SiRNA for inhibiting expression of complement factor B and application thereof
By designing covalent conjugated with the delivery vector to covalently form the GalNAc-siRNA complex, the problem of difficulty in inhibiting the over-activation of complement factor B in the prior art is solved, and effective treatment of related diseases and reduced side effects are achieved.
Patent Information
- Application Number
- CN202311521306.7
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2023-11-15
- Publication Date
- 2025-05-16
AI Technical Summary
The prior art is difficult to effectively inhibit related diseases caused by excessive activation of complement factor B (CFB), and there are safety concerns about the treatment of targeted complement systems.
A siRNA duplex targeting CFB was designed and covalently conjugated with the delivery vector to form a GalNAc-siRNA complex to improve the degradation efficiency of CFB mRNA, reduce the synthesis of CFB in hepatocytes, and reduce the activity of the complement pathway.
Through siRNA technology targeting CFB, it effectively inhibits the expression of CFB, reduces the over-activation of the complement system, treats related diseases such as paroxysmal sleep hemoglobinuria, asthma, rheumatoid arthritis, etc., and reduces the side effects during the treatment process.
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Abstract
Description
Technical Field
[0001] The present invention belongs to the field of biomedicine technology, and specifically, the present invention relates to a siRNA targeting complement factor B (CFB) mRNA and its use. More specifically, the present invention relates to a siRNA duplex, a siRNA-delivery vector conjugate (GalNAc-siRNA), a pharmaceutical composition and its use. Background Art
[0002] The complement system is a key component of the innate immune response, which works in concert with antibodies and phagocytes to remove pathogens. Complement is a major component of the innate immune system and is a bridge between innate immunity and acquired immunity. Over the years, it has been clear that complement has multiple functions, from mediating inflammatory responses to regulating host cell clearance after programmed cell death, and is involved in almost every step of the immune response. It is known that complement activation occurs through three different pathways: the alternative pathway, the classical pathway, and the lectin pathway, involving proteins that exist primarily as inactive zymogens, which are then sequentially cleaved and activated. The classical pathway is often activated by antibody-antigen complexes or by C-reactive protein (CRP), both of which interact with complement component C1q. In addition, the classical pathway can be activated by phosphatidylserine present in apoptotic bodies in the absence of immune complexes. The lectin pathway begins with mannose-binding lectin (MBL), which binds to complex carbohydrate residues on the surface of pathogens. Activation of the classical pathway or the lectin pathway results in activation of the (C4b2b) C3 convertase. The alternative pathway is activated by binding to C3b, which is spontaneously generated by hydrolysis of C3 on a targeted surface. This surface-bound C3b is then recognized by factor B, forming the complex C3bB. In turn, the C3bB complex is cleaved by factor D to produce the active form of the C3 convertase (C3bBb) of the AP. Both types of C3 convertase will cleave C3, forming C3b. C3b can then bind to more factor B, enhancing complement activation through the AP (the so-called alternative or amplification loop), or C3b leads to the formation of an active C5 convertase (C3bBbC3b or C4bC2bC3b), which cleaves C5 and triggers later events that lead to the formation of the membrane attack complex (MAC) (C5b-9).
[0003] Inappropriate activation of the complement system is responsible for the proliferation and / or initiation of lesions in many diseases, including, for example, paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, rheumatoid arthritis, systemic lupus erythematosus (SLE), and immunoglobulin A nephropathy. Despite this recognition, there has been some resistance to targeted therapies of the complement system of innate immunity due to concerns that blocking this system would be unsafe. The demonstration that MAC causes hemolysis in the ultra-rare disease paroxysmal nocturnal hemoglobinuria (PNH) shattered this concern and led to the development of the blockbuster MAC-blocking anti-C5 drug, eculizumab. Eculizumab is a game-changing therapy that was approved by the U.S. Food and Drug Administration (FDA) in 2007 for the treatment of PNH, approximately 40 years after the recognition that complement contributes to this devastating disease. The approval of eculizumab for the treatment of PNH brought much-needed clinical validation and demonstrated that complement blockade can be achieved relatively safely with profound and life-changing outcomes. Eculizumab is the first approved drug that completely blocks the complement pathway at a specific point.
[0004] siRNA is a short RNA molecule that can inhibit the expression of mRNA genes in a targeted manner. Through the RNA interference mechanism, siRNA binds to the mRNA of the target gene and guides RNA nuclease to cut the corresponding mRNA molecule, thereby preventing the translation of mRNA and the synthesis of protein. Compared with other gene silencing technologies, siRNA technology has the advantages of high efficiency, selectivity and repeatability.
[0005] In recent years, siRNA drugs targeting CFB have attracted much attention as a new strategy for treating complement-related diseases. The CFB gene sequence in the human body has been fully studied, and the structure and function of its mRNA have been deeply understood. Therefore, by studying the CFB mRNA sequence, siRNA duplexes targeting CFB can be designed.
[0006] In addition, due to its targeting and reversibility, siRNA can reduce side effects during treatment and restore the patient's normal gene expression level after treatment. siRNA technology can also provide more flexibility for drug design and is expected to become one of the important technical means for the treatment of complement abnormality-related diseases in the future. Summary of the invention
[0007] The present invention aims to solve at least one of the technical problems existing in the prior art to a certain extent. To this end, the present invention provides a siRNA duplex for inhibiting the expression of complement factor B (CFB), a covalent conjugate thereof with a delivery vector and a use thereof. The siRNA of the present invention can inhibit the expression of CFB and effectively treat related diseases caused by excessive activation of the complement system.
[0008] The present invention proposes a siRNA duplex. According to an embodiment of the present invention, the siRNA includes a sense strand and an antisense strand. The antisense strand includes a complementary region that is complementary to the sense strand. The sense strand is selected from a nucleotide sequence that differs from the nucleotide sequence of each strand in SEQ ID NO:1 to SEQ ID NO:59 by no more than 2 nucleotides, and the antisense strand is selected from a nucleotide sequence that differs from the nucleotide sequence of each strand in SEQ ID NO:60 to SEQ ID NO:118 by no more than 2 nucleotides. The inventors have experimentally designed that the above-mentioned suitable small interfering RNA (siRNA) can specifically reduce the synthesis of CFB in hepatocytes while avoiding off-target effects. siRNA forms a silencing complex (RNA-induced silencing The invention relates to a novel complement factor B inhibitor complex (RISC) which is a target gene (CFB) mRNA sequence complementary pairing, thereby degrading CFB mRNA, inhibiting CFB expression, reducing the activity of the complement pathway in the body, and then effectively preventing or treating diseases related to abnormal complement factor B, such as paroxysmal nocturnal hemoglobinuria (PNH), asthma, rheumatoid arthritis, systemic lupus erythematosus, glomerulonephritis, psoriasis, dermatomyositis bullous pemphigoid, atypical hemolytic uremic syndrome, Shiga toxin-infected Escherichia coli-associated hemolytic uremic syndrome, myasthenia gravis, neuromyelitis optica, dense deposit disease, C3 neuropathy, age-related macular degeneration, cold agglutinin disease, anti-neutrophil cytoplasmic antibody-associated vasculitis, humoral and vascular transplant rejection, graft dysfunction, myocardial infarction, sensitized receptors of transplants, immunoglobulin a nephropathy, and sepsis.
[0009] In the present invention, the "difference is no more than 2 nucleotides" means that compared with the target nucleotide sequence, there may be a difference of 1 or 2 nucleotides, and the difference includes but is not limited to the deletion of nucleotides, the insertion of nucleotides (which can be inserted into the 3'-end, 5'-end, or between any two nucleotides of the nucleotide sequence), the replacement of nucleotides, etc.
[0010] According to an embodiment of the present invention, the above siRNA may further include at least one of the following additional technical features:
[0011] According to an embodiment of the present invention, the sense strand includes at least one of SEQ ID NO: 1 to SEQ ID NO: 59 shown in Table 1, and further includes a continuous nucleotide sequence that differs from the sense strand shown in Table 1 by 1 or 2 nucleotides.
[0012] According to an embodiment of the present invention, the antisense strand includes at least one of SEQ ID NO:60 to SEQ ID NO:118 shown in Table 1, and further includes a continuous nucleotide sequence that differs from the antisense strand shown in Table 1 (excluding the 3'-overhanging base) by 1 or 2 nucleotides.
[0013] For example, 5'-UAGAGUGUAACCGUCAUAGCUU-3' (SEQ ID NO: 82) and 5'-UAGAGUGUAACCGUCAUAGC-3', 5'-UAGAGUGUAACCGUCAUAGCTT-3', 5'-IAGAGUGUAACCGUCAUAGCUU-3', etc. should be regarded as the same nucleotide sequence.
[0014] Table 1: Nucleotide sequences of siRNA
[0015]
[0016]
[0017] According to an embodiment of the present invention, the sense chain includes one of the following nucleotide sequences, or a nucleotide sequence that differs therefrom by no more than 2 nucleotides: SEQ ID NO:4, SEQ ID NO:7, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:20, SEQ ID NO:23 and / or SEQ ID NO:40, and the antisense chain includes one of the following nucleotide sequences, or a nucleotide sequence that differs therefrom by no more than 2 nucleotides: SEQ ID NO:63, SEQ ID NO:66, SEQ ID NO:74, SEQ ID NO:75, SEQ ID NO:79, SEQ ID NO:82 and SEQ ID NO:99.
[0018] According to an embodiment of the present invention, the antisense strand comprises at least 19 consecutive nucleotides of any antisense strand nucleotide sequence of the following duplexes:
[0019] NDS-014-3 (SEQ ID NO. 3 and SEQ ID NO. 62)
[0020] NDS-014-4 (SEQ ID NO. 4 and SEQ ID NO. 63)
[0021] NDS-014-5 (SEQ ID NO. 5 and SEQ ID NO. 64)
[0022] NDS-014-6 (SEQ ID NO. 6 and SEQ ID NO. 65)
[0023] NDS-014-7 (SEQ ID NO. 7 and SEQ ID NO. 66)
[0024] NDS-014-8 (SEQ ID NO. 8 and SEQ ID NO. 67)
[0025] NDS-014-9 (SEQ ID NO. 9 and SEQ ID NO. 68)
[0026] NDS-014-12 (SEQ ID NO. 12 and SEQ ID NO. 71)
[0027] NDS-014-15 (SEQ ID NO. 15 and SEQ ID NO. 74)
[0028] NDS-014-16 (SEQ ID NO. 16 and SEQ ID NO. 75)
[0029] NDS-014-18 (SEQ ID NO. 18 and SEQ ID NO. 77)
[0030] NDS-014-20 (SEQ ID NO. 20 and SEQ ID NO. 79)
[0031] NDS-014-21 (SEQ ID NO. 21 and SEQ ID NO. 80)
[0032] NDS-014-23 (SEQ ID NO. 23 and SEQ ID NO. 82)
[0033] NDS-014-29 (SEQ ID NO. 29 and SEQ ID NO. 88)
[0034] NDS-014-38 (SEQ ID NO. 38 and SEQ ID NO. 97)
[0035] NDS-014-39 (SEQ ID NO. 39 and SEQ ID NO. 98)
[0036] NDS-014-40 (SEQ ID NO. 40 and SEQ ID NO. 99)
[0037] NDS-014-44 (SEQ ID NO. 44 and SEQ ID NO. 103)
[0038] NDS-014-50 (SEQ ID NO. 50 and SEQ ID NO. 109)
[0039] NDS-014-55 (SEQ ID NO. 55 and SEQ ID NO. 114).
[0040] According to an embodiment of the present invention, the sense strand comprises at least 17 consecutive nucleotides of any sense strand nucleotide sequence of the following duplexes:
[0041] NDS-014-3 (SEQ ID NO. 3 and SEQ ID NO. 62)
[0042] NDS-014-4 (SEQ ID NO. 4 and SEQ ID NO. 63)
[0043] NDS-014-5 (SEQ ID NO. 5 and SEQ ID NO. 64)
[0044] NDS-014-6 (SEQ ID NO. 6 and SEQ ID NO. 65)
[0045] NDS-014-7 (SEQ ID NO. 7 and SEQ ID NO. 66)
[0046] NDS-014-8 (SEQ ID NO. 8 and SEQ ID NO. 67)
[0047] NDS-014-9 (SEQ ID NO. 9 and SEQ ID NO. 68)
[0048] NDS-014-12 (SEQ ID NO. 12 and SEQ ID NO. 71)
[0049] NDS-014-15 (SEQ ID NO. 15 and SEQ ID NO. 74)
[0050] NDS-014-16 (SEQ ID NO. 16 and SEQ ID NO. 75)
[0051] NDS-014-18 (SEQ ID NO. 18 and SEQ ID NO. 77)
[0052] NDS-014-20 (SEQ ID NO. 20 and SEQ ID NO. 79)
[0053] NDS-014-21 (SEQ ID NO. 21 and SEQ ID NO. 80)
[0054] NDS-014-23 (SEQ ID NO. 23 and SEQ ID NO. 82)
[0055] NDS-014-29 (SEQ ID NO. 29 and SEQ ID NO. 88)
[0056] NDS-014-38 (SEQ ID NO. 38 and SEQ ID NO. 97)
[0057] NDS-014-39 (SEQ ID NO. 39 and SEQ ID NO. 98)
[0058] NDS-014-40 (SEQ ID NO. 40 and SEQ ID NO. 99)
[0059] NDS-014-44 (SEQ ID NO. 44 and SEQ ID NO. 103)
[0060] NDS-014-50 (SEQ ID NO. 50 and SEQ ID NO. 109)
[0061] NDS-014-55 (SEQ ID NO. 55 and SEQ ID NO. 114).
[0062] According to an embodiment of the present invention, the sense and antisense strands comprise duplex nucleotide sequences selected from the group consisting of:
[0063] NDS-014-3 (SEQ ID NO. 3 and SEQ ID NO. 62)
[0064] NDS-014-4 (SEQ ID NO. 4 and SEQ ID NO. 63)
[0065] NDS-014-5 (SEQ ID NO. 5 and SEQ ID NO. 64)
[0066] NDS-014-6 (SEQ ID NO. 6 and SEQ ID NO. 65)
[0067] NDS-014-7 (SEQ ID NO. 7 and SEQ ID NO. 66)
[0068] NDS-014-8 (SEQ ID NO. 8 and SEQ ID NO. 67)
[0069] NDS-014-9 (SEQ ID NO. 9 and SEQ ID NO. 68)
[0070] NDS-014-12 (SEQ ID NO. 12 and SEQ ID NO. 71)
[0071] NDS-014-15 (SEQ ID NO. 15 and SEQ ID NO. 74)
[0072] NDS-014-16 (SEQ ID NO. 16 and SEQ ID NO. 75)
[0073] NDS-014-18 (SEQ ID NO. 18 and SEQ ID NO. 77)
[0074] NDS-014-20 (SEQ ID NO. 20 and SEQ ID NO. 79)
[0075] NDS-014-21 (SEQ ID NO. 21 and SEQ ID NO. 80)
[0076] NDS-014-23 (SEQ ID NO. 23 and SEQ ID NO. 82)
[0077] NDS-014-29 (SEQ ID NO. 29 and SEQ ID NO. 88)
[0078] NDS-014-38 (SEQ ID NO. 38 and SEQ ID NO. 97)
[0079] NDS-014-39 (SEQ ID NO. 39 and SEQ ID NO. 98)
[0080] NDS-014-40 (SEQ ID NO. 40 and SEQ ID NO. 99)
[0081] NDS-014-44 (SEQ ID NO. 44 and SEQ ID NO. 103)
[0082] NDS-014-50 (SEQ ID NO. 50 and SEQ ID NO. 109)
[0083] NDS-014-55 (SEQ ID NO. 55 and SEQ ID NO. 114).
[0084] According to an embodiment of the present invention, the antisense strand comprises at least 19 consecutive nucleotides of the nucleotide sequence of the antisense strand of NDS-014-23 (5'-UAGAGUGUAACCGUCAUAGCUU-3', SEQ ID NO: 82). In certain embodiments, the sense strand comprises at least 19 consecutive nucleotides of the nucleotide sequence of the sense strand of NDS-115 (5'-GCUAUGACGGUUACACUCUA-3', SEQ ID NO: 23). In certain embodiments, the sense and antisense strands comprise the sense and antisense strand nucleotide sequences of NDS-014-23 (5'-GCUAUGACGGUUACACUCUA-3', SEQ ID NO: 23) and (5'-UAGAGUGUAACCGUCAUAGCUU-3', SEQ ID NO: 82).
[0085] According to an embodiment of the present invention, the length of the complementary region is at least 19 bases.
[0086] According to an embodiment of the present invention, the length of the complementary region is 19 to 23 bases.
[0087] According to an embodiment of the present invention, one or more ribonucleotides are added to the 3' end of the sense strand and / or antisense strand of the siRNA as an overhang.
[0088] According to an embodiment of the present invention, the siRNA includes at least one modified nucleotide.
[0089] According to an embodiment of the present invention, the modified nucleotide is selected from at least one of phosphodiester chain modification, ribose modification and base modification, or any combination of these three types of modifications.
[0090] According to an embodiment of the present invention, the modified nucleotide is selected from at least one of the following:
[0091] 2'-O-methyl modified nucleotides : aM, gM, cM and uM are 2'-O-Me A, 2'-O-Me G, 2'-O-Me C and 2'-O-Me U, respectively;
[0092] 2'-Fluoro-modified nucleotides : aF, gF, cF and uF are 2'-fluoro A, 2'-fluoro C, 2'-fluoro G and 2'-fluoro U, respectively;
[0093] 2'-deoxy modified nucleotides : 2'-deoxycytidine-3'-phosphate, 2'-deoxyguanosine-3'-phosphate, 2'-deoxyadenosine-3'-phosphate, 2'-deoxyuridine-3'-phosphate;
[0094] 5'-(1,2,4)-Triazole-modified nucleotides: cTA4, gTA4, aTA4, uTA4 are 2'-O-methyl-5'-deoxy-(1-(1,2,4-triazole))-cytidine-3'-phosphate, 2'-O-methyl-5'-deoxy-(1-(1,2,4-triazole))-guanosine-3'-phosphate, 2'-O-methyl-5'-deoxy-(1-(1,2,4-triazole))-adenosine-3'-phosphate, 2'-O-methyl-5'-deoxy-(1-(1,2,4-triazole))-uridine-3'-phosphate, respectively;
[0095] 5'-Thiomorpholine-modified nucleotides : cSMP, gSMP, aSMP, and uSMP are 2'-O-methyl-5'-N-(thiomorpholino)-cytidine-3'-phosphate, 2'-O-methyl-5'-N-(thiomorpholino)-guanosine-3'-phosphate, 2'-O-methyl-5'-N-(thiomorpholino)-adenosine-3'-phosphate, and 2'-O-methyl-5'-N-(thiomorpholino)-uridine-3'-phosphate, respectively;
[0096] 3'-Fluoro-modified nucleotides : cRF, gRF, aRF, uRF are 3'-fluoro-3'-deoxycytidine-2'-phosphate, 3'-fluoro-3'-deoxyguanosine-2'-phosphate, 3'-fluoro-3'-deoxyadenosine-2'-phosphate, 3'-fluoro-3'-deoxyuridine-2'-phosphate, respectively; cXF, gXF, aXF, uXF are 3'-fluoro-3'-deoxycytidine xylosyl-2'-phosphate, 3'-fluoro-3'-deoxyguanine xylosyl-2'-phosphate, 3'-fluoro-3'-deoxyadenine xylosyl-2'-phosphate, 3'-fluoro-3'-deoxyuridine xylosyl-2'-phosphate, respectively;
[0097] 3'-deoxy modified nucleotides : 3'-deoxycytidine-2'-phosphate, 3'-deoxyguanosine-2'-phosphate, 3'-deoxyadenosine-2'-phosphate, 3'-deoxyuridine-2'-phosphate;
[0098] 5'-phosphothioate diester-linked and / or methylphosphonate nucleotides ;
[0099] Unconventional base nucleotides ;
[0100] 5'-trans-vinylphosphonate (E-VP) modified nucleotides .
[0101] It should be noted that when a modified nucleotide is selected from a 2'-modified nucleotide and a 5'-phosphorothioate diester modified nucleotide, the modified nucleotide has both a 2'-modification and a 5'-phosphorothioate diester chain modification.
[0102] As is known to those skilled in the art, a ribonucleotide molecule is composed of phosphate, ribose and a base. In this article, a "modified nucleotide" refers to a conventional nucleotide, or an unconventional nucleotide such as inosine (I) or pseudouridine (ψ), which has a change in the group attached to a different carbon atom on the ribose, a change in the phosphodiester linker group, or a deletion or replacement of a base compared to a conventional nucleotide such as A, U, C or G.
[0103] According to an embodiment of the present invention, all nucleotides in the sense strand and / or the antisense strand are modified nucleotides, and the modified nucleotides are each independently selected from at least one of 2'-O-methyl modified nucleotides, 2'-fluoro modified nucleotides, 2'-deoxy modified nucleotides, 3'-O-methyl modified nucleotides, 3'-fluoro modified nucleotides, 3'-deoxy modified nucleotides, 5'-(1,2,4)-triazole modified nucleotides, 5'-thiomorpholine modified nucleotides, 5'-phosphorothioate diester modified nucleotides and 5'-VP phosphonate modified nucleotides.
[0104] According to an embodiment of the present invention, in the sense strand and / or the antisense strand, 2'-fluoro-modified nucleotides are present in the following positions: the nucleotides at the 5'-terminus of the sense strand are 2'-fluoro-modified nucleotides at positions 9, 10 and 11 of the starting point, and the remaining positions are 2'-O-methyl-modified nucleotides; and / or the nucleotides at the 5'-terminus of the antisense strand are 2'-fluoro-modified nucleotides at positions 2, 6, 14 and 16 of the starting point, and the remaining positions are 2'-O-methyl-modified nucleotides.
[0105] Exemplarily, the nucleotide at the 5'-terminus of the sense strand is the first nucleotide at the starting point and is a 2'-O-methyl modified nucleotide.
[0106] Exemplarily, the nucleotide at the 5'-terminal end of the antisense strand is the 1st nucleotide at the starting point, and the nucleotide at the 3'-terminal end of the antisense strand is the 1st and 2nd nucleotides at the starting point, which are both 2'-O-methyl modified nucleotides and 5'-phosphorothioate diester modified nucleotides.
[0107] According to an embodiment of the present invention, the 5'-modified nucleotide at the first position of the nucleotide starting point at the 5'-end of the siRNA sense strand can be optionally 5'-(1,2,4)-Triazole-modified nucleotides: cTA4, gTA4, aTA4, uTA4 are 2'-O-methyl-5'-deoxy-(1-(1,2,4-triazole))-cytidine-3'-phosphate, 2'-O-methyl-5'-deoxy-(1-(1,2,4-triazole))-guanosine-3'-phosphate, 2'-O-methyl-5'-deoxy-(1-(1,2,4-triazole))-adenosine-3'-phosphate, 2'-O-methyl-5'-deoxy-(1-(1,2,4-triazole))-uridine-3'-phosphate, respectively; or
[0108] 5'-Thiomorpholine-modified nucleotides : cSMP, gSMP, aSMP, and uSMP are 2'-O-methyl-5'-N-(thiomorpholine)-cytidine-3'-phosphate, 2'-O-methyl-5'-N-(thiomorpholine)-guanosine-3'-phosphate, 2'-O-methyl-5'-N-(thiomorpholine)-adenosine-3'-phosphate, and 2'-O-methyl-5'-N-(thiomorpholine)-uridine-3'-phosphate, respectively.
[0109] For example, the nucleotide at the 5'-terminus of the sense strand may be the starting point, and the nucleotide at position 1 may be 2'-O-methyl-5'-deoxy-(1-(1,2,4-triazole))-cytidine-3'-phosphate.
[0110] According to an embodiment of the present invention, the nucleotide starting point at the 5'-end of the antisense strand of the siRNA is a 5'-unmodified or 5'-trans-vinylphosphonate (E-VP) modified nucleotide at position 1.
[0111] For example, the nucleotide at the 5'-terminal end of the antisense strand is the first nucleotide at the starting point and may be 2'-O-methyl-5'-deoxy-(E)-vinyl phosphate-inosine-3'-phosphate.
[0112] According to an embodiment of the present invention, the nucleotides from position 5 to position 8 at the starting point of the 5'-end of the antisense strand of the siRNA can be optionally 3'-O-methyl or 3'-fluoro modified nucleotides.
[0113] For example, the nucleotide at position 7 at the starting point of the 5'-end of the antisense strand may be 3'-fluoro-3'-deoxyadenosine-2'-phosphate.
[0114] According to an embodiment of the present invention, the siRNA double-stranded molecule, wherein the siRNA double-stranded molecule may further comprise at least one phosphorothioate or methylphosphonate internucleotide connection. In certain embodiments, the phosphorothioate or methylphosphonate internucleotide is connected to the 3'-end of a chain, wherein the chain is an antisense strand and / or a sense strand. In certain embodiments, the phosphorothioate or methylphosphonate internucleotide is connected to the 5'-end of a chain, wherein the chain is an antisense strand and / or a sense strand. In certain embodiments, the phosphorothioate or methylphosphonate internucleotide is connected to the 5'-end and 3'-end of a chain, wherein the chain is an antisense strand.
[0115] According to an embodiment of the present invention, in the siRNA double-stranded molecule, the base pair at position 1 of the 5′-end of the antisense strand of the double-stranded molecule is an A:U base pair or an A:I base pair, wherein I is inosine.
