DsRNA molecule for inhibiting expression of complement MASP2 gene and application thereof

Abstract

Provided are a modified dsRNA molecule and use thereof. Specifically provided is a dsRNA molecule for inhibiting expression of a MASP2 gene, comprising a sense strand and an antisense strand which are complementary to form a double-stranded region, wherein the sense strand and / or the antisense strand comprises or consists of 15-25 nucleotides, and the dsRNA molecule can be used for treating and / or preventing a disease mediated by the MASP2 gene.

Description

A dsRNA molecule for inhibiting complement MASP2 gene expression and its application Technical Field

[0001] The present application belongs to the field of molecular biology and relates to a modified dsRNA molecule and its application, and specifically to a dsRNA molecule and its pharmaceutical composition for inhibiting the expression of the complement MASP2 gene, as well as a method for reducing the expression level of the complement MASP2 gene using the dsRNA molecule or its pharmaceutical composition. Background Art

[0002] RNA interference (RNAi) refers to the highly conserved evolutionary phenomenon of efficient and specific degradation of homologous mRNAs induced by double-stranded RNA (dsRNA). RNAi is a ubiquitous surveillance mechanism in eukaryotes that protects against viral invasion, inhibits transposon activity, and regulates gene expression. Small interfering RNA (dsRNA), a short double-stranded RNA molecule of 19 to 30 bp in length, is a key tool in RNAi technology. In nature, upon entering cells, dsRNA is specifically recognized and cleaved by the enzyme Dicer into small RNA fragments (i.e., 21 to 23 nucleotides in length). The resulting dsRNA fragments unwind into single strands and form complexes with certain proteins (RISC). RISC binds to complementary mRNAs within the cell and cleaves them, degrading them. This prevents protein synthesis and results in gene silencing. In industrial production, chemical synthesis and modification of dsRNA are preferred to further enhance the stability and efficacy of dsRNA therapeutics. In recent years, breakthroughs have been made in dsRNA drug research, with several dsRNA drugs targeting rare diseases now approved by the FDA. The therapeutic areas of dsRNA drugs are also gradually expanding from rare diseases to common ailments.

[0003] Overactivation or inhibition of the complement system plays a crucial role in the pathogenesis of a wide range of diseases, ranging from acute inflammatory conditions such as ophthalmologic and periodontal diseases to chronic conditions such as cancer, autoimmune diseases, neurodegenerative diseases, kidney diseases, and chronic hemolytic disorders. Three known complement activation pathways exist: the classical pathway, the alternative pathway, and the lectin pathway. The complement protein MASP2 is the initiator of the lectin pathway, triggering the complement cascade. Overactivation of complement is implicated in the pathogenesis of numerous diseases, including ophthalmologic conditions such as age-related macular degeneration (AMD); CNS / PNS disorders such as Alzheimer's disease (AD) and myasthenia gravis (gMG); renal diseases such as atypical hemolytic uremic syndrome (aHUS), C3 glomerulopathy (C3G), and IgA nephropathy; and hematologic disorders such as paroxysmal nocturnal hemoglobinuria (PNH) and thrombotic microangiopathy (TMAs). Targeting the MASP2 protein can block the complement cascade signaling mediated by the lectin pathway. To date, several complement-targeting drugs have been investigated for clinical application, primarily antibodies. Antibody drugs targeting MADP-2 are currently in clinical development and show great therapeutic potential in patients with IgA nephropathy. Therefore, there is a need for alternative and combination therapies for patients with MASP2-related complement-related diseases in some difficult-to-treat diseases.

[0004] Summary of the Invention

[0005] The present application provides a modified double-stranded RNAi molecule, a pharmaceutical composition containing the modified double-stranded RNAi molecule, and applications thereof.

[0006] Specifically, in one aspect, the present application provides an engineered dsRNA molecule for inhibiting the expression of the complement MASP2 gene, comprising a sense strand and an antisense strand that complement each other to form a double-stranded region, wherein the sense strand and / or the antisense strand comprises or consists of 15-25 nucleotides, and the antisense strand is complementary to at least 15, 16, 17, 18, 19, 20, or 21 consecutive nucleotides of the nucleic acid sequence shown in SEQ ID NO: 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 71, or 77, and the double-stranded region is 15-25 bp in length.

[0007] In some embodiments, at least one nucleotide in the dsRNA molecule is modified, and the modification is selected from any one or more of the following: locked nucleic acid modification, open ring or non-locked nucleic acid modification, 2′-methoxyethyl modification, 2′-O-methyl modification, 2′-O-allyl modification, 2′-C-allyl modification, 2′-fluoro modification, 2′-deoxy modification, phosphorothioate backbone modification, DNA modification, and ligand modification.

[0008] In some embodiments, with respect to the naked sequence thereof: the sense strand of the dsRNA molecule comprises SEQ ID NO:37 or consists of the nucleic acid sequence shown in SEQ ID NO:37, and the antisense strand comprises SEQ ID NO:38 or consists of the nucleic acid sequence shown in SEQ ID NO:38; the sense strand of the dsRNA molecule comprises SEQ ID NO:39 or consists of the nucleic acid sequence shown in SEQ ID NO:39, and the antisense strand comprises SEQ ID NO:40 or consists of the nucleic acid sequence shown in SEQ ID NO:40; the sense strand of the dsRNA molecule comprises SEQ ID NO:41 or consists of the nucleic acid sequence shown in SEQ ID NO:41, and the antisense strand comprises SEQ ID NO:42 or consists of the nucleic acid sequence shown in SEQ ID NO:42; the sense strand of the dsRNA molecule comprises SEQ ID NO:43 or consists of the nucleic acid sequence shown in SEQ ID NO:43, and the antisense strand comprises SEQ ID NO:44 or consists of the nucleic acid sequence shown in SEQ ID NO:44; the sense strand of the dsRNA molecule comprises SEQ ID NO:45 or consists of the nucleic acid sequence shown in SEQ ID NO:46. NO:45, the antisense strand comprises SEQ ID NO:46 or consists of the nucleic acid sequence shown in SEQ ID NO:46; the sense strand of the dsRNA molecule comprises SEQ ID NO:47 or consists of the nucleic acid sequence shown in SEQ ID NO:47, and the antisense strand comprises SEQ ID NO:48 or consists of the nucleic acid sequence shown in SEQ ID NO:48; the sense strand of the dsRNA molecule comprises SEQ ID NO:49 or consists of the nucleic acid sequence shown in SEQ ID NO:49, and the antisense strand comprises SEQ ID NO:50 or consists of the nucleic acid sequence shown in SEQ ID NO:50; the sense strand of the dsRNA molecule comprises SEQ ID NO:51 or consists of the nucleic acid sequence shown in SEQ ID NO:51, and the antisense strand comprises SEQ ID NO:52 or consists of the nucleic acid sequence shown in SEQ ID NO:52; the sense strand of the dsRNA molecule comprises SEQ ID NO:53 or consists of the nucleic acid sequence shown in SEQ ID NO:53, and the antisense strand comprises SEQ ID NO:54 or consists of the nucleic acid sequence shown in SEQ ID NO:55. NO:54; the sense strand of the dsRNA molecule comprises or consists of the nucleic acid sequence shown in SEQ ID NO:55, and the antisense strand comprises or consists of the nucleic acid sequence shown in SEQ ID NO:56;The sense strand of the dsRNA molecule comprises SEQ ID NO: 71 or consists of the nucleic acid sequence shown in SEQ ID NO: 71, and the antisense strand comprises SEQ ID NO: 72 or consists of the nucleic acid sequence shown in SEQ ID NO: 72; or the sense strand of the dsRNA molecule comprises SEQ ID NO: 77 or consists of the nucleic acid sequence shown in SEQ ID NO: 77, and the antisense strand comprises SEQ ID NO: 78 or consists of the nucleic acid sequence shown in SEQ ID NO: 78.

[0009] In some embodiments, the modification pattern of the dsRNA molecule includes: (1) sense strand: 19-23 nt in length, such as 19, 20, 21, 22 or 23 nt; composed of alternating 2′-O-methyl modified regions and 2′-fluoro modified regions, and the number of consecutive nucleotides in each modified region is any one of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 nucleotides; and (2) antisense strand: 19-25 nt in length, such as 19, 20, 21, 22, 23, 24n or 25 nt; composed of alternating 2′-O-methyl modified regions, 2′-fluoro modified regions, unmodified regions and / or DNA regions, and the number of consecutive nucleotides in each modified region is any one of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 nucleotides; the modification pattern of the first modified region from the 5′ end and the 3′ end is the same; and the sense strand is 19-25 nt in length, such as 19, 20, 21, 22, 23, 24n or 25 nt In the sense strand and the antisense strand, the continuous nucleotide region from positions 1 to 2, 1 to 3, 1 to 4, 1 to 5, 1 to 6, or 1 to 7 from the 5' end, and optionally the continuous nucleotide region from positions 1 to 2, 1 to 3, 1 to 4, 1 to 5, 1 to 6, or 1 to 7 from the 3' end, are all connected by a phosphorothioate backbone; preferably, the continuous nucleotide region from positions 1 to 3 from the 5' end, and optionally the continuous nucleotide region from positions 1 to 3 from the 3' end, are all connected by a phosphorothioate backbone.

[0010] In some embodiments, the ligand in the ligand modification is selected from any one or more of the following groups: cholesterol, biotin, vitamins, galactose derivatives or analogs, lactose derivatives or analogs, N-acetylgalactosamine derivatives or analogs, and N-acetylglucosamine derivatives or analogs.

[0011] In some embodiments, the ligand is linked to the 3' terminal nucleotide of the sense strand and / or antisense strand; the conjugation is linked to the base or the sugar ring; preferably, the ligand is linked to the sugar ring; further preferably, the ligand is linked to the 3' position of the sugar ring.

[0012] In some embodiments, the ligand is one or more GalNAc derivatives connected via a divalent or trivalent branched structure;

[0013] Preferably, the GalNAc derivative comprises the following structure:

[0014] More preferably, the ligand is L96, whose structure is shown in Formula I:

[0015] In some embodiments, the dsRNA molecule comprises a modification motif selected from any one of the following: (1) sense strand: NmsNmsNmNmNmNmNfNmNfNfNfNmNmNmNmNmNmNmNmsNmsNm, antisense strand: NmsNfsNmNmNmNmNmNmNmNmNmNmNmNfNmNfNmNmNmNmNmNmsNmsNm; (2) sense strand: NmsNmsNm NmNmNmNfNmNfNfNfNmNmNmNmNmNmNmNmNmNm, antisense chain: NmsNfsNmNmNmNmNmNmNmNmNmNmNfNmNfNmNmNmNmNmNmsNmsNm; wherein, Nm represents a 2'-O-methyl-modified ribonucleotide; Nf represents a 2'-fluoro-modified ribonucleotide; (s) indicates that the two nucleotides are connected by a phosphorothioate backbone.

