strand of the double-stranded ribonucleic acid conjugate has a structure shown in any one of (b 1 )-(b 15 ):
  • N 1 to N 23 are independently selected from ribonucleotides whose bases are A, U, C or G.
  • the capital letter T represents deoxyribonucleotides whose base is thymine, and the lowercase letter m represents this letter.
  • the ribonucleotide adjacent to the right side of m is a 2'-O-CH 3 modified ribonucleotide.
  • the lowercase letter f indicates that the ribonucleotide adjacent to the left side of the letter f is 2'-F modified.
  • Ribonucleotide indicates that the adjacent nucleotide on the right side of the letter is a 5'-phosphate nucleotide, -(s)- indicates that the two adjacent nucleotides are connected by a phosphorothioate diester bond , (GNA) indicates that the ribonucleotide adjacent to the right side is a ribonucleotide modified by GNA.
  • the double-stranded ribonucleic acid conjugate is an siRNA conjugate, wherein the siRNA molecule connected to the conjugation group in the siRNA conjugate can be unmodified siRNA or siRNA modification. While maintaining high inhibitory activity and stability, siRNA molecules modified with conjugation groups also have better tissue and organ targeting and the ability to promote cell endocytosis, which can reduce the impact on other tissues or organs. As well as reducing the amount of siRNA molecules used, the purpose of reducing toxicity and reducing costs can be achieved. Alternatively, select any siRNA molecule shown in Table 1 or Table 2 and connect it to the conjugation group to obtain a double-stranded ribonucleic acid conjugate.
  • the conjugation site of siRNA and the conjugation group can be at the 3’ end or 5’ end of the sense strand of siRNA, or at the 5’ end of the antisense strand, or in the internal sequence of siRNA. In some embodiments, the conjugation site of the siRNA and the conjugation group is at the 3' end of the sense strand of the siRNA.
  • the conjugation group can be attached to the phosphate group, the 2'-hydroxyl group, or the base of the nucleotide. In some embodiments, the conjugation group can also be connected to the 3'-position hydroxyl group, in which case the nucleotides are connected via a 2',5'-phosphodiester bond.
  • the conjugation group is usually attached to the phosphate group of the nucleotide; when the conjugation group is attached to the internal sequence of the siRNA, the conjugation group Usually attached to the ribose sugar ring or base.
  • connection methods please refer to the literature:
  • the conjugating group may be a ligand commonly used in the field of siRNA delivery.
  • the conjugation group can be selected from one or more ligands formed by the following targeting molecules or derivatives thereof: lipophilic molecules, such as cholesterol, bile acids, vitamins (such as vitamin E ), lipid molecules of different chain lengths; polymers, such as polyethylene glycol; peptides, such as membrane-penetrating peptides; aptamers; antibodies; quantum dots; sugars, such as lactose, polylactose, mannose, galactose, N-acetylgalactosamine (GalNAc); folate; receptor ligands expressed by liver parenchymal cells, such as asialoglycoprotein, asialoglycoside residues, lipoproteins (such as high-density lipoprotein, low-density lipoprotein) Lipoproteins, etc.), glucagon, neurotransmitters (such as epinephrine), glucagon, neuro
  • the conjugation group has the structure shown below:
  • the conjugation group shown in Formula I is GalNAc.
  • GalNAc has liver-targeting properties and can deliver siRNA molecules to liver tissue with high specificity and specifically inhibit the high expression of the C3 gene in the liver.
  • GalNAc is conjugated to the 3' end of the sense strand through a phosphodiester bond, resulting in an siRNA conjugate with the following structure:
  • the double helix structure is unmodified siRNA or siRNA modification.
  • double-stranded ribonucleic acid conjugates include, but are not limited to, siRNA conjugates as shown in Table 3.
  • the fourth aspect of the present disclosure provides a pharmaceutical composition, including the double-stranded ribonucleic acid described in the first aspect, the double-stranded ribonucleic acid modification described in the second aspect, and the double-stranded ribonucleic acid conjugate described in the third aspect. one or more of the compounds.
  • the pharmaceutical composition contains siRNA as described above as an active ingredient and a pharmaceutically acceptable carrier.
  • the purpose of using pharmaceutical compositions is to promote administration to living organisms, facilitate the absorption of active ingredients, and thereby exert biological activity.