[0116] According to an embodiment of the present invention, the siRNA antisense strand comprises any antisense strand nucleotide sequence of a chemically modified duplex selected from the following:
[0117] NPD014s-AD003 (SEQ ID NO.121 and SEQ ID NO.360)
[0118] NPD014s-AD004 (SEQ ID NO.122 and SEQ ID NO.361)
[0119] NPD014s-AD005 (SEQ ID NO.123 and SEQ ID NO.362)
[0120] NPD014s-AD006 (SEQ ID NO.124 and SEQ ID NO.363)
[0121] NPD014s-AD007 (SEQ ID NO.125 and SEQ ID NO.364)
[0122] NPD014s-AD008 (SEQ ID NO.126 and SEQ ID NO.365)
[0123] NPD014s-AD009 (SEQ ID NO.127 and SEQ ID NO.366)
[0124] NPD014s-AD012 (SEQ ID NO.130 and SEQ ID NO.367)
[0125] NPD014s-AD015 (SEQ ID NO.133 and SEQ ID NO.368)
[0126] NPD014s-AD016 (SEQ ID NO.134 and SEQ ID NO.369)
[0127] NPD014s-AD018 (SEQ ID NO.136 and SEQ ID NO.370)
[0128] NPD014s-AD020 (SEQ ID NO.138 and SEQ ID NO.371)
[0129] NPD014s-AD021 (SEQ ID NO.139 and SEQ ID NO.372)
[0130] NPD014s-AD023 (SEQ ID NO.141 and SEQ ID NO.373)
[0131] NPD014s-AD029 (SEQ ID NO.147 and SEQ ID NO.374)
[0132] NPD014s-AD038 (SEQ ID NO.156 and SEQ ID NO.375)
[0133] NPD014s-AD039 (SEQ ID NO.157 and SEQ ID NO.376)
[0134] NPD014s-AD040 (SEQ ID NO.158 and SEQ ID NO.377)
[0135] NPD014s-AD044 (SEQ ID NO.162 and SEQ ID NO.378)
[0136] NPD014s-AD050 (SEQ ID NO.168 and SEQ ID NO.379)
[0137] NPD014s-AD055 (SEQ ID NO. 173 and SEQ ID NO. 380)
[0138] NPD014s-AD060 (SEQ ID NO. 178 and SEQ ID NO. 381)
[0139] NPD014s-AD061 (SEQ ID NO. 179 and SEQ ID NO. 382)
[0140] NPD014s-AD063 (SEQ ID NO.181 and SEQ ID NO.384)
[0141] NPD014s-AD064 (SEQ ID NO.182 and SEQ ID NO.385)
[0142] NPD014s-AD066 (SEQ ID NO. 184 and SEQ ID NO. 387)
[0143] NPD014s-AD067 (SEQ ID NO. 185 and SEQ ID NO. 388)
[0144] NPD014s-AD068 (SEQ ID NO.186 and SEQ ID NO.389)
[0145] NPD014s-AD069 (SEQ ID NO.187 and SEQ ID NO.390)
[0146] NPD014s-AD070 (SEQ ID NO.188 and SEQ ID NO.391)
[0147] NPD014s-AD072 (SEQ ID NO. 190 and SEQ ID NO. 393)
[0148] NPD014s-AD075 (SEQ ID NO. 193 and SEQ ID NO. 396)
[0149] NPD014s-AD076 (SEQ ID NO. 194 and SEQ ID NO. 397)
[0150] NPD014s-AD077 (SEQ ID NO. 195 and SEQ ID NO. 398)
[0151] NPD014s-AD078 (SEQ ID NO. 196 and SEQ ID NO. 399)
[0152] NPD014s-AD081 (SEQ ID NO. 199 and SEQ ID NO. 402)
[0153] NPD014s-AD082 (SEQ ID NO. 200 and SEQ ID NO. 403)
[0154] NPD014s-AD083 (SEQ ID NO. 201 and SEQ ID NO. 404)
[0155] NPD014s-AD084 (SEQ ID NO. 202 and SEQ ID NO. 405)
[0156] NPD014s-AD085 (SEQ ID NO. 203 and SEQ ID NO. 406)
[0157] NPD014s-AD086 (SEQ ID NO. 204 and SEQ ID NO. 407)
[0158] NPD014s-AD087 (SEQ ID NO. 205 and SEQ ID NO. 408)
[0159] NPD014s-AD088 (SEQ ID NO. 206 and SEQ ID NO. 409)
[0160] NPD014s-AD089 (SEQ ID NO. 207 and SEQ ID NO. 410)
[0161] NPD014s-AD090 (SEQ ID NO.208 and SEQ ID NO.411)
[0162] NPD014s-AD091 (SEQ ID NO. 209 and SEQ ID NO. 412)
[0163] NPD014s-AD092 (SEQ ID NO.210 and SEQ ID NO.413)
[0164] NPD014s-AD093 (SEQ ID NO.211 and SEQ ID NO.414)
[0165] NPD014s-AD094 (SEQ ID NO.212 and SEQ ID NO.415)
[0166] NPD014s-AD095 (SEQ ID NO.213 and SEQ ID NO.416)
[0167] NPD014s-AD096 (SEQ ID NO. 214 and SEQ ID NO. 417)
[0168] NPD014s-AD097 (SEQ ID NO. 215 and SEQ ID NO. 418)
[0169] NPD014s-AD098 (SEQ ID NO.216 and SEQ ID NO.419)
[0170] NPD014s-AD099 (SEQ ID NO. 217 and SEQ ID NO. 420)
[0171] NPD014s-AD100 (SEQ ID NO.218 and SEQ ID NO.421)
[0172] NPD014s-AD101 (SEQ ID NO.219 and SEQ ID NO.422)
[0173] NPD014s-AD102 (SEQ ID NO. 220 and SEQ ID NO. 423)
[0174] NPD014s-AD103 (SEQ ID NO.221 and SEQ ID NO.424)
[0175] NPD014s-AD104 (SEQ ID NO. 222 and SEQ ID NO. 425)
[0176] NPD014s-AD105 (SEQ ID NO. 223 and SEQ ID NO. 426)
[0177] NPD014s-AD106 (SEQ ID NO. 224 and SEQ ID NO. 427)
[0178] NPD014s-AD107 (SEQ ID NO. 225 and SEQ ID NO. 428)
[0179] NPD014s-AD108 (SEQ ID NO. 226 and SEQ ID NO. 429)
[0180] NPD014s-AD109 (SEQ ID NO. 227 and SEQ ID NO. 430)
[0181] NPD014s-AD110 (SEQ ID NO.228 and SEQ ID NO.431)
[0182] NPD014s-AD111 (SEQ ID NO.229 and SEQ ID NO.432)
[0183] NPD014s-AD112 (SEQ ID NO. 230 and SEQ ID NO. 433)
[0184] NPD014s-AD113 (SEQ ID NO.231 and SEQ ID NO.434)
[0185] NPD014s-AD114 (SEQ ID NO. 232 and SEQ ID NO. 435)
[0186] NPD014s-AD115 (SEQ ID NO. 233 and SEQ ID NO. 436)
[0187] NPD014s-AD116 (SEQ ID NO. 234 and SEQ ID NO. 437)
[0188] NPD014s-AD117 (SEQ ID NO. 235 and SEQ ID NO. 438)
[0189] NPD014s-AD118 (SEQ ID NO. 236 and SEQ ID NO. 439)
[0190] NPD014s-AD119 (SEQ ID NO. 237 and SEQ ID NO. 440)
[0191] NPD014s-AD120 (SEQ ID NO.238 and SEQ ID NO.441)
[0192] NPD014s-AD121 (SEQ ID NO.239 and SEQ ID NO.442)
[0193] NPD014s-AD122 (SEQ ID NO. 240 and SEQ ID NO. 443)
[0194] NPD014s-AD123 (SEQ ID NO.241 and SEQ ID NO.444)
[0195] NPD014s-AD124 (SEQ ID NO. 242 and SEQ ID NO. 445)
[0196] NPD014s-AD125 (SEQ ID NO. 243 and SEQ ID NO. 446)
[0197] NPD014s-AD126 (SEQ ID NO. 244 and SEQ ID NO. 447)
[0198] NPD014s-AD127 (SEQ ID NO. 245 and SEQ ID NO. 448)
[0199] NPD014s-AD128 (SEQ ID NO. 246 and SEQ ID NO. 449)
[0200] NPD014s-AD129 (SEQ ID NO. 247 and SEQ ID NO. 450)
[0201] NPD014s-AD130 (SEQ ID NO.248 and SEQ ID NO.451)
[0202] NPD014s-AD131 (SEQ ID NO. 249 and SEQ ID NO. 452)
[0203] NPD014s-AD132 (SEQ ID NO. 250 and SEQ ID NO. 453)
[0204] NPD014s-AD133 (SEQ ID NO.251 and SEQ ID NO.454)
[0205] NPD014s-AD134 (SEQ ID NO. 252 and SEQ ID NO. 455)
[0206] NPD014s-AD135 (SEQ ID NO. 253 and SEQ ID NO. 456)
[0207] NPD014s-AD136 (SEQ ID NO. 254 and SEQ ID NO. 457)
[0208] NPD014s-AD137 (SEQ ID NO.255 and SEQ ID NO.458)
[0209] NPD014s-AD138 (SEQ ID NO. 256 and SEQ ID NO. 459)
[0210] NPD014s-AD139 (SEQ ID NO. 257 and SEQ ID NO. 460)
[0211] NPD014s-AD140 (SEQ ID NO. 258 and SEQ ID NO. 461)
[0212] NPD014s-AD141 (SEQ ID NO. 259 and SEQ ID NO. 462)
[0213] NPD014s-AD142 (SEQ ID NO. 260 and SEQ ID NO. 463)
[0214] NPD014s-AD143 (SEQ ID NO.261 and SEQ ID NO.464)
[0215] NPD014s-AD144 (SEQ ID NO. 262 and SEQ ID NO. 465)
[0216] NPD014s-AD145 (SEQ ID NO. 263 and SEQ ID NO. 466)
[0217] NPD014s-AD146 (SEQ ID NO. 264 and SEQ ID NO. 467)
[0218] NPD014s-AD147 (SEQ ID NO. 265 and SEQ ID NO. 468)
[0219] NPD014s-AD148 (SEQ ID NO. 266 and SEQ ID NO. 469)
[0220] NPD014s-AD149 (SEQ ID NO. 267 and SEQ ID NO. 470)
[0221] NPD014s-AD150 (SEQ ID NO.268 and SEQ ID NO.471)
[0222] NPD014s-AD151 (SEQ ID NO.269 and SEQ ID NO.472)
[0223] NPD014s-AD152 (SEQ ID NO. 270 and SEQ ID NO. 473)
[0224] NPD014s-AD153 (SEQ ID NO. 271 and SEQ ID NO. 474)
[0225] NPD014s-AD154 (SEQ ID NO. 272 and SEQ ID NO. 475)
[0226] NPD014s-AD155 (SEQ ID NO. 273 and SEQ ID NO. 476)
[0227] NPD014s-AD156 (SEQ ID NO. 274 and SEQ ID NO. 477)
[0228] NPD014s-AD157 (SEQ ID NO. 275 and SEQ ID NO. 478)
[0229] NPD014s-AD158 (SEQ ID NO. 276 and SEQ ID NO. 479)
[0230] NPD014s-AD159 (SEQ ID NO. 277 and SEQ ID NO. 480)
[0231] NPD014s-AD160 (SEQ ID NO. 278 and SEQ ID NO. 481)
[0232] NPD014s-AD161 (SEQ ID NO. 279 and SEQ ID NO. 482)
[0233] NPD014s-AD162 (SEQ ID NO. 280 and SEQ ID NO. 483)
[0234] NPD014s-AD163 (SEQ ID NO.281 and SEQ ID NO.484)
[0235] NPD014s-AD164 (SEQ ID NO. 282 and SEQ ID NO. 485)
[0236] NPD014s-AD165 (SEQ ID NO. 283 and SEQ ID NO. 486)
[0237] NPD014s-AD166 (SEQ ID NO. 284 and SEQ ID NO. 487)
[0238] NPD014s-AD167 (SEQ ID NO. 285 and SEQ ID NO. 488)
[0239] NPD014s-AD168 (SEQ ID NO. 286 and SEQ ID NO. 489)
[0240] NPD014s-AD169 (SEQ ID NO. 287 and SEQ ID NO. 490)
[0241] NPD014s-AD170 (SEQ ID NO. 288 and SEQ ID NO. 491)
[0242] NPD014s-AD171 (SEQ ID NO. 289 and SEQ ID NO. 492)
[0243] NPD014s-AD172 (SEQ ID NO. 290 and SEQ ID NO. 493)
[0244] NPD014s-AD173 (SEQ ID NO. 291 and SEQ ID NO. 494)
[0245] NPD014s-AD174 (SEQ ID NO. 292 and SEQ ID NO. 495)
[0246] NPD014s-AD175 (SEQ ID NO. 293 and SEQ ID NO. 496)
[0247] NPD014s-AD176 (SEQ ID NO. 294 and SEQ ID NO. 497)
[0248] NPD014s-AD177 (SEQ ID NO. 295 and SEQ ID NO. 498)
[0249] NPD014s-AD178 (SEQ ID NO. 296 and SEQ ID NO. 499)
[0250] NPD014s-AD179 (SEQ ID NO. 297 and SEQ ID NO. 500)
[0251] NPD014s-AD180 (SEQ ID NO. 298 and SEQ ID NO. 501)
[0252] NPD014s-AD181 (SEQ ID NO. 299 and SEQ ID NO. 502)
[0253] NPD014s-AD182 (SEQ ID NO.300 and SEQ ID NO.503)
[0254] NPD014s-AD183 (SEQ ID NO.301 and SEQ ID NO.504)
[0255] NPD014s-AD184 (SEQ ID NO.302 and SEQ ID NO.505)
[0256] NPD014s-AD185 (SEQ ID NO.303 and SEQ ID NO.506)
[0257] NPD014s-AD186 (SEQ ID NO.304 and SEQ ID NO.507)
[0258] NPD014s-AD187 (SEQ ID NO.305 and SEQ ID NO.508)
[0259] NPD014s-AD188 (SEQ ID NO.306 and SEQ ID NO.509)
[0260] NPD014s-AD189 (SEQ ID NO.307 and SEQ ID NO.510)
[0261] NPD014s-AD190 (SEQ ID NO.308 and SEQ ID NO.511)
[0262] NPD014s-AD191 (SEQ ID NO.309 and SEQ ID NO.512)
[0263] NPD014s-AD192 (SEQ ID NO.310 and SEQ ID NO.513)
[0264] NPD014s-AD193 (SEQ ID NO.311 and SEQ ID NO.514)
[0265] NPD014s-AD194 (SEQ ID NO.312 and SEQ ID NO.515)
[0266] NPD014s-AD195 (SEQ ID NO.313 and SEQ ID NO.516)
[0267] NPD014s-AD196 (SEQ ID NO.314 and SEQ ID NO.517)
[0268] NPD014s-AD197 (SEQ ID NO.315 and SEQ ID NO.518)
[0269] NPD014s-AD198 (SEQ ID NO.316 and SEQ ID NO.519)
[0270] NPD014s-AD199 (SEQ ID NO.317 and SEQ ID NO.520)
[0271] NPD014s-AD200 (SEQ ID NO.318 and SEQ ID NO.521)
[0272] NPD014s-AD201 (SEQ ID NO.319 and SEQ ID NO.522)
[0273] NPD014s-AD202 (SEQ ID NO.320 and SEQ ID NO.523)
[0274] NPD014s-AD203 (SEQ ID NO.321 and SEQ ID NO.524)
[0275] NPD014s-AD204 (SEQ ID NO.322 and SEQ ID NO.525)
[0276] NPD014s-AD205 (SEQ ID NO.323 and SEQ ID NO.526) NPD014s-AD206 (SEQ ID NO.324 and SEQ ID NO.527)
[0277] NPD014s-AD207 (SEQ ID NO.325 and SEQ ID NO.528)
[0278] NPD014s-AD208 (SEQ ID NO.326 and SEQ ID NO.529)
[0279] NPD014s-AD209 (SEQ ID NO.327 and SEQ ID NO.530)
[0280] NPD014s-AD210 (SEQ ID NO.328 and SEQ ID NO.531)
[0281] NPD014s-AD211 (SEQ ID NO.329 and SEQ ID NO.532)
[0282] NPD014s-AD212 (SEQ ID NO.330 and SEQ ID NO.533)
[0283] NPD014s-AD213 (SEQ ID NO.331 and SEQ ID NO.534)
[0284] NPD014s-AD214 (SEQ ID NO.332 and SEQ ID NO.535)
[0285] NPD014s-AD215 (SEQ ID NO.333 and SEQ ID NO.536)
[0286] NPD014s-AD216 (SEQ ID NO.334 and SEQ ID NO.537)
[0287] NPD014s-AD217 (SEQ ID NO.335 and SEQ ID NO.538)
[0288] NPD014s-AD218 (SEQ ID NO.336 and SEQ ID NO.539)
[0289] NPD014s-AD219 (SEQ ID NO.337 and SEQ ID NO.540)
[0290] NPD014s-AD220 (SEQ ID NO.338 and SEQ ID NO.541)
[0291] NPD014s-AD221 (SEQ ID NO.339 and SEQ ID NO.542)
[0292] NPD014s-AD222 (SEQ ID NO.340 and SEQ ID NO.543)
[0293] NPD014s-AD223 (SEQ ID NO.341 and SEQ ID NO.544)
[0294] NPD014s-AD224 (SEQ ID NO.342 and SEQ ID NO.545)
[0295] NPD014s-AD225 (SEQ ID NO.343 and SEQ ID NO.546)
[0296] NPD014s-AD226 (SEQ ID NO.344 and SEQ ID NO.547)
[0297] NPD014s-AD227 (SEQ ID NO.345 and SEQ ID NO.548)
[0298] NPD014s-AD228 (SEQ ID NO.346 and SEQ ID NO.549)
[0299] NPD014s-AD229 (SEQ ID NO.347 and SEQ ID NO.550)
[0300] NPD014s-AD230 (SEQ ID NO.348 and SEQ ID NO.551)
[0301] NPD014s-AD231 (SEQ ID NO.349 and SEQ ID NO.552)
[0302] NPD014s-AD232 (SEQ ID NO.350 and SEQ ID NO.553)
[0303] NPD014s-AD233 (SEQ ID NO.351 and SEQ ID NO.554)
[0304] NPD014s-AD234 (SEQ ID NO.352 and SEQ ID NO.555)
[0305] NPD014s-AD235 (SEQ ID NO.353 and SEQ ID NO.556)
[0306] NPD014s-AD236 (SEQ ID NO.354 and SEQ ID NO.557)
[0307] NPD014s-AD237 (SEQ ID NO.355 and SEQ ID NO.558)
[0308] NPD014s-AD238 (SEQ ID NO.356 and SEQ ID NO.559)
[0309] NPD014s-AD239 (SEQ ID NO.357 and SEQ ID NO.560)
[0310] NPD014s-AD240 (SEQ ID NO.358 and SEQ ID NO.561)
[0311] NPD014s-AD241 (SEQ ID NO.359 and SEQ ID NO.562)
[0312] According to an embodiment of the present invention, the siRNA sense strand comprises any sense strand nucleotide sequence of a chemically modified duplex selected from the following:
[0313] NPD014s-AD003 (SEQ ID NO.121 and SEQ ID NO.360)
[0314] NPD014s-AD004 (SEQ ID NO.122 and SEQ ID NO.361)
[0315] NPD014s-AD005 (SEQ ID NO.123 and SEQ ID NO.362)
[0316] NPD014s-AD006 (SEQ ID NO.124 and SEQ ID NO.363)
[0317] NPD014s-AD007 (SEQ ID NO.125 and SEQ ID NO.364)
[0318] NPD014s-AD008 (SEQ ID NO.126 and SEQ ID NO.365)
[0319] NPD014s-AD009 (SEQ ID NO.127 and SEQ ID NO.366)
[0320] NPD014s-AD012 (SEQ ID NO.130 and SEQ ID NO.367)
[0321] NPD014s-AD015 (SEQ ID NO.133 and SEQ ID NO.368)
[0322] NPD014s-AD016 (SEQ ID NO.134 and SEQ ID NO.369)
[0323] NPD014s-AD018 (SEQ ID NO.136 and SEQ ID NO.370)
[0324] NPD014s-AD020 (SEQ ID NO.138 and SEQ ID NO.371)
[0325] NPD014s-AD021 (SEQ ID NO.139 and SEQ ID NO.372)
[0326] NPD014s-AD023 (SEQ ID NO.141 and SEQ ID NO.373)
[0327] NPD014s-AD029 (SEQ ID NO.147 and SEQ ID NO.374)
[0328] NPD014s-AD038 (SEQ ID NO.156 and SEQ ID NO.375)
[0329] NPD014s-AD039 (SEQ ID NO.157 and SEQ ID NO.376)
[0330] NPD014s-AD040 (SEQ ID NO.158 and SEQ ID NO.377)
[0331] NPD014s-AD044 (SEQ ID NO.162 and SEQ ID NO.378)
[0332] NPD014s-AD050 (SEQ ID NO.168 and SEQ ID NO.379)
[0333] NPD014s-AD055 (SEQ ID NO. 173 and SEQ ID NO. 380)
[0334] NPD014s-AD060 (SEQ ID NO. 178 and SEQ ID NO. 381)
[0335] NPD014s-AD061 (SEQ ID NO. 179 and SEQ ID NO. 382)
[0336] NPD014s-AD063 (SEQ ID NO.181 and SEQ ID NO.384)
[0337] NPD014s-AD064 (SEQ ID NO.182 and SEQ ID NO.385)
[0338] NPD014s-AD066 (SEQ ID NO. 184 and SEQ ID NO. 387)
[0339] NPD014s-AD067 (SEQ ID NO. 185 and SEQ ID NO. 388)
[0340] NPD014s-AD068 (SEQ ID NO.186 and SEQ ID NO.389)
[0341] NPD014s-AD069 (SEQ ID NO.187 and SEQ ID NO.390)
[0342] NPD014s-AD070 (SEQ ID NO.188 and SEQ ID NO.391)
[0343] NPD014s-AD072 (SEQ ID NO. 190 and SEQ ID NO. 393)
[0344] NPD014s-AD075 (SEQ ID NO. 193 and SEQ ID NO. 396)
[0345] NPD014s-AD076 (SEQ ID NO. 194 and SEQ ID NO. 397)
[0346] NPD014s-AD077 (SEQ ID NO. 195 and SEQ ID NO. 398)
[0347] NPD014s-AD078 (SEQ ID NO. 196 and SEQ ID NO. 399)
[0348] NPD014s-AD081 (SEQ ID NO. 199 and SEQ ID NO. 402)
[0349] NPD014s-AD082 (SEQ ID NO. 200 and SEQ ID NO. 403)
[0350] NPD014s-AD083 (SEQ ID NO. 201 and SEQ ID NO. 404)
[0351] NPD014s-AD084 (SEQ ID NO. 202 and SEQ ID NO. 405)
[0352] NPD014s-AD085 (SEQ ID NO. 203 and SEQ ID NO. 406)
[0353] NPD014s-AD086 (SEQ ID NO. 204 and SEQ ID NO. 407)
[0354] NPD014s-AD087 (SEQ ID NO. 205 and SEQ ID NO. 408)
[0355] NPD014s-AD088 (SEQ ID NO. 206 and SEQ ID NO. 409)
[0356] NPD014s-AD089 (SEQ ID NO. 207 and SEQ ID NO. 410)
[0357] NPD014s-AD090 (SEQ ID NO.208 and SEQ ID NO.411)
[0358] NPD014s-AD091 (SEQ ID NO. 209 and SEQ ID NO. 412)
[0359] NPD014s-AD092 (SEQ ID NO.210 and SEQ ID NO.413)
[0360] NPD014s-AD093 (SEQ ID NO.211 and SEQ ID NO.414)
[0361] NPD014s-AD094 (SEQ ID NO.212 and SEQ ID NO.415)
[0362] NPD014s-AD095 (SEQ ID NO.213 and SEQ ID NO.416)
[0363] NPD014s-AD096 (SEQ ID NO. 214 and SEQ ID NO. 417)
[0364] NPD014s-AD097 (SEQ ID NO. 215 and SEQ ID NO. 418)
[0365] NPD014s-AD098 (SEQ ID NO.216 and SEQ ID NO.419)
[0366] NPD014s-AD099 (SEQ ID NO. 217 and SEQ ID NO. 420)
[0367] NPD014s-AD100 (SEQ ID NO.218 and SEQ ID NO.421)
[0368] NPD014s-AD101 (SEQ ID NO.219 and SEQ ID NO.422)
[0369] NPD014s-AD102 (SEQ ID NO. 220 and SEQ ID NO. 423)
[0370] NPD014s-AD103 (SEQ ID NO.221 and SEQ ID NO.424)
[0371] NPD014s-AD104 (SEQ ID NO. 222 and SEQ ID NO. 425)
[0372] NPD014s-AD105 (SEQ ID NO. 223 and SEQ ID NO. 426)
[0373] NPD014s-AD106 (SEQ ID NO. 224 and SEQ ID NO. 427)
[0374] NPD014s-AD107 (SEQ ID NO. 225 and SEQ ID NO. 428)
[0375] NPD014s-AD108 (SEQ ID NO. 226 and SEQ ID NO. 429)
[0376] NPD014s-AD109 (SEQ ID NO. 227 and SEQ ID NO. 430)
[0377] NPD014s-AD110 (SEQ ID NO.228 and SEQ ID NO.431)
[0378] NPD014s-AD111 (SEQ ID NO.229 and SEQ ID NO.432)
[0379] NPD014s-AD112 (SEQ ID NO. 230 and SEQ ID NO. 433)
[0380] NPD014s-AD113 (SEQ ID NO.231 and SEQ ID NO.434)
[0381] NPD014s-AD114 (SEQ ID NO. 232 and SEQ ID NO. 435)
[0382] NPD014s-AD115 (SEQ ID NO. 233 and SEQ ID NO. 436)
[0383] NPD014s-AD116 (SEQ ID NO. 234 and SEQ ID NO. 437)
[0384] NPD014s-AD117 (SEQ ID NO. 235 and SEQ ID NO. 438)
[0385] NPD014s-AD118 (SEQ ID NO. 236 and SEQ ID NO. 439)
[0386] NPD014s-AD119 (SEQ ID NO. 237 and SEQ ID NO. 440)
[0387] NPD014s-AD120 (SEQ ID NO.238 and SEQ ID NO.441)
[0388] NPD014s-AD121 (SEQ ID NO.239 and SEQ ID NO.442)
[0389] NPD014s-AD122 (SEQ ID NO. 240 and SEQ ID NO. 443)
[0390] NPD014s-AD123 (SEQ ID NO.241 and SEQ ID NO.444)
[0391] NPD014s-AD124 (SEQ ID NO. 242 and SEQ ID NO. 445)
[0392] NPD014s-AD125 (SEQ ID NO. 243 and SEQ ID NO. 446)
[0393] NPD014s-AD126 (SEQ ID NO. 244 and SEQ ID NO. 447)
[0394] NPD014s-AD127 (SEQ ID NO. 245 and SEQ ID NO. 448)
[0395] NPD014s-AD128 (SEQ ID NO. 246 and SEQ ID NO. 449)
[0396] NPD014s-AD129 (SEQ ID NO. 247 and SEQ ID NO. 450)
[0397] NPD014s-AD130 (SEQ ID NO.248 and SEQ ID NO.451)
[0398] NPD014s-AD131 (SEQ ID NO. 249 and SEQ ID NO. 452)
[0399] NPD014s-AD132 (SEQ ID NO. 250 and SEQ ID NO. 453)
[0400] NPD014s-AD133 (SEQ ID NO.251 and SEQ ID NO.454)
[0401] NPD014s-AD134 (SEQ ID NO. 252 and SEQ ID NO. 455)
[0402] NPD014s-AD135 (SEQ ID NO. 253 and SEQ ID NO. 456)
[0403] NPD014s-AD136 (SEQ ID NO. 254 and SEQ ID NO. 457)
[0404] NPD014s-AD137 (SEQ ID NO.255 and SEQ ID NO.458)
[0405] NPD014s-AD138 (SEQ ID NO. 256 and SEQ ID NO. 459)
[0406] NPD014s-AD139 (SEQ ID NO. 257 and SEQ ID NO. 460)
[0407] NPD014s-AD140 (SEQ ID NO. 258 and SEQ ID NO. 461)
[0408] NPD014s-AD141 (SEQ ID NO. 259 and SEQ ID NO. 462)
[0409] NPD014s-AD142 (SEQ ID NO. 260 and SEQ ID NO. 463)
[0410] NPD014s-AD143 (SEQ ID NO.261 and SEQ ID NO.464)
[0411] NPD014s-AD144 (SEQ ID NO. 262 and SEQ ID NO. 465)
[0412] NPD014s-AD145 (SEQ ID NO. 263 and SEQ ID NO. 466)
[0413] NPD014s-AD146 (SEQ ID NO. 264 and SEQ ID NO. 467)
[0414] NPD014s-AD147 (SEQ ID NO. 265 and SEQ ID NO. 468)
[0415] NPD014s-AD148 (SEQ ID NO. 266 and SEQ ID NO. 469)
[0416] NPD014s-AD149 (SEQ ID NO. 267 and SEQ ID NO. 470)
[0417] NPD014s-AD150 (SEQ ID NO.268 and SEQ ID NO.471)
[0418] NPD014s-AD151 (SEQ ID NO.269 and SEQ ID NO.472)
[0419] NPD014s-AD152 (SEQ ID NO. 270 and SEQ ID NO. 473)
[0420] NPD014s-AD153 (SEQ ID NO. 271 and SEQ ID NO. 474)
[0421] NPD014s-AD154 (SEQ ID NO. 272 and SEQ ID NO. 475)
[0422] NPD014s-AD155 (SEQ ID NO. 273 and SEQ ID NO. 476)
[0423] NPD014s-AD156 (SEQ ID NO. 274 and SEQ ID NO. 477)
[0424] NPD014s-AD157 (SEQ ID NO. 275 and SEQ ID NO. 478)
[0425] NPD014s-AD158 (SEQ ID NO. 276 and SEQ ID NO. 479)
[0426] NPD014s-AD159 (SEQ ID NO. 277 and SEQ ID NO. 480)
[0427] NPD014s-AD160 (SEQ ID NO. 278 and SEQ ID NO. 481)
[0428] NPD014s-AD161 (SEQ ID NO. 279 and SEQ ID NO. 482)
[0429] NPD014s-AD162 (SEQ ID NO. 280 and SEQ ID NO. 483)
[0430] NPD014s-AD163 (SEQ ID NO.281 and SEQ ID NO.484)
[0431] NPD014s-AD164 (SEQ ID NO. 282 and SEQ ID NO. 485)
[0432] NPD014s-AD165 (SEQ ID NO. 283 and SEQ ID NO. 486)
[0433] NPD014s-AD166 (SEQ ID NO. 284 and SEQ ID NO. 487)
[0434] NPD014s-AD167 (SEQ ID NO. 285 and SEQ ID NO. 488)
[0435] NPD014s-AD168 (SEQ ID NO. 286 and SEQ ID NO. 489)
[0436] NPD014s-AD169 (SEQ ID NO. 287 and SEQ ID NO. 490)
[0437] NPD014s-AD170 (SEQ ID NO. 288 and SEQ ID NO. 491)
[0438] NPD014s-AD171 (SEQ ID NO. 289 and SEQ ID NO. 492)
[0439] NPD014s-AD172 (SEQ ID NO. 290 and SEQ ID NO. 493)
[0440] NPD014s-AD173 (SEQ ID NO. 291 and SEQ ID NO. 494)
[0441] NPD014s-AD174 (SEQ ID NO. 292 and SEQ ID NO. 495)
[0442] NPD014s-AD175 (SEQ ID NO. 293 and SEQ ID NO. 496)
[0443] NPD014s-AD176 (SEQ ID NO. 294 and SEQ ID NO. 497)
[0444] NPD014s-AD177 (SEQ ID NO. 295 and SEQ ID NO. 498)
[0445] NPD014s-AD178 (SEQ ID NO. 296 and SEQ ID NO. 499)
[0446] NPD014s-AD179 (SEQ ID NO. 297 and SEQ ID NO. 500)
[0447] NPD014s-AD180 (SEQ ID NO. 298 and SEQ ID NO. 501)
[0448] NPD014s-AD181 (SEQ ID NO. 299 and SEQ ID NO. 502)
[0449] NPD014s-AD182 (SEQ ID NO.300 and SEQ ID NO.503)
[0450] NPD014s-AD183 (SEQ ID NO.301 and SEQ ID NO.504)
[0451] NPD014s-AD184 (SEQ ID NO.302 and SEQ ID NO.505)
[0452] NPD014s-AD185 (SEQ ID NO.303 and SEQ ID NO.506)
[0453] NPD014s-AD186 (SEQ ID NO.304 and SEQ ID NO.507)
[0454] NPD014s-AD187 (SEQ ID NO.305 and SEQ ID NO.508)
[0455] NPD014s-AD188 (SEQ ID NO.306 and SEQ ID NO.509)
[0456] NPD014s-AD189 (SEQ ID NO.307 and SEQ ID NO.510)
[0457] NPD014s-AD190 (SEQ ID NO.308 and SEQ ID NO.511)
[0458] NPD014s-AD191 (SEQ ID NO.309 and SEQ ID NO.512)
[0459] NPD014s-AD192 (SEQ ID NO.310 and SEQ ID NO.513)
[0460] NPD014s-AD193 (SEQ ID NO.311 and SEQ ID NO.514)
[0461] NPD014s-AD194 (SEQ ID NO.312 and SEQ ID NO.515)
[0462] NPD014s-AD195 (SEQ ID NO.313 and SEQ ID NO.516)
[0463] NPD014s-AD196 (SEQ ID NO.314 and SEQ ID NO.517)
[0464] NPD014s-AD197 (SEQ ID NO.315 and SEQ ID NO.518)
[0465] NPD014s-AD198 (SEQ ID NO.316 and SEQ ID NO.519)
[0466] NPD014s-AD199 (SEQ ID NO.317 and SEQ ID NO.520)
[0467] NPD014s-AD200 (SEQ ID NO.318 and SEQ ID NO.521)
[0468] NPD014s-AD201 (SEQ ID NO.319 and SEQ ID NO.522)
[0469] NPD014s-AD202 (SEQ ID NO.320 and SEQ ID NO.523)
[0470] NPD014s-AD203 (SEQ ID NO.321 and SEQ ID NO.524)
[0471] NPD014s-AD204 (SEQ ID NO.322 and SEQ ID NO.525)
[0472] NPD014s-AD205 (SEQ ID NO.323 and SEQ ID NO.526)
[0473] NPD014s-AD206 (SEQ ID NO.324 and SEQ ID NO.527)
[0474] NPD014s-AD207 (SEQ ID NO.325 and SEQ ID NO.528)
[0475] NPD014s-AD208 (SEQ ID NO.326 and SEQ ID NO.529)
[0476] NPD014s-AD209 (SEQ ID NO.327 and SEQ ID NO.530)
[0477] NPD014s-AD210 (SEQ ID NO.328 and SEQ ID NO.531)
[0478] NPD014s-AD211 (SEQ ID NO.329 and SEQ ID NO.532)
[0479] NPD014s-AD212 (SEQ ID NO.330 and SEQ ID NO.533)
[0480] NPD014s-AD213 (SEQ ID NO.331 and SEQ ID NO.534)
[0481] NPD014s-AD214 (SEQ ID NO.332 and SEQ ID NO.535)
[0482] NPD014s-AD215 (SEQ ID NO.333 and SEQ ID NO.536)
[0483] NPD014s-AD216 (SEQ ID NO.334 and SEQ ID NO.537)
[0484] NPD014s-AD217 (SEQ ID NO.335 and SEQ ID NO.538)
[0485] NPD014s-AD218 (SEQ ID NO.336 and SEQ ID NO.539)
[0486] NPD014s-AD219 (SEQ ID NO.337 and SEQ ID NO.540)
[0487] NPD014s-AD220 (SEQ ID NO.338 and SEQ ID NO.541)
[0488] NPD014s-AD221 (SEQ ID NO.339 and SEQ ID NO.542)
[0489] NPD014s-AD222 (SEQ ID NO.340 and SEQ ID NO.543)
[0490] NPD014s-AD223 (SEQ ID NO.341 and SEQ ID NO.544)
[0491] NPD014s-AD224 (SEQ ID NO.342 and SEQ ID NO.545)
[0492] NPD014s-AD225 (SEQ ID NO.343 and SEQ ID NO.546)
[0493] NPD014s-AD226 (SEQ ID NO.344 and SEQ ID NO.547)
[0494] NPD014s-AD227 (SEQ ID NO.345 and SEQ ID NO.548)
[0495] NPD014s-AD228 (SEQ ID NO.346 and SEQ ID NO.549)
[0496] NPD014s-AD229 (SEQ ID NO.347 and SEQ ID NO.550)
[0497] NPD014s-AD230 (SEQ ID NO.348 and SEQ ID NO.551)
[0498] NPD014s-AD231 (SEQ ID NO.349 and SEQ ID NO.552)
[0499] NPD014s-AD232 (SEQ ID NO.350 and SEQ ID NO.553)
[0500] NPD014s-AD233 (SEQ ID NO.351 and SEQ ID NO.554)
[0501] NPD014s-AD234 (SEQ ID NO.352 and SEQ ID NO.555)
[0502] NPD014s-AD235 (SEQ ID NO.353 and SEQ ID NO.556)
[0503] NPD014s-AD236 (SEQ ID NO.354 and SEQ ID NO.557)
[0504] NPD014s-AD237 (SEQ ID NO.355 and SEQ ID NO.558)
[0505] NPD014s-AD238 (SEQ ID NO.356 and SEQ ID NO.559)
[0506] NPD014s-AD239 (SEQ ID NO.357 and SEQ ID NO.560)
[0507] NPD014s-AD240 (SEQ ID NO.358 and SEQ ID NO.561)
[0508] NPD014s-AD241 (SEQ ID NO. 359 and SEQ ID NO. 562).