[0016] In some embodiments, the double-stranded RNAi agent comprises one or more selected from the following: (1) a sense strand consisting of a nucleotide sequence that is at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identical to the nucleotide sequence of SEQ ID NO: 1 and corresponding modifications, and an antisense strand consisting of a nucleotide sequence that is at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identical to the nucleotide sequence of SEQ ID NO: 2 and corresponding modifications; (2) a sense strand consisting of a nucleotide sequence that is at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identical to the nucleotide sequence of SEQ ID NO: 3 and corresponding modifications, and an antisense strand consisting of a nucleotide sequence that is at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identical to the nucleotide sequence of SEQ ID NO: 4 and corresponding modifications; (3) a sense strand consisting of a nucleotide sequence that is at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identical to the nucleotide sequence of SEQ ID NO: 5 and corresponding modifications, and an antisense strand consisting of a nucleotide sequence that is at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identical to the nucleotide sequence of SEQ ID NO: 6 and corresponding modifications. NO:5 and corresponding modifications thereof having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity, and an antisense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity to the nucleotide sequence of SEQ ID NO:6 and corresponding modifications thereof; (4) a sense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity to the nucleotide sequence of SEQ ID NO:7 and corresponding modifications thereof; and an antisense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity to the nucleotide sequence of SEQ ID NO:8 and corresponding modifications thereof; (5) a sense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity to the nucleotide sequence of SEQ ID NO:9 and corresponding modifications thereof; NO:9 and corresponding modifications thereof having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity, and an antisense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity to the nucleotide sequence of SEQ ID NO:10 and corresponding modifications thereof; (6) a sense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity to the nucleotide sequence of SEQ ID NO:11 and corresponding modifications thereof, and an antisense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity to the nucleotide sequence of SEQ ID NO:12 and corresponding modifications thereof;(7) a sense strand consisting of a nucleotide sequence that is at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identical to the nucleotide sequence of SEQ ID NO: 13 and corresponding modifications, and an antisense strand consisting of a nucleotide sequence that is at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identical to the nucleotide sequence of SEQ ID NO: 14 and corresponding modifications; (8) a sense strand consisting of a nucleotide sequence that is at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identical to the nucleotide sequence of SEQ ID NO: 15 and corresponding modifications, and an antisense strand consisting of a nucleotide sequence that is at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identical to the nucleotide sequence of SEQ ID NO: 16 and corresponding modifications; (9) a sense strand consisting of a nucleotide sequence that is at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identical to the nucleotide sequence of SEQ ID NO: 17 and corresponding modifications; NO:17 and corresponding modifications thereof having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity, and an antisense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity to the nucleotide sequence of SEQ ID NO:18 and corresponding modifications thereof; (10) a sense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity to the nucleotide sequence of SEQ ID NO:19 and corresponding modifications thereof; and an antisense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity to the nucleotide sequence of SEQ ID NO:20 and corresponding modifications thereof; (11) a sense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity to the nucleotide sequence of SEQ ID NO:21 and corresponding modifications thereof; NO:21 and corresponding modifications thereof, a sense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity, and an antisense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity, to the nucleotide sequence of SEQ ID NO:22 and corresponding modifications thereof; (12) a sense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity, to the nucleotide sequence of SEQ ID NO:23 and corresponding modifications thereof, and an antisense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity, to the nucleotide sequence of SEQ ID NO:24 and corresponding modifications thereof;(13) a sense strand consisting of a nucleotide sequence that is at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identical to the nucleotide sequence of SEQ ID NO: 25 and corresponding modifications, and an antisense strand consisting of a nucleotide sequence that is at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identical to the nucleotide sequence of SEQ ID NO: 2 and corresponding modifications; (14) a sense strand consisting of a nucleotide sequence that is at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identical to the nucleotide sequence of SEQ ID NO: 26 and corresponding modifications, and an antisense strand consisting of a nucleotide sequence that is at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identical to the nucleotide sequence of SEQ ID NO: 4 and corresponding modifications; (15) a sense strand consisting of a nucleotide sequence that is at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identical to the nucleotide sequence of SEQ ID NO: 5 NO:27 and corresponding modifications thereof having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity to the nucleotide sequence of SEQ ID NO:27 and corresponding modifications thereof, and an antisense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity to the nucleotide sequence of SEQ ID NO:6 and corresponding modifications thereof; (16) a sense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity to the nucleotide sequence of SEQ ID NO:28 and corresponding modifications thereof, and an antisense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity to the nucleotide sequence of SEQ ID NO:8 and corresponding modifications thereof; (17) a sense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity to the nucleotide sequence of SEQ ID NO:8 and corresponding modifications thereof; NO:29 and corresponding modifications thereof, and a sense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity, and an antisense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity, to the nucleotide sequence of SEQ ID NO:10 and corresponding modifications thereof; (18) a sense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity, to the nucleotide sequence of SEQ ID NO:30 and corresponding modifications thereof, and an antisense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity, to the nucleotide sequence of SEQ ID NO:12 and corresponding modifications thereof;(19) a sense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity to the nucleotide sequence of SEQ ID NO: 31 and corresponding modifications, and an antisense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity to the nucleotide sequence of SEQ ID NO: 14 and corresponding modifications; (20) a sense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity to the nucleotide sequence of SEQ ID NO: 32 and corresponding modifications, and an antisense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity to the nucleotide sequence of SEQ ID NO: 16 and corresponding modifications; (21) a sense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity to the nucleotide sequence of SEQ ID NO: 17 and corresponding modifications. NO:33 and corresponding modifications thereof having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity, and an antisense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity to the nucleotide sequence of SEQ ID NO:18 and corresponding modifications thereof; (22) a sense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity to the nucleotide sequence of SEQ ID NO:34 and corresponding modifications thereof; and an antisense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity to the nucleotide sequence of SEQ ID NO:20 and corresponding modifications thereof; (23) a sense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity to the nucleotide sequence of SEQ ID NO:21 and corresponding modifications thereof; NO:35 and corresponding modifications thereof having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity to the nucleotide sequence of SEQ ID NO:35 and corresponding modifications thereof, and an antisense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity to the nucleotide sequence of SEQ ID NO:22 and corresponding modifications thereof; and (24) a sense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity to the nucleotide sequence of SEQ ID NO:36 and corresponding modifications thereof, and an antisense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity to the nucleotide sequence of SEQ ID NO:24 and corresponding modifications thereof.;

[0017] In some embodiments, the nucleic acid sequence of the double-stranded RNAi agent comprises any one or more selected from the following: (1) the sense strand nucleic acid sequence consists of SEQ ID NO: 1 and an additional 0-5 nucleotides at the 5' and / or 3' end, and the antisense strand nucleotide sequence consists of SEQ ID NO: 2 and an additional 0-5 nucleotides at the 5' and / or 3' end; (2) the sense strand nucleic acid sequence consists of SEQ ID NO: 3 and an additional 0-5 nucleotides at the 5' and / or 3' end, and the antisense strand nucleotide sequence consists of SEQ ID NO: 4 and an additional 0-5 nucleotides at the 5' and / or 3' end; (3) the sense strand nucleic acid sequence consists of SEQ ID NO: 5 and an additional 0-5 nucleotides at the 5' and / or 3' end, and the antisense strand nucleotide sequence consists of SEQ ID NO: 6 and an additional 0-5 nucleotides at the 5' and / or 3' end; (4) the sense strand nucleic acid sequence consists of SEQ ID NO: 7 and an additional 0-5 nucleotides at the 5' and / or 3' end, and the antisense strand nucleotide sequence consists of SEQ ID NO: NO:8 and an additional 0-5 nucleotides at the 5' and / or 3' end; (5) the sense strand nucleic acid sequence consists of SEQ ID NO:9 and an additional 0-5 nucleotides at the 5' and / or 3' end, and the antisense strand nucleotide sequence consists of SEQ ID NO:10 and an additional 0-5 nucleotides at the 5' and / or 3' end; (6) the sense strand nucleic acid sequence consists of SEQ ID NO:11 and an additional 0-5 nucleotides at the 5' and / or 3' end, and the antisense strand nucleotide sequence consists of SEQ ID NO:12 and an additional 0-5 nucleotides at the 5' and / or 3' end; (7) the sense strand nucleic acid sequence consists of SEQ ID NO:13 and an additional 0-5 nucleotides at the 5' and / or 3' end, and the antisense strand nucleotide sequence consists of SEQ ID NO:14 and an additional 0-5 nucleotides at the 5' and / or 3' end; (8) the sense strand nucleic acid sequence consists of SEQ ID NO: NO:15 and an additional 0-5 nucleotides at the 5' and / or 3' end, and the antisense strand nucleotide sequence consists of SEQ ID NO:16 and an additional 0-5 nucleotides at the 5' and / or 3' end; (9) the sense strand nucleotide sequence consists of SEQ ID NO:17 and an additional 0-5 nucleotides at the 5' and / or 3' end, and the antisense strand nucleotide sequence consists of SEQ ID NO:18 and an additional 0-5 nucleotides at the 5' and / or 3' end; (10) the sense strand nucleotide sequence consists of SEQ ID NO:19 and an additional 0-5 nucleotides at the 5' and / or 3' end, and the antisense strand nucleotide sequence consists of SEQ ID NO:20 and an additional 0-5 nucleotides at the 5' and / or 3' end;(11) the sense strand nucleic acid sequence consists of SEQ ID NO: 21 and 0-5 additional nucleotides at the 5' and / or 3' end, and the antisense strand nucleic acid sequence consists of SEQ ID NO: 22 and 0-5 additional nucleotides at the 5' and / or 3' end; (12) the sense strand nucleic acid sequence consists of SEQ ID NO: 23 and 0-5 additional nucleotides at the 5' and / or 3' end, and the antisense strand nucleic acid sequence consists of SEQ ID NO: 24 and 0-5 additional nucleotides at the 5' and / or 3' end; (13) the sense strand nucleic acid sequence consists of SEQ ID NO: 25 and 0-5 additional nucleotides at the 5' and / or 3' end, and the antisense strand nucleic acid sequence consists of SEQ ID NO: 2 and 0-5 additional nucleotides at the 5' and / or 3' end; (14) the sense strand nucleic acid sequence consists of SEQ ID NO: 26 and 0-5 additional nucleotides at the 5' and / or 3' end, and the antisense strand nucleic acid sequence consists of SEQ ID NO: NO:4 and an additional 0-5 nucleotides at the 5' and / or 3' end; (15) the sense strand nucleic acid sequence consists of SEQ ID NO:27 and an additional 0-5 nucleotides at the 5' and / or 3' end, and the antisense strand nucleotide sequence consists of SEQ ID NO:6 and an additional 0-5 nucleotides at the 5' and / or 3' end; (16) the sense strand nucleic acid sequence consists of SEQ ID NO:28 and an additional 0-5 nucleotides at the 5' and / or 3' end, and the antisense strand nucleotide sequence consists of SEQ ID NO:8 and an additional 0-5 nucleotides at the 5' and / or 3' end; (17) the sense strand nucleic acid sequence consists of SEQ ID NO:29 and an additional 0-5 nucleotides at the 5' and / or 3' end, and the antisense strand nucleotide sequence consists of SEQ ID NO:10 and an additional 0-5 nucleotides at the 5' and / or 3' end; (18) the sense strand nucleic acid sequence consists of SEQ ID NO: NO:30 and an additional 0-5 nucleotides at the 5' and / or 3' terminus, and the antisense strand nucleotide sequence consists of SEQ ID NO:12 and an additional 0-5 nucleotides at the 5' and / or 3' terminus; (19) the sense strand nucleic acid sequence consists of SEQ ID NO:31 and an additional 0-5 nucleotides at the 5' and / or 3' terminus, and the antisense strand nucleotide sequence consists of SEQ ID NO:14 and an additional 0-5 nucleotides at the 5' and / or 3' terminus; (20) the sense strand nucleic acid sequence consists of SEQ ID NO:32 and an additional 0-5 nucleotides at the 5' and / or 3' terminus, and the antisense strand nucleotide sequence consists of SEQ ID NO:16 and an additional 0-5 nucleotides at the 5' and / or 3' terminus; (21) the sense strand nucleic acid sequence consists of SEQ ID NO:33 and an additional 0-5 nucleotides at the 5' and / or 3' terminus, and the antisense strand nucleotide sequence consists of SEQ ID NO:18 and an additional 0-5 nucleotides at the 5' and / or 3' terminus;(22) the sense strand nucleic acid sequence consists of SEQ ID NO: 34 and an additional 0-5 nucleotides at the 5' and / or 3' end, and the antisense strand nucleic acid sequence consists of SEQ ID NO: 20 and an additional 0-5 nucleotides at the 5' and / or 3' end;

[0018] (23) the sense strand nucleic acid sequence consists of SEQ ID NO:35 and an additional 0-5 nucleotides at the 5' and / or 3' end, and the antisense strand nucleotide sequence consists of SEQ ID NO:22 and an additional 0-5 nucleotides at the 5' and / or 3' end; and (24) the sense strand nucleic acid sequence consists of SEQ ID NO:36 and an additional 0-5 nucleotides at the 5' and / or 3' end, and the antisense strand nucleotide sequence consists of SEQ ID NO:24 and an additional 0-5 nucleotides at the 5' and / or 3' end.

[0019] In some embodiments, the double-stranded RNAi agent is one or more selected from the following groups: (1) the sense strand nucleic acid sequence is SEQ ID NO:25, and the antisense strand nucleotide sequence is SEQ ID NO:2; (2) the sense strand nucleic acid sequence is SEQ ID NO:26, and the antisense strand nucleotide sequence is SEQ ID NO:4; (3) the sense strand nucleic acid sequence is SEQ ID NO:27, and the antisense strand nucleotide sequence is SEQ ID NO:6; (4) the sense strand nucleic acid sequence is SEQ ID NO:28, and the antisense strand nucleotide sequence is SEQ ID NO:8; (5) the sense strand nucleic acid sequence is SEQ ID NO:29, and the antisense strand nucleotide sequence is SEQ ID NO:10; (6) the sense strand nucleic acid sequence is SEQ ID NO:30, and the antisense strand nucleotide sequence is SEQ ID NO:12; (7) the sense strand nucleic acid sequence is SEQ ID NO:31, and the antisense strand nucleotide sequence is SEQ ID NO:14; (8) the sense strand nucleic acid sequence is SEQ ID NO:32, and the antisense strand nucleotide sequence is SEQ ID NO:16; (9) the sense strand nucleic acid sequence is SEQ ID NO:33, and the antisense strand nucleotide sequence is SEQ ID NO:18; (10) the sense strand nucleic acid sequence is SEQ ID NO:34, and the antisense strand nucleotide sequence is SEQ ID NO:20; (11) the sense strand nucleic acid sequence is SEQ ID NO:35, and the antisense strand nucleotide sequence is SEQ ID NO:22; and (12) the sense strand nucleic acid sequence is SEQ ID NO:36, and the antisense strand nucleotide sequence is SEQ ID NO:24; wherein the 3'-OH at the 3' end of the sense strand is linked to the L96 ligand shown in Formula I below:

[0020] On the other hand, the present application provides a biomaterial selected from any one of the following groups:

[0021] (A) a DNA molecule capable of producing any of the aforementioned double-stranded RNAi agents;

[0022] (B) a vector capable of expressing any of the aforementioned double-stranded RNAi agents;

[0023] (C) a reagent or kit comprising any of the aforementioned double-stranded RNAi agents or the DNA molecule or vector described in (A) or (B);

[0024] (D) A pharmaceutical composition consisting of any of the aforementioned double-stranded RNAi agents and other pharmaceutically acceptable components.