  • the pharmaceutical compositions of the present disclosure can be administered in any form, including injection (intra-arterial, intravenous, intramuscular, intraperitoneal, subcutaneous), mucosal, oral (oral solid formulation, oral liquid formulation), rectal, inhalation, implantation , local (such as eye) administration, etc.
  • oral solid preparations include, but are not limited to, powders, capsules, lozenges, granules, tablets, and the like.
  • Non-limiting examples of liquid formulations for oral or mucosal administration include, but are not limited to, suspensions, tinctures, elixirs, solutions, and the like.
  • Non-limiting examples of topical formulations include, but are not limited to, emulsions, gels, ointments, creams, patches, pastes, foams, lotions, drops, or serum formulations.
  • Non-limiting examples of parenteral formulations include, but are not limited to, solutions for injection, dry powders for injection, suspensions for injection, emulsions for injection, and the like.
  • the pharmaceutical compositions of the present disclosure may also be formulated into controlled release or delayed release dosage forms (eg, liposomes or microspheres).
  • the methods of administration can be varied or adapted in any applicable manner to meet the needs of the nature of the drug, convenience of the patient and medical staff, and other relevant factors.
  • a fifth aspect of the present disclosure provides double-stranded ribonucleic acid, double-stranded ribonucleic acid modifications or double-stranded ribonucleic acid conjugates at least one of the following uses:
  • the present disclosure further provides the use of siRNA molecules (including unmodified siRNA, siRNA modifications, siRNA conjugates) or pharmaceutical compositions in at least one of the above (1)-(3).
  • abnormal expression of the C3 gene leads to inappropriate activation of the complement system, causing one or more of the following diseases related to abnormal expression of the C3 gene: paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, Rheumatoid arthritis, chronic kidney disease, ischemia-reperfusion injury, neurodegenerative diseases, asthma, systemic lupus erythematosus, glomerulonephritis, psoriasis, dermatomyositis bullous pemphigoid, Shiga toxin Escherichia coli-related hemolytic uremic syndrome, myasthenia gravis, neuromyelitis optica, dense deposit disease, C3 neurological disease, age-related macular degeneration, cold agglutinin disease, antineutrophil cytoplasmic antibody-related vascular disease inflammation, humoral and vascular graft rejection, graft dysfunction, myocardial infarction, sensitized graft recipients, and sep
  • the siRNA molecule causes the expression of the C3 gene to be inhibited by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least About 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least About 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99%, achieve abnormal expression of the C3 gene Treatment of related diseases.
  • the present disclosure provides a method of inhibiting C3 gene expression in a cell, comprising contacting a double-stranded ribonucleic acid, a double-stranded ribonucleic acid modification, a double-stranded ribonucleic acid conjugate, or a pharmaceutical composition with a cell.
  • a method of inhibiting the expression of C3 gene in cells is to introduce siRNA molecules (including unmodified siRNA, siRNA modifications, and siRNA conjugates) or pharmaceutical compositions into cells.
  • the cells are in vivo cells or in vitro cells. In some specific embodiments, the cells are in a subject.
  • the present disclosure provides methods of preventing or treating disease, comprising administering a double-stranded ribonucleic acid, a double-stranded ribonucleic acid modification, a double-stranded ribonucleic acid conjugate, or a pharmaceutical composition to a subject.
  • a method of preventing or treating disease is to administer siRNA molecules (including unmodified siRNA, siRNA modifications, siRNA conjugates) or pharmaceutical compositions to the subject.
  • siRNA molecules including unmodified siRNA, siRNA modifications, siRNA conjugates
  • pharmaceutical compositions to the subject.
  • subject includes either a human or a non-human animal, preferably a vertebrate, and more preferably a mammal.
  • Subjects may include genetically modified organisms. Most preferably, the subject is human. Further, the subject has at least one of the following characteristics:
  • the experimental techniques and experimental methods used in this example are all conventional technical methods unless otherwise specified.
  • the experimental methods without specifying specific conditions in the following examples usually follow conventional conditions, such as Sambrook et al., Molecular Cloning: Experiment The conditions described in the Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or the conditions recommended by the manufacturer.
  • the materials, reagents, etc. used in the examples can be obtained through regular commercial channels unless otherwise specified.
  • siRNA, siRNA modifications and siRNA conjugates involved in the following examples were synthesized by Tianlin Biotechnology (Shanghai) Co., Ltd.