[0509] According to an embodiment of the present invention, the siRNA antisense strand and the sense strand comprise a chemically modified nucleotide sequence of a duplex selected from the following:
[0510] NPD014s-AD003 (SEQ ID NO.121 and SEQ ID NO.360)
[0511] NPD014s-AD004 (SEQ ID NO.122 and SEQ ID NO.361)
[0512] NPD014s-AD005 (SEQ ID NO.123 and SEQ ID NO.362)
[0513] NPD014s-AD006 (SEQ ID NO.124 and SEQ ID NO.363)
[0514] NPD014s-AD007 (SEQ ID NO.125 and SEQ ID NO.364)
[0515] NPD014s-AD008 (SEQ ID NO.126 and SEQ ID NO.365)
[0516] NPD014s-AD009 (SEQ ID NO.127 and SEQ ID NO.366)
[0517] NPD014s-AD012 (SEQ ID NO.130 and SEQ ID NO.367)
[0518] NPD014s-AD015 (SEQ ID NO.133 and SEQ ID NO.368)
[0519] NPD014s-AD016 (SEQ ID NO.134 and SEQ ID NO.369)
[0520] NPD014s-AD018 (SEQ ID NO.136 and SEQ ID NO.370)
[0521] NPD014s-AD020 (SEQ ID NO.138 and SEQ ID NO.371)
[0522] NPD014s-AD021 (SEQ ID NO.139 and SEQ ID NO.372)
[0523] NPD014s-AD023 (SEQ ID NO.141 and SEQ ID NO.373)
[0524] NPD014s-AD029 (SEQ ID NO.147 and SEQ ID NO.374)
[0525] NPD014s-AD038 (SEQ ID NO.156 and SEQ ID NO.375)
[0526] NPD014s-AD039 (SEQ ID NO.157 and SEQ ID NO.376)
[0527] NPD014s-AD040 (SEQ ID NO.158 and SEQ ID NO.377)
[0528] NPD014s-AD044 (SEQ ID NO.162 and SEQ ID NO.378)
[0529] NPD014s-AD050 (SEQ ID NO.168 and SEQ ID NO.379)
[0530] NPD014s-AD055 (SEQ ID NO. 173 and SEQ ID NO. 380)
[0531] NPD014s-AD060 (SEQ ID NO. 178 and SEQ ID NO. 381)
[0532] NPD014s-AD061 (SEQ ID NO. 179 and SEQ ID NO. 382)
[0533] NPD014s-AD063 (SEQ ID NO.181 and SEQ ID NO.384)
[0534] NPD014s-AD064 (SEQ ID NO.182 and SEQ ID NO.385)
[0535] NPD014s-AD066 (SEQ ID NO. 184 and SEQ ID NO. 387)
[0536] NPD014s-AD067 (SEQ ID NO. 185 and SEQ ID NO. 388)
[0537] NPD014s-AD068 (SEQ ID NO.186 and SEQ ID NO.389)
[0538] NPD014s-AD069 (SEQ ID NO.187 and SEQ ID NO.390)
[0539] NPD014s-AD070 (SEQ ID NO.188 and SEQ ID NO.391)
[0540] NPD014s-AD072 (SEQ ID NO. 190 and SEQ ID NO. 393)
[0541] NPD014s-AD075 (SEQ ID NO. 193 and SEQ ID NO. 396)
[0542] NPD014s-AD076 (SEQ ID NO. 194 and SEQ ID NO. 397)
[0543] NPD014s-AD077 (SEQ ID NO. 195 and SEQ ID NO. 398)
[0544] NPD014s-AD078 (SEQ ID NO. 196 and SEQ ID NO. 399)
[0545] NPD014s-AD081 (SEQ ID NO. 199 and SEQ ID NO. 402)
[0546] NPD014s-AD082 (SEQ ID NO. 200 and SEQ ID NO. 403)
[0547] NPD014s-AD083 (SEQ ID NO. 201 and SEQ ID NO. 404)
[0548] NPD014s-AD084 (SEQ ID NO. 202 and SEQ ID NO. 405)
[0549] NPD014s-AD085 (SEQ ID NO. 203 and SEQ ID NO. 406)
[0550] NPD014s-AD086 (SEQ ID NO. 204 and SEQ ID NO. 407)
[0551] NPD014s-AD087 (SEQ ID NO. 205 and SEQ ID NO. 408)
[0552] NPD014s-AD088 (SEQ ID NO. 206 and SEQ ID NO. 409)
[0553] NPD014s-AD089 (SEQ ID NO. 207 and SEQ ID NO. 410)
[0554] NPD014s-AD090 (SEQ ID NO.208 and SEQ ID NO.411)
[0555] NPD014s-AD091 (SEQ ID NO. 209 and SEQ ID NO. 412)
[0556] NPD014s-AD092 (SEQ ID NO.210 and SEQ ID NO.413)
[0557] NPD014s-AD093 (SEQ ID NO.211 and SEQ ID NO.414)
[0558] NPD014s-AD094 (SEQ ID NO.212 and SEQ ID NO.415)
[0559] NPD014s-AD095 (SEQ ID NO.213 and SEQ ID NO.416)
[0560] NPD014s-AD096 (SEQ ID NO. 214 and SEQ ID NO. 417)
[0561] NPD014s-AD097 (SEQ ID NO. 215 and SEQ ID NO. 418)
[0562] NPD014s-AD098 (SEQ ID NO.216 and SEQ ID NO.419)
[0563] NPD014s-AD099 (SEQ ID NO. 217 and SEQ ID NO. 420)
[0564] NPD014s-AD100 (SEQ ID NO.218 and SEQ ID NO.421)
[0565] NPD014s-AD101 (SEQ ID NO.219 and SEQ ID NO.422)
[0566] NPD014s-AD102 (SEQ ID NO. 220 and SEQ ID NO. 423)
[0567] NPD014s-AD103 (SEQ ID NO.221 and SEQ ID NO.424)
[0568] NPD014s-AD104 (SEQ ID NO. 222 and SEQ ID NO. 425)
[0569] NPD014s-AD105 (SEQ ID NO. 223 and SEQ ID NO. 426)
[0570] NPD014s-AD106 (SEQ ID NO. 224 and SEQ ID NO. 427)
[0571] NPD014s-AD107 (SEQ ID NO. 225 and SEQ ID NO. 428)
[0572] NPD014s-AD108 (SEQ ID NO. 226 and SEQ ID NO. 429)
[0573] NPD014s-AD109 (SEQ ID NO. 227 and SEQ ID NO. 430)
[0574] NPD014s-AD110 (SEQ ID NO.228 and SEQ ID NO.431)
[0575] NPD014s-AD111 (SEQ ID NO.229 and SEQ ID NO.432)
[0576] NPD014s-AD112 (SEQ ID NO. 230 and SEQ ID NO. 433)
[0577] NPD014s-AD113 (SEQ ID NO.231 and SEQ ID NO.434)
[0578] NPD014s-AD114 (SEQ ID NO. 232 and SEQ ID NO. 435)
[0579] NPD014s-AD115 (SEQ ID NO. 233 and SEQ ID NO. 436)
[0580] NPD014s-AD116 (SEQ ID NO. 234 and SEQ ID NO. 437)
[0581] NPD014s-AD117 (SEQ ID NO. 235 and SEQ ID NO. 438)
[0582] NPD014s-AD118 (SEQ ID NO. 236 and SEQ ID NO. 439)
[0583] NPD014s-AD119 (SEQ ID NO. 237 and SEQ ID NO. 440)
[0584] NPD014s-AD120 (SEQ ID NO.238 and SEQ ID NO.441)
[0585] NPD014s-AD121 (SEQ ID NO.239 and SEQ ID NO.442)
[0586] NPD014s-AD122 (SEQ ID NO. 240 and SEQ ID NO. 443)
[0587] NPD014s-AD123 (SEQ ID NO.241 and SEQ ID NO.444)
[0588] NPD014s-AD124 (SEQ ID NO. 242 and SEQ ID NO. 445)
[0589] NPD014s-AD125 (SEQ ID NO. 243 and SEQ ID NO. 446)
[0590] NPD014s-AD126 (SEQ ID NO. 244 and SEQ ID NO. 447)
[0591] NPD014s-AD127 (SEQ ID NO. 245 and SEQ ID NO. 448)
[0592] NPD014s-AD128 (SEQ ID NO. 246 and SEQ ID NO. 449)
[0593] NPD014s-AD129 (SEQ ID NO. 247 and SEQ ID NO. 450)
[0594] NPD014s-AD130 (SEQ ID NO.248 and SEQ ID NO.451)
[0595] NPD014s-AD131 (SEQ ID NO. 249 and SEQ ID NO. 452)
[0596] NPD014s-AD132 (SEQ ID NO. 250 and SEQ ID NO. 453)
[0597] NPD014s-AD133 (SEQ ID NO.251 and SEQ ID NO.454)
[0598] NPD014s-AD134 (SEQ ID NO. 252 and SEQ ID NO. 455)
[0599] NPD014s-AD135 (SEQ ID NO. 253 and SEQ ID NO. 456)
[0600] NPD014s-AD136 (SEQ ID NO. 254 and SEQ ID NO. 457)
[0601] NPD014s-AD137 (SEQ ID NO.255 and SEQ ID NO.458)
[0602] NPD014s-AD138 (SEQ ID NO. 256 and SEQ ID NO. 459)
[0603] NPD014s-AD139 (SEQ ID NO. 257 and SEQ ID NO. 460)
[0604] NPD014s-AD140 (SEQ ID NO. 258 and SEQ ID NO. 461)
[0605] NPD014s-AD141 (SEQ ID NO. 259 and SEQ ID NO. 462)
[0606] NPD014s-AD142 (SEQ ID NO. 260 and SEQ ID NO. 463)
[0607] NPD014s-AD143 (SEQ ID NO.261 and SEQ ID NO.464)
[0608] NPD014s-AD144 (SEQ ID NO. 262 and SEQ ID NO. 465)
[0609] NPD014s-AD145 (SEQ ID NO. 263 and SEQ ID NO. 466)
[0610] NPD014s-AD146 (SEQ ID NO. 264 and SEQ ID NO. 467)
[0611] NPD014s-AD147 (SEQ ID NO. 265 and SEQ ID NO. 468)
[0612] NPD014s-AD148 (SEQ ID NO. 266 and SEQ ID NO. 469)
[0613] NPD014s-AD149 (SEQ ID NO. 267 and SEQ ID NO. 470)
[0614] NPD014s-AD150 (SEQ ID NO.268 and SEQ ID NO.471)
[0615] NPD014s-AD151 (SEQ ID NO.269 and SEQ ID NO.472)
[0616] NPD014s-AD152 (SEQ ID NO. 270 and SEQ ID NO. 473)
[0617] NPD014s-AD153 (SEQ ID NO. 271 and SEQ ID NO. 474)
[0618] NPD014s-AD154 (SEQ ID NO. 272 and SEQ ID NO. 475)
[0619] NPD014s-AD155 (SEQ ID NO. 273 and SEQ ID NO. 476)
[0620] NPD014s-AD156 (SEQ ID NO. 274 and SEQ ID NO. 477)
[0621] NPD014s-AD157 (SEQ ID NO. 275 and SEQ ID NO. 478)
[0622] NPD014s-AD158 (SEQ ID NO. 276 and SEQ ID NO. 479)
[0623] NPD014s-AD159 (SEQ ID NO. 277 and SEQ ID NO. 480)
[0624] NPD014s-AD160 (SEQ ID NO. 278 and SEQ ID NO. 481)
[0625] NPD014s-AD161 (SEQ ID NO. 279 and SEQ ID NO. 482)
[0626] NPD014s-AD162 (SEQ ID NO. 280 and SEQ ID NO. 483)
[0627] NPD014s-AD163 (SEQ ID NO.281 and SEQ ID NO.484)
[0628] NPD014s-AD164 (SEQ ID NO. 282 and SEQ ID NO. 485)
[0629] NPD014s-AD165 (SEQ ID NO. 283 and SEQ ID NO. 486)
[0630] NPD014s-AD166 (SEQ ID NO. 284 and SEQ ID NO. 487)
[0631] NPD014s-AD167 (SEQ ID NO. 285 and SEQ ID NO. 488)
[0632] NPD014s-AD168 (SEQ ID NO. 286 and SEQ ID NO. 489)
[0633] NPD014s-AD169 (SEQ ID NO. 287 and SEQ ID NO. 490)
[0634] NPD014s-AD170 (SEQ ID NO. 288 and SEQ ID NO. 491)
[0635] NPD014s-AD171 (SEQ ID NO. 289 and SEQ ID NO. 492)
[0636] NPD014s-AD172 (SEQ ID NO. 290 and SEQ ID NO. 493)
[0637] NPD014s-AD173 (SEQ ID NO. 291 and SEQ ID NO. 494)
[0638] NPD014s-AD174 (SEQ ID NO. 292 and SEQ ID NO. 495)
[0639] NPD014s-AD175 (SEQ ID NO. 293 and SEQ ID NO. 496)
[0640] NPD014s-AD176 (SEQ ID NO. 294 and SEQ ID NO. 497)
[0641] NPD014s-AD177 (SEQ ID NO. 295 and SEQ ID NO. 498)
[0642] NPD014s-AD178 (SEQ ID NO. 296 and SEQ ID NO. 499)
[0643] NPD014s-AD179 (SEQ ID NO. 297 and SEQ ID NO. 500)
[0644] NPD014s-AD180 (SEQ ID NO. 298 and SEQ ID NO. 501)
[0645] NPD014s-AD181 (SEQ ID NO. 299 and SEQ ID NO. 502)
[0646] NPD014s-AD182 (SEQ ID NO.300 and SEQ ID NO.503)
[0647] NPD014s-AD183 (SEQ ID NO.301 and SEQ ID NO.504)
[0648] NPD014s-AD184 (SEQ ID NO.302 and SEQ ID NO.505)
[0649] NPD014s-AD185 (SEQ ID NO.303 and SEQ ID NO.506)
[0650] NPD014s-AD186 (SEQ ID NO.304 and SEQ ID NO.507)
[0651] NPD014s-AD187 (SEQ ID NO.305 and SEQ ID NO.508)
[0652] NPD014s-AD188 (SEQ ID NO.306 and SEQ ID NO.509)
[0653] NPD014s-AD189 (SEQ ID NO.307 and SEQ ID NO.510)
[0654] NPD014s-AD190 (SEQ ID NO.308 and SEQ ID NO.511)
[0655] NPD014s-AD191 (SEQ ID NO.309 and SEQ ID NO.512)
[0656] NPD014s-AD192 (SEQ ID NO.310 and SEQ ID NO.513)
[0657] NPD014s-AD193 (SEQ ID NO.311 and SEQ ID NO.514)
[0658] NPD014s-AD194 (SEQ ID NO.312 and SEQ ID NO.515)
[0659] NPD014s-AD195 (SEQ ID NO.313 and SEQ ID NO.516)
[0660] NPD014s-AD196 (SEQ ID NO.314 and SEQ ID NO.517)
[0661] NPD014s-AD197 (SEQ ID NO.315 and SEQ ID NO.518)
[0662] NPD014s-AD198 (SEQ ID NO.316 and SEQ ID NO.519)
[0663] NPD014s-AD199 (SEQ ID NO.317 and SEQ ID NO.520)
[0664] NPD014s-AD200 (SEQ ID NO.318 and SEQ ID NO.521)
[0665] NPD014s-AD201 (SEQ ID NO.319 and SEQ ID NO.522)
[0666] NPD014s-AD202 (SEQ ID NO.320 and SEQ ID NO.523)
[0667] NPD014s-AD203 (SEQ ID NO.321 and SEQ ID NO.524)
[0668] NPD014s-AD204 (SEQ ID NO.322 and SEQ ID NO.525)
[0669] NPD014s-AD205 (SEQ ID NO.323 and SEQ ID NO.526)
[0670] NPD014s-AD206 (SEQ ID NO.324 and SEQ ID NO.527)
[0671] NPD014s-AD207 (SEQ ID NO.325 and SEQ ID NO.528)
[0672] NPD014s-AD208 (SEQ ID NO.326 and SEQ ID NO.529)
[0673] NPD014s-AD209 (SEQ ID NO.327 and SEQ ID NO.530)
[0674] NPD014s-AD210 (SEQ ID NO.328 and SEQ ID NO.531)
[0675] NPD014s-AD211 (SEQ ID NO.329 and SEQ ID NO.532)
[0676] NPD014s-AD212 (SEQ ID NO.330 and SEQ ID NO.533)
[0677] NPD014s-AD213 (SEQ ID NO.331 and SEQ ID NO.534)
[0678] NPD014s-AD214 (SEQ ID NO.332 and SEQ ID NO.535)
[0679] NPD014s-AD215 (SEQ ID NO.333 and SEQ ID NO.536)
[0680] NPD014s-AD216 (SEQ ID NO.334 and SEQ ID NO.537)
[0681] NPD014s-AD217 (SEQ ID NO.335 and SEQ ID NO.538)
[0682] NPD014s-AD218 (SEQ ID NO.336 and SEQ ID NO.539)
[0683] NPD014s-AD219 (SEQ ID NO.337 and SEQ ID NO.540)
[0684] NPD014s-AD220 (SEQ ID NO.338 and SEQ ID NO.541)
[0685] NPD014s-AD221 (SEQ ID NO.339 and SEQ ID NO.542)
[0686] NPD014s-AD222 (SEQ ID NO.340 and SEQ ID NO.543)
[0687] NPD014s-AD223 (SEQ ID NO.341 and SEQ ID NO.544)
[0688] NPD014s-AD224 (SEQ ID NO.342 and SEQ ID NO.545)
[0689] NPD014s-AD225 (SEQ ID NO.343 and SEQ ID NO.546)
[0690] NPD014s-AD226 (SEQ ID NO.344 and SEQ ID NO.547)
[0691] NPD014s-AD227 (SEQ ID NO.345 and SEQ ID NO.548)
[0692] NPD014s-AD228 (SEQ ID NO.346 and SEQ ID NO.549)
[0693] NPD014s-AD229 (SEQ ID NO.347 and SEQ ID NO.550)
[0694] NPD014s-AD230 (SEQ ID NO.348 and SEQ ID NO.551)
[0695] NPD014s-AD231 (SEQ ID NO.349 and SEQ ID NO.552)
[0696] NPD014s-AD232 (SEQ ID NO.350 and SEQ ID NO.553)
[0697] NPD014s-AD233 (SEQ ID NO.351 and SEQ ID NO.554)
[0698] NPD014s-AD234 (SEQ ID NO.352 and SEQ ID NO.555)
[0699] NPD014s-AD235 (SEQ ID NO.353 and SEQ ID NO.556)
[0700] NPD014s-AD236 (SEQ ID NO.354 and SEQ ID NO.557)
[0701] NPD014s-AD237 (SEQ ID NO.355 and SEQ ID NO.558)
[0702] NPD014s-AD238 (SEQ ID NO.356 and SEQ ID NO.559)
[0703] NPD014s-AD239 (SEQ ID NO.357 and SEQ ID NO.560)
[0704] NPD014s-AD240 (SEQ ID NO.358 and SEQ ID NO.561)
[0705] NPD014s-AD241 (SEQ ID NO. 359 and SEQ ID NO. 562).
[0706] In another aspect of the present invention, the present invention provides an siRNA conjugate. According to an embodiment of the present invention, the siRNA conjugate comprises: the aforementioned siRNA and a delivery vector, wherein the siRNA is covalently linked to the delivery vector. The inventors have found through experiments that, by adding a delivery vector to the above-mentioned siRNA conjugate, the degradation of CFB mRNA can be further improved, the synthesis of CFB by hepatocytes can be specifically reduced, the activity of the complement pathway in the body can be reduced, and the related diseases caused by abnormal activation of complement signals, such as paroxysmal nocturnal hemoglobinuria (PNH), asthma, rheumatoid arthritis, systemic lupus erythematosus, glomerulonephritis, psoriasis, dermatomyositis bullous pemphigoid, atypical hemolytic uremic syndrome, Shiga toxin-infected Escherichia coli-associated hemolytic uremic syndrome, myasthenia gravis, neuromyelitis optica, dense deposit disease, C3 neuropathy, age-related macular degeneration, cold agglutinin disease, anti-neutrophil cytoplasmic antibody-associated vasculitis, humoral and vascular transplant rejection, graft dysfunction, myocardial infarction, sensitized receptors of transplants, IgA nephropathy, and sepsis, can be effectively treated.
[0707] A delivery vector refers to a class of substances that can change the tissue distribution of siRNA and target specific tissues. For example, compared with species without the delivery vector, the delivery vector provides an enhanced affinity for the selected target (e.g., molecule, cell or cell type, compartment (e.g., cell or organ compartment, body tissue, organ or region). The delivery vector can be a natural protein (e.g., human serum albumin (HSA)), a carbohydrate (e.g., dextran and chitosan, etc.) or a lipid; it can also be a recombinant or synthetic molecule, such as a synthetic polymer. Preferably, the delivery vector does not participate in the pairing of the sense strand and the antisense strand in the siRNA.
[0708] According to an embodiment of the present invention, the delivery vector is connected to the sense strand in the siRNA.
[0709] According to an embodiment of the present invention, the ligand is linked to the 5'-end or 3'-end of the sense strand in the siRNA via a phosphate bond or a phosphorothioate bond.
[0710] According to an embodiment of the present invention, the delivery vector is a GalNAc derivative compound;
[0711] According to an embodiment of the present invention, the GalNAc derivative compound includes at least one selected from 1043, 1046, 1048, 1059 and 1060:
[0712]
[0713]
[0714] According to an embodiment of the present invention, the antisense strand of the siRNA conjugate comprises a chemically modified nucleotide sequence of a duplex selected from the following:
[0715] NPD014s-AD244 (SEQ ID NO.603 and SEQ ID NO.844)
[0716] NPD014s-AD245 (SEQ ID NO.604 and SEQ ID NO.845)
[0717] NPD014s-AD246 (SEQ ID NO.605 and SEQ ID NO.846)
[0718] NPD014s-AD247 (SEQ ID NO.606 and SEQ ID NO.847)
[0719] NPD014s-AD248 (SEQ ID NO.607 and SEQ ID NO.848)
[0720] NPD014s-AD249 (SEQ ID NO.608 and SEQ ID NO.849)
[0721] NPD014s-AD250 (SEQ ID NO.609 and SEQ ID NO.850)
[0722] NPD014s-AD253 (SEQ ID NO.612 and SEQ ID NO.853)
[0723] NPD014s-AD256 (SEQ ID NO.615 and SEQ ID NO.856)
[0724] NPD014s-AD257 (SEQ ID NO.616 and SEQ ID NO.857)
[0725] NPD014s-AD259 (SEQ ID NO.618 and SEQ ID NO.859)
[0726] NPD014s-AD261 (SEQ ID NO.620 and SEQ ID NO.861)
[0727] NPD014s-AD262 (SEQ ID NO.621 and SEQ ID NO.862)
[0728] NPD014s-AD264 (SEQ ID NO.623 and SEQ ID NO.864)
[0729] NPD014s-AD270 (SEQ ID NO.629 and SEQ ID NO.870)
[0730] NPD014s-AD279 (SEQ ID NO.638 and SEQ ID NO.879)
[0731] NPD014s-AD280 (SEQ ID NO.639 and SEQ ID NO.880)
[0732] NPD014s-AD281 (SEQ ID NO.640 and SEQ ID NO.881)
[0733] NPD014s-AD285 (SEQ ID NO.644 and SEQ ID NO.885)
[0734] NPD014s-AD291 (SEQ ID NO.650 and SEQ ID NO.891)
[0735] NPD014s-AD296 (SEQ ID NO.655 and SEQ ID NO.896)
[0736] NPD014s-AD301 (SEQ ID NO.660 and SEQ ID NO.901)
[0737] NPD014s-AD302 (SEQ ID NO.661 and SEQ ID NO.902)
[0738] NPD014s-AD304 (SEQ ID NO.663 and SEQ ID NO.904)
[0739] NPD014s-AD305 (SEQ ID NO.664 and SEQ ID NO.905)
[0740] NPD014s-AD307 (SEQ ID NO. 666 and SEQ ID NO. 907)
[0741] NPD014s-AD308 (SEQ ID NO. 667 and SEQ ID NO. 908)
[0742] NPD014s-AD309 (SEQ ID NO.668 and SEQ ID NO.909)
[0743] NPD014s-AD310 (SEQ ID NO.669 and SEQ ID NO.910)
[0744] NPD014s-AD311 (SEQ ID NO.670 and SEQ ID NO.911)
[0745] NPD014s-AD313 (SEQ ID NO.672 and SEQ ID NO.913)
[0746] NPD014s-AD316 (SEQ ID NO. 675 and SEQ ID NO. 916)
[0747] NPD014s-AD317 (SEQ ID NO.676 and SEQ ID NO.917)
[0748] NPD014s-AD318 (SEQ ID NO.677 and SEQ ID NO.918)
[0749] NPD014s-AD319 (SEQ ID NO.678 and SEQ ID NO.919)
[0750] NPD014s-AD322 (SEQ ID NO.681 and SEQ ID NO.922)
[0751] NPD014s-AD323 (SEQ ID NO.682 and SEQ ID NO.923)
[0752] NPD014s-AD324 (SEQ ID NO.683 and SEQ ID NO.924)
[0753] NPD014s-AD325 (SEQ ID NO.684 and SEQ ID NO.925)
[0754] NPD014s-AD326 (SEQ ID NO.685 and SEQ ID NO.926)
[0755] NPD014s-AD327 (SEQ ID NO.686 and SEQ ID NO.927)
[0756] NPD014s-AD328 (SEQ ID NO.687 and SEQ ID NO.928)
[0757] NPD014s-AD329 (SEQ ID NO.688 and SEQ ID NO.929)
[0758] NPD014s-AD330 (SEQ ID NO.689 and SEQ ID NO.930)
[0759] NPD014s-AD331 (SEQ ID NO.690 and SEQ ID NO.931)
[0760] NPD014s-AD332 (SEQ ID NO.691 and SEQ ID NO.932)
[0761] NPD014s-AD333 (SEQ ID NO.692 and SEQ ID NO.933)
[0762] NPD014s-AD334 (SEQ ID NO.693 and SEQ ID NO.934)
[0763] NPD014s-AD335 (SEQ ID NO.694 and SEQ ID NO.935)
[0764] NPD014s-AD336 (SEQ ID NO. 695 and SEQ ID NO. 936)
[0765] NPD014s-AD337 (SEQ ID NO. 696 and SEQ ID NO. 937)
[0766] NPD014s-AD338 (SEQ ID NO. 697 and SEQ ID NO. 938)
[0767] NPD014s-AD339 (SEQ ID NO.698 and SEQ ID NO.939)
[0768] NPD014s-AD340 (SEQ ID NO.699 and SEQ ID NO.940)
[0769] NPD014s-AD341 (SEQ ID NO.700 and SEQ ID NO.941)
[0770] NPD014s-AD342 (SEQ ID NO.701 and SEQ ID NO.942)
[0771] NPD014s-AD343 (SEQ ID NO.702 and SEQ ID NO.943)
[0772] NPD014s-AD344 (SEQ ID NO.703 and SEQ ID NO.944)
[0773] NPD014s-AD345 (SEQ ID NO.704 and SEQ ID NO.945)
[0774] NPD014s-AD346 (SEQ ID NO.705 and SEQ ID NO.946)
[0775] NPD014s-AD347 (SEQ ID NO.706 and SEQ ID NO.947)
[0776] NPD014s-AD348 (SEQ ID NO.707 and SEQ ID NO.948)
[0777] NPD014s-AD349 (SEQ ID NO.708 and SEQ ID NO.949)
[0778] NPD014s-AD350 (SEQ ID NO.709 and SEQ ID NO.950)
[0779] NPD014s-AD351 (SEQ ID NO.710 and SEQ ID NO.951)
[0780] NPD014s-AD352 (SEQ ID NO.711 and SEQ ID NO.952)
[0781] NPD014s-AD353 (SEQ ID NO.712 and SEQ ID NO.953)
[0782] NPD014s-AD354 (SEQ ID NO.713 and SEQ ID NO.954)
[0783] NPD014s-AD355 (SEQ ID NO.714 and SEQ ID NO.955)
[0784] NPD014s-AD356 (SEQ ID NO.715 and SEQ ID NO.956)
[0785] NPD014s-AD357 (SEQ ID NO.716 and SEQ ID NO.957)
[0786] NPD014s-AD358 (SEQ ID NO.717 and SEQ ID NO.958)
[0787] NPD014s-AD359 (SEQ ID NO.718 and SEQ ID NO.959)
[0788] NPD014s-AD360 (SEQ ID NO.719 and SEQ ID NO.960)
[0789] NPD014s-AD361 (SEQ ID NO.720 and SEQ ID NO.961)
[0790] NPD014s-AD362 (SEQ ID NO.721 and SEQ ID NO.962)
[0791] NPD014s-AD363 (SEQ ID NO.722 and SEQ ID NO.963)
[0792] NPD014s-AD364 (SEQ ID NO.723 and SEQ ID NO.964)
[0793] NPD014s-AD365 (SEQ ID NO.724 and SEQ ID NO.965)
[0794] NPD014s-AD366 (SEQ ID NO.725 and SEQ ID NO.966)
[0795] NPD014s-AD367 (SEQ ID NO.726 and SEQ ID NO.967)
[0796] NPD014s-AD368 (SEQ ID NO.727 and SEQ ID NO.968)
[0797] NPD014s-AD369 (SEQ ID NO.728 and SEQ ID NO.969)
[0798] NPD014s-AD370 (SEQ ID NO.729 and SEQ ID NO.970)
[0799] NPD014s-AD371 (SEQ ID NO.730 and SEQ ID NO.971)
[0800] NPD014s-AD372 (SEQ ID NO.731 and SEQ ID NO.972)
[0801] NPD014s-AD373 (SEQ ID NO.732 and SEQ ID NO.973)
[0802] NPD014s-AD374 (SEQ ID NO.733 and SEQ ID NO.974)
[0803] NPD014s-AD375 (SEQ ID NO.734 and SEQ ID NO.975)
[0804] NPD014s-AD376 (SEQ ID NO.735 and SEQ ID NO.976)
[0805] NPD014s-AD377 (SEQ ID NO.736 and SEQ ID NO.977)
[0806] NPD014s-AD378 (SEQ ID NO.737 and SEQ ID NO.978)
[0807] NPD014s-AD379 (SEQ ID NO.738 and SEQ ID NO.979)
[0808] NPD014s-AD380 (SEQ ID NO.739 and SEQ ID NO.980)
[0809] NPD014s-AD381 (SEQ ID NO.740 and SEQ ID NO.981)
[0810] NPD014s-AD382 (SEQ ID NO.741 and SEQ ID NO.982)
[0811] NPD014s-AD383 (SEQ ID NO.742 and SEQ ID NO.983)
[0812] NPD014s-AD384 (SEQ ID NO.743 and SEQ ID NO.984)
[0813] NPD014s-AD385 (SEQ ID NO.744 and SEQ ID NO.985)
[0814] NPD014s-AD386 (SEQ ID NO.745 and SEQ ID NO.986)
[0815] NPD014s-AD387 (SEQ ID NO.746 and SEQ ID NO.987)
[0816] NPD014s-AD388 (SEQ ID NO.747 and SEQ ID NO.988)
[0817] NPD014s-AD389 (SEQ ID NO.748 and SEQ ID NO.989)
[0818] NPD014s-AD390 (SEQ ID NO.749 and SEQ ID NO.990)
[0819] NPD014s-AD391 (SEQ ID NO.750 and SEQ ID NO.991)
[0820] NPD014s-AD392 (SEQ ID NO.751 and SEQ ID NO.992)
[0821] NPD014s-AD393 (SEQ ID NO.752 and SEQ ID NO.993)
[0822] NPD014s-AD394 (SEQ ID NO.753 and SEQ ID NO.994)
[0823] NPD014s-AD395 (SEQ ID NO.754 and SEQ ID NO.995)
[0824] NPD014s-AD396 (SEQ ID NO.755 and SEQ ID NO.996)
[0825] NPD014s-AD397 (SEQ ID NO.756 and SEQ ID NO.997)
[0826] NPD014s-AD398 (SEQ ID NO.757 and SEQ ID NO.998)
[0827] NPD014s-AD399 (SEQ ID NO.758 and SEQ ID NO.999)
[0828] NPD014s-AD400 (SEQ ID NO.759 and SEQ ID NO.1000)
[0829] NPD014s-AD401 (SEQ ID NO.760 and SEQ ID NO.1001)
[0830] NPD014s-AD402 (SEQ ID NO.761 and SEQ ID NO.1002)
[0831] NPD014s-AD403 (SEQ ID NO.762 and SEQ ID NO.1003)
[0832] NPD014s-AD404 (SEQ ID NO.763 and SEQ ID NO.1004)
[0833] NPD014s-AD405 (SEQ ID NO.764 and SEQ ID NO.1005)
[0834] NPD014s-AD406 (SEQ ID NO.765 and SEQ ID NO.1006)
[0835] NPD014s-AD407 (SEQ ID NO.766 and SEQ ID NO.1007)
[0836] NPD014s-AD408 (SEQ ID NO.767 and SEQ ID NO.1008)
[0837] NPD014s-AD409 (SEQ ID NO.768 and SEQ ID NO.1009)
[0838] NPD014s-AD410 (SEQ ID NO.769 and SEQ ID NO.1010)
[0839] NPD014s-AD411 (SEQ ID NO.770 and SEQ ID NO.1011)
[0840] NPD014s-AD412 (SEQ ID NO.771 and SEQ ID NO.1012)
[0841] NPD014s-AD413 (SEQ ID NO.772 and SEQ ID NO.1013)
[0842] NPD014s-AD414 (SEQ ID NO.773 and SEQ ID NO.1014)
[0843] NPD014s-AD415 (SEQ ID NO.774 and SEQ ID NO.1015)
[0844] NPD014s-AD416 (SEQ ID NO.775 and SEQ ID NO.1016)
[0845] NPD014s-AD417 (SEQ ID NO.776 and SEQ ID NO.1017)
[0846] NPD014s-AD418 (SEQ ID NO.777 and SEQ ID NO.1018)
[0847] NPD014s-AD419 (SEQ ID NO.778 and SEQ ID NO.1019)
[0848] NPD014s-AD420 (SEQ ID NO.779 and SEQ ID NO.1020)
[0849] NPD014s-AD421 (SEQ ID NO.780 and SEQ ID NO.1021)
[0850] NPD014s-AD422 (SEQ ID NO.781 and SEQ ID NO.1022)
[0851] NPD014s-AD423 (SEQ ID NO.782 and SEQ ID NO.1023)
[0852] NPD014s-AD424 (SEQ ID NO.783 and SEQ ID NO.1024)
[0853] NPD014s-AD425 (SEQ ID NO.784 and SEQ ID NO.1025)
[0854] NPD014s-AD426 (SEQ ID NO.785 and SEQ ID NO.1026)
[0855] NPD014s-AD427 (SEQ ID NO.786 and SEQ ID NO.1027)
[0856] NPD014s-AD428 (SEQ ID NO.787 and SEQ ID NO.1028)
[0857] NPD014s-AD429 (SEQ ID NO.788 and SEQ ID NO.1029)
[0858] NPD014s-AD430 (SEQ ID NO.789 and SEQ ID NO.1030)
[0859] NPD014s-AD431 (SEQ ID NO.790 and SEQ ID NO.1031)
[0860] NPD014s-AD432 (SEQ ID NO.791 and SEQ ID NO.1032)
[0861] NPD014s-AD433 (SEQ ID NO.792 and SEQ ID NO.1033)
[0862] NPD014s-AD434 (SEQ ID NO.793 and SEQ ID NO.1034)
[0863] NPD014s-AD435 (SEQ ID NO.794 and SEQ ID NO.1035)
[0864] NPD014s-AD436 (SEQ ID NO.795 and SEQ ID NO.1036)
[0865] NPD014s-AD437 (SEQ ID NO.796 and SEQ ID NO.1037)
[0866] NPD014s-AD438 (SEQ ID NO.797 and SEQ ID NO.1038)
[0867] NPD014s-AD439 (SEQ ID NO.798 and SEQ ID NO.1039)
[0868] NPD014s-AD440 (SEQ ID NO.799 and SEQ ID NO.1040)
[0869] NPD014s-AD441 (SEQ ID NO.800 and SEQ ID NO.1041)
[0870] NPD014s-AD442 (SEQ ID NO.801 and SEQ ID NO.1042)
[0871] NPD014s-AD443 (SEQ ID NO.802 and SEQ ID NO.1043)
[0872] NPD014s-AD444 (SEQ ID NO.803 and SEQ ID NO.1044)
[0873] NPD014s-AD445 (SEQ ID NO.804 and SEQ ID NO.1045)
[0874] NPD014s-AD446 (SEQ ID NO.805 and SEQ ID NO.1046)
[0875] NPD014s-AD447 (SEQ ID NO.806 and SEQ ID NO.1047)
[0876] NPD014s-AD448 (SEQ ID NO.807 and SEQ ID NO.1048)
[0877] NPD014s-AD449 (SEQ ID NO.808 and SEQ ID NO.1049)
[0878] NPD014s-AD450 (SEQ ID NO.809 and SEQ ID NO.1050)
[0879] NPD014s-AD451 (SEQ ID NO.810 and SEQ ID NO.1051)
[0880] NPD014s-AD452 (SEQ ID NO.811 and SEQ ID NO.1052)
[0881] NPD014s-AD453 (SEQ ID NO.812 and SEQ ID NO.1053)
[0882] NPD014s-AD454 (SEQ ID NO.813 and SEQ ID NO.1054)
[0883] NPD014s-AD455 (SEQ ID NO.814 and SEQ ID NO.1055)
[0884] NPD014s-AD456 (SEQ ID NO.815 and SEQ ID NO.1056)
[0885] NPD014s-AD457 (SEQ ID NO.816 and SEQ ID NO.1057)
[0886] NPD014s-AD458 (SEQ ID NO.817 and SEQ ID NO.1058)
[0887] NPD014s-AD459 (SEQ ID NO.818 and SEQ ID NO.1059)
[0888] NPD014s-AD460 (SEQ ID NO.819 and SEQ ID NO.1060)
[0889] NPD014s-AD461 (SEQ ID NO.820 and SEQ ID NO.1061)
[0890] NPD014s-AD462 (SEQ ID NO.821 and SEQ ID NO.1062)
[0891] NPD014s-AD463 (SEQ ID NO.822 and SEQ ID NO.1063)
[0892] NPD014s-AD464 (SEQ ID NO.823 and SEQ ID NO.1064)
[0893] NPD014s-AD465 (SEQ ID NO.824 and SEQ ID NO.1065)
[0894] NPD014s-AD466 (SEQ ID NO.825 and SEQ ID NO.1066)
[0895] NPD014s-AD467 (SEQ ID NO.826 and SEQ ID NO.1067)
[0896] NPD014s-AD468 (SEQ ID NO.827 and SEQ ID NO.1068)
[0897] NPD014s-AD469 (SEQ ID NO.828 and SEQ ID NO.1069)
[0898] NPD014s-AD470 (SEQ ID NO.829 and SEQ ID NO.1070)
[0899] NPD014s-AD471 (SEQ ID NO.830 and SEQ ID NO.1071)
[0900] NPD014s-AD472 (SEQ ID NO.831 and SEQ ID NO.1072)
[0901] NPD014s-AD473 (SEQ ID NO.832 and SEQ ID NO.1073)
[0902] NPD014s-AD474 (SEQ ID NO.833 and SEQ ID NO.1074)
[0903] NPD014s-AD475 (SEQ ID NO.834 and SEQ ID NO.1075)
[0904] NPD014s-AD476 (SEQ ID NO.835 and SEQ ID NO.1076)
[0905] NPD014s-AD477 (SEQ ID NO.836 and SEQ ID NO.1077)
[0906] NPD014s-AD478 (SEQ ID NO.837 and SEQ ID NO.1078)
[0907] NPD014s-AD479 (SEQ ID NO.838 and SEQ ID NO.1079)
[0908] NPD014s-AD480 (SEQ ID NO.839 and SEQ ID NO.1080)
[0909] NPD014s-AD481 (SEQ ID NO.840 and SEQ ID NO.1081)
[0910] NPD014s-AD482 (SEQ ID NO. 841 and SEQ ID NO. 1082).