[0025] In another aspect, the present application provides a use of the dsRNA or double-stranded RNAi agent, which is selected from any one of the following groups:

[0026] (1) Use of the dsRNA according to any one of claims 1 to 11 or the biological material according to claim 12 for inhibiting the expression of the complement MASP2 gene or for preparing a product for inhibiting the expression of the complement MASP2 gene;

[0027] (II) Use of the dsRNA according to any one of claims 1 to 11 or the biomaterial according to claim 12 in a product for reducing MASP2 protein in serum;

[0028] (III) Use of the dsRNA according to any one of claims 1 to 11 or the biomaterial according to claim 12 for preventing and / or treating a disease mediated by the complement MASP2 gene, or for preparing a product for preventing and / or treating a disease mediated by the complement MASP2 gene;

[0029] (IV) Use of the dsRNA of any one of claims 1 to 11 or the biomaterial of claim 12 for alleviating symptoms of a disease mediated by the complement MASP2 gene, or for preparing a product for alleviating symptoms of a disease mediated by the complement MASP2 gene;

[0030] Diseases mediated by the complement MASP2 gene include: ophthalmic diseases, blood diseases, cardiovascular diseases, autoimmune diseases, kidney diseases, neurological diseases or tumor diseases; ophthalmic diseases include wet / dry age-related macular degeneration (AMD), geographic atrophy (GA), etc.; neurological diseases include: Alzheimer's disease (AD), myasthenia gravis (gMG), etc.; kidney diseases include: classic hemolytic uremic syndrome (aHUS), C3 glomerulopathy (C3G) and IgA nephropathy; blood diseases include: paroxysmal nocturnal hemoglobinuria (PNH) and thrombotic microangiopathy (TMAs); autoimmune diseases include: rheumatoid arthritis, lupus erythematosus, etc.; tumor diseases include: complement-related liver cancer or lung cancer.

[0031] It should be understood that the aspects and embodiments of the present application described herein include aspects and embodiments that "comprise," "consist of," and "consist essentially of." The preferred embodiments of the present application are described in detail above, but the present application is not limited thereto. Within the technical concept of the present application, various simple variations of the technical solution of the present application may be made, including combining the various technical features in any other suitable manner. These simple variations and combinations should also be considered as disclosed in the present application and fall within the scope of protection of the present application.

[0032] Technical effect:

[0033] The unexpected technical effects of the present application are reflected in the following aspects: 1) The modified dsRNA molecules have high stability and high inhibitory activity; 2) While maintaining high inhibitory activity and stability, the ligand-modified dsRNA molecules also have good liver targeting and the ability to promote cell endocytosis, which can reduce the impact on other tissues or organs and reduce the amount of dsRNA molecules used, thereby achieving the purpose of reducing toxicity and reducing costs; 3) The ligand-modified dsRNA molecules can enter target cells and target tissues without the need for transfection reagents, reducing the negative effects of transfection reagents, such as cell or tissue toxicity. This provides the possibility for targeted therapy. Although many modifications can be attempted to improve the performance of dsRNA, these attempts are generally difficult to explain both mediating RNA interference and having improved stability in serum (for example, having increased resistance to nucleases and / or extended duration). The modified dsRNA of the present application has high stability while maintaining high inhibitory activity, achieving unexpected technical effects. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figure 1: dsRNA high-throughput screening results.

[0035] Figure 2: Results of a single screening of modified candidate dsRNA sequences at 1 nM in HepG2 cells.

[0036] Figure 3: Results of single screening of modified candidate dsRNA sequences at 0.1 nM in HepG2 cells.

[0037] Detailed Description of the Invention

[0038] The present application provides a dsRNA molecule, reagent, kit, and pharmaceutical composition for inhibiting complement MASP2 gene expression, as well as methods and uses of the dsRNA molecule, reagent, kit, or pharmaceutical composition for inhibiting or reducing complement MASP2 gene expression and preventing or treating diseases or symptoms mediated by the complement MASP2 gene. The dsRNA molecule promotes sequence-specific degradation of MASP2 mRNA through RNAi, thereby inhibiting complement MASP2 gene expression or reducing the expression level of the complement MASP2 gene.

[0039] In one aspect, the present application provides a double-stranded ribonucleic acid (dsRNA) molecule for inhibiting the expression of complement component MASP2, wherein the dsRNA comprises a sense strand and an antisense strand that complement each other to form a double-stranded region, wherein the sense strand and / or the antisense strand comprises or consists of 15-25 nucleotides, the antisense strand is complementary to at least 15, 16, 17, 18, 19, 20, or 21 consecutive nucleotides of the nucleic acid sequence of SEQ ID NO: 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 71, or 77, and the length of the double-stranded region is 15-25 bp, preferably 19-21 bp.

[0040] In some embodiments, at least one nucleotide in the dsRNA molecule is modified, and the modification is selected from any one or more of the following: locked nucleic acid (LNA) modification, open ring or unlocked (UNA) modification, 2′-methoxyethyl modification, 2′-O-methyl modification, 2′-O-allyl modification, 2′-C-allyl modification, 2′-fluoro modification, 2′-deoxy modification, 2′-hydroxyl modification, thiophosphate backbone modification, DNA modification, fluorescent probe modification, and ligand modification.

[0041] In some embodiments, the dsRNA molecule can be selected from the dsRNA listed in Table 1 of the Examples; the dsRNA molecule can be selected from dsRNAs having 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with the dsRNA listed in Table 1 of the Examples.

[0042] In some embodiments, the naked sequence of the dsRNA molecule can be selected from one or more of the following: the sense strand of the dsRNA molecule comprises SEQ ID NO: 37 or consists of the nucleic acid sequence shown in SEQ ID NO: 37, and the antisense strand comprises SEQ ID NO: 38 or consists of the nucleic acid sequence shown in SEQ ID NO: 38; the sense strand of the dsRNA molecule comprises SEQ ID NO: 39 or consists of the nucleic acid sequence shown in SEQ ID NO: 39, and the antisense strand comprises SEQ ID NO: 40 or consists of the nucleic acid sequence shown in SEQ ID NO: 40; the sense strand of the dsRNA molecule comprises SEQ ID NO: 41 or consists of the nucleic acid sequence shown in SEQ ID NO: 41, and the antisense strand comprises SEQ ID NO: 42 or consists of the nucleic acid sequence shown in SEQ ID NO: 42; the sense strand of the dsRNA molecule comprises SEQ ID NO: 43 or consists of the nucleic acid sequence shown in SEQ ID NO: 43, and the antisense strand comprises SEQ ID NO: 44 or consists of the nucleic acid sequence shown in SEQ ID NO: 44; the sense strand of the dsRNA molecule comprises SEQ ID NO: NO:45 or consists of the nucleic acid sequence set forth in SEQ ID NO:45, the antisense strand comprises SEQ ID NO:46 or consists of the nucleic acid sequence set forth in SEQ ID NO:46; the sense strand of the dsRNA molecule comprises SEQ ID NO:47 or consists of the nucleic acid sequence set forth in SEQ ID NO:47, the antisense strand comprises SEQ ID NO:48 or consists of the nucleic acid sequence set forth in SEQ ID NO:48; the sense strand of the dsRNA molecule comprises SEQ ID NO:49 or consists of the nucleic acid sequence set forth in SEQ ID NO:49, the antisense strand comprises SEQ ID NO:50 or consists of the nucleic acid sequence set forth in SEQ ID NO:50; the sense strand of the dsRNA molecule comprises SEQ ID NO:51 or consists of the nucleic acid sequence set forth in SEQ ID NO:51, the antisense strand comprises SEQ ID NO:52 or consists of the nucleic acid sequence set forth in SEQ ID NO:52; the sense strand of the dsRNA molecule comprises SEQ ID NO:53 or consists of the nucleic acid sequence set forth in SEQ ID NO:53, the antisense strand comprises SEQ ID NO:54 or consists of the nucleic acid sequence set forth in SEQ ID NO:54. NO:54; the sense strand of the dsRNA molecule comprises or consists of the nucleic acid sequence shown in SEQ ID NO:55, and the antisense strand comprises or consists of the nucleic acid sequence shown in SEQ ID NO:56;The sense strand of the dsRNA molecule comprises SEQ ID NO: 71 or consists of the nucleic acid sequence shown in SEQ ID NO: 71, and the antisense strand comprises SEQ ID NO: 72 or consists of the nucleic acid sequence shown in SEQ ID NO: 72; or the sense strand of the dsRNA molecule comprises SEQ ID NO: 77 or consists of the nucleic acid sequence shown in SEQ ID NO: 77, and the antisense strand comprises SEQ ID NO: 78 or consists of the nucleic acid sequence shown in SEQ ID NO: 78.

[0043] In some embodiments, the modification methods of the dsRNA molecules provided herein include: (1) sense strand: 19-23 nt in length, such as 19, 20, 21, 22 or 23 nt, preferably 21 nt; composed of 2′-O-methyl modified regions and 2′-fluoro modified regions alternately, and the number of consecutive nucleotides in each modified region is any one of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 nucleotides; (2) antisense strand: 19-25 nt in length, such as 19, 20, 21, 22, 23 nt, 24n or 25 nt, preferably 23 nt; composed of 2′-O-methyl modified regions, 2′-fluoro modified regions, unmodified regions and / or DNA regions alternately, and the number of consecutive nucleotides in each modified region is any one of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 nucleotides; , 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 nucleotides; the modification mode of the first modified region from the 5' end and the 3' end is the same; and in the sense strand and the antisense strand, the continuous nucleotide region from positions 1 to 2, 1 to 3, 1 to 4, 1 to 5, 1 to 6, or 1 to 7 from the 5' end, and optionally the continuous nucleotide region from positions 1 to 2, 1 to 3, 1 to 4, 1 to 5, 1 to 6, or 1 to 7 from the 3' end, are all connected by a thiophosphate backbone; preferably, the continuous nucleotide region from positions 1 to 3 from the 5' end, and optionally the continuous nucleotide region from positions 1 to 3 from the 3' end, are all connected by a thiophosphate backbone.

[0044] In some embodiments, the ligand in the ligand modification of the dsRNA molecule is selected from any one or more of the following groups: cholesterol, biotin, vitamins, galactose derivatives or analogs, lactose derivatives or analogs, N-acetylgalactosamine derivatives or analogs, and N-acetylglucosamine derivatives or analogs.

[0045] In some embodiments, the ligand is linked to the 3' terminal nucleotide of the sense strand and / or antisense strand; the conjugation is linked to the base or the sugar ring; preferably, the ligand is linked to the sugar ring; further preferably, the ligand is linked to the 3' position of the sugar ring.

[0046] In some embodiments, the ligand in the ligand modification of the dsRNA molecule is one or more GalNAc derivatives connected by a divalent or trivalent branched structure;

[0047] Preferably, the GalNAc derivative comprises the following structure:

[0048] More preferably, the ligand is L96, whose structure is shown in Formula I:

[0049] In some preferred embodiments, the dsRNA molecule comprises a modification motif selected from any one of the following: (1) sense strand: NmsNmsNmNmNmNmNfNmNfNfNfNmNmNmNmNmNmNmNmsNmsNm, antisense strand: NmsNfsNmNmNmNmNmNmNmNmNmNmNmNfNmNfNmNmNmNmNmNmsNmsNm; (2) sense strand: NmsNmsNmNmNmNmNmNfNmNfNfNmNfNmNmNmNmNmNmNmsNmsNm mNmNmNmNfNmNfNfNfNmNmNmNmNmNmNmNmNmNm, antisense chain: NmsNfsNmNmNmNmNmNmNmNmNmNmNfNmNfNmNmNmNmNmNmsNmsNm; wherein, Nm represents a 2'-O-methyl-modified ribonucleotide; Nf represents a 2'-fluoro-modified ribonucleotide; (s) indicates that the two nucleotides are connected by a phosphorothioate backbone.