  • the cells, reagents and instrument consumables used in the examples are as shown in Table 4 and Table 5:
  • the target sequence used to design siRNA is shown below.
  • the target sequence is derived from the gene mRNA sequence of C3 (see NM_000064.4).
  • the nucleoside monomers are connected one by one from the 3'-5' direction in the order of nucleotide arrangement.
  • Each connection of a nucleoside monomer involves four steps of deprotection, coupling, capping, oxidation or sulfation.
  • deprotection, coupling, capping, oxidation or sulfation when two nucleotides are connected using a phosphate ester, when the next nucleoside monomer is connected, it includes four steps of deprotection, coupling, capping, and oxidation.
  • two nucleotides are connected using phosphorothioate, when the next nucleoside monomer is connected, it includes four steps of protection, coupling, capping and sulfation.
  • the nucleoside monomer is provided in an acetonitrile solution with a concentration of 0.1M.
  • the conditions for the deprotection reaction in each step are the same, that is, the temperature is 25°C, the reaction time is 70 seconds, and the deprotection reagent is dichloroacetic acid in dichloromethane (3% V/V), the molar ratio of dichloroacetic acid to the 4,4'-dimethoxytrityl protecting group on the solid support is 5:1.
  • the coupling reaction conditions for each step are the same, including a temperature of 25°C, a molar ratio of the nucleic acid sequence connected to the solid phase carrier to the nucleoside monomer of 1:10, and a molar ratio of the nucleic acid sequence connected to the solid phase carrier to the coupling reagent.
  • the ratio is 1:65
  • the reaction time is 600 seconds
  • the coupling reagent is a 0.5M acetonitrile solution of 5-ethylthio-1H-tetrazole.
  • the capping conditions in each step are the same, including a temperature of 25°C and a reaction time of 15 seconds.
  • the capping reagent solution is a mixed solution of CapA and CapB with a molar ratio of 1:1.
  • the oxidation reaction conditions for each step are the same, including a temperature of 25°C, a reaction time of 15 seconds, and the oxidizing reagent is iodine water with a concentration of 0.05M.
  • the molar ratio of iodine to the nucleic acid sequence attached to the solid support during the coupling step is 30:1.
  • the conditions for each step of the vulcanization reaction are the same, including a temperature of 25°C, a reaction time of 300 seconds, and vulcanization reagents. It is hydrogenated xanthogen.
  • the molar ratio of the sulfide reagent to the nucleic acid sequence connected to the solid support in the coupling step is 120:1.
  • the nucleic acid sequence connected to the solid phase carrier is sequentially cut, deprotected, purified, and desalted, and then freeze-dried to obtain the sense strand and antisense strand; finally, the two strands are heated and annealed.
  • the product is obtained, freeze-dried, and freeze-dried powder is obtained.
  • siRNA conjugate has the structure shown in Formula II below:
  • compound L96-A is obtained by reacting DMTr-L96 and succinic anhydride:
  • Preparation process Add DMTr-L96, succinic anhydride, 4-dimethylaminopyridine and diisopropylethylamine into dichloromethane, stir and react at 25°C for 24 hours, and then wash with 0.5M triethylamine phosphate.
  • the reaction solution and aqueous phase were washed three times with methylene chloride, and the organic phases were combined and evaporated to dryness under reduced pressure to obtain a crude product. Then column chromatography purified to obtain pure product L96-A.
  • Preparation process Mix L96-A, O-benzotriazole-tetramethylurea hexafluorophosphate (HBTU) and diisopropylethylamine in acetonitrile, stir at room temperature for 5 minutes to obtain a uniform solution, add ammonia Add methyl resin (NH 2 -SPS, 100-200 mesh) to the reaction liquid, start shaking reaction at 25°C, filter after 18 hours of reaction, and wash the filter cake with dichloromethane and acetonitrile in sequence to obtain a filter cake. The obtained filter cake is capped with a CapA/CapB mixed solution to obtain L96-B, which is a solid-phase carrier containing the conjugated molecule.
  • HBTU O-benzotriazole-tetramethylurea hexafluorophosphate
  • diisopropylethylamine diisopropylethylamine in acetonitrile
  • the nucleoside monomer is connected to the conjugated molecule under the coupling reaction, and then the nucleoside monomer is connected to the conjugated molecule as described above.