[0911] According to an embodiment of the present invention, the sense strand of the siRNA conjugate comprises a chemically modified nucleotide sequence of a duplex selected from the following:
[0912] NPD014s-AD244 (SEQ ID NO.603 and SEQ ID NO.844)
[0913] NPD014s-AD245 (SEQ ID NO.604 and SEQ ID NO.845)
[0914] NPD014s-AD246 (SEQ ID NO.605 and SEQ ID NO.846)
[0915] NPD014s-AD247 (SEQ ID NO.606 and SEQ ID NO.847)
[0916] NPD014s-AD248 (SEQ ID NO.607 and SEQ ID NO.848)
[0917] NPD014s-AD249 (SEQ ID NO.608 and SEQ ID NO.849)
[0918] NPD014s-AD250 (SEQ ID NO.609 and SEQ ID NO.850)
[0919] NPD014s-AD253 (SEQ ID NO.612 and SEQ ID NO.853)
[0920] NPD014s-AD256 (SEQ ID NO.615 and SEQ ID NO.856)
[0921] NPD014s-AD257 (SEQ ID NO.616 and SEQ ID NO.857)
[0922] NPD014s-AD259 (SEQ ID NO.618 and SEQ ID NO.859)
[0923] NPD014s-AD261 (SEQ ID NO.620 and SEQ ID NO.861)
[0924] NPD014s-AD262 (SEQ ID NO.621 and SEQ ID NO.862)
[0925] NPD014s-AD264 (SEQ ID NO.623 and SEQ ID NO.864)
[0926] NPD014s-AD270 (SEQ ID NO.629 and SEQ ID NO.870)
[0927] NPD014s-AD279 (SEQ ID NO.638 and SEQ ID NO.879)
[0928] NPD014s-AD280 (SEQ ID NO.639 and SEQ ID NO.880)
[0929] NPD014s-AD281 (SEQ ID NO.640 and SEQ ID NO.881)
[0930] NPD014s-AD285 (SEQ ID NO.644 and SEQ ID NO.885)
[0931] NPD014s-AD291 (SEQ ID NO.650 and SEQ ID NO.891)
[0932] NPD014s-AD296 (SEQ ID NO.655 and SEQ ID NO.896)
[0933] NPD014s-AD301 (SEQ ID NO.660 and SEQ ID NO.901)
[0934] NPD014s-AD302 (SEQ ID NO.661 and SEQ ID NO.902)
[0935] NPD014s-AD304 (SEQ ID NO.663 and SEQ ID NO.904)
[0936] NPD014s-AD305 (SEQ ID NO.664 and SEQ ID NO.905)
[0937] NPD014s-AD307 (SEQ ID NO. 666 and SEQ ID NO. 907)
[0938] NPD014s-AD308 (SEQ ID NO. 667 and SEQ ID NO. 908)
[0939] NPD014s-AD309 (SEQ ID NO.668 and SEQ ID NO.909)
[0940] NPD014s-AD310 (SEQ ID NO.669 and SEQ ID NO.910)
[0941] NPD014s-AD311 (SEQ ID NO.670 and SEQ ID NO.911)
[0942] NPD014s-AD313 (SEQ ID NO.672 and SEQ ID NO.913)
[0943] NPD014s-AD316 (SEQ ID NO. 675 and SEQ ID NO. 916)
[0944] NPD014s-AD317 (SEQ ID NO.676 and SEQ ID NO.917)
[0945] NPD014s-AD318 (SEQ ID NO.677 and SEQ ID NO.918)
[0946] NPD014s-AD319 (SEQ ID NO.678 and SEQ ID NO.919)
[0947] NPD014s-AD322 (SEQ ID NO.681 and SEQ ID NO.922)
[0948] NPD014s-AD323 (SEQ ID NO.682 and SEQ ID NO.923)
[0949] NPD014s-AD324 (SEQ ID NO.683 and SEQ ID NO.924)
[0950] NPD014s-AD325 (SEQ ID NO.684 and SEQ ID NO.925)
[0951] NPD014s-AD326 (SEQ ID NO.685 and SEQ ID NO.926)
[0952] NPD014s-AD327 (SEQ ID NO.686 and SEQ ID NO.927)
[0953] NPD014s-AD328 (SEQ ID NO.687 and SEQ ID NO.928)
[0954] NPD014s-AD329 (SEQ ID NO.688 and SEQ ID NO.929)
[0955] NPD014s-AD330 (SEQ ID NO.689 and SEQ ID NO.930)
[0956] NPD014s-AD331 (SEQ ID NO.690 and SEQ ID NO.931)
[0957] NPD014s-AD332 (SEQ ID NO.691 and SEQ ID NO.932)
[0958] NPD014s-AD333 (SEQ ID NO.692 and SEQ ID NO.933)
[0959] NPD014s-AD334 (SEQ ID NO.693 and SEQ ID NO.934)
[0960] NPD014s-AD335 (SEQ ID NO.694 and SEQ ID NO.935)
[0961] NPD014s-AD336 (SEQ ID NO. 695 and SEQ ID NO. 936)
[0962] NPD014s-AD337 (SEQ ID NO. 696 and SEQ ID NO. 937)
[0963] NPD014s-AD338 (SEQ ID NO. 697 and SEQ ID NO. 938)
[0964] NPD014s-AD339 (SEQ ID NO.698 and SEQ ID NO.939)
[0965] NPD014s-AD340 (SEQ ID NO.699 and SEQ ID NO.940)
[0966] NPD014s-AD341 (SEQ ID NO.700 and SEQ ID NO.941)
[0967] NPD014s-AD342 (SEQ ID NO.701 and SEQ ID NO.942)
[0968] NPD014s-AD343 (SEQ ID NO.702 and SEQ ID NO.943)
[0969] NPD014s-AD344 (SEQ ID NO.703 and SEQ ID NO.944)
[0970] NPD014s-AD345 (SEQ ID NO.704 and SEQ ID NO.945)
[0971] NPD014s-AD346 (SEQ ID NO.705 and SEQ ID NO.946)
[0972] NPD014s-AD347 (SEQ ID NO.706 and SEQ ID NO.947)
[0973] NPD014s-AD348 (SEQ ID NO.707 and SEQ ID NO.948)
[0974] NPD014s-AD349 (SEQ ID NO.708 and SEQ ID NO.949)
[0975] NPD014s-AD350 (SEQ ID NO.709 and SEQ ID NO.950)
[0976] NPD014s-AD351 (SEQ ID NO.710 and SEQ ID NO.951)
[0977] NPD014s-AD352 (SEQ ID NO.711 and SEQ ID NO.952)
[0978] NPD014s-AD353 (SEQ ID NO.712 and SEQ ID NO.953)
[0979] NPD014s-AD354 (SEQ ID NO.713 and SEQ ID NO.954)
[0980] NPD014s-AD355 (SEQ ID NO.714 and SEQ ID NO.955)
[0981] NPD014s-AD356 (SEQ ID NO.715 and SEQ ID NO.956)
[0982] NPD014s-AD357 (SEQ ID NO.716 and SEQ ID NO.957)
[0983] NPD014s-AD358 (SEQ ID NO.717 and SEQ ID NO.958)
[0984] NPD014s-AD359 (SEQ ID NO.718 and SEQ ID NO.959)
[0985] NPD014s-AD360 (SEQ ID NO.719 and SEQ ID NO.960)
[0986] NPD014s-AD361 (SEQ ID NO.720 and SEQ ID NO.961)
[0987] NPD014s-AD362 (SEQ ID NO.721 and SEQ ID NO.962)
[0988] NPD014s-AD363 (SEQ ID NO.722 and SEQ ID NO.963)
[0989] NPD014s-AD364 (SEQ ID NO.723 and SEQ ID NO.964)
[0990] NPD014s-AD365 (SEQ ID NO.724 and SEQ ID NO.965)
[0991] NPD014s-AD366 (SEQ ID NO.725 and SEQ ID NO.966)
[0992] NPD014s-AD367 (SEQ ID NO.726 and SEQ ID NO.967)
[0993] NPD014s-AD368 (SEQ ID NO.727 and SEQ ID NO.968)
[0994] NPD014s-AD369 (SEQ ID NO.728 and SEQ ID NO.969)
[0995] NPD014s-AD370 (SEQ ID NO.729 and SEQ ID NO.970)
[0996] NPD014s-AD371 (SEQ ID NO.730 and SEQ ID NO.971)
[0997] NPD014s-AD372 (SEQ ID NO.731 and SEQ ID NO.972)
[0998] NPD014s-AD373 (SEQ ID NO.732 and SEQ ID NO.973)
[0999] NPD014s-AD374 (SEQ ID NO.733 and SEQ ID NO.974)
[1000] NPD014s-AD375 (SEQ ID NO.734 and SEQ ID NO.975)
[1001] NPD014s-AD376 (SEQ ID NO.735 and SEQ ID NO.976)
[1002] NPD014s-AD377 (SEQ ID NO.736 and SEQ ID NO.977)
[1003] NPD014s-AD378 (SEQ ID NO.737 and SEQ ID NO.978)
[1004] NPD014s-AD379 (SEQ ID NO.738 and SEQ ID NO.979)
[1005] NPD014s-AD380 (SEQ ID NO.739 and SEQ ID NO.980)
[1006] NPD014s-AD381 (SEQ ID NO.740 and SEQ ID NO.981)
[1007] NPD014s-AD382 (SEQ ID NO.741 and SEQ ID NO.982)
[1008] NPD014s-AD383 (SEQ ID NO.742 and SEQ ID NO.983)
[1009] NPD014s-AD384 (SEQ ID NO.743 and SEQ ID NO.984)
[1010] NPD014s-AD385 (SEQ ID NO.744 and SEQ ID NO.985)
[1011] NPD014s-AD386 (SEQ ID NO.745 and SEQ ID NO.986)
[1012] NPD014s-AD387 (SEQ ID NO.746 and SEQ ID NO.987)
[1013] NPD014s-AD388 (SEQ ID NO.747 and SEQ ID NO.988)
[1014] NPD014s-AD389 (SEQ ID NO.748 and SEQ ID NO.989)
[1015] NPD014s-AD390 (SEQ ID NO.749 and SEQ ID NO.990)
[1016] NPD014s-AD391 (SEQ ID NO.750 and SEQ ID NO.991)
[1017] NPD014s-AD392 (SEQ ID NO.751 and SEQ ID NO.992)
[1018] NPD014s-AD393 (SEQ ID NO.752 and SEQ ID NO.993)
[1019] NPD014s-AD394 (SEQ ID NO.753 and SEQ ID NO.994)
[1020] NPD014s-AD395 (SEQ ID NO.754 and SEQ ID NO.995)
[1021] NPD014s-AD396 (SEQ ID NO.755 and SEQ ID NO.996)
[1022] NPD014s-AD397 (SEQ ID NO.756 and SEQ ID NO.997)
[1023] NPD014s-AD398 (SEQ ID NO.757 and SEQ ID NO.998)
[1024] NPD014s-AD399 (SEQ ID NO.758 and SEQ ID NO.999)
[1025] NPD014s-AD400 (SEQ ID NO.759 and SEQ ID NO.1000)
[1026] NPD014s-AD401 (SEQ ID NO.760 and SEQ ID NO.1001)
[1027] NPD014s-AD402 (SEQ ID NO.761 and SEQ ID NO.1002)
[1028] NPD014s-AD403 (SEQ ID NO.762 and SEQ ID NO.1003)
[1029] NPD014s-AD404 (SEQ ID NO.763 and SEQ ID NO.1004)
[1030] NPD014s-AD405 (SEQ ID NO.764 and SEQ ID NO.1005)
[1031] NPD014s-AD406 (SEQ ID NO.765 and SEQ ID NO.1006)
[1032] NPD014s-AD407 (SEQ ID NO.766 and SEQ ID NO.1007)
[1033] NPD014s-AD408 (SEQ ID NO.767 and SEQ ID NO.1008)
[1034] NPD014s-AD409 (SEQ ID NO.768 and SEQ ID NO.1009)
[1035] NPD014s-AD410 (SEQ ID NO.769 and SEQ ID NO.1010)
[1036] NPD014s-AD411 (SEQ ID NO.770 and SEQ ID NO.1011)
[1037] NPD014s-AD412 (SEQ ID NO.771 and SEQ ID NO.1012)
[1038] NPD014s-AD413 (SEQ ID NO.772 and SEQ ID NO.1013)
[1039] NPD014s-AD414 (SEQ ID NO.773 and SEQ ID NO.1014)
[1040] NPD014s-AD415 (SEQ ID NO.774 and SEQ ID NO.1015)
[1041] NPD014s-AD416 (SEQ ID NO.775 and SEQ ID NO.1016)
[1042] NPD014s-AD417 (SEQ ID NO.776 and SEQ ID NO.1017)
[1043] NPD014s-AD418 (SEQ ID NO.777 and SEQ ID NO.1018)
[1044] NPD014s-AD419 (SEQ ID NO.778 and SEQ ID NO.1019)
[1045] NPD014s-AD420 (SEQ ID NO.779 and SEQ ID NO.1020)
[1046] NPD014s-AD421 (SEQ ID NO.780 and SEQ ID NO.1021)
[1047] NPD014s-AD422 (SEQ ID NO.781 and SEQ ID NO.1022)
[1048] NPD014s-AD423 (SEQ ID NO.782 and SEQ ID NO.1023)
[1049] NPD014s-AD424 (SEQ ID NO.783 and SEQ ID NO.1024)
[1050] NPD014s-AD425 (SEQ ID NO.784 and SEQ ID NO.1025)
[1051] NPD014s-AD426 (SEQ ID NO.785 and SEQ ID NO.1026)
[1052] NPD014s-AD427 (SEQ ID NO.786 and SEQ ID NO.1027)
[1053] NPD014s-AD428 (SEQ ID NO.787 and SEQ ID NO.1028)
[1054] NPD014s-AD429 (SEQ ID NO.788 and SEQ ID NO.1029)
[1055] NPD014s-AD430 (SEQ ID NO.789 and SEQ ID NO.1030)
[1056] NPD014s-AD431 (SEQ ID NO.790 and SEQ ID NO.1031)
[1057] NPD014s-AD432 (SEQ ID NO.791 and SEQ ID NO.1032)
[1058] NPD014s-AD433 (SEQ ID NO.792 and SEQ ID NO.1033)
[1059] NPD014s-AD434 (SEQ ID NO.793 and SEQ ID NO.1034)
[1060] NPD014s-AD435 (SEQ ID NO.794 and SEQ ID NO.1035)
[1061] NPD014s-AD436 (SEQ ID NO.795 and SEQ ID NO.1036)
[1062] NPD014s-AD437 (SEQ ID NO.796 and SEQ ID NO.1037)
[1063] NPD014s-AD438 (SEQ ID NO.797 and SEQ ID NO.1038)
[1064] NPD014s-AD439 (SEQ ID NO.798 and SEQ ID NO.1039)
[1065] NPD014s-AD440 (SEQ ID NO.799 and SEQ ID NO.1040)
[1066] NPD014s-AD441 (SEQ ID NO.800 and SEQ ID NO.1041)
[1067] NPD014s-AD442 (SEQ ID NO.801 and SEQ ID NO.1042)
[1068] NPD014s-AD443 (SEQ ID NO.802 and SEQ ID NO.1043)
[1069] NPD014s-AD444 (SEQ ID NO.803 and SEQ ID NO.1044)
[1070] NPD014s-AD445 (SEQ ID NO.804 and SEQ ID NO.1045)
[1071] NPD014s-AD446 (SEQ ID NO.805 and SEQ ID NO.1046)
[1072] NPD014s-AD447 (SEQ ID NO.806 and SEQ ID NO.1047)
[1073] NPD014s-AD448 (SEQ ID NO.807 and SEQ ID NO.1048)
[1074] NPD014s-AD449 (SEQ ID NO.808 and SEQ ID NO.1049)
[1075] NPD014s-AD450 (SEQ ID NO.809 and SEQ ID NO.1050)
[1076] NPD014s-AD451 (SEQ ID NO.810 and SEQ ID NO.1051)
[1077] NPD014s-AD452 (SEQ ID NO.811 and SEQ ID NO.1052)
[1078] NPD014s-AD453 (SEQ ID NO.812 and SEQ ID NO.1053)
[1079] NPD014s-AD454 (SEQ ID NO.813 and SEQ ID NO.1054)
[1080] NPD014s-AD455 (SEQ ID NO.814 and SEQ ID NO.1055)
[1081] NPD014s-AD456 (SEQ ID NO.815 and SEQ ID NO.1056)
[1082] NPD014s-AD457 (SEQ ID NO.816 and SEQ ID NO.1057)
[1083] NPD014s-AD458 (SEQ ID NO.817 and SEQ ID NO.1058)
[1084] NPD014s-AD459 (SEQ ID NO.818 and SEQ ID NO.1059)
[1085] NPD014s-AD460 (SEQ ID NO.819 and SEQ ID NO.1060)
[1086] NPD014s-AD461 (SEQ ID NO.820 and SEQ ID NO.1061)
[1087] NPD014s-AD462 (SEQ ID NO.821 and SEQ ID NO.1062)
[1088] NPD014s-AD463 (SEQ ID NO.822 and SEQ ID NO.1063)
[1089] NPD014s-AD464 (SEQ ID NO.823 and SEQ ID NO.1064)
[1090] NPD014s-AD465 (SEQ ID NO.824 and SEQ ID NO.1065)
[1091] NPD014s-AD466 (SEQ ID NO.825 and SEQ ID NO.1066)
[1092] NPD014s-AD467 (SEQ ID NO.826 and SEQ ID NO.1067)
[1093] NPD014s-AD468 (SEQ ID NO.827 and SEQ ID NO.1068)
[1094] NPD014s-AD469 (SEQ ID NO.828 and SEQ ID NO.1069)
[1095] NPD014s-AD470 (SEQ ID NO.829 and SEQ ID NO.1070)
[1096] NPD014s-AD471 (SEQ ID NO.830 and SEQ ID NO.1071)
[1097] NPD014s-AD472 (SEQ ID NO.831 and SEQ ID NO.1072)
[1098] NPD014s-AD473 (SEQ ID NO.832 and SEQ ID NO.1073)
[1099] NPD014s-AD474 (SEQ ID NO.833 and SEQ ID NO.1074)
[1100] NPD014s-AD475 (SEQ ID NO.834 and SEQ ID NO.1075)
[1101] NPD014s-AD476 (SEQ ID NO.835 and SEQ ID NO.1076)
[1102] NPD014s-AD477 (SEQ ID NO.836 and SEQ ID NO.1077)
[1103] NPD014s-AD478 (SEQ ID NO.837 and SEQ ID NO.1078)
[1104] NPD014s-AD479 (SEQ ID NO.838 and SEQ ID NO.1079)
[1105] NPD014s-AD480 (SEQ ID NO.839 and SEQ ID NO.1080)
[1106] NPD014s-AD481 (SEQ ID NO.840 and SEQ ID NO.1081)
[1107] NPD014s-AD482 (SEQ ID NO. 841 and SEQ ID NO. 1082).
[1108] According to an embodiment of the present invention, the sense strand and the antisense strand of the siRNA conjugate comprise a chemically modified nucleotide sequence of a duplex selected from the following:
[1109] NPD014s-AD244 (SEQ ID NO.603 and SEQ ID NO.844)
[1110] NPD014s-AD245 (SEQ ID NO.604 and SEQ ID NO.845)
[1111] NPD014s-AD246 (SEQ ID NO.605 and SEQ ID NO.846)
[1112] NPD014s-AD247 (SEQ ID NO.606 and SEQ ID NO.847)
[1113] NPD014s-AD248 (SEQ ID NO.607 and SEQ ID NO.848)
[1114] NPD014s-AD249 (SEQ ID NO.608 and SEQ ID NO.849)
[1115] NPD014s-AD250 (SEQ ID NO.609 and SEQ ID NO.850)
[1116] NPD014s-AD253 (SEQ ID NO.612 and SEQ ID NO.853)
[1117] NPD014s-AD256 (SEQ ID NO.615 and SEQ ID NO.856)
[1118] NPD014s-AD257 (SEQ ID NO.616 and SEQ ID NO.857)
[1119] NPD014s-AD259 (SEQ ID NO.618 and SEQ ID NO.859)
[1120] NPD014s-AD261 (SEQ ID NO.620 and SEQ ID NO.861)
[1121] NPD014s-AD262 (SEQ ID NO.621 and SEQ ID NO.862)
[1122] NPD014s-AD264 (SEQ ID NO.623 and SEQ ID NO.864)
[1123] NPD014s-AD270 (SEQ ID NO.629 and SEQ ID NO.870)
[1124] NPD014s-AD279 (SEQ ID NO.638 and SEQ ID NO.879)
[1125] NPD014s-AD280 (SEQ ID NO.639 and SEQ ID NO.880)
[1126] NPD014s-AD281 (SEQ ID NO.640 and SEQ ID NO.881)
[1127] NPD014s-AD285 (SEQ ID NO.644 and SEQ ID NO.885)
[1128] NPD014s-AD291 (SEQ ID NO.650 and SEQ ID NO.891)
[1129] NPD014s-AD296 (SEQ ID NO.655 and SEQ ID NO.896)
[1130] NPD014s-AD301 (SEQ ID NO.660 and SEQ ID NO.901)
[1131] NPD014s-AD302 (SEQ ID NO.661 and SEQ ID NO.902)
[1132] NPD014s-AD304 (SEQ ID NO.663 and SEQ ID NO.904)
[1133] NPD014s-AD305 (SEQ ID NO.664 and SEQ ID NO.905)
[1134] NPD014s-AD307 (SEQ ID NO. 666 and SEQ ID NO. 907)
[1135] NPD014s-AD308 (SEQ ID NO. 667 and SEQ ID NO. 908)
[1136] NPD014s-AD309 (SEQ ID NO.668 and SEQ ID NO.909)
[1137] NPD014s-AD310 (SEQ ID NO.669 and SEQ ID NO.910)
[1138] NPD014s-AD311 (SEQ ID NO.670 and SEQ ID NO.911)
[1139] NPD014s-AD313 (SEQ ID NO.672 and SEQ ID NO.913)
[1140] NPD014s-AD316 (SEQ ID NO. 675 and SEQ ID NO. 916)
[1141] NPD014s-AD317 (SEQ ID NO.676 and SEQ ID NO.917)
[1142] NPD014s-AD318 (SEQ ID NO.677 and SEQ ID NO.918)
[1143] NPD014s-AD319 (SEQ ID NO.678 and SEQ ID NO.919)
[1144] NPD014s-AD322 (SEQ ID NO.681 and SEQ ID NO.922)
[1145] NPD014s-AD323 (SEQ ID NO.682 and SEQ ID NO.923)
[1146] NPD014s-AD324 (SEQ ID NO.683 and SEQ ID NO.924)
[1147] NPD014s-AD325 (SEQ ID NO.684 and SEQ ID NO.925)
[1148] NPD014s-AD326 (SEQ ID NO.685 and SEQ ID NO.926)
[1149] NPD014s-AD327 (SEQ ID NO.686 and SEQ ID NO.927)
[1150] NPD014s-AD328 (SEQ ID NO.687 and SEQ ID NO.928)
[1151] NPD014s-AD329 (SEQ ID NO.688 and SEQ ID NO.929)
[1152] NPD014s-AD330 (SEQ ID NO.689 and SEQ ID NO.930)
[1153] NPD014s-AD331 (SEQ ID NO.690 and SEQ ID NO.931)
[1154] NPD014s-AD332 (SEQ ID NO.691 and SEQ ID NO.932)
[1155] NPD014s-AD333 (SEQ ID NO.692 and SEQ ID NO.933)
[1156] NPD014s-AD334 (SEQ ID NO.693 and SEQ ID NO.934)
[1157] NPD014s-AD335 (SEQ ID NO.694 and SEQ ID NO.935)
[1158] NPD014s-AD336 (SEQ ID NO. 695 and SEQ ID NO. 936)
[1159] NPD014s-AD337 (SEQ ID NO. 696 and SEQ ID NO. 937)
[1160] NPD014s-AD338 (SEQ ID NO. 697 and SEQ ID NO. 938)
[1161] NPD014s-AD339 (SEQ ID NO.698 and SEQ ID NO.939)
[1162] NPD014s-AD340 (SEQ ID NO.699 and SEQ ID NO.940)
[1163] NPD014s-AD341 (SEQ ID NO.700 and SEQ ID NO.941)
[1164] NPD014s-AD342 (SEQ ID NO.701 and SEQ ID NO.942)
[1165] NPD014s-AD343 (SEQ ID NO.702 and SEQ ID NO.943)
[1166] NPD014s-AD344 (SEQ ID NO.703 and SEQ ID NO.944)
[1167] NPD014s-AD345 (SEQ ID NO.704 and SEQ ID NO.945)
[1168] NPD014s-AD346 (SEQ ID NO.705 and SEQ ID NO.946)
[1169] NPD014s-AD347 (SEQ ID NO.706 and SEQ ID NO.947)
[1170] NPD014s-AD348 (SEQ ID NO.707 and SEQ ID NO.948)
[1171] NPD014s-AD349 (SEQ ID NO.708 and SEQ ID NO.949)
[1172] NPD014s-AD350 (SEQ ID NO.709 and SEQ ID NO.950)
[1173] NPD014s-AD351 (SEQ ID NO.710 and SEQ ID NO.951)
[1174] NPD014s-AD352 (SEQ ID NO.711 and SEQ ID NO.952)
[1175] NPD014s-AD353 (SEQ ID NO.712 and SEQ ID NO.953)
[1176] NPD014s-AD354 (SEQ ID NO.713 and SEQ ID NO.954)
[1177] NPD014s-AD355 (SEQ ID NO.714 and SEQ ID NO.955)
[1178] NPD014s-AD356 (SEQ ID NO.715 and SEQ ID NO.956)
[1179] NPD014s-AD357 (SEQ ID NO.716 and SEQ ID NO.957)
[1180] NPD014s-AD358 (SEQ ID NO.717 and SEQ ID NO.958)
[1181] NPD014s-AD359 (SEQ ID NO.718 and SEQ ID NO.959)
[1182] NPD014s-AD360 (SEQ ID NO.719 and SEQ ID NO.960)
[1183] NPD014s-AD361 (SEQ ID NO.720 and SEQ ID NO.961)
[1184] NPD014s-AD362 (SEQ ID NO.721 and SEQ ID NO.962)
[1185] NPD014s-AD363 (SEQ ID NO.722 and SEQ ID NO.963)
[1186] NPD014s-AD364 (SEQ ID NO.723 and SEQ ID NO.964)
[1187] NPD014s-AD365 (SEQ ID NO.724 and SEQ ID NO.965)
[1188] NPD014s-AD366 (SEQ ID NO.725 and SEQ ID NO.966)
[1189] NPD014s-AD367 (SEQ ID NO.726 and SEQ ID NO.967)
[1190] NPD014s-AD368 (SEQ ID NO.727 and SEQ ID NO.968)
[1191] NPD014s-AD369 (SEQ ID NO.728 and SEQ ID NO.969)
[1192] NPD014s-AD370 (SEQ ID NO.729 and SEQ ID NO.970)
[1193] NPD014s-AD371 (SEQ ID NO.730 and SEQ ID NO.971)
[1194] NPD014s-AD372 (SEQ ID NO.731 and SEQ ID NO.972)
[1195] NPD014s-AD373 (SEQ ID NO.732 and SEQ ID NO.973)
[1196] NPD014s-AD374 (SEQ ID NO.733 and SEQ ID NO.974)
[1197] NPD014s-AD375 (SEQ ID NO.734 and SEQ ID NO.975)
[1198] NPD014s-AD376 (SEQ ID NO.735 and SEQ ID NO.976)
[1199] NPD014s-AD377 (SEQ ID NO.736 and SEQ ID NO.977)
[1200] NPD014s-AD378 (SEQ ID NO.737 and SEQ ID NO.978)
[1201] NPD014s-AD379 (SEQ ID NO.738 and SEQ ID NO.979)
[1202] NPD014s-AD380 (SEQ ID NO.739 and SEQ ID NO.980)
[1203] NPD014s-AD381 (SEQ ID NO.740 and SEQ ID NO.981)
[1204] NPD014s-AD382 (SEQ ID NO.741 and SEQ ID NO.982)
[1205] NPD014s-AD383 (SEQ ID NO.742 and SEQ ID NO.983)
[1206] NPD014s-AD384 (SEQ ID NO.743 and SEQ ID NO.984)
[1207] NPD014s-AD385 (SEQ ID NO.744 and SEQ ID NO.985)
[1208] NPD014s-AD386 (SEQ ID NO.745 and SEQ ID NO.986)
[1209] NPD014s-AD387 (SEQ ID NO.746 and SEQ ID NO.987)
[1210] NPD014s-AD388 (SEQ ID NO.747 and SEQ ID NO.988)
[1211] NPD014s-AD389 (SEQ ID NO.748 and SEQ ID NO.989)
[1212] NPD014s-AD390 (SEQ ID NO.749 and SEQ ID NO.990)
[1213] NPD014s-AD391 (SEQ ID NO.750 and SEQ ID NO.991)
[1214] NPD014s-AD392 (SEQ ID NO.751 and SEQ ID NO.992)
[1215] NPD014s-AD393 (SEQ ID NO.752 and SEQ ID NO.993)
[1216] NPD014s-AD394 (SEQ ID NO.753 and SEQ ID NO.994)
[1217] NPD014s-AD395 (SEQ ID NO.754 and SEQ ID NO.995)
[1218] NPD014s-AD396 (SEQ ID NO.755 and SEQ ID NO.996)
[1219] NPD014s-AD397 (SEQ ID NO.756 and SEQ ID NO.997)
[1220] NPD014s-AD398 (SEQ ID NO.757 and SEQ ID NO.998)
[1221] NPD014s-AD399 (SEQ ID NO.758 and SEQ ID NO.999)
[1222] NPD014s-AD400 (SEQ ID NO.759 and SEQ ID NO.1000)
[1223] NPD014s-AD401 (SEQ ID NO.760 and SEQ ID NO.1001)
[1224] NPD014s-AD402 (SEQ ID NO.761 and SEQ ID NO.1002)
[1225] NPD014s-AD403 (SEQ ID NO.762 and SEQ ID NO.1003)
[1226] NPD014s-AD404 (SEQ ID NO.763 and SEQ ID NO.1004)
[1227] NPD014s-AD405 (SEQ ID NO.764 and SEQ ID NO.1005)
[1228] NPD014s-AD406 (SEQ ID NO.765 and SEQ ID NO.1006)
[1229] NPD014s-AD407 (SEQ ID NO.766 and SEQ ID NO.1007)
[1230] NPD014s-AD408 (SEQ ID NO.767 and SEQ ID NO.1008)
[1231] NPD014s-AD409 (SEQ ID NO.768 and SEQ ID NO.1009)
[1232] NPD014s-AD410 (SEQ ID NO.769 and SEQ ID NO.1010)
[1233] NPD014s-AD411 (SEQ ID NO.770 and SEQ ID NO.1011)
[1234] NPD014s-AD412 (SEQ ID NO.771 and SEQ ID NO.1012)
[1235] NPD014s-AD413 (SEQ ID NO.772 and SEQ ID NO.1013)
[1236] NPD014s-AD414 (SEQ ID NO.773 and SEQ ID NO.1014)
[1237] NPD014s-AD415 (SEQ ID NO.774 and SEQ ID NO.1015)
[1238] NPD014s-AD416 (SEQ ID NO.775 and SEQ ID NO.1016)
[1239] NPD014s-AD417 (SEQ ID NO.776 and SEQ ID NO.1017)
[1240] NPD014s-AD418 (SEQ ID NO.777 and SEQ ID NO.1018)
[1241] NPD014s-AD419 (SEQ ID NO.778 and SEQ ID NO.1019)
[1242] NPD014s-AD420 (SEQ ID NO.779 and SEQ ID NO.1020)
[1243] NPD014s-AD421 (SEQ ID NO.780 and SEQ ID NO.1021)
[1244] NPD014s-AD422 (SEQ ID NO.781 and SEQ ID NO.1022)
[1245] NPD014s-AD423 (SEQ ID NO.782 and SEQ ID NO.1023)
[1246] NPD014s-AD424 (SEQ ID NO.783 and SEQ ID NO.1024)
[1247] NPD014s-AD425 (SEQ ID NO.784 and SEQ ID NO.1025)
[1248] NPD014s-AD426 (SEQ ID NO.785 and SEQ ID NO.1026)
[1249] NPD014s-AD427 (SEQ ID NO.786 and SEQ ID NO.1027)
[1250] NPD014s-AD428 (SEQ ID NO.787 and SEQ ID NO.1028)
[1251] NPD014s-AD429 (SEQ ID NO.788 and SEQ ID NO.1029)
[1252] NPD014s-AD430 (SEQ ID NO.789 and SEQ ID NO.1030)
[1253] NPD014s-AD431 (SEQ ID NO.790 and SEQ ID NO.1031)
[1254] NPD014s-AD432 (SEQ ID NO.791 and SEQ ID NO.1032)
[1255] NPD014s-AD433 (SEQ ID NO.792 and SEQ ID NO.1033)
[1256] NPD014s-AD434 (SEQ ID NO.793 and SEQ ID NO.1034)
[1257] NPD014s-AD435 (SEQ ID NO.794 and SEQ ID NO.1035)
[1258] NPD014s-AD436 (SEQ ID NO.795 and SEQ ID NO.1036)
[1259] NPD014s-AD437 (SEQ ID NO.796 and SEQ ID NO.1037)
[1260] NPD014s-AD438 (SEQ ID NO.797 and SEQ ID NO.1038)
[1261] NPD014s-AD439 (SEQ ID NO.798 and SEQ ID NO.1039)
[1262] NPD014s-AD440 (SEQ ID NO.799 and SEQ ID NO.1040)
[1263] NPD014s-AD441 (SEQ ID NO.800 and SEQ ID NO.1041)
[1264] NPD014s-AD442 (SEQ ID NO.801 and SEQ ID NO.1042)
[1265] NPD014s-AD443 (SEQ ID NO.802 and SEQ ID NO.1043)
[1266] NPD014s-AD444 (SEQ ID NO.803 and SEQ ID NO.1044)
[1267] NPD014s-AD445 (SEQ ID NO.804 and SEQ ID NO.1045)
[1268] NPD014s-AD446 (SEQ ID NO.805 and SEQ ID NO.1046)
[1269] NPD014s-AD447 (SEQ ID NO.806 and SEQ ID NO.1047)
[1270] NPD014s-AD448 (SEQ ID NO.807 and SEQ ID NO.1048)
[1271] NPD014s-AD449 (SEQ ID NO.808 and SEQ ID NO.1049)
[1272] NPD014s-AD450 (SEQ ID NO.809 and SEQ ID NO.1050)
[1273] NPD014s-AD451 (SEQ ID NO.810 and SEQ ID NO.1051)
[1274] NPD014s-AD452 (SEQ ID NO.811 and SEQ ID NO.1052)
[1275] NPD014s-AD453 (SEQ ID NO.812 and SEQ ID NO.1053)
[1276] NPD014s-AD454 (SEQ ID NO.813 and SEQ ID NO.1054)
[1277] NPD014s-AD455 (SEQ ID NO.814 and SEQ ID NO.1055)
[1278] NPD014s-AD456 (SEQ ID NO.815 and SEQ ID NO.1056)
[1279] NPD014s-AD457 (SEQ ID NO.816 and SEQ ID NO.1057)
[1280] NPD014s-AD458 (SEQ ID NO.817 and SEQ ID NO.1058)
[1281] NPD014s-AD459 (SEQ ID NO.818 and SEQ ID NO.1059)
[1282] NPD014s-AD460 (SEQ ID NO.819 and SEQ ID NO.1060)
[1283] NPD014s-AD461 (SEQ ID NO.820 and SEQ ID NO.1061)
[1284] NPD014s-AD462 (SEQ ID NO.821 and SEQ ID NO.1062)
[1285] NPD014s-AD463 (SEQ ID NO.822 and SEQ ID NO.1063)
[1286] NPD014s-AD464 (SEQ ID NO.823 and SEQ ID NO.1064)
[1287] NPD014s-AD465 (SEQ ID NO.824 and SEQ ID NO.1065)
[1288] NPD014s-AD466 (SEQ ID NO.825 and SEQ ID NO.1066)
[1289] NPD014s-AD467 (SEQ ID NO.826 and SEQ ID NO.1067)
[1290] NPD014s-AD468 (SEQ ID NO.827 and SEQ ID NO.1068)
[1291] NPD014s-AD469 (SEQ ID NO.828 and SEQ ID NO.1069)
[1292] NPD014s-AD470 (SEQ ID NO.829 and SEQ ID NO.1070)
[1293] NPD014s-AD471 (SEQ ID NO.830 and SEQ ID NO.1071)
[1294] NPD014s-AD472 (SEQ ID NO.831 and SEQ ID NO.1072)
[1295] NPD014s-AD473 (SEQ ID NO.832 and SEQ ID NO.1073)
[1296] NPD014s-AD474 (SEQ ID NO.833 and SEQ ID NO.1074)
[1297] NPD014s-AD475 (SEQ ID NO.834 and SEQ ID NO.1075)
[1298] NPD014s-AD476 (SEQ ID NO.835 and SEQ ID NO.1076)
[1299] NPD014s-AD477 (SEQ ID NO.836 and SEQ ID NO.1077)
[1300] NPD014s-AD478 (SEQ ID NO.837 and SEQ ID NO.1078)
[1301] NPD014s-AD479 (SEQ ID NO.838 and SEQ ID NO.1079)
[1302] NPD014s-AD480 (SEQ ID NO.839 and SEQ ID NO.1080)
[1303] NPD014s-AD481 (SEQ ID NO.840 and SEQ ID NO.1081)
[1304] NPD014s-AD482 (SEQ ID NO. 841 and SEQ ID NO. 1082).