[0050] In some preferred embodiments, the dsRNA molecule comprises one or more selected from the group consisting of: (1) a sense strand consisting of a nucleotide sequence that is at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identical to the nucleotide sequence of SEQ ID NO: 1 and corresponding modifications, and an antisense strand consisting of a nucleotide sequence that is at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identical to the nucleotide sequence of SEQ ID NO: 2 and corresponding modifications; (2) a sense strand consisting of a nucleotide sequence that is at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identical to the nucleotide sequence of SEQ ID NO: 3 and corresponding modifications, and an antisense strand consisting of a nucleotide sequence that is at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identical to the nucleotide sequence of SEQ ID NO: 4 and corresponding modifications; (3) a sense strand consisting of a nucleotide sequence that is at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identical to the nucleotide sequence of SEQ ID NO: 5 and corresponding modifications, and an antisense strand consisting of a nucleotide sequence that is at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identical to the nucleotide sequence of SEQ ID NO: 6 and corresponding modifications. NO:5 and corresponding modifications thereof having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity, and an antisense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity to the nucleotide sequence of SEQ ID NO:6 and corresponding modifications thereof; (4) a sense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity to the nucleotide sequence of SEQ ID NO:7 and corresponding modifications thereof; and an antisense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity to the nucleotide sequence of SEQ ID NO:8 and corresponding modifications thereof; (5) a sense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity to the nucleotide sequence of SEQ ID NO:9 and corresponding modifications thereof; NO:9 and corresponding modifications thereof having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity, and an antisense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity to the nucleotide sequence of SEQ ID NO:10 and corresponding modifications thereof; (6) a sense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity to the nucleotide sequence of SEQ ID NO:11 and corresponding modifications thereof, and an antisense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity to the nucleotide sequence of SEQ ID NO:12 and corresponding modifications thereof;(7) a sense strand consisting of a nucleotide sequence that is at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identical to the nucleotide sequence of SEQ ID NO: 13 and corresponding modifications, and an antisense strand consisting of a nucleotide sequence that is at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identical to the nucleotide sequence of SEQ ID NO: 14 and corresponding modifications; (8) a sense strand consisting of a nucleotide sequence that is at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identical to the nucleotide sequence of SEQ ID NO: 15 and corresponding modifications, and an antisense strand consisting of a nucleotide sequence that is at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identical to the nucleotide sequence of SEQ ID NO: 16 and corresponding modifications; (9) a sense strand consisting of a nucleotide sequence that is at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identical to the nucleotide sequence of SEQ ID NO: 17 and corresponding modifications; NO:17 and corresponding modifications thereof having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity, and an antisense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity to the nucleotide sequence of SEQ ID NO:18 and corresponding modifications thereof; (10) a sense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity to the nucleotide sequence of SEQ ID NO:19 and corresponding modifications thereof; and an antisense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity to the nucleotide sequence of SEQ ID NO:20 and corresponding modifications thereof; (11) a sense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity to the nucleotide sequence of SEQ ID NO:21 and corresponding modifications thereof; NO:21 and corresponding modifications thereof, a sense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity, and an antisense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity, to the nucleotide sequence of SEQ ID NO:22 and corresponding modifications thereof; (12) a sense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity, to the nucleotide sequence of SEQ ID NO:23 and corresponding modifications thereof, and an antisense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity, to the nucleotide sequence of SEQ ID NO:24 and corresponding modifications thereof;(13) a sense strand consisting of a nucleotide sequence that is at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identical to the nucleotide sequence of SEQ ID NO: 25 and corresponding modifications, and an antisense strand consisting of a nucleotide sequence that is at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identical to the nucleotide sequence of SEQ ID NO: 2 and corresponding modifications; (14) a sense strand consisting of a nucleotide sequence that is at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identical to the nucleotide sequence of SEQ ID NO: 26 and corresponding modifications, and an antisense strand consisting of a nucleotide sequence that is at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identical to the nucleotide sequence of SEQ ID NO: 4 and corresponding modifications; (15) a sense strand consisting of a nucleotide sequence that is at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identical to the nucleotide sequence of SEQ ID NO: 5 NO:27 and corresponding modifications thereof having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity to the nucleotide sequence of SEQ ID NO:27 and corresponding modifications thereof, and an antisense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity to the nucleotide sequence of SEQ ID NO:6 and corresponding modifications thereof; (16) a sense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity to the nucleotide sequence of SEQ ID NO:28 and corresponding modifications thereof, and an antisense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity to the nucleotide sequence of SEQ ID NO:8 and corresponding modifications thereof; (17) a sense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity to the nucleotide sequence of SEQ ID NO:8 and corresponding modifications thereof; NO:29 and corresponding modifications thereof, and a sense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity, and an antisense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity, to the nucleotide sequence of SEQ ID NO:10 and corresponding modifications thereof; (18) a sense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity, to the nucleotide sequence of SEQ ID NO:30 and corresponding modifications thereof, and an antisense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity, to the nucleotide sequence of SEQ ID NO:12 and corresponding modifications thereof;(19) a sense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity to the nucleotide sequence of SEQ ID NO: 31 and corresponding modifications, and an antisense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity to the nucleotide sequence of SEQ ID NO: 14 and corresponding modifications; (20) a sense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity to the nucleotide sequence of SEQ ID NO: 32 and corresponding modifications, and an antisense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity to the nucleotide sequence of SEQ ID NO: 16 and corresponding modifications; (21) a sense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity to the nucleotide sequence of SEQ ID NO: 17 and corresponding modifications. NO:33 and corresponding modifications thereof having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity, and an antisense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity to the nucleotide sequence of SEQ ID NO:18 and corresponding modifications thereof; (22) a sense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity to the nucleotide sequence of SEQ ID NO:34 and corresponding modifications thereof; and an antisense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity to the nucleotide sequence of SEQ ID NO:20 and corresponding modifications thereof; (23) a sense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity to the nucleotide sequence of SEQ ID NO:21 and corresponding modifications thereof; NO:35 and corresponding modifications thereof having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity to the nucleotide sequence of SEQ ID NO:35 and corresponding modifications thereof, and an antisense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity to the nucleotide sequence of SEQ ID NO:22 and corresponding modifications thereof; and (24) a sense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity to the nucleotide sequence of SEQ ID NO:36 and corresponding modifications thereof, and an antisense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity to the nucleotide sequence of SEQ ID NO:24 and corresponding modifications thereof.;

[0051] In some embodiments, the nucleic acid sequence of the double-stranded RNAi agent comprises any one or more selected from the following: (1) the sense strand nucleic acid sequence consists of SEQ ID NO: 1 and an additional 0-5 nucleotides at the 5' and / or 3' end, and the antisense strand nucleotide sequence consists of SEQ ID NO: 2 and an additional 0-5 nucleotides at the 5' and / or 3' end; (2) the sense strand nucleic acid sequence consists of SEQ ID NO: 3 and an additional 0-5 nucleotides at the 5' and / or 3' end, and the antisense strand nucleotide sequence consists of SEQ ID NO: 4 and an additional 0-5 nucleotides at the 5' and / or 3' end; (3) the sense strand nucleic acid sequence consists of SEQ ID NO: 5 and an additional 0-5 nucleotides at the 5' and / or 3' end, and the antisense strand nucleotide sequence consists of SEQ ID NO: 6 and an additional 0-5 nucleotides at the 5' and / or 3' end; (4) the sense strand nucleic acid sequence consists of SEQ ID NO: 7 and an additional 0-5 nucleotides at the 5' and / or 3' end, and the antisense strand nucleotide sequence consists of SEQ ID NO: NO:8 and an additional 0-5 nucleotides at the 5' and / or 3' end; (5) the sense strand nucleic acid sequence consists of SEQ ID NO:9 and an additional 0-5 nucleotides at the 5' and / or 3' end, and the antisense strand nucleotide sequence consists of SEQ ID NO:10 and an additional 0-5 nucleotides at the 5' and / or 3' end; (6) the sense strand nucleic acid sequence consists of SEQ ID NO:11 and an additional 0-5 nucleotides at the 5' and / or 3' end, and the antisense strand nucleotide sequence consists of SEQ ID NO:12 and an additional 0-5 nucleotides at the 5' and / or 3' end; (7) the sense strand nucleic acid sequence consists of SEQ ID NO:13 and an additional 0-5 nucleotides at the 5' and / or 3' end, and the antisense strand nucleotide sequence consists of SEQ ID NO:14 and an additional 0-5 nucleotides at the 5' and / or 3' end; (8) the sense strand nucleic acid sequence consists of SEQ ID NO: NO:15 and an additional 0-5 nucleotides at the 5' and / or 3' end, and the antisense strand nucleotide sequence consists of SEQ ID NO:16 and an additional 0-5 nucleotides at the 5' and / or 3' end; (9) the sense strand nucleotide sequence consists of SEQ ID NO:17 and an additional 0-5 nucleotides at the 5' and / or 3' end, and the antisense strand nucleotide sequence consists of SEQ ID NO:18 and an additional 0-5 nucleotides at the 5' and / or 3' end; (10) the sense strand nucleotide sequence consists of SEQ ID NO:19 and an additional 0-5 nucleotides at the 5' and / or 3' end, and the antisense strand nucleotide sequence consists of SEQ ID NO:20 and an additional 0-5 nucleotides at the 5' and / or 3' end;(11) the sense strand nucleic acid sequence consists of SEQ ID NO: 21 and 0-5 additional nucleotides at the 5' and / or 3' end, and the antisense strand nucleic acid sequence consists of SEQ ID NO: 22 and 0-5 additional nucleotides at the 5' and / or 3' end; (12) the sense strand nucleic acid sequence consists of SEQ ID NO: 23 and 0-5 additional nucleotides at the 5' and / or 3' end, and the antisense strand nucleic acid sequence consists of SEQ ID NO: 24 and 0-5 additional nucleotides at the 5' and / or 3' end; (13) the sense strand nucleic acid sequence consists of SEQ ID NO: 25 and 0-5 additional nucleotides at the 5' and / or 3' end, and the antisense strand nucleic acid sequence consists of SEQ ID NO: 2 and 0-5 additional nucleotides at the 5' and / or 3' end; (14) the sense strand nucleic acid sequence consists of SEQ ID NO: 26 and 0-5 additional nucleotides at the 5' and / or 3' end, and the antisense strand nucleic acid sequence consists of SEQ ID NO: NO:4 and an additional 0-5 nucleotides at the 5' and / or 3' end; (15) the sense strand nucleic acid sequence consists of SEQ ID NO:27 and an additional 0-5 nucleotides at the 5' and / or 3' end, and the antisense strand nucleotide sequence consists of SEQ ID NO:6 and an additional 0-5 nucleotides at the 5' and / or 3' end; (16) the sense strand nucleic acid sequence consists of SEQ ID NO:28 and an additional 0-5 nucleotides at the 5' and / or 3' end, and the antisense strand nucleotide sequence consists of SEQ ID NO:8 and an additional 0-5 nucleotides at the 5' and / or 3' end; (17) the sense strand nucleic acid sequence consists of SEQ ID NO:29 and an additional 0-5 nucleotides at the 5' and / or 3' end, and the antisense strand nucleotide sequence consists of SEQ ID NO:10 and an additional 0-5 nucleotides at the 5' and / or 3' end; (18) the sense strand nucleic acid sequence consists of SEQ ID NO: NO:30 and an additional 0-5 nucleotides at the 5' and / or 3' end, and the antisense strand nucleotide sequence consists of SEQ ID NO:12 and an additional 0-5 nucleotides at the 5' and / or 3' end; (19) the sense strand nucleic acid sequence consists of SEQ ID NO:31 and an additional 0-5 nucleotides at the 5' and / or 3' end, and the antisense strand nucleotide sequence consists of SEQ ID NO:14 and an additional 0-5 nucleotides at the 5' and / or 3' end; (20) the sense strand nucleic acid sequence consists of SEQ ID NO:32 and an additional 0-5 nucleotides at the 5' and / or 3' end, and the antisense strand nucleotide sequence consists of SEQ ID NO:16 and an additional 0-5 nucleotides at the 5' and / or 3' end; (21) the sense strand nucleic acid sequence consists of SEQ ID NO:33 and an additional 0-5 nucleotides at the 5' and / or 3' end, and the antisense strand nucleotide sequence consists of SEQ ID NO:18 and an additional 0-5 nucleotides at the 5' and / or 3' end;(22) the sense strand nucleic acid sequence consists of SEQ ID NO: 34 and an additional 0-5 nucleotides at the 5' and / or 3' end, and the antisense strand nucleic acid sequence consists of SEQ ID NO: 20 and an additional 0-5 nucleotides at the 5' and / or 3' end;

[0052] (23) the sense strand nucleic acid sequence consists of SEQ ID NO:35 and an additional 0-5 nucleotides at the 5' and / or 3' end, and the antisense strand nucleotide sequence consists of SEQ ID NO:22 and an additional 0-5 nucleotides at the 5' and / or 3' end; and (24) the sense strand nucleic acid sequence consists of SEQ ID NO:36 and an additional 0-5 nucleotides at the 5' and / or 3' end, and the antisense strand nucleotide sequence consists of SEQ ID NO:24 and an additional 0-5 nucleotides at the 5' and / or 3' end.

[0053] In some embodiments, the double-stranded RNAi agent is one or more selected from the following groups: (1) the sense strand nucleic acid sequence is SEQ ID NO:25, and the antisense strand nucleotide sequence is SEQ ID NO:2; (2) the sense strand nucleic acid sequence is SEQ ID NO:26, and the antisense strand nucleotide sequence is SEQ ID NO:4; (3) the sense strand nucleic acid sequence is SEQ ID NO:27, and the antisense strand nucleotide sequence is SEQ ID NO:6; (4) the sense strand nucleic acid sequence is SEQ ID NO:28, and the antisense strand nucleotide sequence is SEQ ID NO:8; (5) the sense strand nucleic acid sequence is SEQ ID NO:29, and the antisense strand nucleotide sequence is SEQ ID NO:10; (6) the sense strand nucleic acid sequence is SEQ ID NO:30, and the antisense strand nucleotide sequence is SEQ ID NO:12; (7) the sense strand nucleic acid sequence is SEQ ID NO:31, and the antisense strand nucleotide sequence is SEQ ID NO:14; (8) the sense strand nucleic acid sequence is SEQ ID NO:32, and the antisense strand nucleotide sequence is SEQ ID NO:16; (9) the sense strand nucleic acid sequence is SEQ ID NO:33, and the antisense strand nucleotide sequence is SEQ ID NO:18; (10) the sense strand nucleic acid sequence is SEQ ID NO:34, and the antisense strand nucleotide sequence is SEQ ID NO:20; (11) the sense strand nucleic acid sequence is SEQ ID NO:35, and the antisense strand nucleotide sequence is SEQ ID NO:22; and (12) the sense strand nucleic acid sequence is SEQ ID NO:36, and the antisense strand nucleotide sequence is SEQ ID NO:24; wherein the 3'-OH at the 3' end of the sense strands SEQ ID NOs:25-36 is linked to an L96 ligand as shown in Formula I below:

[0054] As used herein, a "ligand" is a lipophilic moiety that is taken up by host cells. Ligand modification can improve properties of a dsRNA molecule, such as cellular uptake, intracellular targeting, half-life, or drug metabolism or kinetics. In some embodiments, a ligand-modified dsRNA has enhanced affinity or cellular uptake for a selected target (e.g., a specific tissue type, cell type, organelle, etc.), such as hepatocytes, compared to a dsRNA not modified with a ligand. Ligand modification does not interfere with the activity of the dsRNA.