  • the siRNA molecule synthesis method is used to synthesize the siRNA sense strand connected to the conjugate molecule, and the siRNA molecule synthesis method described above is used to synthesize the siRNA antisense strand, and annealed to generate the siRNA conjugate of the present application.
  • Hep3B cells were purchased from ATCC, catalog number HB-8064;
  • EMEM medium purchased from ATCC, product number 30-2003;
  • Lipofectamine RNAiMax transfection reagent purchased from Invitrogen, product number 13778-150;
  • Opti-medium reduced serum medium, purchased from Gibco, Cat. No. 31985-070;
  • SiNTC No target control: RNA not related to the target.
  • siRNA in the experimental process description of this example Centrifuge the dry powder of the siRNA to be tested and siRNA modifications (for convenience of description, collectively referred to as siRNA in the experimental process description of this example) at low temperature and high speed, then dissolve it with ultrapure distilled water (ULtraPure Distilled Water) to prepare 100 ⁇ M siRNA. mother liquor.
  • ULP Ultrapure distilled water
  • step b) Take 2 ⁇ l of the 10 ⁇ M siRNA dilution prepared in step a) and add 18 ⁇ l of ultrapure distilled water to obtain a siRNA dilution with a final concentration of 1 ⁇ M;
  • step c) Take 2 ⁇ l of the 1 ⁇ M siRNA dilution prepared in step b) and add 18 ⁇ l of ultrapure distilled water to obtain a siRNA stock solution with a final concentration of 0.1 ⁇ M;
  • the Mock group indicates: compared with the experimental group, the group without siRNA was added.
  • the siRNA and siRNA modifications provided by the present disclosure show excellent inhibitory effects on the C3 gene.
  • the inhibition rate was as high as 93.22%.
  • siRNA measurement concentration range settings to be tested 2 2, 0.5, 0.125, 0.0313, 0.00781, 0.00195, 0.000488, 0.000122, and then measure IC 50 according to a method similar to 3.2.
  • Inhibition rate (%) (relative expression of mRNA in the Mock group – relative expression of mRNA in the sample group)/relative expression of mRNA in the Mock group ⁇ 100%;
  • the Mock group represents the group in which siRNA was not added compared with the experimental group.
  • Top represents the percentage inhibition rate at the top platform, and the Top standard of the curve is generally between 80% and 120%;
  • Bottom represents the percentage inhibition rate at the bottom platform, and the Bottom of the curve is generally between –20% and 20%;
  • HillSlope represents The slope of the percent inhibition curve.
  • the siRNA and siRNA modifications provided by the present disclosure have excellent C3 gene inhibitory activity, and can still have good C3 gene inhibitory activity at an IC 50 as low as 0.01778nM.
  • PHH medium invitroGRO CP Meduim serum free BIOVIT, Cat. No.: S03316
  • Lipofectamine RNAiMax transfection reagent purchased from Invitrogen, product number: 13778-150;
  • Reverse transcription kit FastKing RT Kit (With gDNase), product number: Tiangen-KR116-02;
  • siRNA conjugates (siRNA conjugate final concentrations are 10nM, 2.5nM, 0.63nM, 0.16nM, 0.04nM, 0.01nM, 0.0024nM and 0.0006nM, duplicate wells) into PHH cells through transfection, the process is as follows: Take the frozen PHH cells, resuscitate, count, adjust the cells to 6 ⁇ 10 5 cells/ml, and use Lipofectamine RNAiMax to transfer the siRNA conjugate into the cells, and seed them into a 96-well plate at a density of 54,000 cells per well. Add 100 ⁇ L of PPH medium to each well. Cells were cultured in 5% CO 2 and 37°C incubator. After 48 hours, the medium was removed and cells were collected for RNA extraction. Use according to instructions 96Kit extracted total RNA.
  • siRNA conjugates enter PHH cells through free uptake.
  • the process is as follows: take freeze The stored PHH cells were resuscitated, counted, and the cells were adjusted to 6 ⁇ 10 5 cells/ml.
  • siRNA conjugate was added and seeded into a 96-well plate at a density of 54,000 cells per well, with 100 ⁇ l of culture medium per well. Cells were cultured in 5% CO 2 and 37°C incubator. After 48 hours, the medium was removed and cells were collected for RNA extraction. Use according to instructions 96Kit extracted total RNA.