[1305] In another aspect of the present invention, the present invention proposes a pharmaceutical composition. According to an embodiment of the present invention, the pharmaceutical composition includes: the aforementioned siRNA; or the aforementioned siRNA conjugate. The pharmaceutical composition according to the embodiment of the present invention can specifically reduce the synthesis of CFB by hepatocytes, reduce the complement activity in the body, and effectively treat related diseases caused by abnormal activation of the complement pathway, such as paroxysmal nocturnal hemoglobinuria (PNH), asthma, rheumatoid arthritis, systemic lupus erythematosus, glomerulonephritis, psoriasis, dermatomyositis bullous pemphigoid, atypical hemolytic uremic syndrome, Shiga toxin Escherichia coli-associated hemolytic uremic syndrome, myasthenia gravis, neuromyelitis optica, dense deposit disease, C3 neuropathy, age-related macular degeneration, cold agglutinin disease, anti-neutrophil cytoplasmic antibody-associated vasculitis, humoral and vascular transplant rejection, graft dysfunction, myocardial infarction, sensitized receptors of transplants, immunoglobulin a nephropathy, and sepsis.
[1306] It should be noted that the pharmaceutical composition herein may include one or more of the aforementioned siRNAs or siRNA conjugates.
[1307] According to an embodiment of the present invention, the pharmaceutical composition further comprises: a pharmaceutically acceptable excipient.
[1308] In another aspect of the present invention, the present invention provides a use of the aforementioned siRNA, the aforementioned siRNA conjugate or the aforementioned pharmaceutical composition in preparing a drug, wherein the drug is used to inhibit the expression of CFB.
[1309] In another aspect of the present invention, the present invention provides a use of the aforementioned siRNA, the aforementioned siRNA conjugate or the aforementioned pharmaceutical composition in the preparation of a drug, wherein the drug is used to treat related diseases caused by abnormal activation of the complement pathway.
[1310] According to an embodiment of the present invention, the related diseases caused by abnormal activation of the complement pathway include paroxysmal nocturnal hemoglobinuria (PNH), glomerulonephritis, immunoglobulin a nephropathy, age-related macular degeneration or rheumatoid arthritis.
[1311] In another aspect of the present invention, the present invention provides a method for treating related diseases caused by abnormal activation of the complement pathway. According to an embodiment of the present invention, the method comprises: administering a pharmaceutically acceptable amount of the aforementioned siRNA, the aforementioned siRNA conjugate, or the aforementioned pharmaceutical composition to a subject. According to an embodiment of the present invention, the method can effectively prevent and / or treat related diseases caused by excessive CFB.
[1312] The effective amount of the siRNA, siRNA conjugate or pharmaceutical composition of the present invention may vary depending on the mode of administration and the severity of the disease to be treated. The selection of the preferred effective amount can be determined by a person of ordinary skill in the art based on various factors (e.g., through clinical trials). The factors include, but are not limited to: pharmacokinetic parameters of the active ingredient such as bioavailability, metabolism, half-life, etc.; the severity of the disease to be treated by the patient, the patient's weight, the patient's immune status, the route of administration, etc. For example, depending on the urgency of the treatment situation, several divided doses may be administered daily, such as once every several days, weeks, or months.
[1313] The drug can be administered to a subject by any suitable route known in the art, including but not limited to subcutaneous administration, intravenous administration, intramuscular administration, transdermal administration, airway administration (aerosol), pulmonary administration, nasal administration, rectal administration, and topical administration (including buccal administration and sublingual administration), preferably subcutaneous administration.
[1314] According to an embodiment of the present invention, the administration route of the method is subcutaneous injection.
[1315] According to an embodiment of the present invention, the related diseases caused by abnormal activation of the complement pathway include paroxysmal nocturnal hemoglobinuria (PNH), IgA nephropathy, and age-related macular degeneration.
[1316] Additional aspects and advantages of the present invention will be given in part in the following description and in part will be obvious from the following description, or will be learned through practice of the present invention. DETAILED DESCRIPTION
[1317] The embodiments of the present invention are described in detail below. The embodiments described below are exemplary and are only used to explain the present invention, and should not be understood as limiting the present invention.
[1318] It should be noted that the terms "first" and "second" are used for descriptive purposes only and should not be understood as indicating or implying relative importance or implicitly indicating the number of the indicated technical features. Therefore, the features defined as "first" and "second" may explicitly or implicitly include one or more of the features. Further, in the description of the present invention, unless otherwise specified, the meaning of "plurality" is two or more.
[1319] In this document, the terms “include” or “comprising” are open expressions, that is, including the contents specified in the present invention but not excluding other contents.
[1320] As used herein, the terms "optionally", "optional" or "optionally" generally mean that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.
[1321] As used herein, the term "small interfering RNA (siRNA)" is a double-stranded RNA of 17 to 25 nucleotides in length, comprising a sense strand and an antisense strand. siRNA mediates the targeted cutting of target mRNAs in the RISC pathway by forming a silencing complex (RISC). Specifically, siRNA guides the specific degradation of mRNA sequences through the known RNA interference (RNAi) process, inhibiting the translation of mRNA into proteins. For example, siRNA can regulate (e.g., inhibit) the expression of CFB in cells.
[1322] As used herein, the term "antisense strand (or guide strand)" includes a region that is substantially complementary to a target sequence, such as CFB mRNA. "Sense strand (or follower strand)" refers to an RNAi strand that is substantially complementary to the antisense strand. The term "substantially complementary" refers to complete complementarity or at least partial complementarity, for example, the antisense strand is completely complementary to the target sequence or at least partially complementary. In the case of partial complementarity, mismatches can exist in the interior or terminal regions of the molecule, wherein the most tolerated mismatches exist in the terminal regions, for example, within 5, 4, 3 or 2 nucleotides of the 5' end and / or 3' end of the RNAi.
[1323] It should be noted that "at least part of the antisense strand is substantially complementary to the mRNA" means that the antisense strand has a polynucleotide that is substantially complementary to a continuous portion of the mRNA of interest (e.g., the mRNA encoding CFB). Alternatively, if a polynucleotide is substantially non-interruptedly complementary to a portion of the mRNA encoding CFB, the antisense strand is complementary to at least a portion of the CFB mRNA.
[1324] Herein, the term "target sequence" refers to a continuous portion of the nucleotide sequence of an mRNA molecule formed during transcription of a CFB gene, including mRNA that is an RNA processing product of a primary transcription product.
[1325] As used herein, the term "inhibiting the expression of a CFB gene" includes any level of inhibition of a CFB gene, for example, at least partial inhibition of CFB gene expression, such as inhibition of at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99%. The expression of a CFB gene can be evaluated based on the level of any variable associated with the expression of the CFB gene, for example, the mRNA level of CFB or the protein level of CFB. Inhibition can be evaluated by a decrease in the absolute or relative level of one or more of these variables compared to a control level. The control level can be any type of control level utilized in the art, e.g., a baseline level prior to administration, or a level measured from a similar subject, cell, or sample that has not been treated or that has been treated with a control (e.g., a buffer-only control or a no active agent control).
[1326] In this article, the term "CFB" includes the mRNA of CFB or its complete coding sequence, such as human CFB, which can be found in, for example, GenBank accession search (NM_001737). Other examples of mRNA sequences of CFB are obtained using publicly available databases, such as genome project websites such as GenBank and UniProt. The term "CFB" can also refer to naturally occurring DNA sequence variants of the CFB gene, such as single nucleotide polymorphisms (SNPs) in the CFB gene.
[1327] As used herein, the terms "expression vector" and "construct" are used interchangeably and are capable of delivering one or more genes or sequences of interest into a host cell and preferably expressing the genes or sequences in the host cell. Examples of vectors include, but are not limited to, viral vectors, plasmids, cosmids, or phage vectors.
[1328] In this article, "pharmaceutical composition" may refer to a composition used for the treatment of a disease, and may also be used for in vitro culture experiments of cells. When used for the treatment of a disease, the term "pharmaceutical composition" generally refers to a unit dosage form, and may be prepared by any of the methods well known in the pharmaceutical field. All methods include the step of combining the active ingredient with an excipient that constitutes one or more accessory ingredients. Typically, the composition is prepared by uniformly and fully combining the active siRNA or siRNA conjugate with a liquid excipient, a finely divided solid excipient, or both.
[1329] In this article, the term "pharmaceutically acceptable" means that the substance or composition must be chemically and / or toxicologically compatible with the other ingredients of the formulation and / or the mammals treated therewith. Preferably, the "pharmaceutically acceptable" of the present invention refers to those approved by federal regulatory agencies or national governments or listed in the U.S. Pharmacopoeia or other generally recognized pharmacopeias for use in animals, particularly humans.
[1330] As used herein, the term "pharmaceutically acceptable excipient" is recognized in the art and includes pharmaceutically acceptable materials, compositions or carriers suitable for administering the siRNA or siRNA conjugates of the present disclosure to mammals. The excipients include liquid or solid fillers, diluents, excipients, solvents or encapsulating materials that participate in carrying the principal substance or transferring it from one organ or part of the body to another organ or part of the body. Each excipient must be "acceptable" in the sense of being compatible with the other ingredients in the formulation and not harmful to the patient. Some examples of materials that can be used as pharmaceutically acceptable excipients include: sugars, such as lactose, glucose and sucrose; cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose and cellulose acetate, powdered tragacanth, malt, gelatin, talc, excipients such as cocoa butter and suppository waxes; oleyl glycols, such as propylene glycol; polyols, such as glycerol, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; buffers, such as magnesium hydroxide and aluminum hydroxide; ethanol; phosphate buffers; and other nontoxic, compatible substances used in pharmaceutical formulations.
[1331] In addition to any conventional excipients, to the extent that they are incompatible with the siRNA or siRNA conjugates of the present invention, such as any adverse biological effects produced or interactions with any other components of the pharmaceutically acceptable composition in a deleterious manner, their use is also contemplated by the present invention.
[1332] Pharmaceutical compositions of the present disclosure include preparations suitable for oral, nasal, topical, buccal, sublingual, rectal and / or parenteral administration. The preparation can be conveniently present in unit dosage form and can be prepared by any method known in the pharmaceutical field. The amount of active ingredient that can be combined with auxiliary materials to prepare a single dose form is generally the amount of siRNA or siRNA conjugate that produces a therapeutic effect. Generally speaking, in units of one percent, the amount is about 1% to about 99% active ingredient, preferably about 5% to about 70%, and most preferably about 10% to about 30%.
[1333] As used herein, the term "treatment" refers to the use of the term to refer to obtaining a desired pharmacological and / or physiological effect. The effect may be preventive in terms of completely or partially preventing a disease or its symptoms, and / or may be therapeutic in terms of partially or completely curing a disease and / or the adverse effects caused by the disease. "Treatment" as used herein covers diseases in mammals, particularly humans, and includes: (a) preventing the occurrence of a disease or condition in an individual who is susceptible to the disease but has not yet been diagnosed with the disease; (b) inhibiting the disease, such as blocking the progression of the disease; or (c) alleviating the disease, such as alleviating symptoms associated with the disease. "Treatment" as used herein covers any medication that administers siRNA, siRNA conjugates or drugs to an individual to treat, cure, alleviate, improve, reduce or inhibit the individual's disease, including but not limited to administering a drug containing siRNA or siRNA conjugates described herein to an individual in need.
[1334] The scheme of the present invention will be explained below in conjunction with the embodiments. It will be appreciated by those skilled in the art that the following embodiments are only used to illustrate the present invention and should not be considered as limiting the scope of the present invention. Where specific techniques or conditions are not indicated in the embodiments, the techniques or conditions described in the literature in this area or the product specifications are used. The reagents or instruments used are not indicated by the manufacturer and are conventional products that can be purchased commercially.
[1335] Example 1: Design of siRNA
[1336] siRNA technology is an innovative gene knockout method with the advantages of high efficiency, specificity and reliability. It has received extensive attention in the fields of disease treatment and gene research. The 59 siRNAs designed by the custom Python script proposed in this embodiment for the human CFB gene (NCBI refseqID NM_001737) are an important progress in this technology. Different from the traditional siRNA design method, the siRNA design method of this embodiment relies on the Python script developed independently, which can quickly and accurately determine the suitable siRNA sequence. This experiment prepared 59 unmodified siRNA duplexes, named NDS-014-1 to NDS-014-59. The nucleotide sequences of the sense strand and antisense strand of these siRNAs are given in Table 1.
[1337] Example 2: Synthesis of siRNA and conjugates
[1338] Table 2: Nucleotide monomer abbreviations used in nucleic acid sequences
[1339]
[1340]
[1341] Deprotection, condensation, capping, oxidation or thiolation were performed according to standard oligonucleotide solid phase synthesis protocols using commercially available 5'-DMT-2'-OMe-U phosphoramidite monomers, 5'-DMT-2'-OMe-A(Bz) phosphoramidite monomers, 5'-DMT-2'-OMe-C(Ac) phosphoramidite monomers, 5'-DMT-2'-OMe-G(ibu) phosphoramidite monomers, 5'-DMT-2'-F-dU phosphoramidite monomers, 5'-DMT-2'-F-Ac-dC phosphoramidite monomers, 5'-DMT-2'-F-ibu-dG phosphoramidite monomers, 5'-DMT-2'-F-Bz-dA phosphoramidite monomers and synthetic GalNAc phosphoramidite monomers. RNA was synthesized at a scale of 500 nmol or 4 μmol, 50 mM RNA phosphoramidite solution and 200 mM GalNAc monomer solution were prepared in acetonitrile, and 0.3 M benzylthiotetrazolyl (BTT) acetonitrile solution was used as an activator to synthesize the sense strand and antisense strand in the 3'- to 5'-direction. During the synthesis process, 0.1 M oxidizing agent (I2: pyridine: THF: water) or 0.2 M hydrogenated xanthan / pyridine solution was used to convert trivalent phosphorus into pentavalent phosphorus to stabilize the phosphate skeleton. After the synthesis was completed, AMA solution (40% methylamine: ammonia water = 1:1) was aminolyzed at 55°C for 50 min or 28% ammonia water at 65°C for 5 h, and AMA or ammonia water was removed by vacuum centrifugation. Purification was performed using a PS-15Q ion purification column under the condition of phosphate and sodium chloride solution as the mobile phase or using a C18 reverse phase column under the condition of triethylamine acetate aqueous solution and acetonitrile as the mobile phase. LCMS and HPLC were used for in-process control detection. The sense strand and the antisense strand were mixed in a molar ratio of 1:1 and annealed at 90°C to form double-stranded siRNA and siRNA conjugates. The inventors verified the prepared conjugates (compound 1048 connected to the 5' end of the sense strand; compounds 1059 and 1060 connected to the 3' end of the sense strand). The mass spectrometry data of the modified siRNA sequence are shown in Table 3
[1342]
[1343]
[1344]
[1345]
[1346]
[1347]
[1348]
[1349]
[1350]
[1351]
[1352]
[1353]
[1354]
[1355]
[1356]
[1357]
[1358] aM represents 2'-O-methyladenosine, uM represents 2'-O-methyluridine, gM represents 2'-O-methylguanosine, cM represents 2'-O-methylcytosine, aF represents 2'-fluoroadenosine, uF represents 2'-fluorouridine, gF represents 2'-fluoroguanosine, cF represents 2'-fluorocytosine, dA represents deoxyadenosine-3'-phosphate, dC represents deoxycytidine-3'-phosphate, dG represents deoxyguanosine-3'-phosphate, dT represents deoxythymidine-3'-phosphate acid, iVPM represents 2'-O-methyl-5'-deoxy-(E)-vinylphosphonate-inosine-3'-phosphate, uVPM represents 2'-O-methyl-5'-deoxy-(E)-vinylphosphonate-uridine-3'-phosphate, aTA4 represents 2'-O-methyl-5'-deoxy-(1-(1,2,4-triazole))-adenosine-3'-phosphate, cTA4 represents 2'-O-methyl-5'-deoxy-(1-(1,2,4-triazole))-cytidine-3'-phosphate, and gTA4 represents 2'-O-methyl-5 '-deoxy-(1-(1,2,4-triazole))-guanosine-3'-phosphate, uTA4 represents 2'-O-methyl-5'-deoxy-(1-(1,2,4-triazole))-uridine-3'-phosphate, aSMP represents 2'-O-methyl-5'-N-(thiomorpholino)-adenosine-3'-phosphate, cSMP represents 2'-O-methyl-5'-N-(thiomorpholino)-cytidine-3'-phosphate, gSMP represents 2'-O-methyl-5'-N-(thiomorpholino)-guanosine-3'-phosphate, and uSMP represents 2 '-O-methyl-5'-N-(thiomorpholino)-uridine-3'-phosphate, aRF represents 3'-fluoro-3'-deoxyadenosine-2'-phosphate, cRF represents 3'-fluoro-3'-deoxycytidine-2'-phosphate, gRF represents 3'-fluoro-3'-deoxyguanosine-2'-phosphate, uRF represents 3'-fluoro-3'-deoxyuridine-2'-phosphate, * represents that two nucleotides (or compounds 1048, 1059, 1060 and nucleotides) are connected by a phosphorothioate diester bond, and there is no symbol between directly adjacent nucleotides.
[1359] The raw materials (phosphoramidite monomers) and auxiliary materials required for the synthesis of the above nucleic acid chains were purchased from the following companies:
[1360]
[1361] iVP was prepared according to the method described in patent CN202110008013.3; aTA4, cTA4, gTA4, uTA4, aSMP, cSMP, gSMP and uSMP were prepared according to the method described in patent CN202110008013.3; aRF, cRF, gRF and uRF were prepared according to the method described in patent CN202110008013.3; compounds 1059 and 1060 were prepared according to the method described in patent CN202110008013.3; compound 1048 was prepared according to the method described in patent CN202110008013.3.
[1362] Example 3: In vitro cell model (Hep 3B cells) testing the activity of small interfering nucleic acids (siRNA)
[1363] Human hepatoma Hep 3B cells (Shanghai Cell Bank, Chinese Academy of Sciences) were cultured in DMEM medium (Gibco, US) supplemented with 10% fetal bovine serum (Gibco, US) at 37°C and 5% CO2 (il60, Thermos Fisher). On the day of the transfection experiment, cells were digested with 0.25% Trypsin (Gibco, US), counted and seeded in 24-well plates at a density of 70,000 / well. RNAiMAX (Thermos Fisher) was used as a vector for transfection according to the standard configuration method, RNAiMAX 1μL / well. The final concentration of siRNA was 10nM and 0.1nM or 1nM and 0.01nM, and two parallel wells were set for each test substance at each measured dose. The experimental group containing only transfection reagent without siRNA in the transfection system was used as the control group.
[1364] 24 hours after transfection, RNA was extracted from cells using Trizol (Solarbio R1100). Subsequently, a one-step SYBR green qPCR kit (HiScript II One Step qRT-PCR SYBR Green Kit, VAZYME Q221-01) was used to configure the QPCR reaction system according to the standard method in the instruction manual, and a high-throughput QPCR instrument (Analytikjena qTOWER384G) was used to quantify the changes in the expression level of the target gene. Experimental results: The ΔΔCT method was used to analyze the relative changes in the expression of the target gene in the test sample and the control sample.
[1365] The activities of the siRNA sequences are shown in Table 5 below.
[1366] Table 5: In vitro silencing efficiency of siRNA duplexes (0.01 nM and 1 nM)
[1367]
[1368]
[1369] In the description of this specification, the description with reference to the terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" etc. means that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described may be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art may combine and combine the different embodiments or examples described in this specification and the features of the different embodiments or examples, without contradiction.
[1370] Although the embodiments of the present invention have been shown and described above, it is to be understood that the above embodiments are exemplary and are not to be construed as limitations of the present invention. A person skilled in the art may change, modify, replace and vary the above embodiments within the scope of the present invention.
Claims
1. A siRNA double-stranded molecule for targeting complement factor B (CFB) mRNA, characterized in that: The siRNA duplex is composed of a sense strand and an antisense strand through related base pairing, wherein the sense strand is selected from a nucleotide sequence that differs from the nucleotide sequence of each strand in SEQ ID NO:1 to SEQ ID NO:59 by no more than 2 nucleotides, and the antisense strand is selected from a nucleotide sequence that differs from the nucleotide sequence of each strand in SEQ ID NO:60 to SEQ ID NO:118 by no more than 2 nucleotides.
2. The siRNA duplex according to claim 1, wherein The sense strand is selected from at least 17 consecutive identical nucleotides in any one of nucleotide sequences in SEQ ID NO: 1 to SEQ ID NO:
59.
3. The siRNA duplex according to any one of claims 1 to 2, characterized in that The antisense strand is selected from at least 19 consecutive nucleotides consistent with any one of the nucleotide sequences in SEQ ID NO: 60 to SEQ ID NO:
118.
4. The siRNA duplex according to any one of claims 1 to 3, characterized in that The sense strand comprises at least 17 consecutive identical nucleotides selected from any sense strand nucleotide sequence of the following duplexes: NDS-014-3 (SEQ ID NO. 3 and SEQ ID NO. 62) NDS-014-4 (SEQ ID NO. 4 and SEQ ID NO. 63) NDS-014-5 (SEQ ID NO. 5 and SEQ ID NO. 64) NDS-014-6 (SEQ ID NO. 6 and SEQ ID NO. 65) NDS-014-7 (SEQ ID NO. 7 and SEQ ID NO. 66) NDS-014-8 (SEQ ID NO. 8 and SEQ ID NO. 67) NDS-014-9 (SEQ ID NO. 9 and SEQ ID NO. 68) NDS-014-12 (SEQ ID NO. 12 and SEQ ID NO. 71) NDS-014-15 (SEQ ID NO. 15 and SEQ ID NO. 74) NDS-014-16 (SEQ ID NO. 16 and SEQ ID NO. 75) NDS-014-18 (SEQ ID NO. 18 and SEQ ID NO. 77) NDS-014-20 (SEQ ID NO. 20 and SEQ ID NO. 79) NDS-014-21 (SEQ ID NO. 21 and SEQ ID NO. 80) NDS-014-23 (SEQ ID NO. 23 and SEQ ID NO. 82) NDS-014-29 (SEQ ID NO. 29 and SEQ ID NO. 88) NDS-014-38 (SEQ ID NO. 38 and SEQ ID NO. 97) NDS-014-39 (SEQ ID NO. 39 and SEQ ID NO. 98) NDS-014-40 (SEQ ID NO. 40 and SEQ ID NO. 99) NDS-014-44 (SEQ ID NO. 44 and SEQ ID NO. 103) NDS-014-50 (SEQ ID NO. 50 and SEQ ID NO. 109) NDS-014-55 (SEQ ID NO. 55 and SEQ ID NO. 114).
5. The siRNA duplex according to any one of claims 1 to 4, characterized in that The antisense strand comprises at least 19 consecutive identical nucleotides in any antisense strand nucleotide sequence selected from the following duplexes: NDS-014-3 (SEQ ID NO. 3 and SEQ ID NO. 62) NDS-014-4 (SEQ ID NO. 4 and SEQ ID NO. 63) NDS-014-5 (SEQ ID NO. 5 and SEQ ID NO. 64) NDS-014-6 (SEQ ID NO. 6 and SEQ ID NO. 65) NDS-014-7 (SEQ ID NO. 7 and SEQ ID NO. 66) NDS-014-8 (SEQ ID NO. 8 and SEQ ID NO. 67) NDS-014-9 (SEQ ID NO. 9 and SEQ ID NO. 68) NDS-014-12 (SEQ ID NO. 12 and SEQ ID NO. 71) NDS-014-15 (SEQ ID NO. 15 and SEQ ID NO. 74) NDS-014-16 (SEQ ID NO. 16 and SEQ ID NO. 75) NDS-014-18 (SEQ ID NO. 18 and SEQ ID NO. 77) NDS-014-20 (SEQ ID NO. 20 and SEQ ID NO. 79) NDS-014-21 (SEQ ID NO. 21 and SEQ ID NO. 80) NDS-014-23 (SEQ ID NO. 23 and SEQ ID NO. 82) NDS-014-29 (SEQ ID NO. 29 and SEQ ID NO. 88) NDS-014-38 (SEQ ID NO. 38 and SEQ ID NO. 97) NDS-014-39 (SEQ ID NO. 39 and SEQ ID NO. 98) NDS-014-40 (SEQ ID NO. 40 and SEQ ID NO. 99) NDS-014-44 (SEQ ID NO. 44 and SEQ ID NO. 103) NDS-014-50 (SEQ ID NO. 50 and SEQ ID NO. 109) NDS-014-55 (SEQ ID NO. 55 and SEQ ID NO. 114).