[0055] In some embodiments, the ligand modification is to perform one or more ligand modifications on the 3' end, the 5' end and / or the middle of the sequence of the dsRNA molecule;

[0056] In some preferred embodiments, the ligand is selected from the group consisting of cholesterol, biotin, vitamins, galactose derivatives or analogs, lactose derivatives or analogs, N-acetylgalactosamine derivatives or analogs, and N-acetylglucosamine derivatives or analogs. The ligand targets a cell surface receptor comprising a galactose, galactosamine, lactose, or N-acetylgalactosamine / glucosamine moiety. The ligand is preferably targeted to the liver, particularly to the parenchymal cells of the liver.

[0057] In some preferred embodiments, the ligand targets the ASGPR receptor.

[0058] In some preferred embodiments, the ligand may also be human serum albumin (HSA), hyaluronic acid, polypeptide, etc.

[0059] In some preferred embodiments, the ligand-modified dsRNA is characterized in that the dsRNA molecule comprises a sense strand and an antisense strand, wherein:

[0060] (1) The sense strand sequence is shown in SEQ ID NO: 25, and the antisense strand sequence is shown in SEQ ID NO: 2;

[0061] (2) the sense strand sequence is shown in SEQ ID NO: 26, and the antisense strand sequence is shown in SEQ ID NO: 4;

[0062] (3) the sense strand sequence is shown in SEQ ID NO: 27, and the antisense strand sequence is shown in SEQ ID NO: 6;

[0063] (4) the sense strand sequence is shown in SEQ ID NO: 28, and the antisense strand sequence is shown in SEQ ID NO: 8;

[0064] (5) the sense strand sequence is shown in SEQ ID NO: 29, and the antisense strand sequence is shown in SEQ ID NO: 10;

[0065] (6) the sense strand sequence is shown in SEQ ID NO: 30, and the antisense strand sequence is shown in SEQ ID NO: 12;

[0066] (7) the sense strand sequence is shown in SEQ ID NO: 31, and the antisense strand sequence is shown in SEQ ID NO: 14;

[0067] (8) the sense strand sequence is shown in SEQ ID NO: 32, and the antisense strand sequence is shown in SEQ ID NO: 16;

[0068] (9) the sense strand sequence is shown in SEQ ID NO: 33, and the antisense strand sequence is shown in SEQ ID NO: 18;

[0069] (10) the sense strand sequence is shown in SEQ ID NO: 34, and the antisense strand sequence is shown in SEQ ID NO: 20;

[0070] (11) the sense strand sequence is shown in SEQ ID NO: 35, and the antisense strand sequence is shown in SEQ ID NO: 22;

[0071] (12) The sense strand sequence is shown in SEQ ID NO: 36, and the antisense strand sequence is shown in SEQ ID NO: 24

[0072] Wherein, Am, Um, Cm, and Gm represent 2′-O-methyl modified ribonucleotides A, U, C, and G, respectively; Af, Uf, Cf, and Gf represent 2′-fluoro modified ribonucleotides A, U, C, and G, respectively; (s) represents the two nucleotides connected by a thiophosphate backbone. The ligand is L96, and its structure is shown in Formula I:

[0073] In some embodiments, the dsRNA has a structure as shown in Formula II:

[0074] In some preferred embodiments, each strand of the dsRNA molecule may contain 0% to 100% modified nucleotides, such as 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% modified nucleotides. The modifications may be in the overhang region or the double-stranded region. The modifications may be used to improve the in vitro or in vivo characteristics of the dsRNA molecule, such as stability, biodistribution, inhibitory activity, etc. The above modifications may be used in combination.

[0075] In some preferred embodiments, each end of the dsRNA molecule has an overhang or a blunt end, including 1-8 overhangs, such as 1, 2, 3, 4, 5, 6, 7, or 8 overhangs, at the 5' and / or 3' ends of either or both strands, wherein the overhangs are arbitrarily selected from U, A, G, C, T, and dT.

[0076] In some preferred embodiments, the dsRNA molecule is capable of inhibiting the expression of MASP2 genes in humans and cynomolgus monkeys.

[0077] In another aspect, the present application also relates to biological materials associated with dsRNA;

[0078] In some embodiments, the dsRNA-associated biological material can be selected from any one of the following:

[0079] (A) a DNA molecule capable of producing the dsRNA;

[0080] (B) a vector capable of expressing the dsRNA;

[0081] (C) a reagent or kit containing the dsRNA or the DNA molecule or the vector;

[0082] (D) A pharmaceutical composition, consisting of the dsRNA molecule and other pharmaceutically acceptable components.

[0083] In some embodiments, the pharmaceutical composition includes a pharmacologically effective amount of the dsRNA molecule of the present application and other pharmaceutically acceptable components. The "effective amount" refers to the amount of the dsRNA molecule that can effectively produce the expected pharmacological therapeutic effect.

[0084] In some embodiments, "other components" include water, saline, glucose, buffer (such as PBS), excipients, diluents, disintegrants, binders, lubricants, sweeteners, flavorings, preservatives, or combinations thereof.

[0085] In another aspect, the present application relates to dsRNA or related biological materials that can be used to prevent and / or treat diseases mediated by the MASP2 gene, or to alleviate the symptoms of diseases mediated by the MASP2 gene.

[0086] Diseases mediated by the MASP2 gene include, but are not limited to, paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), asthma, rheumatoid arthritis (RA), antiphospholipid antibody syndrome, lupus nephritis, ischemia-reperfusion injury, classic or infectious 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, pauci-immune vasculitis, epidermolysis bullosa, recurrent miscarriage, preeclampsia, traumatic brain injury, myasthenia gravis, cold agglutinin disease, dermatomyositis bullous pemphigoid, Shiga toxin toxin) Escherichia coli (E. coli) associated hemolytic uremic syndrome, C3 nephropathy, antineutrophil cytoplasmic antibody-associated vasculitis, humoral and vascular transplant 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 mellitus, psoriasis, pemphigus, autoimmune hemolytic anemia (AIHA), ITP, Goodpasture's syndrome, Degos' disease, antiphospholipid syndrome (APS), catastrophic APS (CAPS), cardiovascular disorders, myocarditis, cerebrovascular disease, peripheral vascular disease, Renal vascular disease, mesenteric / intestinal vascular disease, vasculitis, Henoch-Schönlein purpura nephritis, vasculitis associated with systemic lupus erythematosus, vasculitis associated with rheumatoid arthritis, immune complex vasculitis, Takayasu's disease, dilated cardiomyopathy, diabetic vasculopathy, Kawasaki's disease (arteritis), diseases associated with viral infections (such as COVID-19), chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS), MASP2-related tumors (such as liver cancer, lung cancer, etc.), venous gas embolism (VGE) and restenosis after stent placement, rotational atherectomy, membranous nephropathy, Guillain-Barre syndrome and percutaneous transluminal coronary angioplasty (PTCA).

[0087] In some embodiments, the present application further provides any of the following uses: use of the dsRNA or biomaterial for inhibiting MASP2 gene expression or preparing a product for inhibiting MASP2 gene expression. The inhibition of MASP2 gene expression is the inhibition or reduction of MASP2 gene expression levels in humans or cynomolgus monkeys in vivo or in vitro cells. The inhibition of MASP2 gene expression is the inhibition or reduction of MASP2 gene expression levels by at least 95%, 90%, 85%, 80%, 75%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, or 5%. Detection of target gene, target RNA, or target protein levels can be used to predict or assess activity, efficacy, or therapeutic outcomes.

[0088] In some embodiments, the cells are mammalian cells expressing MASP2, such as primate cells or human cells. More preferably, the target cells express high levels of the MASP2 gene. More preferably, the cells are derived from the brain, salivary glands, heart, spleen, lung, liver, kidney, intestine, or tumor. Even more preferably, the cells are hepatocellular carcinoma cells.

[0089] In some embodiments, the cells are selected from HepG2, HEP3B, Huh7, MHCC97H, Hela, cynomolgus monkey primary cells, and human primary cells.

[0090] In some embodiments, the final cellular concentration of the dsRNA molecule is 0.001-1000 nM, such as 0.001-10 nM, 10-500 nM, 25-300 nM or 50-100 nM.

[0091] In some embodiments, the dsRNA or related biological materials can be administered by any suitable means, such as parenteral administration, including intramuscular, intravenous, arterial, peritoneal, or subcutaneous injection. Modes of administration include, but are not limited to, single administration or multiple administration.

[0092] In some preferred embodiments, the dosage range is 0.1 mg / kg to 100 mg / kg, 0.5 mg / kg to 50 mg / kg, 3 mg / kg to 36 mg / kg, 2.5 mg / kg to 20 mg / kg, 5 mg / kg to 15 mg / kg, for example: 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 11 mg / kg, 12 mg / kg, 13 mg / kg, 14 mg / kg, 15 mg / kg, 16 mg / kg, 17 mg / kg, 18 mg / kg, 19 mg / kg, 20 mg / kg, 21 mg / kg, 22 mg / kg, 23 mg / kg, 24 mg / kg, 25 mg / kg, 26 mg / kg, 27 mg / kg, 28mg / kg, 29mg / kg, 30mg / kg, 31mg / kg, 32mg / kg, 33mg / kg, 34mg / kg, 35mg / kg, 36mg / kg.

[0093] In some embodiments, a single dose of the pharmaceutical composition can provide long-lasting, reduced MASP2 expression for at least 3, 5, 7, 10, 14, or more periods of time.

[0094] In some embodiments, the dsRNA or biomaterial is used to reduce serum MASP2 levels or to prepare a product for reducing serum MASP2 levels. The reduction in serum MASP2 concentration is achieved by reducing serum MASP2 concentration in humans or cynomolgus monkeys. For example, the serum MASP2 concentration or content is reduced by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 98%.

[0095] In some embodiments, the use of the dsRNA or the biological material in preventing and / or treating a disease mediated by the MASP2 gene or in preparing a product for preventing and / or treating a disease mediated by the MASP2 gene;

[0096] In some embodiments, the use of the dsRNA or the biological material in alleviating the symptoms of a disease mediated by the MASP2 gene or in preparing a product for alleviating the symptoms of a disease mediated by the MASP2 gene;

[0097] In some embodiments, the disease mediated by the MASP2 gene is preferably a cardiovascular disease, dyslipidemia or a tumor disease.

[0098] In some embodiments, the MASP2 gene-mediated disease or symptom can be caused by overexpression of the MASP2 gene or overproduction of the MASP2 protein, and can be regulated by downregulating MASP2 gene expression. Treatment refers to alleviation, reduction, or cure of the MASP2 gene-mediated disease or symptom, such as a reduction in serum MASP2 levels. For example, the serum MASP2 content or concentration may be reduced by 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, or 95%.

[0099] In some embodiments, the present application also provides the use of the ligand-modified dsRNA molecules in the preparation of liver-targeted drugs; the liver-targeted drugs can be used to treat liver diseases mediated by the MASP2 gene.

[0100] In another aspect, the present application also provides methods and / or combination therapies for treating a subject suffering from a condition that would benefit from inhibition or reduction of expression of the MASP2 gene, such as a complement component MASP2-associated disease, such as paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS), using RNAi compositions that affect RNA-induced silencing complex (RISC)-mediated cleavage of RNA transcripts of the complement component MASP2 gene.

[0101] The combination therapies of the present invention comprise administering an RNAi agent of the present invention and an additional therapeutic agent, such as an anti-complement component MASP2 antibody or antigen-binding fragment thereof, e.g., Narsoplimab, to a patient suffering from a disease associated with complement component MASP2. The combination therapies of the present invention reduce MASP2 levels in the subject (e.g., by about 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or about 99%) by targeting MASP2 mRNA with an RNAi agent of the present invention, and thus, allow a reduction in the therapeutically (or prophylactically) effective amount of eculizumab required to treat the subject, thereby reducing treatment costs and allowing for simpler and more convenient methods of administering eculizumab, such as subcutaneous administration.

[0102] In some embodiments, the additional therapeutic agent can be an anti-complement component MASP2 antibody or an antigen-binding fragment or derivative thereof.

[0103] In some embodiments, the anti-complement component MASP2 antibody is Narsoplimab or an antigen-binding fragment or derivative thereof.

[0104] the term:

[0105] REL (Relative expression level): relative expression level of mRNA.

[0106] "G," "C," "A," "T," and "U" generally represent nucleotides based on guanine, cytosine, adenine, thymine, and uracil, respectively.

[0107] N: refers to ribonucleotides, including: ribonucleotides are divided into adenine ribonucleotides, guanine ribonucleotides, cytosine ribonucleotides, and uracil ribonucleotides.

[0108] dN: refers to deoxyribonucleotide.