  • the extracted total RNA was reverse transcribed into cDNA through reverse transcription reaction.
  • C3cDNA will be detected by qPCR.
  • GAPDH cDNA will be used as an internal control for parallel testing.
  • the PCR reaction program is: 95°C for 10 minutes, then enter the cycle mode, 95°C for 15 seconds, then 60°C for 60 seconds, a total of 40 cycles.
  • Inhibition rate (%) (relative expression of mRNA in the Mock group – relative expression of mRNA in the sample group)/relative expression of mRNA in the Mock group ⁇ 100%.
  • the Mock group represents the group without adding siRNA conjugate compared with the experimental group.
  • Top represents the percentage inhibition rate at the top platform, and the Top standard of the curve is generally between 80% and 120%;
  • Bottom represents the percentage inhibition rate at the bottom platform, and the Bottom of the curve is generally between –20% and 20%;
  • HillSlope represents The slope of the percent inhibition curve.
  • L96 in Table 11 is also the conjugate group GalNAc shown in Formula I.
  • the siRNA conjugates provided by the present disclosure have excellent C3 gene inhibition activity.
  • the siRNA conjugate of the present disclosure can still have good C3 gene inhibitory activity at an IC 50 as low as 0.122 nM; when entering PHH cells through transfection, the siRNA conjugate can have an IC 50 as low as 0.013 It still has good C3 gene inhibitory activity at nM.
  • the siRNA sequence design ideas and methods in this example are the same, and the target sequence used to design siRNA is as follows.
  • the target sequence is derived from the C3 gene mRNA sequence (see NM_000064.4).
  • siRNA in the experimental process description of this example Centrifuge the dry powder of the siRNA to be tested and siRNA modifications (for convenience of description, collectively referred to as siRNA in the experimental process description of this example) at low temperature and high speed, then dissolve it with ultrapure distilled water (ULtraPure Distilled Water) to prepare 100 ⁇ M siRNA. mother liquor.
  • ULP Ultrapure distilled water
  • step b) Take 2 ⁇ l of the 10 ⁇ M siRNA dilution prepared in step a) and add 18 ⁇ l of ultrapure distilled water to obtain a siRNA dilution with a final concentration of 1 ⁇ M;
  • step c) Take 2 ⁇ l of the 1 ⁇ M siRNA dilution prepared in step b) and add 18 ⁇ l of ultrapure distilled water to obtain a siRNA stock solution Q with a final concentration of 0.1 ⁇ M;
  • siRNA stock solution E with a final concentration of 0.01 ⁇ M
  • the siRNA and siRNA modifications provided by the present disclosure show excellent inhibitory effects on the C3 gene.
  • the inhibition rate is as high as 94.07% at the concentration of 0.1nM, and the inhibition rate is as high as 85.65% at the concentration of 0.01nM.
  • Example 7 siRNA modifications and siRNA conjugates inhibit C3 gene expression

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Abstract

La présente divulgation concerne un acide ribonucléique double brin pour inhiber l'expression du gène C3, un modificateur, un conjugué et son utilisation. Plus particulièrement, la présente divulgation concerne un acide ribonucléique double brin, un modificateur d'acide ribonucléique double brin, un conjugué d'acide ribonucléique double brin, une composition pharmaceutique et une utilisation pour inhiber l'expression du gène C3, ainsi qu'un procédé pour inhiber l'expression du gène C3 dans les cellules. L'acide ribonucléique double brin présenté peut être combiné dans les cellules pour constituer un complexe d'extinction induite par l'ARN (RISC), et clive l'ARNm transcrit par le gène du complément C3, inhibant efficacement et particulièrement l'expression du gène du complément C3, ce qui est utilisé pour traiter une maladie médiée par une activation incorrecte du système du complément, et présente d'importantes perspectives d'application dans le traitement clinique de la maladie.
PCT/CN2023/096337 2022-05-27 2023-05-25 Acide ribonucléique double brin pour l'inhibition de l'expression du gène c3 et modificateur, conjugué et son utilisation Ceased WO2023227070A1 (fr)

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WO2025043720A1 (fr) * 2023-09-01 2025-03-06 苏州炫景生物科技有限公司 Oligonucléotide double brin et conjugué pour inhiber l'expression de gènes c3, et leurs utilisations
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