6. The siRNA duplex according to any one of claims 1 to 5, characterized in that The sense strand and antisense strand are selected from any of the following duplex nucleotide sequences: NDS-014-3 (SEQ ID NO. 3 and SEQ ID NO. 62) NDS-014-4 (SEQ ID NO. 4 and SEQ ID NO. 63) NDS-014-5 (SEQ ID NO. 5 and SEQ ID NO. 64) NDS-014-6 (SEQ ID NO. 6 and SEQ ID NO. 65) NDS-014-7 (SEQ ID NO. 7 and SEQ ID NO. 66) NDS-014-8 (SEQ ID NO. 8 and SEQ ID NO. 67) NDS-014-9 (SEQ ID NO. 9 and SEQ ID NO. 68) NDS-014-12 (SEQ ID NO. 12 and SEQ ID NO. 71) NDS-014-15 (SEQ ID NO. 15 and SEQ ID NO. 74) NDS-014-16 (SEQ ID NO. 16 and SEQ ID NO. 75) NDS-014-18 (SEQ ID NO. 18 and SEQ ID NO. 77) NDS-014-20 (SEQ ID NO. 20 and SEQ ID NO. 79) NDS-014-21 (SEQ ID NO. 21 and SEQ ID NO. 80) NDS-014-23 (SEQ ID NO. 23 and SEQ ID NO. 82) NDS-014-29 (SEQ ID NO. 29 and SEQ ID NO. 88) NDS-014-38 (SEQ ID NO. 38 and SEQ ID NO. 97) NDS-014-39 (SEQ ID NO. 39 and SEQ ID NO. 98) NDS-014-40 (SEQ ID NO. 40 and SEQ ID NO. 99) NDS-014-44 (SEQ ID NO. 44 and SEQ ID NO. 103) NDS-014-50 (SEQ ID NO. 50 and SEQ ID NO. 109) NDS-014-55 (SEQ ID NO. 55 and SEQ ID NO. 114).
7. The siRNA duplex according to any one of claims 1 to 6, wherein The siRNA duplex comprises at least one modified nucleotide.
8. The siRNA duplex according to any one of claims 1 to 7, wherein Substantially all nucleotides of the sense strand and substantially all nucleotides of the antisense strand comprise modifications.
9. The siRNA duplex according to any one of claims 1 to 7, wherein All nucleotides of the sense strand and all nucleotides of the antisense strand contain modifications.
10. The siRNA duplex according to any one of claims 7 to 9, characterized in that the modified nucleotides are selected from at least one of phosphodiester linker modification, ribosyl modification and base modification, or any combination of these three types of modifications.
11. The siRNA duplex according to claim 10, characterized in that The modification of the phosphodiester linker in the modified nucleotide is selected from one of the following general formula I: Wherein, X=O or S, preferably O R 1 Optional: OH, SH, BH 3+ ,NHCH2CH2NMe2,NHS(O)2R 2 , (R 2 is a C1-C4 alkyl), OCH2CH2SC(O)t-But, etc., wherein t-But is a tert-butyl group. Preferably, OH or SH is used.
12. The siRNA duplex according to claim 10, characterized in that The ribose modification in the modified nucleotide is selected from one of the following general formula II and general formula III: Wherein, X=O or S, preferably O Y is optionally H, OH, F, OCH3, OCH2OCH2CH3, OCH2SCH3, OCH2CH2CONHR 3 (R 3 is H, or a C1-C3 alkyl), etc.; preferably H, F, or OMe. PA is the general formula I as described in claim 11, preferably a phosphodiester linker or a thiophosphate diester linker. Bx is a base.
13. The siRNA duplex according to claim 10, characterized in that In the modified nucleotide, Bx is a conventional base or an unconventional base. The conventional nucleoside bases are adenine, guanine, cytosine, uracil and thymine; the unconventional bases are unconventional purine, pyrimidine or nitrogen-containing heterocyclic bases other than conventional nucleoside bases. The unconventional bases are preferably selected from one of the following nitrogen-containing heterocyclics:
14. The siRNA duplex according to any one of claims 10 to 13, characterized in that All nucleotides in the sense strand and / or the antisense strand are independently optionally modified nucleotides.
15. The siRNA duplex according to any one of claims 10 to 14, characterized in that The ribose modification of the modified nucleotide is independently selected from position 2 or position 3 of the ribose group: 2'-O-methyl modified nucleotide, 3'-O-methyl modified nucleotide, 2'-fluoro modified nucleotide, 3'-fluoro modified nucleotide, 2'-deoxy nucleotide, 3'-deoxy nucleotide; optionally, the phosphodiester linker modification of the modified nucleotide can be independently a 5'-phosphothioate diester linker.
16. The siRNA duplex according to claim 15, wherein The modification of the ribose group of the modified nucleotide is 2'-O-methyl or 2'-fluoro modification or 2'-deoxy modification.
17. The siRNA duplex according to claim 16, wherein The nucleotides at the 5'-end of the sense strand are 2'-fluoro-modified nucleotides at positions 9, 10 and 11 of the starting point, and the remaining positions are 2'-O-methyl-modified nucleotides; and / or The nucleotides at the 5'-end of the antisense strand are 2'-fluoro-modified nucleotides at the 2nd, 6th, 14th and 16th positions at the starting point, and the remaining positions are 2'-O-methyl-modified nucleotides.
18. The siRNA duplex according to claim 15, wherein The ribose modification of the nucleotides at positions 5 to 8 starting from the 5'-end of the siRNA antisense strand can be 3'-methoxy or 3'-fluoro or 3'-deoxy, preferably nucleotide modification at position 7. For this purpose, the phosphodiester linkage is a 2',5'-phosphodiester linkage as shown in general formula (III).
19. The siRNA duplex according to any one of claims 10 to 18, characterized in that The 5'-modified nucleotide at the first nucleotide starting point of the 5'-terminal nucleotide of the siRNA sense strand can be optionally one of the general formula (IV): Wherein, X=O or S, preferably O; Y is optionally H, OH, F, OCH3, OCH2OCH2CH3, OCH2SCH3, OCH2CH2CONHR 3 (R 3 is H, or a C1-C3 alkyl), etc.; preferably H, F or OMe; PA is the general formula (I) according to claim 11, preferably a phosphodiester linker or a thiophosphodiester linker, Bx is the base according to claim 13; R 4 is hydroxyl or one of the following optional groups: Among them, R 5 is H, F, Cl, Br, or a C1-C3 alkyl or alkoxy substituent; Preferably:
20. The siRNA duplex according to any one of claims 10 to 19, characterized in that The first nucleotide at the 5'-terminus of the antisense strand of the siRNA can be optionally 5'-unmodified, or a nucleotide (VP) modified as follows: Preferably: More preferably: Wherein, X=O or S, preferably O; Y is optionally H, OH, F, OCH3, OCH2OCH2CH3, OCH2SCH3, OCH2CH2CONHR 3 (R 3 is H, or a C1-C3 alkyl), etc.; preferably H, F or OMe.
21. The siRNA duplex according to any one of claims 10 to 20, characterized in that The siRNA duplex sense strand and antisense strand include the following optional combinations of one or more groups of different types of modifications: 2'-O-methyl modified nucleotides : aM, gM, cM and uM are 2'-O-Me A, 2'-O-Me G, 2'-O-Me C and 2'-O-Me U, respectively; 2'-Fluoro-modified nucleotides : aF, gF, cF and uF are 2'-fluoro A, 2'-fluoro C, 2'-fluoro G and 2'-fluoro U, respectively; 2'-deoxy modified nucleotides: 2'-deoxycytidine-3'-phosphate, 2'-deoxyguanosine-3'-phosphate, 2'-deoxyadenosine-3'-phosphate, 2'-deoxyuridine-3'-phosphate; 5'-(1,2,4)-Triazole-modified nucleotides : cTA4, gTA4, aTA4, uTA4 are 2'-O-methyl-5'-deoxy-(1-(1,2,4-triazole))-cytidine-3'-phosphate, 2'-O-methyl-5'-deoxy-(1-(1,2,4-triazole))-guanosine-3'-phosphate, 2'-O-methyl-5'-deoxy-(1-(1,2,4-triazole))-adenosine-3'-phosphate, 2'-O-methyl-5'-deoxy-(1-(1,2,4-triazole))-uridine-3'-phosphate, respectively; 5'-Thiomorpholine-modified nucleotides : cSMP, gSMP, aSMP, and uSMP are 2'-O-methyl-5'-N-(thiomorpholino)-cytidine-3'-phosphate, 2'-O-methyl-5'-N-(thiomorpholino)-guanosine-3'-phosphate, 2'-O-methyl-5'-N-(thiomorpholino)-adenosine-3'-phosphate, and 2'-O-methyl-5'-N-(thiomorpholino)-uridine-3'-phosphate, respectively; 3'-Fluoro-modified nucleotides : cRF, gRF, aRF, uRF are 3'-fluoro-3'-deoxycytidine-2'-phosphate, 3'-fluoro-3'-deoxyguanosine-2'-phosphate, 3'-fluoro-3'-deoxyadenosine-2'-phosphate, 3'-fluoro-3'-deoxyuridine-2'-phosphate, respectively; cXF, gXF, aXF, uXF are 3'-fluoro-3'-deoxycytidine xylosyl-2'-phosphate, 3'-fluoro-3'-deoxyguanine xylosyl-2'-phosphate, 3'-fluoro-3'-deoxyadenine xylosyl-2'-phosphate, 3'-fluoro-3'-deoxyuridine xylosyl-2'-phosphate, respectively; 3'-deoxy modified nucleotides : 3'-deoxycytidine-2'-phosphate, 3'-deoxyguanosine-2'-phosphate, 3'-deoxyadenosine-2'-phosphate, 3'-deoxyuridine-2'-phosphate; 5'-phosphothioate diester-linked or methylphosphonate nucleotides ； Nucleotides with unconventional bases ； 5'-trans-vinylphosphonate (E-VP) modified nucleotides.
22. The siRNA duplex according to any one of claims 1 to 21, wherein The length of each strand of the siRNA molecule is independently no more than 30 nucleotides.
23. The siRNA duplex of claim 22, wherein: The length of the siRNA double strand is 19-23 nucleotides.
24. The siRNA duplex of claim 23, wherein: The length of the siRNA double-stranded region can be 21 nucleotides.
25. The siRNA duplex of claim 23, wherein: At least one strand of the siRNA comprises a 3'-overhang of at least 1 nucleotide.
26. The siRNA duplex of claim 23, wherein: At least one strand of the siRNA comprises a 3'-overhang of at least 2 nucleotides.
27. The siRNA duplex according to any one of claims 1 to 26, wherein The siRNA duplex further comprises at least one 5'-phosphothioate diester or methylphosphonate nucleotide linkage.
28. The siRNA duplex of claim 27, wherein The 5'-phosphorothioate diester or methylphosphonate nucleotide is linked to the 3'-end of one chain.
29. The siRNA duplex of claim 28, wherein The strand is the antisense strand.
30. The siRNA duplex of claim 28, wherein The strand described is the sense strand.
31. The siRNA duplex of claim 27, wherein the 5'-phosphorothioate diester or methylphosphonate nucleotide is linked to the 5'-end of one strand.
32. The siRNA duplex of claim 31, wherein The strand is the antisense strand.
33. The siRNA duplex of claim 31, wherein The strand described is the sense strand.
34. The siRNA duplex of claim 27, wherein the 5'-phosphorothioate diester or methylphosphonate nucleotides are linked at the 5'-end and the 3'-end of one strand.
35. The siRNA duplex of claim 34, wherein: The strand is the antisense strand.
36. The siRNA duplex according to any one of claims 1 to 35, wherein The first base pair at the 5′-end of the antisense strand of the siRNA duplex is an A:U base pair or an A:I base pair, wherein I is inosine.
37. The siRNA duplex according to any one of claims 7 to 36, wherein The siRNA antisense strand comprises any antisense strand nucleotide sequence of a chemically modified duplex selected from the following: NPD014s-AD003 (SEQ ID NO.121 and SEQ ID NO.360) NPD014s-AD004 (SEQ ID NO.122 and SEQ ID NO.361) NPD014s-AD005 (SEQ ID NO.123 and SEQ ID NO.362) NPD014s-AD006 (SEQ ID NO.124 and SEQ ID NO.363) NPD014s-AD007 (SEQ ID NO.125 and SEQ ID NO.364) NPD014s-AD008 (SEQ ID NO.126 and SEQ ID NO.365) NPD014s-AD009 (SEQ ID NO.127 and SEQ ID NO.366) NPD014s-AD012 (SEQ ID NO.130 and SEQ ID NO.367) NPD014s-AD015 (SEQ ID NO.133 and SEQ ID NO.368) NPD014s-AD016 (SEQ ID NO.134 and SEQ ID NO.369) NPD014s-AD018 (SEQ ID NO.136 and SEQ ID NO.370) NPD014s-AD020 (SEQ ID NO.138 and SEQ ID NO.371) NPD014s-AD021 (SEQ ID NO.139 and SEQ ID NO.372) NPD014s-AD023 (SEQ ID NO.141 and SEQ ID NO.373) NPD014s-AD029 (SEQ ID NO.147 and SEQ ID NO.374) NPD014s-AD038 (SEQ ID NO.156 and SEQ ID NO.375) NPD014s-AD039 (SEQ ID NO.157 and SEQ ID NO.376) NPD014s-AD040 (SEQ ID NO.158 and SEQ ID NO.377) NPD014s-AD044 (SEQ ID NO.162 and SEQ ID NO.378) NPD014s-AD050 (SEQ ID NO.168 and SEQ ID NO.379) NPD014s-AD055 (SEQ ID NO.173 and SEQ ID NO.380) NPD014s-AD060 (SEQ ID NO.178 and SEQ ID NO.381) NPD014s-AD061 (SEQ ID NO.179 and SEQ ID NO.382) NPD014s-AD063 (SEQ ID NO.181 and SEQ ID NO.383) NO.384)NPD014s-AD064 (SEQ ID NO.182 and SEQ ID NO.385)NPD014s-AD066 (SEQ ID NO.184 and SEQ ID NO.387)NPD014s-AD067 (SEQ ID NO.185 and SEQ ID NO.388)NPD014s-AD068 (SEQ ID NO.186 and SEQ ID NO.389)NPD014s-AD069 (SEQ ID NO.187 and SEQ ID NO.390)NPD014s-AD070 (SEQ ID NO.188 and SEQ ID NO.391)NPD014s-AD072 (SEQ ID NO.190 and SEQ ID NO.393)NPD014s-AD075 (SEQ ID NO.193 and SEQ ID NO.396)NPD014s-AD076 (SEQ ID NO.197 and SEQ ID NO.398) NO.194 and SEQ ID NO.397) NPD014s-AD077 (SEQ ID NO.195 and SEQ ID NO.398) NPD014s-AD078 (SEQ ID NO.196 and SEQ ID NO.399) NPD014s-AD081 (SEQ ID NO.199 and SEQ ID NO.402) NPD014s-AD082 (SEQ ID NO.200 and SEQ ID NO.403) NPD014s-AD083 (SEQ ID NO.201 and SEQ ID NO.404) NPD014s-AD084 (SEQ ID NO.202 and SEQ ID NO.405) NPD014s-AD085 (SEQ ID NO.203 and SEQ ID NO.406) NPD014s-AD086 (SEQ ID NO.204 and SEQ ID NO.407) NPD014s-AD087 (SEQ ID NO.205 and SEQ ID NO.408) NPD014s-AD088 (SEQ ID NO.206 and SEQ ID NO.409) NPD014s-AD089 (SEQ ID NO.207 and SEQ ID NO.410) NPD014s-AD090 (SEQ ID NO.208 and SEQ ID NO.411) NPD014s-AD091 (SEQ ID NO.209 and SEQ ID NO.412) NPD014s-AD092 (SEQ ID NO.210 and SEQ ID NO.413) NPD014s-AD093 (SEQ ID NO.214 and SEQ ID NO.415) NO.211 and SEQ ID NO.414) NPD014s-AD094 (SEQ ID NO.212 and SEQ ID NO.415) NPD014s-AD095 (SEQ ID NO.213 and SEQ ID NO.416) NPD014s-AD096 (SEQ ID NO.214 and SEQ ID NO.417) NPD014s-AD097 (SEQ ID NO.215 and SEQ ID NO.418) NPD014s-AD098 (SEQ ID NO.216 and SEQ ID NO.419) NPD014s-AD099 (SEQ ID NO.217 and SEQ ID NO.420) NPD014s-AD100 (SEQ ID NO.218 and SEQ ID NO.421) NPD014s-AD101 (SEQ ID NO.219 and SEQ ID NO. NO.422) NPD014s-AD102 (SEQ ID NO.220 and SEQ ID NO.423) NPD014s-AD103 (SEQ ID NO.221 and SEQ ID NO.424) NPD014s-AD104 (SEQ ID NO.222 and SEQ ID NO.425) NPD014s-AD105 (SEQ ID NO.223 and SEQ ID NO.426) NPD014s-AD106 (SEQ ID NO.224 and SEQ ID NO.427) NPD014s-AD107 (SEQ ID NO.225 and SEQ ID NO.428) NPD014s-AD108 (SEQ ID NO.226 and SEQ ID NO.429) NPD014s-AD109 (SEQ ID NO.227 and SEQ ID NO.430) NPD014s-AD110 (SEQ ID NO.228 and SEQ ID NO.431) NPD014s-AD111 (SEQ ID NO.229 and SEQ ID NO.432) NPD014s-AD112 (SEQ ID NO.230 and SEQ ID NO.433) NPD014s-AD113 (SEQ ID NO.231 and SEQ ID NO.434) NPD014s-AD114 (SEQ ID NO.232 and SEQ ID NO.435) NPD014s-AD115 (SEQ ID NO.233 and SEQ ID NO.436) NPD014s-AD116 (SEQ ID NO.234 and SEQ ID NO.437) NPD014s-AD117 (SEQ ID NO.238 and SEQ ID NO.439) NO.235 and SEQ ID NO.438) NPD014s-AD118 (SEQ ID NO.236 and SEQ ID NO.439) NPD014s-AD119 (SEQ ID NO.237 and SEQ ID NO.440) NPD014s-AD120 (SEQ ID NO.238 and SEQ ID NO.441) NPD014s-AD121 (SEQ ID NO.239 and SEQ ID NO.442) NPD014s-AD122 (SEQ ID NO.240 and SEQ ID NO.443) NPD014s-AD123 (SEQ ID NO.241 and SEQ ID NO.444) NPD014s-AD124 (SEQ ID NO.242 and SEQ ID NO.445) NPD014s-AD125 (SEQ ID NO.243 and SEQ ID NO. NO.446) NPD014s-AD126 (SEQ ID NO.244 and SEQ ID NO.447) NPD014s-AD127 (SEQ ID NO.245 and SEQ ID NO.448) NPD014s-AD128 (SEQ ID NO.246 and SEQ ID NO.449) NPD014s-AD129 (SEQ ID NO.247 and SEQ ID NO.450) NPD014s-AD130 (SEQ ID NO.248 and SEQ ID NO.451) NPD014s-AD131 (SEQ ID NO.249 and SEQ ID NO.452) NPD014s-AD132 (SEQ ID NO.250 and SEQ ID NO.453) NPD014s-AD133 (SEQ ID NO.251 and SEQ ID NO.454) NPD014s-AD134 (SEQ ID NO.252 and SEQ ID NO.455) NPD014s-AD135 (SEQ ID NO.253 and SEQ ID NO.456) NPD014s-AD136 (SEQ ID NO.254 and SEQ ID NO.457) NPD014s-AD137 (SEQ ID NO.255 and SEQ ID NO.458) NPD014s-AD138 (SEQ ID NO.256 and SEQ ID NO.459) NPD014s-AD139 (SEQ ID NO.257 and SEQ ID NO.460) NPD014s-AD140 (SEQ ID NO.258 and SEQ ID NO.461) NPD014s-AD141 (SEQ ID NO.254 and SEQ ID NO.457) NO.259 and SEQ ID NO.462) NPD014s-AD142 (SEQ ID NO.260 and SEQ ID NO.463) NPD014s-AD143 (SEQ ID NO.261 and SEQ ID NO.464) NPD014s-AD144 (SEQ ID NO.262 and SEQ ID NO.465) NPD014s-AD145 (SEQ ID NO.263 and SEQ ID NO.466) NPD014s-AD146 (SEQ ID NO.264 and SEQ ID NO.467) NPD014s-AD147 (SEQ ID NO.265 and SEQ ID NO.468) NPD014s-AD148 (SEQ ID NO.266 and SEQ ID NO.469) NPD014s-AD149 (SEQ ID NO.267 and SEQ ID NO. NO.470) NPD014s-AD150 (SEQ ID NO.268 and SEQ ID NO.471) NPD014s-AD151 (SEQ ID NO.269 and SEQ ID NO.472) NPD014s-AD152 (SEQ ID NO.270 and SEQ ID NO.473) NPD014s-AD153 (SEQ ID NO.271 and SEQ ID NO.474) NPD014s-AD154 (SEQ ID NO.272 and SEQ ID NO.475) NPD014s-AD155 (SEQID NO.273 and SEQ ID NO.476) NPD014s-AD156 (SEQ ID NO.274 and SEQ ID NO.477) NPD014s-AD157 (SEQ ID NO.275 and SEQ ID NO.478) NPD014s-AD158 (SEQ ID NO.276 and SEQ ID NO.479) NPD014s-AD159 (SEQ ID NO.277 and SEQ ID NO.480) NPD014s-AD160 (SEQ ID NO.278 and SEQ ID NO.481) NPD014s-AD161 (SEQ ID NO.279 and SEQ ID NO.482) NPD014s-AD162 (SEQ ID NO.280 and SEQ ID NO.483) NPD014s-AD163 (SEQ ID NO.281 and SEQ ID NO.484) NPD014s-AD164 (SEQ ID NO.282 and SEQ ID NO.485) NPD014s-AD165 (SEQ ID NO. NO.283 and SEQ ID NO.486) NPD014s-AD166 (SEQ ID NO.284 and SEQ ID NO.487) NPD014s-AD167 (SEQ ID NO.285 and SEQ ID NO.488) NPD014s-AD168 (SEQ ID NO.286 and SEQ ID NO.489) NPD014s-AD169 (SEQ ID NO.287 and SEQ ID NO.490) NPD014s-AD170 (SEQ ID NO.288 and SEQ ID NO.491) NPD014s-AD171 (SEQ ID NO.289 and SEQ ID NO.492) NPD014s-AD172 (SEQ ID NO.290 and SEQ ID NO.493) NPD014s-AD173 (SEQ ID NO.291 and SEQ ID NO. NO.494) NPD014s-AD174 (SEQ ID NO.292 and SEQ ID NO.495) NPD014s-AD175 (SEQ ID NO.293 and SEQ ID NO.496) NPD014s-AD176 (SEQ ID NO.294 and SEQ ID NO.497) NPD014s-AD177 (SEQ ID NO.295 and SEQ ID NO.498) NPD014s-AD178 (SEQ ID NO.296 and SEQ ID NO.499) NPD014s-AD179 (SEQ ID NO.297 and SEQ ID NO.500) NPD014s-AD180 (SEQ ID NO.298 and SEQ ID NO.501) NPD014s-AD181 (SEQ ID NO.299 and SEQ ID NO.502) NPD014s-AD182 (SEQ ID NO.300 and SEQ ID NO.503) NPD014s-AD183 (SEQ ID NO.301 and SEQ ID NO.504) NPD014s-AD184 (SEQ ID NO.302 and SEQ ID NO.505) NPD014s-AD185 (SEQ ID NO.303 and SEQ ID NO.506) NPD014s-AD186 (SEQ ID NO.304 and SEQ ID NO.507) NPD014s-AD187 (SEQ ID NO.305 and SEQ ID NO.508) NPD014s-AD188 (SEQ ID NO.306 and SEQ ID NO.509) NPD014s-AD189 (SEQ ID NO.301 and SEQ ID NO.504) 514) NPD014s-AD195 (SEQ ID NO.313 and SEQ ID NO.516) NPD014s-AD196 (SEQ ID NO.314 and SEQ ID NO.517) NPD014s-AD197 (SEQ ID NO.315 and SEQ ID NO.518) NO.518) NPD014s-AD198 (SEQ ID NO.316 and SEQ ID NO.519) NPD014s-AD199 (SEQ ID NO.317 and SEQ ID NO.520) NPD014s-AD200 (SEQ ID NO.318 and SEQ ID NO.521) NPD014s-AD201 (SEQ ID NO.319 and SEQ ID NO.522) NPD014s-AD202 (SEQ ID NO.320 and SEQ ID NO.523) NPD014s-AD203 (SEQ ID NO.321 and SEQ ID NO.524) NPD014s-AD204 (SEQ ID NO.322 and SEQ ID NO.525) NPD014s-AD205 (SEQ ID NO.323 and SEQ ID NO.526) NPD014s-AD206 (SEQ ID NO.324 and SEQ ID NO.527) NPD014s-AD207 (SEQ ID NO.325 and SEQ ID NO.528) NPD014s-AD208 (SEQ ID NO.326 and SEQ ID NO.529). NPD014s-AD209 (SEQ ID NO.327 and SEQ ID NO.530) NPD014s-AD210 (SEQ ID NO.328 and SEQ ID NO.531) NPD014s-AD211 (SEQ ID NO.329 and SEQ ID NO.532) NPD014s-AD212 (SEQ ID NO.330 and SEQ ID NO.533) NPD014s-AD213 (SEQ ID NO.331 and SEQ ID NO.534) NPD014s-AD214 (SEQ ID NO.332 and SEQ ID NO.535) NPD014s-AD215 (SEQ ID NO.333 and SEQ ID NO.536) NPD014s-AD216 (SEQ ID NO.334 and SEQ ID NO.537) NPD014s-AD217 (SEQ ID NO.335 and SEQ ID NO.538) NPD014s-AD218 (SEQ ID NO.336 and SEQ ID NO.539) NPD014s-AD219 (SEQ ID NO.337 and SEQ ID NO.540) NPD014s-AD220 (SEQ ID NO.338 and SEQ ID NO.541) NPD014s-AD221 (SEQ ID NO.339 and SEQ ID NO.542) NPD014s-AD222 (SEQ ID NO.340 and SEQ ID NO.543) NPD014s-AD223 (SEQ ID NO.341 and SEQ ID NO.544) NPD014s-AD224 (SEQ ID NO.342 and SEQ ID NO.545) NPD014s-AD225 (SEQ ID NO.343 and SEQ ID NO.546) NPD014s-AD226 (SEQ ID NO.344 and SEQ ID NO.547) NPD014s-AD227 (SEQ ID NO.345 and SEQ ID NO.548) NPD014s-AD228 (SEQ ID NO.346 and SEQ ID NO.549) NPD014s-AD229 (SEQ ID NO.347 and SEQ ID NO.550) NPD014s-AD230 (SEQ ID NO.348 and SEQ ID NO.551) NPD014s-AD231 (SEQ ID NO.349 and SEQ ID NO.552) NPD014s-AD232 (SEQ ID NO.350 and SEQ ID NO.553) NPD014s-AD233 (SEQ ID NO.351 and SEQ ID NO.554) NPD014s-AD234 (SEQ ID NO.352 and SEQ ID NO.555) NPD014s-AD235 (SEQ ID NO.353 and SEQ ID NO.556) NPD014s-AD236 (SEQ ID NO.354 and SEQ ID NO.557) NPD014s-AD237 (SEQ ID NO.355 and SEQ ID NO.558) NPD014s-AD238 (SEQ ID NO.356 and SEQ ID NO.559) NPD014s-AD239 (SEQ ID NO.357 and SEQ ID NO.560) NPD014s-AD240 (SEQ ID NO.358 and SEQ ID NO.561) NPD014s-AD241 (SEQ ID NO. 359 and SEQ ID NO. 562).