[0109] GalNAc: N-acetylgalactosamine

[0110] Nm = 2'OMe modified ribonucleotide;

[0111] Nf = 2'F modified ribonucleotide;

[0112] (s) in the nucleotide sequence = PS backbone, i.e., 5'-thio-modified phosphate backbone;

[0113] DNA modification: The DNA modification of dsRNA described in this application refers to replacing ribonucleotides in the dsRNA with deoxyribonucleotides, wherein the nucleotides are the same but the type of ribose is different.

[0114] CAPA: Capping reagent A (20% acetic anhydride in acetonitrile, v / v).

[0115] CAPB: Capping reagent B (N-methylimidazole:pyridine:acetonitrile=2:3:5).

[0116] ACN: acetonitrile.

[0117] TEAA: triethylamineacetic acid.

[0118] Trityl-off synthesis: Trityl-off synthesis

[0119] ESI-MS: electrospray ionization mass spectrometry;

[0120] IEX HPLC: ion-exchange high-performance liquid chromatography;

[0121] GAPDH: glyceraldehyde-3-phosphate dehydrogenase;

[0122] Mock group: negative control group, i.e. transfection reagent control group;

[0123] As used herein, percentages of "identity," such as 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 98.5%, 99%, or 99.5% identity, refer to a degree of similarity between amino acid sequences or nucleotide sequences determined by sequence alignment of 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 98.5%, 99%, or 99.5%. For example, the percentage of positions with identical bases or amino acid residues is determined as the ratio of the total number of positions after two sequences have been aligned to have identical residues at as many positions as possible, such as by introducing gaps. Percentages of "identity" can be determined using software programs known in the art. Preferably, the alignment is performed using default parameters. A preferred alignment program is BLAST. Preferred programs are BLASTN and BLASTP. Details of these programs can be found on the corresponding pages of the NCBI website. It should be noted that when describing a nucleotide sequence that has at least a certain percentage of identity with a certain nucleotide sequence and the corresponding modifications (for example, "a nucleotide sequence that has at least 90% identity with the nucleotide sequence UmsAmsGmCmUmGmUfAmGfAfAfAmUmGmUmAmUmCmCmsUmsGm (SEQ ID NO: 5) and the corresponding modifications"), the sequence alignment needs to take into account the modification of each nucleotide monomer of the nucleotide sequence, that is, the two nucleotides are considered to be the same nucleotides only when the entire monomers (including artificial modifications) of the two nucleotides are completely identical.

[0124] As used herein, "complementarity" of nucleic acids refers to the ability of one nucleic acid to form hydrogen bonds with another nucleic acid through traditional Watson-Crick base pairing. Percent complementarity represents the percentage of nucleotides in the shorter of two nucleic acid molecules that can form hydrogen bonds (i.e., Watson-Crick base pairing) with the other nucleic acid molecule (e.g., about 5, 6, 7, 8, 9, and 10 out of 10 are approximately 50%, 60%, 70%, 80%, 90%, and 100% complementary, respectively). "Complete complementarity" means that all consecutive residues of a nucleic acid sequence form hydrogen bonds with the same number of consecutive residues in a second nucleic acid sequence. As used herein, "substantially complementary" refers to a degree of complementarity of at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% over a region of about 40, 50, 60, 70, 80, 100, 150, 200, 250, or more nucleotides, or refers to two nucleic acids that hybridize under stringent conditions. For single bases or single nucleotides, according to the Watson-Crick base pairing rules, when A pairs with T or U, or C pairs with G or I, and vice versa, they are said to be complementary, paired, or matched; base pairings other than these are said to be non-complementary.

[0125] As used herein, "hybridization" of nucleic acids refers to the reaction of one or more polynucleotides to form a complex that is stabilized by hydrogen bonding between the nucleotide residues. Hydrogen bonding can occur by Watson-Crick base pairing, Hoogstein binding, or any other sequence-specific manner. The complex can include two chains forming a double-stranded structure, three or more chains forming a multi-stranded complex, a single self-hybridizing chain, or a combination thereof.

[0126] The term "nucleotide", in addition to referring to naturally occurring ribonucleotides or deoxyribonucleotide monomers, is also understood herein to refer to related structural variants thereof, including derivatives and analogs, which are functionally equivalent with respect to the specific context in which the nucleotide is used, unless the context clearly indicates otherwise. For example, "nucleotide" refers to a deoxyribonucleotide or a ribonucleotide. A nucleotide can be a standard nucleotide (i.e., adenosine, guanosine, cytidine, thymidine, and uridine), a nucleotide isomer, or a nucleotide analog. A nucleotide analog refers to a nucleotide having a modified purine or pyrimidine base or a modified ribose moiety. A nucleotide analog can be a naturally occurring nucleotide (e.g., inosine, pseudouridine, etc.) or a non-naturally occurring nucleotide. Non-limiting examples of modifications on the sugar or base portion of a nucleotide include the addition (or removal) of an acetyl group, an amino group, a carboxyl group, a carboxymethyl group, a hydroxyl group, a methyl group, a phosphoryl group, and a thiol group, and the substitution of the carbon and nitrogen atoms of the base by other atoms (e.g., 7-deazapurine). Nucleotide analogs also include dideoxynucleotides, 2'-O-methyl nucleotides, locked nucleic acids (LNA), peptide nucleic acids (PNA) and morpholino oligonucleotides. In some embodiments, the "nucleotides" of the present application do not include non-natural nucleotides with modified bases. In some embodiments, the "nucleotides" of the present application do not include nucleotides with modified bases. In the present application, "G", "C", "A", "T" and "U" generally represent nucleotides with guanine, cytosine, adenine, thymine and uracil as bases, respectively. However, in the context of RNA and in RNA sequences, unless otherwise specified, "T" refers to uridine or uracil. It should be understood that in the context of nucleotide sequences in this application, "nucleotides", "nucleotide residues" and "bases" can be used interchangeably. The number of base pairs is in bp, and one bp is one base pair. The number of nucleotides is in nt, and one nt is one nucleotide.

[0127] As used herein, the term "3' end" specifically refers to the position of the first nucleotide or base pair at the 3' end of a single nucleotide sequence or a double-stranded polynucleotide, and thus "3' end" and "3' terminal nucleotide" are used interchangeably. The term "5' end" specifically refers to the position of the first nucleotide or base pair at the 5' end of a single nucleotide sequence or a double-stranded polynucleotide, and thus "5' end" and "5' terminal nucleotide" are used interchangeably.

[0128] As used herein, the term "nucleic acid molecule" may be used to refer to any molecule having a nucleotide sequence composed of two or more nucleotides linked by a phosphate backbone, or a modified phosphate backbone (eg, a phosphorothioate backbone).

[0129] "Complement component MASP2" or "complement MASP2," used interchangeably with the term "MASP2," refers to the well-known gene and polypeptide, which is also known in the art as MAP-2, MAP19, MASP2, MASP1P1, sMAP; the sequence of the human MASP2 mRNA transcript can be found, for example, in GenBank Accession No. GI: ​​1653961883 (NM_006610.4). The sequence of the rhesus monkey MASP2 mRNA can be found, for example, in GenBank Accession No. GI: ​​1622835000 (XM_001118827.4). The sequence of the mouse MASP2 mRNA can be found, for example, in GenBank Accession No. GI: ​​90962989 (NM_001003893.2). The sequence of the rat MASP2 mRNA can be found, for example, in GenBank Accession No. GI: ​​78042604 (NM_172043.1). Additional examples of MASP2 mRNA sequences are readily obtained using publicly available databases such as GenBank.

[0130] Typically, the majority of the nucleotides in each strand of a dsRNA molecule are ribonucleotides, but as described in detail herein, each strand or both strands may also include one or more non-ribonucleotides, such as deoxyribonucleotides and / or modified nucleotides. Additionally, as used herein, an "RNAi agent" may include ribonucleotides with chemical modifications; an RNAi agent may include a variety of modifications on multiple nucleotides. Such modifications may include all types of modifications disclosed herein or known in the art. Any such modification as used in siRNA-type molecules is encompassed within an "RNAi agent" for the purposes of this specification and claims.

[0131] In this article, siRNA, dsRNA or RNAi reagent have similar meanings and can be used interchangeably.

[0132] As used herein, the singular forms "a," "an," and "the" include plural forms unless otherwise indicated.

[0133] Unless otherwise defined herein, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which this application belongs. Unless otherwise indicated, the practice of this application will employ conventional techniques of cell biology, cell culture, molecular biology, transgenic biology, microbiology, recombinant DNA, and immunology.

[0134] It should be understood that the present application includes various aspects, embodiments, and combinations of the aspects and / or embodiments described herein. The above description and subsequent examples are intended to illustrate rather than limit the scope of the present application. Within the scope of the technical concept of the present application, the technical solution of the present application can be subjected to a variety of simple modifications, including combining various technical features in any other suitable manner. These simple modifications and combinations should also be regarded as the contents disclosed in the present application and all fall within the scope of protection of the present application. Example

[0135] Example 1. MASP2-dsRNA activity screening experiment

[0136] 1.1 dsRNA design

[0137] With reference to the human MASP2 gene (Gene ID, 104710) mRNA sequence (NM_006610.4), 100 MASP2 dsRNAs (i.e., dsRNAs numbered 1-100) were designed at different sites. The bare or unmodified molecular sequences of some dsRNAs are shown in Table 1. These sequences showed minimal homology with all other non-target gene sequences using sequence similarity software.

[0138] Table 1: Some dsRNA sequences screened by high-throughput screening

[0139] 1.2 Synthesis and purification of dsRNA (conjugate)

[0140] The dsRNA in this application contains only ribonucleotides or 2'-methoxy or 2'-fluoro modified oligonucleotides, which are synthesized according to the theoretical yield of 1 μmol, using 1 μmol of a universal Frit solid phase carrier ( All oligonucleotides were prepared on an LK-192X synthesizer using a controlled pore glass (CPG) solid-phase support (California Biotech) or the protected GalNAc derivative L96. Depending on the sequence requirements, all phosphoramidite monomers of the corresponding nucleoside (e.g., native ribonucleotide monomers, 2'-OMe-modified phosphoramidite nucleomonomers, and 2'-F-modified phosphoramidite nucleomonomers) were diluted 1:40 (g / mL) in anhydrous acetonitrile. The coupling was repeated twice for 3 minutes. Deprotection was performed using 3% trichloroacetic acid (TCA), activation was performed using 0.3 M benzylthiotetrazolyl in acetonitrile, and capping and oxidation were performed using CAPA / CAPB and 50 mM I2 solutions, respectively. After trityl-off synthesis, the solid-phase support was transferred to a 2 mL centrifuge tube, 1.2 mL of ammonia was added, and the tube was heated in a 65°C oven for 3 hours to remove the protecting groups. The oligonucleotide was then cooled to room temperature and concentrated under vacuum for 30 minutes. The solution was filtered through a 0.22 μm filter into a vial and purified using a semi-preparative reverse-phase instrument with a 10-minute elution gradient of 7% to 30% (ACN:100 mM TEAA) at a flow rate of 5 mL / min. After preparative purification, the oligonucleotide was concentrated under vacuum and dried at room temperature. Finally, the sample was dissolved in water, and each solution was desalted on a GE Hi-Trap desalting column to elute the final oligonucleotide product. All identities and purity were confirmed using ESI-MS and IEX HPLC, respectively. Concentration was determined using a microplate reader under UV light. Equimolar amounts of the sense and antisense strands were mixed and transferred to a new shipping tube. The product was heated at 95°C for 5 minutes and slowly annealed to room temperature. Finally, the final product was dried using a vacuum concentrator at room temperature.

[0141] 1.3. High-throughput screening assay for MASP2-dsRNA in vitro activity

[0142] 1.3.1. MASP2 dsRNA transfection into HepG2 cells

[0143] HepG2 cells were cultured in DMEM medium (Gibco) containing 10% fetal bovine serum in a 5% CO2, 37°C incubator. When the cells were in the logarithmic growth phase and in good condition (70% confluence), they were plated for transfection. The cell density was adjusted to 2×10 cells per well. 5 Cells were plated into 24-well plates and cultured overnight in a 5% CO2, 37°C incubator. Prepare transfection complexes: 250 μL Opti-MEM (Gibco) and 5 μL 1 nM or 0.1 nM dsRNA were mixed, 250 μL Opti-MEM and 1.5 μL Lipofectamine TMRNAiMax transfection reagent (Thermo Fisher Scientific) was mixed and allowed to stand for 5 minutes. The two mixtures were then mixed and allowed to stand for 20 minutes. The MEM medium in the 24-well plate was aspirated and the transfection complex was added to each well. The cells were incubated in a 5% CO2, 37°C incubator for 6 hours. The supernatant from the 24-well plate was aspirated and 1 mL of complete medium (DMEM + 10% FBS) was added to each well. The cells were incubated in a 5% CO2, 37°C incubator for another 24 hours.

[0144] In addition to the experimental group, a transfection reagent control group was also set up for each cell plating. Both the experimental group and the control group were repeated three times.

[0145] 1.3.2 Real-time fluorescence quantitative PCR analysis of target mRNA levels

[0146] 24 hours after transfection, the transfected HepG2 cells were lysed and total RNA was extracted using the Novagen FastPure Cell / Tissue Total RNA Isolation Kit V2 (refer to the Novagen RC112-01 instructions). Reverse transcription was performed into cDNA using Takara PrimeScript RT Master Mix RR036Q. Table 2 shows the q-PCR primer sequences. The human GAPDH gene (NCBI accession number: NM_002046.7) was used as the internal reference gene. PCR reactions were performed using a Bio-Rad CFX96 fluorescence quantitative PCR instrument. Mock (negative control) cells were used as the control for normalization; the MASP2 mRNA expression level in the mock group was set to 1.

[0147] Table 2: QPCR primer sequence information

[0148] 1.3.3 Data Analysis

[0149] After the PCR reaction, relative quantitative analysis was performed using the internal reference gene (human GAPDH gene) as a standard using CFX96 software, and statistical analysis was performed using GarphPad software. Table 3 shows the results of high-throughput screening and validation of dsRNA molecules in HepG2 cells.

[0150] Table 3: Results of high-throughput screening of single-dose 1 nM in HepG2 cells

[0151] The results are shown in FIG1 . The MASP2 dsRNA screening performed in HepG2 cells revealed multiple preferred sequences (numbers 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 32, and 40), and dsRNA molecules with good effects and sequences targeting both human and cynomolgus macaque MASP2 were retained as candidate sequences.

[0152] Example 2. Optimization of MASP2-dsRNA: Inhibitory Activity Detection

[0153] To further identify preferred dsRNA molecules, we optimized the aforementioned sequences (numbers 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 32, and 40) through sequence modification (Table 4). Fluoro and methoxy modifications were combined at different positions in the candidate sequences. The overall modification strategy was to replace the antisense strand with methoxy modifications whenever possible. The sequence designs are shown in Table 4. HepG2 cells were used for transfection, and the synthesis, transfection, and quantitative PCR detection procedures and PCR primers were the same as in Example 1. Tables 5 and 6 show the average target gene expression levels relative to the mock group (the relative mRNA expression level in the mock group is 1).

[0154] Table 4: Modified dsRNA sequences

[0155] Table 5: 1 nM single-dose screening of modified dsRNA in HepG2 cells

[0156] Table 6: 0.1 nM single-dose screening of modified dsRNA in HepG2 cells

[0157] As shown in Figures 2 and 3, multiple chemically modified dsRNA molecules exhibited high inhibitory activity against the target MASP2 mRNA in HepG2 cells. Even at a concentration of 0.1 nM, the inhibition rates of dsRNA molecules such as E10, E11, and E18 remained greater than 70%.

[0158] Example 3: In vivo effectiveness testing

[0159] The experiment used SPF-grade humanized MASP2 mice (Shanghai Model Biological Laboratory Animal Co., Ltd.), 6 to 8 weeks old, and were randomly divided into five groups: a saline group and drug-treated groups (including E10, E11, E17, and E18 groups). Each group consisted of 10 mice (N=10, 5 males and 5 females). L96-modified siRNA was administered subcutaneously at a dose of 3 mg / kg. Blood was collected on D-3 (day 3 before drug administration), D3, D7, and D12 (the day of drug administration was designated D0). Serum was collected from the back of the eye and MASP2 protein levels were measured by ELISA.

[0160] Preliminary in vivo data showed that on day 12, the MASP2 protein inhibition rate in the serum of each treatment group was >50% or even higher.

[0161] The above description is merely a preferred embodiment, which is intended to be an example and not to limit the combination of features necessary for implementing the present application. The titles provided are not intended to limit the various embodiments of the present application. Terms such as "comprise", "contain" and "include" are not intended to be limiting. In addition, unless otherwise indicated, plural forms are included when there is no numeral modification, and "or" and "or" mean "and / or". Unless otherwise defined herein, the meaning of all technical and scientific terms used herein is the same as that generally understood by those skilled in the art. All publications and patents mentioned in this application are incorporated herein by reference. Without departing from the scope and spirit of the present application, various modifications and variations of the methods and compositions described herein are obvious to those skilled in the art. Although the present application has been described by specific preferred embodiments, it should be understood that the present application claimed for protection should not be unduly limited to these specific embodiments. In fact, various variations of the described modes for implementing the present application that are obvious to those skilled in the relevant art are intended to be included within the scope of the appended claims.

Claims

1. An engineered dsRNA molecule for inhibiting complement MASP2 gene expression, comprising a sense strand and an antisense strand that complement each other to form a double-stranded region, wherein the sense strand and / or the antisense strand comprises or consists of 15-25 nucleotides, the antisense strand is complementary to at least 15, 16, 17, 18, 19, 20, or 21 consecutive nucleotides of the nucleic acid sequence shown in SEQ ID NO: 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 71, or 77, and the length of the double-stranded region is 15-25 bp.

2. At least one nucleotide in the dsRNA molecule is modified, and the modification is selected from any one or more of the following: locked nucleic acid modification, open ring or non-locked nucleic acid modification, 2′-methoxyethyl modification, 2′-O-methyl modification, 2′-O-allyl modification, 2′-C-allyl modification, 2′-fluoro modification, 2′-deoxy modification, thiophosphate backbone modification, DNA modification, and ligand modification.

3. The dsRNA molecule according to claim 1 or 2, for its naked sequence: The sense strand of the dsRNA molecule comprises SEQ ID NO: 37 or consists of the nucleic acid sequence shown in SEQ ID NO: 37; the antisense strand comprises SEQ ID NO: 38 or consists of the nucleic acid sequence shown in SEQ ID NO: 38; The sense strand of the dsRNA molecule includes or consists of the nucleic acid sequence shown in SEQ ID NO:39; the antisense strand includes or consists of the nucleic acid sequence shown in SEQ ID NO:40; The sense strand of the dsRNA molecule comprises SEQ ID NO:41 or consists of the nucleic acid sequence shown in SEQ ID NO:41; the antisense strand comprises SEQ ID NO:42 or consists of the nucleic acid sequence shown in SEQ ID NO:42; The sense strand of the dsRNA molecule comprises SEQ ID NO:43 or consists of the nucleic acid sequence shown in SEQ ID NO:43; the antisense strand comprises SEQ ID NO:44 or consists of the nucleic acid sequence shown in SEQ ID NO:44; The sense strand of the dsRNA molecule comprises SEQ ID NO:45 or consists of the nucleic acid sequence shown in SEQ ID NO:45; the antisense strand comprises SEQ ID NO:46 or consists of the nucleic acid sequence shown in SEQ ID NO:46; The sense strand of the dsRNA molecule comprises SEQ ID NO:47 or consists of the nucleic acid sequence shown in SEQ ID NO:47; the antisense strand comprises SEQ ID NO:48 or consists of the nucleic acid sequence shown in SEQ ID NO:48; The sense strand of the dsRNA molecule comprises SEQ ID NO:49 or consists of the nucleic acid sequence shown in SEQ ID NO:49; the antisense strand comprises SEQ ID NO:50 or consists of the nucleic acid sequence shown in SEQ ID NO:50; The sense strand of the dsRNA molecule comprises SEQ ID NO:51 or consists of the nucleic acid sequence shown in SEQ ID NO:51; the antisense strand comprises SEQ ID NO:52 or consists of the nucleic acid sequence shown in SEQ ID NO:52; The sense strand of the dsRNA molecule comprises SEQ ID NO:53 or consists of the nucleic acid sequence shown in SEQ ID NO:53; the antisense strand comprises SEQ ID NO:54 or consists of the nucleic acid sequence shown in SEQ ID NO:54; The sense strand of the dsRNA molecule comprises SEQ ID NO:55 or consists of the nucleic acid sequence shown in SEQ ID NO:55; the antisense strand comprises SEQ ID NO:56 or consists of the nucleic acid sequence shown in SEQ ID NO:56; The sense strand of the dsRNA molecule comprises SEQ ID NO: 71 or consists of the nucleic acid sequence shown in SEQ ID NO: 71; the antisense strand comprises SEQ ID NO: 72 or consists of the nucleic acid sequence shown in SEQ ID NO: 72; or The sense strand of the dsRNA molecule includes or consists of the nucleic acid sequence shown in SEQ ID NO:77; the antisense strand includes or consists of the nucleic acid sequence shown in SEQ ID NO:

78.

4. The dsRNA molecule according to any one of claims 1 to 3, wherein: The modification methods of the dsRNA molecule include: (1) sense strand: 19-23 nt in length, such as 19, 20, 21, 22 or 23 nt; composed of alternating 2′-O-methyl modified regions and 2′-fluoro modified regions, with the number of consecutive nucleotides in each modified region being any one of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 nucleotides; and (2) Antisense strand: 19-25 nt in length, such as 19, 20, 21, 22, 23, 24 or 25 nt; composed of alternating 2′-O-methyl modified regions, 2′-fluoro modified regions, unmodified regions and / or DNA regions, with each modified region having a continuous nucleotide length of 1, 2, 3, 4, 5, 6, 7, 8, 9, Any of 10, 11, or 12 nucleotides; the first modified region from the 5′ end and the 3′ end is modified in the same manner; In the sense strand and the antisense strand, a continuous nucleotide region from positions 1 to 2, 1 to 3, 1 to 4, 1 to 5, 1 to 6, or 1 to 7 from the 5' end, and optionally a continuous nucleotide region from positions 1 to 2, 1 to 3, 1 to 4, 1 to 5, 1 to 6, or 1 to 7 from the 3' end, are all connected by a thiophosphate backbone; preferably, a continuous nucleotide region from positions 1 to 3 from the 5' end, and optionally a continuous nucleotide region from positions 1 to 3 from the 3' end, are all connected by a thiophosphate backbone.

5. The dsRNA molecule according to any one of claims 1 to 4, wherein The ligand in the ligand modification is selected from any one or more of the following groups: cholesterol, biotin, vitamins, galactose derivatives or analogs, lactose derivatives or analogs, N-acetylgalactosamine derivatives or analogs, and N-acetylglucosamine derivatives or analogs.

6. The dsRNA molecule according to claim 5, wherein The ligand is linked to the 3' terminal nucleotide of the sense strand and / or antisense strand; the conjugation is linked to the base or the sugar ring; preferably, the ligand is linked to the sugar ring; more preferably, the ligand is linked to the 3' position of the sugar ring.

7. The dsRNA molecule according to claim 6, wherein The ligand is one or more GalNAc derivatives connected by a divalent or trivalent branched structure; Preferably, the GalNAc derivative comprises the following structure: More preferably, the ligand is L96, whose structure is as shown in Formula I:

8. The dsRNA molecule according to any one of claims 1 to 7, comprising a modification motif selected from any one of the following: (1) Sense chain: NmsNmsNmNmNmNmNfNmNfNfNfNmNmNmNmN mNmNmNmsNmsNm, Antisense strand: NmsNfsNmNmNmNmNmNmNmNmNmNmNmNmNfNmNf NmNmNmNmNmsNmsNm; (2) Sense chain: NmsNmsNmNmNmNmNfNmNfNfNfNmNmNmNmN mNmNmNmNmNm, Antisense strand: NmsNfsNmNmNmNmNmNmNmNmNmNmNmNmNfNmNf NmNmNmNmNmsNmsNm; in, Nm represents a ribonucleotide modified with 2'-O-methyl; Nf represents a ribonucleotide modified with 2'-fluoro; (s) represents that the two nucleotides are connected by a phosphorothioate backbone.