38. The siRNA duplex according to any one of claims 7 to 36, wherein The siRNA sense strand comprises any sense strand nucleotide sequence of a chemically modified duplex selected from the following: NPD014s-AD003 (SEQ ID NO.121 and SEQ ID NO.360) NPD014s-AD004 (SEQ ID NO.122 and SEQ ID NO.361) NPD014s-AD005 (SEQ ID NO.123 and SEQ ID NO.362) NPD014s-AD006 (SEQ ID NO.124 and SEQ ID NO.363) NPD014s-AD007 (SEQ ID NO.125 and SEQ ID NO.364) NPD014s-AD008 (SEQ ID NO.126 and SEQ ID NO.365) NPD014s-AD009 (SEQ ID NO.127 and SEQ ID NO.366) NPD014s-AD012 (SEQ ID NO.130 and SEQ ID NO.367) NPD014s-AD015 (SEQ ID NO.133 and SEQ ID NO.368) NPD014s-AD016 (SEQ ID NO.134 and SEQ ID NO.369) NPD014s-AD018 (SEQ ID NO.136 and SEQ ID NO.369) NO.370)NPD014s-AD020 (SEQ ID NO.138 and SEQ ID NO.371)NPD014s-AD021 (SEQ ID NO.139 and SEQ ID NO.372)NPD014s-AD023 (SEQ ID NO.141 and SEQ ID NO.373)NPD014s-AD029 (SEQ ID NO.147 and SEQ ID NO.374)NPD014s-AD038 (SEQ ID NO.156 and SEQ ID NO.375)NPD014s-AD039 (SEQ ID NO.157 and SEQ ID NO.376)NPD014s-AD040 (SEQ ID NO.158 and SEQ ID NO.377)NPD014s-AD044 (SEQ ID NO.162 and SEQ ID NO.378)NPD014s-AD050 (SEQ ID NO.163 and SEQ ID NO.379) NO.168 and SEQ ID NO.379) NPD014s-AD055 (SEQ ID NO.173 and SEQ ID NO.380) NPD014s-AD060 (SEQ ID NO.178 and SEQ ID NO.381) NPD014s-AD061 (SEQ ID NO.179 and SEQ ID NO.382) NPD014s-AD063 (SEQ ID NO.181 and SEQ ID NO.384) NPD014s-AD064 (SEQ ID NO.182 and SEQ ID NO.385) NPD014s-AD066 (SEQ ID NO.184 and SEQ ID NO.387) NPD014s-AD067 (SEQ ID NO.185 and SEQ ID NO.388) NPD014s-AD068 (SEQ ID NO.186 and SEQ ID NO.389) NPD014s-AD069 (SEQ ID NO.187 and SEQ ID NO.390) NPD014s-AD070 (SEQ ID NO.188 and SEQ ID NO.391) NPD014s-AD072 (SEQ ID NO.190 and SEQ ID NO.393) NPD014s-AD075 (SEQ ID NO.193 and SEQ ID NO.396) NPD014s-AD076 (SEQ ID NO.194 and SEQ ID NO.397) NPD014s-AD077 (SEQ ID NO.195 and SEQ ID NO.398) NPD014s-AD078 (SEQ ID NO.196 and SEQ ID NO.399) NO.196 and SEQ ID NO.399) NPD014s-AD081 (SEQ ID NO.199 and SEQ ID NO.402) NPD014s-AD082 (SEQ ID NO.200 and SEQ ID NO.403) NPD014s-AD083 (SEQ ID NO.201 and SEQ ID NO.404) NPD014s-AD084 (SEQ ID NO.202 and SEQ ID NO.405) NPD014s-AD085 (SEQ ID NO.203 and SEQ ID NO.406) NPD014s-AD086 (SEQ ID NO.204 and SEQ ID NO.407) NPD014s-AD087 (SEQ ID NO.205 and SEQ ID NO.408) NPD014s-AD088 (SEQ ID NO.206 and SEQ ID NO. NO.409) NPD014s-AD089 (SEQ ID NO.207 and SEQ ID NO.410) NPD014s-AD090 (SEQ ID NO.208 and SEQ ID NO.411) NPD014s-AD091 (SEQ ID NO.209 and SEQ ID NO.412) NPD014s-AD092 (SEQ ID NO.210 and SEQ ID NO.413) NPD014s-AD093 (SEQID NO.211 and SEQ ID NO.414) NPD014s-AD094 (SEQ ID NO.212 and SEQ ID NO.415) NPD014s-AD095 (SEQ ID NO.213 and SEQ ID NO.416) NPD014s-AD096 (SEQ ID NO.214 and SEQ ID NO.417) NPD014s-AD097 (SEQ ID NO.215 and SEQ ID NO.418) NPD014s-AD098 (SEQ ID NO.216 and SEQ ID NO.419) NPD014s-AD099 (SEQ ID NO.217 and SEQ ID NO.420) NPD014s-AD100 (SEQ ID NO.218 and SEQ ID NO.421) NPD014s-AD101 (SEQ ID NO.219 and SEQ ID NO.422) NPD014s-AD102 (SEQ ID NO.220 and SEQ ID NO.423) NPD014s-AD103 (SEQ ID NO.221 and SEQ ID NO.424) NPD014s-AD104 (SEQ ID NO.225 and SEQ ID NO.426) 422 and SEQ ID NO.425) NPD014s-AD105 (SEQ ID NO.223 and SEQ ID NO.426) NPD014s-AD106 (SEQ ID NO.224 and SEQ ID NO.427) NPD014s-AD107 (SEQ ID NO.225 and SEQ ID NO.428) NPD014s-AD108 (SEQ ID NO.226 and SEQ ID NO.429) NPD014s-AD109 (SEQ ID NO.227 and SEQ ID NO.430) NPD014s-AD110 (SEQ ID NO.228 and SEQ ID NO.431) NPD014s-AD111 (SEQ ID NO.229 and SEQ ID NO.432) NPD014s-AD112 (SEQ ID NO.230 and SEQ ID NO. NO.433) NPD014s-AD113 (SEQ ID NO.231 and SEQ ID NO.434) NPD014s-AD114 (SEQ ID NO.232 and SEQ ID NO.435) NPD014s-AD115 (SEQ ID NO.233 and SEQ ID NO.436) NPD014s-AD116 (SEQ ID NO.234 and SEQ ID NO.437) NPD014s-AD117 (SEQ ID NO.235 and SEQ ID NO.438) NPD014s-AD118 (SEQ ID NO.236 and SEQ ID NO.439) NPD014s-AD119 (SEQ ID NO.237 and SEQ ID NO.440) NPD014s-AD120 (SEQ ID NO.238 and SEQ ID NO.441) NPD014s-AD121 (SEQ ID NO.239 and SEQ ID NO.442) NPD014s-AD122 (SEQ ID NO.240 and SEQ ID NO.443) NPD014s-AD123 (SEQ ID NO.241 and SEQ ID NO.444) NPD014s-AD124 (SEQ ID NO.242 and SEQ ID NO.445) NPD014s-AD125 (SEQ ID NO.243 and SEQ ID NO.446) NPD014s-AD126 (SEQ ID NO.244 and SEQ ID NO.447) NPD014s-AD127 (SEQ ID NO.245 and SEQ ID NO.448) NPD014s-AD128 (SEQ ID NO.249 and SEQ ID NO.450) NO.246 and SEQ ID NO.449) NPD014s-AD129 (SEQ ID NO.247 and SEQ ID NO.450) NPD014s-AD130 (SEQ ID NO.248 and SEQ ID NO.451) NPD014s-AD131 (SEQ ID NO.249 and SEQ ID NO.452) NPD014s-AD132 (SEQ ID NO.250 and SEQ ID NO.453) NPD014s-AD133 (SEQ ID NO.251 and SEQ ID NO.454) NPD014s-AD134 (SEQ ID NO.252 and SEQ ID NO.455) NPD014s-AD135 (SEQID NO.253 and SEQ ID NO.456) NPD014s-AD136 (SEQ ID NO.254 and SEQ ID NO. NO.457) NPD014s-AD137 (SEQ ID NO.255 and SEQ ID NO.458) NPD014s-AD138 (SEQ ID NO.256 and SEQ ID NO.459) NPD014s-AD139 (SEQ ID NO.257 and SEQ ID NO.460) NPD014s-AD140 (SEQ ID NO.258 and SEQ ID NO.461) NPD014s-AD141 (SEQ ID NO.259 and SEQ ID NO.462) NPD014s-AD142 (SEQ ID NO.260 and SEQ ID NO.463) NPD014s-AD143 (SEQ ID NO.261 and SEQ ID NO.464) NPD014s-AD144 (SEQ ID NO.262 and SEQ ID NO.465) NPD014s-AD145 (SEQ ID NO.263 and SEQ ID NO.466) NPD014s-AD146 (SEQ ID NO.264 and SEQ ID NO.467) NPD014s-AD147 (SEQ ID NO.265 and SEQ ID NO.468) NPD014s-AD148 (SEQ ID NO.266 and SEQ ID NO.469) NPD014s-AD149 (SEQ ID NO.267 and SEQ ID NO.470) NPD014s-AD150 (SEQ ID NO.268 and SEQ ID NO.471) NPD014s-AD151 (SEQ ID NO.269 and SEQ ID NO.472) NPD014s-AD152 (SEQ ID NO.264 and SEQ ID NO.467) NO.270 and SEQ ID NO.473) NPD014s-AD153 (SEQ ID NO.271 and SEQ ID NO.474) NPD014s-AD154 (SEQ ID NO.272 and SEQ ID NO.475) NPD014s-AD155 (SEQ ID NO.273 and SEQ ID NO.476) NPD014s-AD156 (SEQ ID NO.274 and SEQ ID NO.477) NPD014s-AD157 (SEQ ID NO.275 and SEQ ID NO.478) NPD014s-AD158 (SEQ ID NO.276 and SEQ ID NO.479) NPD014s-AD159 (SEQ ID NO.277 and SEQ ID NO.480) NPD014s-AD160 (SEQ ID NO.278 and SEQ ID NO. NO.481) NPD014s-AD161 (SEQ ID NO.279 and SEQ ID NO.482) NPD014s-AD162 (SEQ ID NO.280 and SEQ ID NO.483) NPD014s-AD163 (SEQ ID NO.281 and SEQ ID NO.484) NPD014s-AD164 (SEQ ID NO.282 and SEQ ID NO.485) NPD014s-AD165 (SEQ ID NO.283 and SEQ ID NO.486) NPD014s-AD166 (SEQ ID NO.284 and SEQ ID NO.487) NPD014s-AD167 (SEQ ID NO.285 and SEQ ID NO.488) NPD014s-AD168 (SEQ ID NO.286 and SEQ ID NO.489) NPD014s-AD169 (SEQ ID NO.287 and SEQ ID NO.490) NPD014s-AD170 (SEQ ID NO.288 and SEQ ID NO.491) NPD014s-AD171 (SEQ ID NO.289 and SEQ ID NO.492) NPD014s-AD172 (SEQ ID NO.290 and SEQ ID NO.493) NPD014s-AD173 (SEQ ID NO.291 and SEQ ID NO.494) NPD014s-AD174 (SEQ ID NO.292 and SEQ ID NO.495) NPD014s-AD175 (SEQ ID NO.293 and SEQ ID NO.496) NPD014s-AD176 (SEQ ID NO.297 and SEQ ID NO.498) NO.294 and SEQ ID NO.497) NPD014s-AD177 (SEQ ID NO.295 and SEQ ID NO.498) NPD014s-AD178 (SEQ ID NO.296 and SEQ ID NO.499) NPD014s-AD179 (SEQ ID NO.297 and SEQ ID NO.500) NPD014s-AD180 (SEQ ID NO.298 and SEQ ID NO.501) NPD014s-AD181 (SEQ ID NO.299 and SEQ ID NO.502) NPD014s-AD182 (SEQ ID NO.300 and SEQ ID NO.503) NPD014s-AD183 (SEQ ID NO.301 and SEQ ID NO.504) NPD014s-AD184 (SEQ ID NO.302 and SEQ ID NO. NO.505) NPD014s-AD185 (SEQ ID NO.303 and SEQ ID NO.506) NPD014s-AD186 (SEQ ID NO.304 and SEQ ID NO.507) NPD014s-AD187 (SEQ ID NO.305 and SEQ ID NO.508) NPD014s-AD188 (SEQ ID NO.306 and SEQ ID NO.509) NPD014s-AD189 (SEQ ID NO.307 and SEQ ID NO.510) NPD014s-AD190 (SEQ ID NO.308 and SEQ ID NO.511) NPD014s-AD191 (SEQ ID NO.309 and SEQ ID NO.512) NPD014s-AD192 (SEQ ID NO.310 and SEQ ID NO.513) NPD014s-AD193 (SEQ ID NO.311 and SEQ ID NO.514) NPD014s-AD194 (SEQ ID NO.312 and SEQ ID NO.515) NPD014s-AD195 (SEQ ID NO.313 and SEQ ID NO.516) NPD014s-AD196 (SEQ ID NO.314 and SEQ ID NO.517) NPD014s-AD197 (SEQ ID NO.315 and SEQ ID NO.518) NPD014s-AD198 (SEQ ID NO.316 and SEQ ID NO.519) NPD014s-AD199 (SEQ ID NO.317 and SEQ ID NO.520) NPD014s-AD200 (SEQ ID NO.313 and SEQ ID NO.521) NO.318 and SEQ ID NO.521) NPD014s-AD201 (SEQ ID NO.319 and SEQ ID NO.522) NPD014s-AD202 (SEQ ID NO.320 and SEQ ID NO.523) NPD014s-AD203 (SEQ ID NO.321 and SEQ ID NO.524) NPD014s-AD204 (SEQ ID NO.322 and SEQ ID NO.525) NPD014s-AD205 (SEQID NO.323 and SEQ ID NO.526) NPD014s-AD206 (SEQ ID NO.324 and SEQ ID NO.527) NPD014s-AD207 (SEQ ID NO.325 and SEQ ID NO.528) NPD014s-AD208 (SEQ ID NO.326 and SEQ ID NO. ID NO.529) NPD014s-AD209 (SEQ ID NO.327 and SEQ ID NO.530) NPD014s-AD210 (SEQ ID NO.328 and SEQ ID NO.531) NPD014s-AD211 (SEQ ID NO.329 and SEQ ID NO.532) NPD014s-AD212 (SEQ ID NO.330 and SEQ ID NO.533) NPD014s-AD213 (SEQ ID NO.331 and SEQ ID NO.534) NPD014s-AD214 (SEQ ID NO.332 and SEQ ID NO.535) NPD014s-AD215 (SEQ ID NO.333 and SEQ ID NO.536) NPD014s-AD216 (SEQ ID NO.334 and SEQ ID NO.537) NPD014s-AD217 (SEQ ID NO.335 and SEQ ID NO.538) NPD014s-AD218 (SEQ ID NO.336 and SEQ ID NO.539) NPD014s-AD219 (SEQ ID NO.337 and SEQ ID NO.540) NPD014s-AD220 (SEQ ID NO.338 and SEQ ID NO.541) NPD014s-AD221 (SEQ ID NO.339 and SEQ ID NO.542) NPD014s-AD222 (SEQ ID NO.340 and SEQ ID NO.543) NPD014s-AD223 (SEQ ID NO.341 and SEQ ID NO.544) NPD014s-AD224 (SEQ ID NO.345 and SEQ ID NO.546) NO.342 and SEQ ID NO.545) NPD014s-AD225 (SEQ ID NO.343 and SEQ ID NO.546) NPD014s-AD226 (SEQ ID NO.344 and SEQ ID NO.547) NPD014s-AD227 (SEQ ID NO.345 and SEQ ID NO.548) NPD014s-AD228 (SEQ ID NO.346 and SEQ ID NO.549) NPD014s-AD229 (SEQ ID NO.347 and SEQ ID NO.550) NPD014s-AD230 (SEQ ID NO.348 and SEQ ID NO.551) NPD014s-AD231 (SEQ ID NO.349 and SEQ ID NO.552) NPD014s-AD232 (SEQ ID NO.350 and SEQ ID NO.553). NPD014s-AD233 (SEQ ID NO.351 and SEQ ID NO.554) NPD014s-AD234 (SEQ ID NO.352 and SEQ ID NO.555) NPD014s-AD235 (SEQ ID NO.353 and SEQ ID NO.556) NPD014s-AD236 (SEQ ID NO.354 and SEQ ID NO.557) NPD014s-AD237 (SEQ ID NO.355 and SEQ ID NO.558) NPD014s-AD238 (SEQ ID NO.356 and SEQ ID NO.559) NPD014s-AD239 (SEQ ID NO.357 and SEQ ID NO.560) NPD014s-AD240 (SEQ ID NO.358 and SEQ ID NO.561) NPD014s-AD241 (SEQ ID NO. 359 and SEQ ID NO. 562).
39. The siRNA duplex according to any one of claims 7 to 36, wherein The siRNA antisense strand and the sense strand comprise a chemically modified nucleotide sequence of a duplex selected from the following: NPD014s-AD003 (SEQ ID NO.121 and SEQ ID NO.360) NPD014s-AD004 (SEQ ID NO.122 and SEQ ID NO.361) NPD014s-AD005 (SEQ ID NO.123 and SEQ ID NO.362) NPD014s-AD006 (SEQ ID NO.124 and SEQ ID NO.363) NPD014s-AD007 (SEQ ID NO.125 and SEQ ID NO.364) NPD014s-AD008 (SEQ ID NO.126 and SEQ ID NO.365) NPD014s-AD009 (SEQ ID NO.127 and SEQ ID NO.366) NPD014s-AD012 (SEQ ID NO.130 and SEQ ID NO.367) NPD014s-AD015 (SEQ ID NO.133 and SEQ ID NO.368) NPD014s-AD016 (SEQ ID NO.134 and SEQ ID NO.369) NPD014s-AD018 (SEQ ID NO.136 and SEQ ID NO.370) NPD014s-AD020 (SEQ ID NO.138 and SEQ ID NO.371) NPD014s-AD021 (SEQ ID NO.139 and SEQ ID NO.372) NPD014s-AD023 (SEQ ID NO.141 and SEQ ID NO.373) NPD014s-AD029 (SEQ ID NO.147 and SEQ ID NO.374) NPD014s-AD038 (SEQ ID NO.156 and SEQ ID NO.375) NPD014s-AD039 (SEQ ID NO.157 and SEQ ID NO.376) NPD014s-AD040 (SEQ ID NO.158 and SEQ ID NO.377) NPD014s-AD044 (SEQ ID NO.162 and SEQ ID NO.378) NPD014s-AD050 (SEQ ID NO.168 and SEQ ID NO.379) NPD014s-AD055 (SEQ ID NO. 173 and SEQ ID NO. 380) NPD014s-AD060 (SEQ ID NO. 178 and SEQ ID NO. 381) NPD014s-AD061 (SEQ ID NO. 179 and SEQ ID NO. 382) NPD014s-AD063 (SEQ ID NO.181 and SEQ ID NO.384) NPD014s-AD064 (SEQ ID NO.182 and SEQ ID NO.385) NPD014s-AD066 (SEQ ID NO. 184 and SEQ ID NO. 387) NPD014s-AD067 (SEQ ID NO.185 and SEQ ID NO.388) NPD014s-AD068 (SEQ ID NO.186 and SEQ ID NO.389) NPD014s-AD069 (SEQ ID NO.187 and SEQ ID NO.390) NPD014s-AD070 (SEQ ID NO.188 and SEQ ID NO.391) NPD014s-AD072 (SEQ ID NO.190 and SEQ ID NO.393) NPD014s-AD075 (SEQ ID NO.193 and SEQ ID NO.396) NPD014s-AD076 (SEQ ID NO.194 and SEQ ID NO.397) NPD014s-AD077 (SEQ ID NO.195 and SEQ ID NO.398) NPD014s-AD078 (SEQ ID NO.196 and SEQ ID NO.399)NPD014s-AD081 (SEQ ID NO.199 and SEQ ID NO.402)NPD014s-AD082 (SEQ ID NO.200 and SEQ ID NO.403)NPD014s-AD083 (SEQ ID NO.201 and SEQ ID NO.404)NPD014s-AD084 (SEQ ID NO.202 and SEQ ID NO.405)NPD014s-AD085 (SEQ ID NO.203 and SEQ ID NO.406)NPD014s-AD086 (SEQ ID NO.204 and SEQ ID NO.407)NPD014s-AD087 (SEQ ID NO.205 and SEQ ID NO.408)NPD014s-AD088 (SEQ ID NO.206 and SEQ ID NO.409)NPD014s-AD089 (SEQ ID NO.201 and SEQ ID NO.404) NO.207 and SEQ ID NO.410) NPD014s-AD090 (SEQ ID NO.208 and SEQ ID NO.411) NPD014s-AD091 (SEQ ID NO.209 and SEQ ID NO.412) NPD014s-AD092 (SEQ ID NO.210 and SEQ ID NO.413) NPD014s-AD093 (SEQ ID NO.211 and SEQ ID NO.414) NPD014s-AD094 (SEQ ID NO.212 and SEQ ID NO.415) NPD014s-AD095 (SEQ ID NO.213 and SEQ ID NO.416) NPD014s-AD096 (SEQ ID NO.214 and SEQ ID NO.417) NPD014s-AD097 (SEQ ID NO.215 and SEQ ID NO.418) NPD014s-AD098 (SEQ ID NO.216 and SEQ ID NO.419) NPD014s-AD099 (SEQ ID NO.217 and SEQ ID NO.420) NPD014s-AD100 (SEQ ID NO.218 and SEQ ID NO.421) NPD014s-AD101 (SEQ ID NO.219 and SEQ ID NO.422) NPD014s-AD102 (SEQ ID NO.220 and SEQ ID NO.423) NPD014s-AD103 (SEQ ID NO.221 and SEQ ID NO.424) NPD014s-AD104 (SEQ ID NO.225 and SEQ ID NO.426) 422 and SEQ ID NO.425) NPD014s-AD105 (SEQ ID NO.223 and SEQ ID NO.426) NPD014s-AD106 (SEQ ID NO.224 and SEQ ID NO.427) NPD014s-AD107 (SEQ ID NO.225 and SEQ ID NO.428) NPD014s-AD108 (SEQ ID NO.226 and SEQ ID NO.429) NPD014s-AD109 (SEQ ID NO.227 and SEQ ID NO.430) NPD014s-AD110 (SEQ ID NO.228 and SEQ ID NO.431) NPD014s-AD111 (SEQ ID NO.229 and SEQ ID NO.432) NPD014s-AD112 (SEQ ID NO.230 and SEQ ID NO. NO.433) NPD014s-AD113 (SEQ ID NO.231 and SEQ ID NO.434) NPD014s-AD114 (SEQ ID NO.232 and SEQ ID NO.435) NPD014s-AD115 (SEQ ID NO.233 and SEQ ID NO.436) NPD014s-AD116 (SEQ ID NO.234 and SEQ ID NO.437) NPD014s-AD117 (SEQ ID NO.235 and SEQ ID NO.438) NPD014s-AD118 (SEQ ID NO.236 and SEQ ID NO.439) NPD014s-AD119 (SEQ ID NO.237 and SEQ ID NO.440) NPD014s-AD120 (SEQ ID NO.238 and SEQ ID NO.441) NPD014s-AD121 (SEQ ID NO.239 and SEQ ID NO.442) NPD014s-AD122 (SEQ ID NO.240 and SEQ ID NO.443) NPD014s-AD123 (SEQ ID NO.241 and SEQ ID NO.444) NPD014s-AD124 (SEQ ID NO.242 and SEQ ID NO.445) NPD014s-AD125 (SEQ ID NO.243 and SEQ ID NO.446) NPD014s-AD126 (SEQ ID NO.244 and SEQ ID NO.447) NPD014s-AD127 (SEQ ID NO.245 and SEQ ID NO.448) NPD014s-AD128 (SEQ ID NO.249 and SEQ ID NO.450) NO.246 and SEQ ID NO.449) NPD014s-AD129 (SEQ ID NO.247 and SEQ ID NO.450) NPD014s-AD130 (SEQ ID NO.248 and SEQ ID NO.451) NPD014s-AD131 (SEQ ID NO.249 and SEQ ID NO.452) NPD014s-AD132 (SEQ ID NO.250 and SEQ ID NO.453) NPD014s-AD133 (SEQ ID NO.251 and SEQ ID NO.454) NPD014s-AD134 (SEQ ID NO.252 and SEQ ID NO.455) NPD014s-AD135 (SEQ ID NO.253 and SEQ ID NO.456) NPD014s-AD136 (SEQ ID NO.254 and SEQ ID NO. NO.457) NPD014s-AD137 (SEQ ID NO.255 and SEQ ID NO.458) NPD014s-AD138 (SEQ ID NO.256 and SEQ ID NO.459) NPD014s-AD139 (SEQ ID NO.257 and SEQ ID NO.460) NPD014s-AD140 (SEQ ID NO.258 and SEQ ID NO.461) NPD014s-AD141 (SEQ ID NO.259 and SEQ ID NO.462) NPD014s-AD142 (SEQ ID NO.260 and SEQ ID NO.463) NPD014s-AD143 (SEQ ID NO.261 and SEQ ID NO.464) NPD014s-AD144 (SEQ ID NO.262 and SEQ ID NO.465) NPD014s-AD145 (SEQ ID NO.263 and SEQ ID NO.466) NPD014s-AD146 (SEQ ID NO.264 and SEQ ID NO.467) NPD014s-AD147 (SEQ ID NO.265 and SEQ ID NO.468) NPD014s-AD148 (SEQ ID NO.266 and SEQ ID NO.469) NPD014s-AD149 (SEQ ID NO.267 and SEQ ID NO.470) NPD014s-AD150 (SEQ ID NO.268 and SEQ ID NO.471) NPD014s-AD151 (SEQ ID NO.269 and SEQ ID NO.472) NPD014s-AD152 (SEQ ID NO.263 and SEQ ID NO.464) NO.270 and SEQ ID NO.473) NPD014s-AD153 (SEQ ID NO.271 and SEQ ID NO.474) NPD014s-AD154 (SEQ ID NO.272 and SEQ ID NO.475) NPD014s-AD155 (SEQ ID NO.273 and SEQ ID NO.476) NPD014s-AD156 (SEQ ID NO.274 and SEQ ID NO.477) NPD014s-AD157 (SEQ ID NO.275 and SEQ ID NO.478) NPD014s-AD158 (SEQ ID NO.276 and SEQ ID NO.479) NPD014s-AD159 (SEQ ID NO.277 and SEQ ID NO.480) NPD014s-AD160 (SEQ ID NO.278 and SEQ ID NO. NO.481) NPD014s-AD161 (SEQ ID NO.279 and SEQ ID NO.482) NPD014s-AD162 (SEQ ID NO.280 and SEQ ID NO.483) NPD014s-AD163 (SEQ ID NO.281 and SEQ ID NO.484) NPD014s-AD164 (SEQ ID NO.282 and SEQ ID NO.485) NPD014s-AD165 (SEQ ID NO.283 and SEQ ID NO.486) NPD014s-AD166 (SEQ ID NO.284 and SEQ ID NO.487) NPD014s-AD167 (SEQ ID NO.285 and SEQ ID NO.488) NPD014s-AD168 (SEQ ID NO.286 and SEQ ID NO.489) NPD014s-AD169 (SEQ ID NO.287 and SEQ ID NO.490) NPD014s-AD170 (SEQ ID NO.288 and SEQ ID NO.491) NPD014s-AD171 (SEQ ID NO.289 and SEQ ID NO.492) NPD014s-AD172 (SEQ ID NO.290 and SEQ ID NO.493) NPD014s-AD173 (SEQ ID NO.291 and SEQ ID NO.494) NPD014s-AD174 (SEQ ID NO.292 and SEQ ID NO.495) NPD014s-AD175 (SEQ ID NO.293 and SEQ ID NO.496) NPD014s-AD176 (SEQ ID NO.297 and SEQ ID NO.498) NO.294 and SEQ ID NO.497) NPD014s-AD177 (SEQ ID NO.295 and SEQ ID NO.498) NPD014s-AD178 (SEQ ID NO.296 and SEQ ID NO.499) NPD014s-AD179 (SEQ ID NO.297 and SEQ ID NO.500) NPD014s-AD180 (SEQ ID NO.298 and SEQ ID NO.501) NPD014s-AD181 (SEQ ID NO.299 and SEQ ID NO.502) NPD014s-AD182 (SEQ ID NO.300 and SEQ ID NO.503) NPD014s-AD183 (SEQ ID NO.301 and SEQ ID NO.504) NPD014s-AD184 (SEQ ID NO.302 and SEQ ID NO. NO.505) NPD014s-AD185 (SEQ ID NO.303 and SEQ ID NO.506) NPD014s-AD186 (SEQ ID NO.304 and SEQ ID NO.507) NPD014s-AD187 (SEQ ID NO.305 and SEQ ID NO.508) NPD014s-AD188 (SEQ ID NO.306 and SEQ ID NO.509) NPD014s-AD189 (SEQ ID NO.307 and SEQ ID NO.510) NPD014s-AD190 (SEQ ID NO.308 and SEQ ID NO.511) NPD014s-AD191 (SEQ ID NO.309 and SEQ ID NO.512) NPD014s-AD192 (SEQ ID NO.310 and SEQ ID NO.513) NPD014s-AD193 (SEQ ID NO.311 and SEQ ID NO.514) NPD014s-AD194 (SEQ ID NO.312 and SEQ ID NO.515) NPD014s-AD195 (SEQ ID NO.313 and SEQ ID NO.516) NPD014s-AD196 (SEQ ID NO.314 and SEQ ID NO.517) NPD014s-AD197 (SEQ ID NO.315 and SEQ ID NO.518) NPD014s-AD198 (SEQ ID NO.316 and SEQ ID NO.519) NPD014s-AD199 (SEQ ID NO.317 and SEQ ID NO.520) NPD014s-AD200 (SEQ ID NO. 526) NPD014s-AD206 (SEQ ID NO.324 and SEQ ID NO.527) NPD014s-AD207 (SEQ ID NO.325 and SEQ ID NO.528) NPD014s-AD208 (SEQ ID NO.326 and SEQ ID NO.529) NO.529) NPD014s-AD209 (SEQ ID NO.327 and SEQ ID NO.530) NPD014s-AD210 (SEQ ID NO.328 and SEQ ID NO.531) NPD014s-AD211 (SEQ ID NO.329 and SEQ ID NO.532) NPD014s-AD212 (SEQ ID NO.330 and SEQ ID NO.533) NPD014s-AD213 (SEQ ID NO.331 and SEQ ID NO.534) NPD014s-AD214 (SEQ ID NO.332 and SEQ ID NO.535) NPD014s-AD215 (SEQ ID NO.333 and SEQ ID NO.536) NPD014s-AD216 (SEQ ID NO.334 and SEQ ID NO.537) NPD014s-AD217 (SEQ ID NO.335 and SEQ ID NO.538) NPD014s-AD218 (SEQ ID NO.336 and SEQ ID NO.539) NPD014s-AD219 (SEQ ID NO.337 and SEQ ID NO.540). NPD014s-AD220 (SEQ ID NO.338 and SEQ ID NO.541) NPD014s-AD221 (SEQ ID NO.339 and SEQ ID NO.542) NPD014s-AD222 (SEQ ID NO.340 and SEQ ID NO.543) NPD014s-AD223 (SEQ ID NO.341 and SEQ ID NO.544) NPD014s-AD224 (SEQ ID NO.342 and SEQ ID NO.545) NPD014s-AD225 (SEQ ID NO.343 and SEQ ID NO.546) NPD014s-AD226 (SEQ ID NO.344 and SEQ ID NO.547) NPD014s-AD227 (SEQ ID NO.345 and SEQ ID NO.548) NPD014s-AD228 (SEQ ID NO.346 and SEQ ID NO.549) NPD014s-AD229 (SEQ ID NO.347 and SEQ ID NO.550) NPD014s-AD230 (SEQ ID NO.348 and SEQ ID NO.551) NPD014s-AD231 (SEQ ID NO.349 and SEQ ID NO.552) NPD014s-AD232 (SEQ ID NO.350 and SEQ ID NO.553) NPD014s-AD233 (SEQ ID NO.351 and SEQ ID NO.554) NPD014s-AD234 (SEQ ID NO.352 and SEQ ID NO.555) NPD014s-AD235 (SEQ ID NO.353 and SEQ ID NO.556) NPD014s-AD236 (SEQ ID NO.354 and SEQ ID NO.557) NPD014s-AD237 (SEQ ID NO.355 and SEQ ID NO.558) NPD014s-AD238 (SEQ ID NO.356 and SEQ ID NO.559) NPD014s-AD239 (SEQ ID NO.357 and SEQ ID NO.560) NPD014s-AD240 (SEQ ID NO.358 and SEQ ID NO.561) NPD014s-AD241 (SEQ ID NO. 359 and SEQ ID NO. 562).
40. The siRNA duplex according to any one of claims 7 to 39, wherein The siRNA molecules can be further conjugated to a delivery vector.
41. The siRNA duplex of claim 40, wherein The delivery vector is covalently conjugated to the 5'-end or 3'-end of the sense strand of the siRNA duplex to form a covalent conjugate of the siRNA and the delivery vector.