9. The double-stranded RNAi agent according to any one of claims 1 to 8, comprising one or more selected from the following: (1) a sense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity to the nucleotide sequence of SEQ ID NO: 1 and corresponding modifications, and an antisense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity to the nucleotide sequence of SEQ ID NO: 2 and corresponding modifications; (2) a sense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity to the nucleotide sequence of SEQ ID NO: 3 and corresponding modifications, and an antisense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity to the nucleotide sequence of SEQ ID NO: 4 and corresponding modifications; (3) a sense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity to the nucleotide sequence of SEQ ID NO: 5 and corresponding modifications, and an antisense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity to the nucleotide sequence of SEQ ID NO: 6 and corresponding modifications; (4) a sense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity to the nucleotide sequence of SEQ ID NO: 7 and corresponding modifications, and an antisense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity to the nucleotide sequence of SEQ ID NO: 8 and corresponding modifications; (5) a sense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity to the nucleotide sequence of SEQ ID NO: 9 and corresponding modifications, and an antisense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity to the nucleotide sequence of SEQ ID NO: 10 and corresponding modifications; (6) a sense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity to the nucleotide sequence of SEQ ID NO: 11 and corresponding modifications, and an antisense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity to the nucleotide sequence of SEQ ID NO: 12 and corresponding modifications; (7) a sense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity to the nucleotide sequence of SEQ ID NO: 13 and corresponding modifications, and an antisense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity to the nucleotide sequence of SEQ ID NO: 14 and corresponding modifications; (8) a sense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity to the nucleotide sequence of SEQ ID NO: 15 and corresponding modifications, and an antisense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity to the nucleotide sequence of SEQ ID NO: 16 and corresponding modifications; (9) a sense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity to the nucleotide sequence of SEQ ID NO: 17 and corresponding modifications, and an antisense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity to the nucleotide sequence of SEQ ID NO: 18 and corresponding modifications; (10) a sense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity to the nucleotide sequence of SEQ ID NO: 19 and corresponding modifications, and an antisense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity to the nucleotide sequence of SEQ ID NO: 20 and corresponding modifications; (11) a sense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity to the nucleotide sequence of SEQ ID NO: 21 and corresponding modifications, and an antisense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity to the nucleotide sequence of SEQ ID NO: 22 and corresponding modifications; (12) a sense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity to the nucleotide sequence of SEQ ID NO: 23 and corresponding modifications, and an antisense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity to the nucleotide sequence of SEQ ID NO: 24 and corresponding modifications; (13) a sense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity to the nucleotide sequence of SEQ ID NO: 25 and corresponding modifications, and an antisense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity to the nucleotide sequence of SEQ ID NO: 2 and corresponding modifications; (14) a sense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity to the nucleotide sequence of SEQ ID NO: 26 and corresponding modifications, and an antisense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity to the nucleotide sequence of SEQ ID NO: 4 and corresponding modifications; (15) a sense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity to the nucleotide sequence of SEQ ID NO: 27 and corresponding modifications, and an antisense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity to the nucleotide sequence of SEQ ID NO: 6 and corresponding modifications; (16) a sense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity to the nucleotide sequence of SEQ ID NO: 28 and corresponding modifications, and an antisense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity to the nucleotide sequence of SEQ ID NO: 8 and corresponding modifications; (17) a sense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity to the nucleotide sequence of SEQ ID NO: 29 and corresponding modifications, and an antisense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity to the nucleotide sequence of SEQ ID NO: 10 and corresponding modifications; (18) a sense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity to the nucleotide sequence of SEQ ID NO: 30 and corresponding modifications, and an antisense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity to the nucleotide sequence of SEQ ID NO: 12 and corresponding modifications; (19) a sense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity to the nucleotide sequence of SEQ ID NO: 31 and corresponding modifications, and an antisense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity to the nucleotide sequence of SEQ ID NO: 14 and corresponding modifications; (20) a sense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity to the nucleotide sequence of SEQ ID NO: 32 and corresponding modifications, and an antisense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity to the nucleotide sequence of SEQ ID NO: 16 and corresponding modifications; (21) a sense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity to the nucleotide sequence of SEQ ID NO: 33 and corresponding modifications, and an antisense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity to the nucleotide sequence of SEQ ID NO: 18 and corresponding modifications; (22) a sense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity to the nucleotide sequence of SEQ ID NO: 34 and corresponding modifications, and an antisense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity to the nucleotide sequence of SEQ ID NO: 20 and corresponding modifications; (23) a sense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity to the nucleotide sequence of SEQ ID NO: 35 and corresponding modifications, and an antisense strand consisting of a nucleotide sequence having at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identity to the nucleotide sequence of SEQ ID NO: 22 and corresponding modifications; and (24) A sense strand consisting of a nucleotide sequence that is at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identical to the nucleotide sequence of SEQ ID NO:36 and corresponding modifications, and an antisense strand consisting of a nucleotide sequence that is at least 90%, preferably 95%, 96%, 97%, 98%, 99%, or 100% identical to the nucleotide sequence of SEQ ID NO:24 and corresponding modifications.

10. The double-stranded RNAi agent according to claim 9, wherein the nucleic acid sequence comprises any one or more selected from the following: (1) the sense strand nucleic acid sequence consists of SEQ ID NO: 1 and another 0-5 nucleotides at the 5' and / or 3' end, and the antisense strand nucleic acid sequence consists of SEQ ID NO: 2 and another 0-5 nucleotides at the 5' and / or 3' end; (2) the sense strand nucleic acid sequence consists of SEQ ID NO: 3 and another 0-5 nucleotides at the 5' and / or 3' end, and the antisense strand nucleic acid sequence consists of SEQ ID NO: 4 and another 0-5 nucleotides at the 5' and / or 3' end; (3) The sense strand nucleic acid sequence consists of SEQ ID NO: 5 and another 0-5 nucleotides at the 5' and / or 3' end, and the antisense strand nucleic acid sequence consists of SEQ ID NO: 6 and another 0-5 nucleotides at the 5' and / or 3' end. The other 0-5 nucleotides at the end; (4) the sense strand nucleic acid sequence consists of SEQ ID NO:7 and another 0-5 nucleotides at the 5' and / or 3' end, and the antisense strand nucleic acid sequence consists of SEQ ID NO:8 and another 0-5 nucleotides at the 5' and / or 3' end; (5) the sense strand nucleic acid sequence consists of SEQ ID NO: 9 and another 0-5 nucleotides at the 5' and / or 3' end, and the antisense strand nucleic acid sequence consists of SEQ ID NO: 10 and another 0-5 nucleotides at the 5' and / or 3' end; (6) the sense strand nucleic acid sequence consists of SEQ ID NO: 11 and another 0-5 nucleotides at the 5' and / or 3' end, and the antisense strand nucleic acid sequence consists of SEQ ID NO: 12 and another 0-5 nucleotides at the 5' and / or 3' end; (7) the sense strand nucleic acid sequence consists of SEQ ID NO: 13 and another 0-5 nucleotides at the 5' and / or 3' end, and the antisense strand nucleic acid sequence consists of SEQ ID NO: 14 and another 0-5 nucleotides at the 5' and / or 3' end; (8) the sense strand nucleic acid sequence consists of SEQ ID NO: 15 and another 0-5 nucleotides at the 5' and / or 3' end, and the antisense strand nucleic acid sequence consists of SEQ ID NO: 16 and another 0-5 nucleotides at the 5' and / or 3' end; (9) the sense strand nucleic acid sequence consists of SEQ ID NO: 17 and another 0-5 nucleotides at the 5' and / or 3' end, and the antisense strand nucleic acid sequence consists of SEQ ID NO: 18 and another 0-5 nucleotides at the 5' and / or 3' end; (10) the sense strand nucleic acid sequence consists of SEQ ID NO: 19 and another 0-5 nucleotides at the 5' and / or 3' end, and the antisense strand nucleic acid sequence consists of SEQ ID NO: 20 and another 0-5 nucleotides at the 5' and / or 3' end; (11) the sense strand nucleic acid sequence consists of SEQ ID NO: 21 and another 0-5 nucleotides at the 5' and / or 3' end, and the antisense strand nucleic acid sequence consists of SEQ ID NO: 22 and another 0-5 nucleotides at the 5' and / or 3' end; (12) the sense strand nucleic acid sequence consists of SEQ ID NO: 23 and another 0-5 nucleotides at the 5' and / or 3' end, and the antisense strand nucleic acid sequence consists of SEQ ID NO: 24 and another 0-5 nucleotides at the 5' and / or 3' end; (13) The sense strand nucleic acid sequence consists of SEQ ID NO: 25 and another 0-5 nucleotides at the 5' and / or 3' end, and the antisense strand nucleic acid sequence consists of SEQ ID NO: 2 and another 0-5 nucleotides at the 5' and / or 3' end. The other 0-5 nucleotides at the end; (14) the sense strand nucleic acid sequence consists of SEQ ID NO: 26 and another 0-5 nucleotides at the 5' and / or 3' end, and the antisense strand nucleic acid sequence consists of SEQ ID NO: 4 and another 0-5 nucleotides at the 5' and / or 3' end; (15) the sense strand nucleic acid sequence consists of SEQ ID NO: 27 and another 0-5 nucleotides at the 5' and / or 3' end, and the antisense strand nucleic acid sequence consists of SEQ ID NO: 6 and another 0-5 nucleotides at the 5' and / or 3' end; (16) the sense strand nucleic acid sequence consists of SEQ ID NO: 28 and another 0-5 nucleotides at the 5' and / or 3' end, and the antisense strand nucleic acid sequence consists of SEQ ID NO: 8 and another 0-5 nucleotides at the 5' and / or 3' end; (17) the sense strand nucleic acid sequence consists of SEQ ID NO: 29 and another 0-5 nucleotides at the 5' and / or 3' end, and the antisense strand nucleic acid sequence consists of SEQ ID NO: 10 and another 0-5 nucleotides at the 5' and / or 3' end; (18) the sense strand nucleic acid sequence consists of SEQ ID NO: 30 and another 0-5 nucleotides at the 5' and / or 3' end, and the antisense strand nucleic acid sequence consists of SEQ ID NO: 12 and another 0-5 nucleotides at the 5' and / or 3' end; (19) the sense strand nucleic acid sequence consists of SEQ ID NO:31 and another 0-5 nucleotides at the 5' and / or 3' end, and the antisense strand nucleic acid sequence consists of SEQ ID NO:14 and another 0-5 nucleotides at the 5' and / or 3' end; (20) the sense strand nucleic acid sequence consists of SEQ ID NO:32 and another 0-5 nucleotides at the 5' and / or 3' end, and the antisense strand nucleic acid sequence consists of SEQ ID NO:16 and another 0-5 nucleotides at the 5' and / or 3' end; (21) the sense strand nucleic acid sequence consists of SEQ ID NO:33 and another 0-5 nucleotides at the 5' and / or 3' end, and the antisense strand nucleic acid sequence consists of SEQ ID NO:18 and another 0-5 nucleotides at the 5' and / or 3' end; (22) the sense strand nucleic acid sequence consists of SEQ ID NO:34 and another 0-5 nucleotides at the 5' and / or 3' end, and the antisense strand nucleic acid sequence consists of SEQ ID NO:20 and another 0-5 nucleotides at the 5' and / or 3' end; (23) The sense strand nucleic acid sequence consists of SEQ ID NO: 35 and another 0-5 nucleotides at the 5' and / or 3' end, and the antisense strand nucleic acid sequence consists of SEQ ID NO: 22 and another 0-5 nucleotides at the 5' and / or 3' end. An additional 0-5 nucleotides at the end; and (24) The sense strand nucleic acid sequence consists of SEQ ID NO: 36 and another 0-5 nucleotides at the 5' and / or 3' end, and the antisense strand nucleotide sequence consists of SEQ ID NO: 24 and another 0-5 nucleotides at the 5' and / or 3' end.

11. The double-stranded RNAi agent according to any one of claims 1 to 10, which is one or more selected from the following: (1) the sense strand nucleotide sequence is SEQ ID NO: 25, and the antisense strand nucleotide sequence is SEQ ID NO: 2; (2) the sense strand nucleotide sequence is SEQ ID NO: 26, and the antisense strand nucleotide sequence is SEQ ID NO: 4; (3) the sense strand nucleotide sequence is SEQ ID NO: 27, and the antisense strand nucleotide sequence is SEQ ID NO: 6; (4) the sense strand nucleotide sequence is SEQ ID NO: 28, and the antisense strand nucleotide sequence is SEQ ID NO: 8; (5) the sense strand nucleotide sequence is SEQ ID NO: 29, and the antisense strand nucleotide sequence is SEQ ID NO: 10; (6) the sense strand nucleotide sequence is SEQ ID NO:30, and the antisense strand nucleotide sequence is SEQ ID NO:12; (7) the sense strand nucleotide sequence is SEQ ID NO:31, and the antisense strand nucleotide sequence is SEQ ID NO:14; (8) the sense strand nucleotide sequence is SEQ ID NO:32, and the antisense strand nucleotide sequence is SEQ ID NO:16; (9) the sense strand nucleotide sequence is SEQ ID NO:33, and the antisense strand nucleotide sequence is SEQ ID NO:18; (10) the sense strand nucleotide sequence is SEQ ID NO:34, and the antisense strand nucleotide sequence is SEQ ID NO:20; (11) the sense strand nucleotide sequence is SEQ ID NO:35, and the antisense strand nucleotide sequence is SEQ ID NO:22; and (12) the sense strand nucleotide sequence is SEQ ID NO:36, and the antisense strand nucleotide sequence is SEQ ID NO:24; The 3'-OH at the 3' end of the sense strand is connected to the L96 ligand shown in the following formula I:

12. A biomaterial selected from any one of the following groups: (A) a reagent or a kit comprising the dsRNA according to any one of claims 1 to 11 or a DNA molecule encoding the dsRNA; (B) A pharmaceutical composition, consisting of the dsRNA molecule according to any one of claims 1 to 11 and other pharmaceutically acceptable components.

13. A use of dsRNA, selected from any one of the following groups: (I) Use of the dsRNA according to any one of claims 1 to 11 or the biological material according to claim 12 in inhibiting the expression of complement MASP2 gene or in preparing a product for inhibiting the expression of complement MASP2 gene; (II) Use of the dsRNA according to any one of claims 1 to 11 or the biomaterial according to claim 12 in a product for reducing MASP2 protein in serum; (III) Use of the dsRNA according to any one of claims 1 to 11 or the biological material according to claim 12 in preventing and / or treating a disease mediated by the complement MASP2 gene, or in preparing a product for preventing and / or treating a disease mediated by the complement MASP2 gene; (IV) Use of the dsRNA of any one of claims 1 to 11 or the biological material of claim 12 for alleviating the symptoms of a disease mediated by the complement MASP2 gene, or for preparing a product for alleviating the symptoms of a disease mediated by the complement MASP2 gene; The diseases mediated by complement MASP2 gene include: Ophthalmological diseases, blood diseases, cardiovascular diseases, autoimmune diseases, kidney diseases, neurological diseases or tumor diseases; The ophthalmic diseases include dry / wet age-related macular degeneration (AMD), geographic atrophy (GA), etc.; The neurological diseases include: Alzheimer's disease (AD), myasthenia gravis (gMG), etc.; the kidney diseases include: typical hemolytic uremic syndrome (aHUS), C3 glomerulopathy (C3G) and IgA nephropathy; the blood diseases include: paroxysmal nocturnal hemoglobinuria (PNH), thrombotic microangiopathy (TMAs); the autoimmune diseases include: rheumatoid arthritis, Lupus erythematosus, etc.; the tumor diseases include complement-related liver cancer or lung cancer.

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