42. The covalent conjugate of siRNA and a delivery vector as claimed in claim 40, characterized in that The siRNA is covalently coupled to an N-acetylgalactosamine (GalNAc) derivative carrier, wherein the GalNAc derivative carrier is selected from one of the following:
43. The siRNA duplex-GalNAc delivery vector conjugate according to any one of claims 42, characterized in that, The siRNA antisense strand comprises a chemically modified nucleotide sequence selected from the following duplexes: NPD014s-AD244 (SEQ ID NO.603 and SEQ ID NO.844) NPD014s-AD245 (SEQ ID NO.604 and SEQ ID NO.845) NPD014s-AD246 (SEQ ID NO.605 and SEQ ID NO.846) NPD014s-AD247 (SEQ ID NO.606 and SEQ ID NO.847) NPD014s-AD248 (SEQ ID NO.607 and SEQ ID NO.848) NPD014s-AD249 (SEQ ID NO.608 and SEQ ID NO.849) NPD014s-AD250 (SEQ ID NO.609 and SEQ ID NO.850) NPD014s-AD253 (SEQ ID NO.612 and SEQ ID NO.853) NPD014s-AD256 (SEQ ID NO.615 and SEQ ID NO.856) NPD014s-AD257 (SEQ ID NO.616 and SEQ ID NO.857) NPD014s-AD259 (SEQ ID NO.618 and SEQ ID NO.859) NPD014s-AD261 (SEQ ID NO.620 and SEQ ID NO.861) NPD014s-AD262 (SEQ ID NO.621 and SEQ ID NO.862) NPD014s-AD264 (SEQ ID NO.623 and SEQ ID NO.864) NPD014s-AD270 (SEQ ID NO.629 and SEQ ID NO.870) NPD014s-AD279 (SEQ ID NO.638 and SEQ ID NO.879) NPD014s-AD280 (SEQ ID NO.639 and SEQ ID NO.880) NPD014s-AD281 (SEQ ID NO.640 and SEQ ID NO.881) NPD014s-AD285 (SEQ ID NO.644 and SEQ ID NO.885) NPD014s-AD291 (SEQ ID NO.650 and SEQ ID NO.891) NPD014s-AD296 (SEQ ID NO.655 and SEQ ID NO.896) NPD014s-AD301 (SEQ ID NO.660 and SEQ ID NO.901) NPD014s-AD302 (SEQ ID NO.661 and SEQ ID NO. NO.902) NPD014s-AD304 (SEQ ID NO.663 and SEQ ID NO.904) NPD014s-AD305 (SEQ ID NO.664 and SEQ ID NO.905) NPD014s-AD307 (SEQ ID NO.666 and SEQ ID NO.907) NPD014s-AD308 (SEQ ID NO.667 and SEQ ID NO.908) NPD014s-AD309 (SEQ ID NO.668 and SEQ ID NO.909) NPD014s-AD310 (SEQ ID NO.669 and SEQ ID NO.910) NPD014s-AD311 (SEQ ID NO.670 and SEQ ID NO.911) NPD014s-AD313 (SEQ ID NO.672 and SEQ ID NO.913) NPD014s-AD316 (SEQ ID NO.677 and SEQ ID NO.917) NO.675 and SEQ ID NO.916) NPD014s-AD317 (SEQ ID NO.676 and SEQ ID NO.917) NPD014s-AD318 (SEQ ID NO.677 and SEQ ID NO.918) NPD014s-AD319 (SEQ ID NO.678 and SEQ ID NO.919) NPD014s-AD322 (SEQ ID NO.681 and SEQ ID NO.922) NPD014s-AD323 (SEQ ID NO.682 and SEQ ID NO.923) NPD014s-AD324 (SEQ ID NO.683 and SEQ ID NO.924) NPD014s-AD325 (SEQ ID NO.684 and SEQ ID NO.925) NPD014s-AD326 (SEQ ID NO.685 and SEQ ID NO.926) NPD014s-AD327 (SEQ ID NO.686 and SEQ ID NO.927) NPD014s-AD328 (SEQ ID NO.687 and SEQ ID NO.928) NPD014s-AD329 (SEQ ID NO.688 and SEQ ID NO.929) NPD014s-AD330 (SEQ ID NO.689 and SEQ ID NO.930) NPD014s-AD331 (SEQ ID NO.690 and SEQ ID NO.931) NPD014s-AD332 (SEQ ID NO.691 and SEQ ID NO.932) NPD014s-AD333 (SEQ ID NO.692 and SEQ ID NO.933) 14s-AD334 (SEQ ID NO.693 and SEQ ID NO.934) NPD014s-AD335 (SEQ ID NO.694 and SEQ ID NO.935) NPD014s-AD336 (SEQ ID NO.695 and SEQ ID NO.936) NPD014s-AD337 (SEQ ID NO.696 and SEQ ID NO.937) NPD014s-AD338 (SEQ ID NO.697 and SEQ ID NO.938) NPD014s-AD339 (SEQ ID NO.698 and SEQ ID NO.939) NPD014s-AD340 (SEQ ID NO.699 and SEQ ID NO.940) NPD014s-AD341 (SEQ ID NO.700 and SEQ ID NO. NO.941) NPD014s-AD342 (SEQ ID NO.701 and SEQ ID NO.942) NPD014s-AD343 (SEQ ID NO.702 and SEQ ID NO.943) NPD014s-AD344 (SEQ ID NO.703 and SEQ ID NO.944) NPD014s-AD345 (SEQ ID NO.704 and SEQ ID NO.945) NPD014s-AD346 (SEQ ID NO.705 and SEQ ID NO.946) NPD014s-AD347 (SEQ ID NO.706 and SEQ ID NO.947) NPD014s-AD348 (SEQ ID NO.707 and SEQ ID NO.948) NPD014s-AD349 (SEQ ID NO.708 and SEQ ID NO.949) NPD014s-AD350 (SEQ ID NO.709 and SEQ ID NO.950) NPD014s-AD351 (SEQ ID NO.710 and SEQ ID NO.951) NPD014s-AD352 (SEQ ID NO.711 and SEQ ID NO.952) NPD014s-AD353 (SEQ ID NO.712 and SEQ ID NO.953) NPD014s-AD354 (SEQ ID NO.713 and SEQ ID NO.954) NPD014s-AD355 (SEQ ID NO.714 and SEQ ID NO.955) NPD014s-AD356 (SEQ ID NO.715 and SEQ ID NO.956) NPD014s-AD357 (SEQ ID NO.718 and SEQ ID NO.959) NO.716 and SEQ ID NO.957) NPD014s-AD358 (SEQ ID NO.717 and SEQ ID NO.958) NPD014s-AD359 (SEQ ID NO.718 and SEQ ID NO.959) NPD014s-AD360 (SEQ ID NO.719 and SEQ ID NO.960) NPD014s-AD361 (SEQ ID NO.720 and SEQ ID NO.961) NPD014s-AD362 (SEQ ID NO.721 and SEQ ID NO.962) NPD014s-AD363 (SEQ ID NO.722 and SEQ ID NO.963) NPD014s-AD364 (SEQ ID NO.723 and SEQ ID NO.964) NPD014s-AD365 (SEQ ID NO.724 and SEQ ID NO.966) NO.965) NPD014s-AD366 (SEQ ID NO.725 and SEQ ID NO.966) NPD014s-AD367 (SEQ ID NO.726 and SEQ ID NO.967) NPD014s-AD368 (SEQ ID NO.727 and SEQ ID NO.968) NPD014s-AD369 (SEQ ID NO.728 and SEQ ID NO.969) NPD014s-AD370 (SEQ ID NO.729 and SEQ ID NO.970) NPD014s-AD371 (SEQ ID NO.730 and SEQ ID NO.971) NPD014s-AD372 (SEQ ID NO.731 and SEQ ID NO.972) NPD014s-AD373 (SEQ ID NO.732 and SEQ ID NO.973) NPD014s-AD374 (SEQ ID NO.733 and SEQ ID NO.974) NPD014s-AD375 (SEQ ID NO.734 and SEQ ID NO.975) NPD014s-AD376 (SEQ ID NO.735 and SEQ ID NO.976) NPD014s-AD377 (SEQ ID NO.736 and SEQ ID NO.977) NPD014s-AD378 (SEQ ID NO.737 and SEQ ID NO.978) NPD014s-AD379 (SEQ ID NO.738 and SEQ ID NO.979) NPD014s-AD380 (SEQ ID NO.739 and SEQ ID NO.980) NPD014s-AD381 (SEQ ID NO.732 and SEQ ID NO.973) NO.740 and SEQ ID NO.981) NPD014s-AD382 (SEQ ID NO.741 and SEQ ID NO.982) NPD014s-AD383 (SEQ ID NO.742 and SEQ ID NO.983) NPD014s-AD384 (SEQ ID NO.743 and SEQ ID NO.984) NPD014s-AD385 (SEQ ID NO.744 and SEQ ID NO.985) NPD014s-AD386 (SEQ ID NO.745 and SEQ ID NO.986) NPD014s-AD387 (SEQ ID NO.746 and SEQ ID NO.987) NPD014s-AD388 (SEQID NO.747 and SEQ ID NO.988) NPD014s-AD389 (SEQ ID NO.748 and SEQ ID NO.989) NO.989) NPD014s-AD390 (SEQ ID NO.749 and SEQ ID NO.990) NPD014s-AD391 (SEQ ID NO.750 and SEQ ID NO.991) NPD014s-AD392 (SEQ ID NO.751 and SEQ ID NO.992) NPD014s-AD393 (SEQ ID NO.752 and SEQ ID NO.993) NPD014s-AD394 (SEQ ID NO.753 and SEQ ID NO.994) NPD014s-AD395 (SEQ ID NO.754 and SEQ ID NO.995) NPD014s-AD396 (SEQ ID NO.755 and SEQ ID NO.996) NPD014s-AD397 (SEQ ID NO.756 and SEQ ID NO.997) NPD014s-AD398 (SEQ ID NO.757 and SEQ ID NO.998) NPD014s-AD399 (SEQ ID NO.758 and SEQ ID NO.999) NPD014s-AD400 (SEQ ID NO.759 and SEQ ID NO.1000) NPD014s-AD401 (SEQ ID NO.760 and SEQ ID NO.1001) NPD014s-AD402 (SEQ ID NO.761 and SEQ ID NO.1002) NPD014s-AD403 (SEQ ID NO.762 and SEQ ID NO.1003) NPD014s-AD404 (SEQ ID NO.763 and SEQ ID NO.1004) NO.1004) NPD014s-AD405 (SEQ ID NO.764 and SEQ ID NO.1005) NPD014s-AD406 (SEQ ID NO.765 and SEQ ID NO.1006) NPD014s-AD407 (SEQ ID NO.766 and SEQ ID NO.1007) NPD014s-AD408 (SEQ ID NO.767 and SEQ ID NO.1008) NPD014s-AD409 (SEQ ID NO.768 and SEQ ID NO.1009) NPD014s-AD410 (SEQ ID NO.769 and SEQ ID NO.1010) NPD014s-AD411 (SEQ ID NO.770 and SEQ ID NO.1011) NPD014s-AD412 (SEQ ID NO.771 and SEQ ID NO.1013) NO.1012) NPD014s-AD413 (SEQ ID NO.772 and SEQ ID NO.1013) NPD014s-AD414 (SEQ ID NO.773 and SEQ ID NO.1014) NPD014s-AD415 (SEQ ID NO.774 and SEQ ID NO.1015) NPD014s-AD416 (SEQ ID NO.775 and SEQ ID NO.1016) NPD014s-AD417 (SEQ ID NO.776 and SEQ ID NO.1017) NPD014s-AD418 (SEQ ID NO.777 and SEQ ID NO.1018) NPD014s-AD419 (SEQ ID NO.778 and SEQ ID NO.1019) NPD014s-AD420 (SEQ ID NO.779 and SEQ ID NO.1020) NPD014s-AD421 (SEQ ID NO.780 and SEQ ID NO.1021) NPD014s-AD422 (SEQ ID NO.781 and SEQ ID NO.1022) NPD014s-AD423 (SEQ ID NO.782 and SEQ ID NO.1023) NPD014s-AD424 (SEQ ID NO.783 and SEQ ID NO.1024) NPD014s-AD425 (SEQ ID NO.784 and SEQ ID NO.1025) NPD014s-AD426 (SEQ ID NO.785 and SEQ ID NO.1026) NPD014s-AD427 (SEQ ID NO.786 and SEQ ID NO.1028) NO.1027) NPD014s-AD428 (SEQ ID NO.787 and SEQ ID NO.1028) NPD014s-AD429 (SEQ ID NO.788 and SEQ ID NO.1029) NPD014s-AD430 (SEQ ID NO.789 and SEQ ID NO.1030) NPD014s-AD431 (SEQ ID NO.790 and SEQ ID NO.1031) NPD014s-AD432 (SEQ ID NO.791 and SEQ ID NO.1032) NPD014s-AD433 (SEQ ID NO.792 and SEQ ID NO.1033) NPD014s-AD434 (SEQ ID NO.793 and SEQ ID NO.1034) NPD014s-AD435 (SEQ ID NO.794 and SEQ ID NO.1036) ID NO.1035) NPD014s-AD436 (SEQ ID NO.795 and SEQ ID NO.1036) NPD014s-AD437 (SEQ ID NO.796 and SEQ ID NO.1037) NPD014s-AD438 (SEQ ID NO.797 and SEQ ID NO.1038) NPD014s-AD439 (SEQ ID NO.798 and SEQ ID NO.1039) NPD014s-AD440 (SEQ ID NO.799 and SEQ ID NO.1040) NPD014s-AD441 (SEQ ID NO.800 and SEQ ID NO.1041) NPD014s-AD442 (SEQ ID NO.801 and SEQ ID NO.1042) NPD014s-AD443 (SEQ ID NO.802 and SEQ ID NO.1043) NPD014s-AD444 (SEQ ID NO.803 and SEQ ID NO.1044) NPD014s-AD445 (SEQ ID NO.804 and SEQ ID NO.1045) NPD014s-AD446 (SEQ ID NO.805 and SEQ ID NO.1046) NPD014s-AD447 (SEQ ID NO.806 and SEQ ID NO.1047) NPD014s-AD448 (SEQ ID NO.807 and SEQ ID NO.1048). NPD014s-AD449 (SEQ ID NO.808 and SEQ ID NO.1049) NPD014s-AD450 (SEQ ID NO.809 and SEQ ID NO.1050) NPD014s-AD451 (SEQ ID NO.810 and SEQ ID NO.1051) NPD014s-AD452 (SEQ ID NO.811 and SEQ ID NO.1052) NPD014s-AD453 (SEQ ID NO.812 and SEQ ID NO.1053) NPD014s-AD454 (SEQ ID NO.813 and SEQ ID NO.1054) NPD014s-AD455 (SEQ ID NO.814 and SEQ ID NO.1055) NPD014s-AD456 (SEQ ID NO.815 and SEQ ID NO.1056) NPD014s-AD457 (SEQ ID NO.816 and SEQ ID NO.1057) NPD014s-AD458 (SEQ ID NO.817 and SEQ ID NO.1058) NPD014s-AD459 (SEQ ID NO.818 and SEQ ID NO.1059) NPD014s-AD460 (SEQ ID NO.819 and SEQ ID NO.1060) NPD014s-AD461 (SEQ ID NO.820 and SEQ ID NO.1061) NPD014s-AD462 (SEQ ID NO.821 and SEQ ID NO.1062) NPD014s-AD463 (SEQ ID NO.822 and SEQ ID NO.1063) NPD014s-AD464 (SEQ ID NO.823 and SEQ ID NO.1064) NPD014s-AD465 (SEQ ID NO.824 and SEQ ID NO.1065) NPD014s-AD466 (SEQ ID NO.825 and SEQ ID NO.1066) NPD014s-AD467 (SEQ ID NO.826 and SEQ ID NO.1067) NPD014s-AD468 (SEQ ID NO.827 and SEQ ID NO.1068) NPD014s-AD469 (SEQ ID NO.828 and SEQ ID NO.1069) NPD014s-AD470 (SEQ ID NO.829 and SEQ ID NO.1070) NPD014s-AD471 (SEQ ID NO.830 and SEQ ID NO.1071) NPD014s-AD472 (SEQ ID NO.831 and SEQ ID NO.1072) NPD014s-AD473 (SEQ ID NO.832 and SEQ ID NO.1073) NPD014s-AD474 (SEQ ID NO.833 and SEQ ID NO.1074) NPD014s-AD475 (SEQ ID NO.834 and SEQ ID NO.1075) NPD014s-AD476 (SEQ ID NO.835 and SEQ ID NO.1076) NPD014s-AD477 (SEQ ID NO.836 and SEQ ID NO.1077) NPD014s-AD478 (SEQ ID NO.837 and SEQ ID NO.1078) NPD014s-AD479 (SEQ ID NO.838 and SEQ ID NO.1079) NPD014s-AD480 (SEQ ID NO.839 and SEQ ID NO.1080) NPD014s-AD481 (SEQ ID NO.840 and SEQ ID NO.1081) NPD014s-AD482 (SEQ ID NO. 841 and SEQ ID NO. 1082).
44. The siRNA duplex-GalNAc delivery vector conjugate according to any one of claims 42, characterized in that The siRNA sense strand comprises a chemically modified nucleotide sequence selected from the following duplexes: NPD014s-AD223 (SEQ ID NO.561 and SEQ ID NO.781) NPD014s-AD244 (SEQ ID NO.603 and SEQ ID NO.844) NPD014s-AD245 (SEQ ID NO.604 and SEQ ID NO.845) NPD014s-AD246 (SEQ ID NO.605 and SEQ ID NO.846) NPD014s-AD247 (SEQ ID NO.606 and SEQ ID NO.847) NPD014s-AD248 (SEQ ID NO.607 and SEQ ID NO.848) NPD014s-AD249 (SEQ ID NO.608 and SEQ ID NO.849) NPD014s-AD250 (SEQ ID NO.609 and SEQ ID NO.850) NPD014s-AD253 (SEQ ID NO.612 and SEQ ID NO.853) NPD014s-AD256 (SEQ ID NO.615 and SEQ ID NO.856) NPD014s-AD257 (SEQ ID NO.616 and SEQ ID NO.857) NPD014s-AD259 (SEQ ID NO.618 and SEQ ID NO.859) NPD014s-AD261 (SEQ ID NO.620 and SEQ ID NO.861) NPD014s-AD262 (SEQ ID NO.621 and SEQ ID NO.862) NPD014s-AD264 (SEQ ID NO.623 and SEQ ID NO.864) NPD014s-AD270 (SEQ ID NO.629 and SEQ ID NO.870) NPD014s-AD279 (SEQ ID NO.638 and SEQ ID NO.879) NPD014s-AD280 (SEQ ID NO.639 and SEQ ID NO.880) NPD014s-AD281 (SEQ ID NO.630 and SEQ ID NO.881) NO.640 and SEQ ID NO.881) NPD014s-AD285 (SEQ ID NO.644 and SEQ ID NO.885) NPD014s-AD291 (SEQ ID NO.650 and SEQ ID NO.891) NPD014s-AD296 (SEQ ID NO.655 and SEQ ID NO.896) NPD014s-AD301 (SEQ ID NO.660 and SEQ ID NO.901) NPD014s-AD302 (SEQ ID NO.661 and SEQ ID NO.902) NPD014s-AD304 (SEQ ID NO.663 and SEQ ID NO.904) NPD014s-AD305 (SEQ ID NO.664 and SEQ ID NO.905) NPD014s-AD307 (SEQ ID NO.666 and SEQ ID NO.907) NPD014s-AD308 (SEQ ID NO.667 and SEQ ID NO.908) NPD014s-AD309 (SEQ ID NO.668 and SEQ ID NO.909) NPD014s-AD310 (SEQ ID NO.669 and SEQ ID NO.910) NPD014s-AD311 (SEQ ID NO.670 and SEQ ID NO.911) NPD014s-AD313 (SEQ ID NO.672 and SEQ ID NO.913) NPD014s-AD316 (SEQ ID NO.675 and SEQ ID NO.916) NPD014s-AD317 (SEQ ID NO.676 and SEQ ID NO.918) NO.676 and SEQ ID NO.917) NPD014s-AD318 (SEQ ID NO.677 and SEQ ID NO.918) NPD014s-AD319 (SEQ ID NO.678 and SEQ ID NO.919) NPD014s-AD322 (SEQ ID NO.681 and SEQ ID NO.922) NPD014s-AD323 (SEQ ID NO.682 and SEQ ID NO.923) NPD014s-AD324 (SEQ ID NO.683 and SEQ ID NO.924) NPD014s-AD325 (SEQ ID NO.684 and SEQ ID NO.925) NPD014s-AD326 (SEQ ID NO.685 and SEQ ID NO.926) NPD014s-AD327 (SEQ ID NO.686 and SEQ ID NO.928) NO.927) NPD014s-AD328 (SEQ ID NO.687 and SEQ ID NO.928) NPD014s-AD329 (SEQ ID NO.688 and SEQ ID NO.929) NPD014s-AD330 (SEQ ID NO.689 and SEQ ID NO.930) NPD014s-AD331 (SEQ ID NO.690 and SEQ ID NO.931) NPD014s-AD332 (SEQ ID NO.691 and SEQ ID NO.932) NPD014s-AD333 (SEQ ID NO.692 and SEQ ID NO.933) NPD014s-AD334 (SEQ ID NO.693 and SEQ ID NO.934) NPD014s-AD335 (SEQ ID NO.694 and SEQ ID NO.935) NPD014s-AD336 (SEQ ID NO.695 and SEQ ID NO.936) NPD014s-AD337 (SEQ ID NO.696 and SEQ ID NO.937) NPD014s-AD338 (SEQ ID NO.697 and SEQ ID NO.938) NPD014s-AD339 (SEQ ID NO.698 and SEQ ID NO.939) NPD014s-AD340 (SEQ ID NO.699 and SEQ ID NO.940) NPD014s-AD341 (SEQ ID NO.700 and SEQ ID NO.941) NPD014s-AD342 (SEQ ID NO.701 and SEQ ID NO.942) NPD014s-AD343 (SEQ ID NO. NO.702 and SEQ ID NO.943) NPD014s-AD344 (SEQ ID NO.703 and SEQ ID NO.944) NPD014s-AD345 (SEQ ID NO.704 and SEQ ID NO.945) NPD014s-AD346 (SEQ ID NO.705 and SEQ ID NO.946) NPD014s-AD347 (SEQ ID NO.706 and SEQ ID NO.947) NPD014s-AD348 (SEQ ID NO.707 and SEQ ID NO.948) NPD014s-AD349 (SEQ ID NO.708 and SEQ ID NO.949) NPD014s-AD350 (SEQ ID NO.709 and SEQ ID NO.950) NPD014s-AD351 (SEQ ID NO.710 and SEQ ID NO. NO.951) NPD014s-AD352 (SEQ ID NO.711 and SEQ ID NO.952) NPD014s-AD353 (SEQ ID NO.712 and SEQ ID NO.953) NPD014s-AD354 (SEQ ID NO.713 and SEQ ID NO.954) NPD014s-AD355 (SEQ ID NO.714 and SEQ ID NO.955) NPD014s-AD356 (SEQ ID NO.715 and SEQ ID NO.956) NPD014s-AD357 (SEQ ID NO.716 and SEQ ID NO.957) NPD014s-AD358 (SEQ ID NO.717 and SEQ ID NO.958) NPD014s-AD359 (SEQ ID NO.718 and SEQ ID NO.959) NPD014s-AD360 (SEQ ID NO.719 and SEQ ID NO.960) NPD014s-AD361 (SEQ ID NO.720 and SEQ ID NO.961) NPD014s-AD362 (SEQ ID NO.721 and SEQ ID NO.962) NPD014s-AD363 (SEQ ID NO.722 and SEQ ID NO.963) NPD014s-AD364 (SEQ ID NO.723 and SEQ ID NO.964) NPD014s-AD365 (SEQ ID NO.724 and SEQ ID NO.965) NPD014s-AD366 (SEQ ID NO.725 and SEQ ID NO.966) NPD014s-AD367 (SEQ ID NO.728 and SEQ ID NO.969) NO.726 and SEQ ID NO.967) NPD014s-AD368 (SEQ ID NO.727 and SEQ ID NO.968) NPD014s-AD369 (SEQ ID NO.728 and SEQ ID NO.969) NPD014s-AD370 (SEQ ID NO.729 and SEQ ID NO.970) NPD014s-AD371 (SEQ ID NO.730 and SEQ ID NO.971) NPD014s-AD372 (SEQ ID NO.731 and SEQ ID NO.972) NPD014s-AD373 (SEQ ID NO.732 and SEQ ID NO.973) NPD014s-AD374 (SEQ ID NO.733 and SEQ ID NO.974) NPD014s-AD375 (SEQ ID NO.734 and SEQ ID NO.976) NO.975) NPD014s-AD376 (SEQ ID NO.735 and SEQ ID NO.976) NPD014s-AD377 (SEQ ID NO.736 and SEQ ID NO.977) NPD014s-AD378 (SEQ ID NO.737 and SEQ ID NO.978) NPD014s-AD379 (SEQ ID NO.738 and SEQ ID NO.979) NPD014s-AD380 (SEQ ID NO.739 and SEQ ID NO.980) NPD014s-AD381 (SEQ ID NO.740 and SEQ ID NO.981) NPD014s-AD382 (SEQ ID NO.741 and SEQ ID NO.982) NPD014s-AD383 (SEQ ID NO.742 and SEQ ID NO.983) NPD014s-AD384 (SEQ ID NO.743 and SEQ ID NO.984) NPD014s-AD385 (SEQ ID NO.744 and SEQ ID NO.985) NPD014s-AD386 (SEQ ID NO.745 and SEQ ID NO.986) NPD014s-AD387 (SEQ ID NO.746 and SEQ ID NO.987) NPD014s-AD388 (SEQID NO.747 and SEQ ID NO.988) NPD014s-AD389 (SEQ ID NO.748 and SEQ ID NO.989) NPD014s-AD390 (SEQ ID NO.749 and SEQ ID NO.990) NPD014s-AD391 (SEQ ID NO.742 and SEQ ID NO.982) NPD014s-AD383 (SEQ ID NO.742 and SEQ ID NO.983) NPD014s-AD384 (SEQ ID NO.743 and SEQ ID NO.984) NPD014s-AD385 (SEQ ID NO.744 and SEQ ID NO.985) NPD014s-AD386 (SEQ ID NO.745 and SEQ ID NO.986) NPD014s-AD387 (SEQ ID NO.746 and SEQ ID NO.987) NPD014s-AD388 (SEQID NO.747 and SEQ ID NO.988) NPD014s-AD389 (SEQ ID NO.748 and SEQ ID NO.989) NPD014s-AD390 (SEQ ID NO.749 and SEQ ID NO.990) NO.750 and SEQ ID NO.991) NPD014s-AD392 (SEQ ID NO.751 and SEQ ID NO.992) NPD014s-AD393 (SEQ ID NO.752 and SEQ ID NO.993) NPD014s-AD394 (SEQ ID NO.753 and SEQ ID NO.994) NPD014s-AD395 (SEQ ID NO.754 and SEQ ID NO.995) NPD014s-AD396 (SEQ ID NO.755 and SEQ ID NO.996) NPD014s-AD397 (SEQ ID NO.756 and SEQ ID NO.997) NPD014s-AD398 (SEQ ID NO.757 and SEQ ID NO.998) NPD014s-AD399 (SEQ ID NO.758 and SEQ ID NO.999) NO.999) NPD014s-AD400 (SEQ ID NO.759 and SEQ ID NO.1000) NPD014s-AD401 (SEQ ID NO.760 and SEQ ID NO.1001) NPD014s-AD402 (SEQ ID NO.761 and SEQ ID NO.1002) NPD014s-AD403 (SEQ ID NO.762 and SEQ ID NO.1003) NPD014s-AD404 (SEQ ID NO.763 and SEQ ID NO.1004) NPD014s-AD405 (SEQ ID NO.764 and SEQID NO.1005) NPD014s-AD406 (SEQ ID NO.765 and SEQ ID NO.1006) NPD014s-AD407 (SEQ ID NO.766 and SEQ ID NO.1007) NPD014s-AD408 (SEQ ID NO.767 and SEQ ID NO.1008) NPD014s-AD409 (SEQ ID NO.768 and SEQ ID NO.1009) NPD014s-AD410 (SEQ ID NO.769 and SEQ ID NO.1010) NPD014s-AD411 (SEQ ID NO.770 and SEQ ID NO.1011) NPD014s-AD412 (SEQ ID NO.771 and SEQ ID NO.1012) NPD014s-AD413 (SEQ ID NO.772 and SEQ ID NO.1013) NPD014s-AD414 (SEQ ID NO.773 and SEQ ID NO.1014) NO.1014)NPD014s-AD415 (SEQ ID NO.774 and SEQ ID NO.1015)NPD014s-AD416 (SEQ ID NO.775 and SEQ ID NO.1016)NPD014s-AD417 (SEQ ID NO.776 and SEQ ID NO.1017)NPD014s-AD418 (SEQ ID NO.777 and SEQ ID NO.1018)NPD014s-AD419 (SEQ ID NO.778 and SEQ ID NO.1019)NPD014s-AD420 (SEQ ID NO.779 and SEQ ID NO.1020)NPD014s-AD421 (SEQ ID NO.780 and SEQ ID NO.1021)NPD014s-AD422 (SEQ ID NO.781 and SEQ ID NO.1022) NO.1022) NPD014s-AD423 (SEQ ID NO.782 and SEQ ID NO.1023) NPD014s-AD424 (SEQ ID NO.783 and SEQ ID NO.1024) NPD014s-AD425 (SEQ ID NO.784 and SEQ ID NO.1025) NPD014s-AD426 (SEQ ID NO.785 and SEQ ID NO.1026) NPD014s-AD427 (SEQ ID NO.786 and SEQ ID NO.1027) NPD014s-AD428 (SEQ ID NO.787 and SEQ ID NO.1028) NPD014s-AD429 (SEQ ID NO.788 and SEQ ID NO.1029) NPD014s-AD430 (SEQ ID NO.789 and SEQ ID NO.1030) NPD014s-AD431 (SEQ ID NO.790 and SEQ ID NO.1031) NPD014s-AD432 (SEQ ID NO.791 and SEQ ID NO.1032) NPD014s-AD433 (SEQ ID NO.792 and SEQ ID NO.1033) NPD014s-AD434 (SEQ ID NO.793 and SEQ ID NO.1034) NPD014s-AD435 (SEQ ID NO.794 and SEQ ID NO.1035) NPD014s-AD436 (SEQ ID NO.795 and SEQ ID NO.1036) NPD014s-AD437 (SEQ ID NO.796 and SEQ ID NO.1037) NO.1037) NPD014s-AD438 (SEQ ID NO.797 and SEQ ID NO.1038) NPD014s-AD439 (SEQ ID NO.798 and SEQ ID NO.1039) NPD014s-AD440 (SEQ ID NO.799 and SEQ ID NO.1040) NPD014s-AD441 (SEQ ID NO.800 and SEQ ID NO.1041) NPD014s-AD442 (SEQ ID NO.801 and SEQ ID NO.1042) NPD014s-AD443 (SEQ ID NO.802 and SEQ ID NO.1043) NPD014s-AD444 (SEQ ID NO.803 and SEQ ID NO.1044) NPD014s-AD445 (SEQ ID NO.804 and SEQ ID NO.1046) ID NO.1045) NPD014s-AD446 (SEQ ID NO.805 and SEQ ID NO.1046) NPD014s-AD447 (SEQ ID NO.806 and SEQ ID NO.1047) NPD014s-AD448 (SEQ ID NO.807 and SEQ ID NO.1048) NPD014s-AD449 (SEQ ID NO.808 and SEQ ID NO.1049) NPD014s-AD450 (SEQ ID NO.809 and SEQ ID NO.1050) NPD014s-AD451 (SEQ ID NO.810 and SEQ ID NO.1051) NPD014s-AD452 (SEQ ID NO.811 and SEQ ID NO.1052) NPD014s-AD453 (SEQ ID NO.812 and SEQ ID NO.1053) NPD014s-AD454 (SEQ ID NO.813 and SEQ ID NO.1054) NPD014s-AD455 (SEQ ID NO.814 and SEQ ID NO.1055) NPD014s-AD456 (SEQ ID NO.815 and SEQ ID NO.1056) NPD014s-AD457 (SEQ ID NO.816 and SEQ ID NO.1057) NPD014s-AD458 (SEQ ID NO.817 and SEQ ID NO.1058) NPD014s-AD459 (SEQ ID NO.818 and SEQ ID NO.1059) NPD014s-AD460 (SEQ ID NO.819 and SEQ ID NO.1060) NPD014s-AD461 (SEQ ID NO.820 and SEQ ID NO.1061) NPD014s-AD462 (SEQ ID NO.821 and SEQ ID NO.1062) NPD014s-AD463 (SEQ ID NO.822 and SEQ ID NO.1063) NPD014s-AD464 (SEQ ID NO.823 and SEQ ID NO.1064) NPD014s-AD465 (SEQ ID NO.824 and SEQ ID NO.1065) NPD014s-AD466 (SEQ ID NO.825 and SEQ ID NO.1066) NPD014s-AD467 (SEQ ID NO.826 and SEQ ID NO.1067) NPD014s-AD468 (SEQ ID NO.827 and SEQ ID NO.1068) NO.1068) NPD014s-AD469 (SEQ ID NO.828 and SEQ ID NO.1069) NPD014s-AD470 (SEQ ID NO.829 and SEQ ID NO.1070) NPD014s-AD471 (SEQ ID NO.830 and SEQ ID NO.1071). NPD014s-AD472 (SEQ ID NO.831 and SEQ ID NO.1072) NPD014s-AD473 (SEQ ID NO.832 and SEQ ID NO.1073) NPD014s-AD474 (SEQ ID NO.833 and SEQ ID NO.1074) NPD014s-AD475 (SEQ ID NO.834 and SEQ ID NO.1075) NPD014s-AD476 (SEQ ID NO.835 and SEQ ID NO.1076) NPD014s-AD477 (SEQ ID NO.836 and SEQ ID NO.1077) NPD014s-AD478 (SEQ ID NO.837 and SEQ ID NO.1078) NPD014s-AD479 (SEQ ID NO.838 and SEQ ID NO.1079) NPD014s-AD480 (SEQ ID NO.839 and SEQ ID NO.1080) NPD014s-AD481 (SEQ ID NO.840 and SEQ ID NO.1081) NPD014s-AD482 (SEQ ID NO. 841 and SEQ ID NO. 1082).
45. The siRNA duplex-GalNAc delivery vector conjugate according to any one of claims 42, characterized in that, The siRNA sense strand and antisense strand contain a chemically modified nucleotide sequence selected from the following duplexes: NPD014s-AD244 (SEQ ID NO.603 and SEQ ID NO.844) NPD014s-AD245 (SEQ ID NO.604 and SEQ ID NO.845) NPD014s-AD246 (SEQ ID NO.605 and SEQ ID NO.846) NPD014s-AD247 (SEQ ID NO.606 and SEQ ID NO.847) NPD014s-AD248 (SEQ ID NO.607 and SEQ ID NO.848) NPD014s-AD249 (SEQ ID NO.608 and SEQ ID NO.849) NPD014s-AD250 (SEQ ID NO.609 and SEQ ID NO.850) NPD014s-AD253 (SEQ ID NO.612 and SEQ ID NO.853) NPD014s-AD256 (SEQ ID NO.615 and SEQ ID NO.856) NPD014s-AD257 (SEQ ID NO.616 and SEQ ID NO.857) NPD014s-AD259 (SEQ ID NO.618 and SEQ ID NO.859) NPD014s-AD261 (SEQ ID NO.620 and SEQ ID NO.861) NPD014s-AD262 (SEQ ID NO.621 and SEQ ID NO.862) NPD014s-AD264 (SEQ ID NO.623 and SEQ ID NO.864) NPD014s-AD270 (SEQ ID NO.629 and SEQ ID NO.870) NPD014s-AD279 (SEQ ID NO.638 and SEQ ID NO.879) NPD014s-AD280 (SEQ ID NO.639 and SEQ ID NO.880) NPD014s-AD281 (SEQ ID NO.640 and SEQ ID NO.881) NPD014s-AD285 (SEQ ID NO.644 and SEQ ID NO.885) NPD014s-AD291 (SEQ ID NO.650 and SEQ ID NO.891) NPD014s-AD296 (SEQ ID NO.655 and SEQ ID NO.896) NPD014s-AD301 (SEQ ID NO.660 and SEQ ID NO.901) NPD014s-AD302 (SEQ ID NO.661 and SEQ ID NO.902) NPD014s-AD304 (SEQ ID NO.663 and SEQ ID NO.904) NPD014s-AD305 (SEQ ID NO.664 and SEQ ID NO.905) NPD014s-AD307 (SEQ ID NO.666 and SEQ ID NO.907) NPD014s-AD308 (SEQ ID NO.667 and SEQ ID NO.908) NPD014s-AD309 (SEQ ID NO.668 and SEQ ID NO.909) NPD014s-AD310 (SEQ ID NO.669 and SEQ ID NO.910) NPD014s-AD311 (SEQ ID NO.670 and SEQ ID NO.911) NPD014s-AD313 (SEQ ID NO.672 and SEQ ID NO.913) NPD014s-AD316 (SEQ ID NO.675 and SEQ ID NO.916) NPD014s-AD317 (SEQ ID NO.676 and SEQ ID NO.918) NO.917) NPD014s-AD318 (SEQ ID NO.677 and SEQ ID NO.918) NPD014s-AD319 (SEQ ID NO.678 and SEQ ID NO.919) NPD014s-AD322 (SEQ ID NO.681 and SEQ ID NO.922) NPD014s-AD323 (SEQ ID NO.682 and SEQ ID NO.923) NPD014s-AD324 (SEQ ID NO.683 and SEQ ID NO.924) NPD014s-AD325 (SEQ ID NO.684 and SEQ ID NO.925) NPD014s-AD326 (SEQ ID NO.685 and SEQ ID NO.926) NPD014s-AD327 (SEQ ID NO.686 and SEQ ID NO.927) NPD014s-AD328 (SEQ ID NO.681 and SEQ ID NO.922) NO.687 and SEQ ID NO.928) NPD014s-AD329 (SEQ ID NO.688 and SEQ ID NO.929) NPD014s-AD330 (SEQ ID NO.689 and SEQ ID NO.930) NPD014s-AD331 (SEQ ID NO.690 and SEQ ID NO.931) NPD014s-AD332 (SEQ ID NO.691 and SEQ ID NO.932) NPD014s-AD333 (SEQ ID NO.692 and SEQ ID NO.933) NPD014s-AD334 (SEQ ID NO.693 and SEQ ID NO.934) NPD014s-AD335 (SEQ ID NO.694 and SEQ ID NO.935) NPD014s-AD336 (SEQ ID NO.695 and SEQ ID NO.936) NPD014s-AD337 (SEQ ID NO.696 and SEQ ID NO.937) NPD014s-AD338 (SEQ ID NO.697 and SEQ ID NO.938) NPD014s-AD339 (SEQ ID NO.698 and SEQ ID NO.939) NPD014s-AD340 (SEQ ID NO.699 and SEQ ID NO.940) NPD014s-AD341 (SEQ ID NO.700 and SEQ ID NO.941) NPD014s-AD342 (SEQ ID NO.701 and SEQ ID NO.942) NPD014s-AD343 (SEQ ID NO. NO.702 and SEQ ID NO.943) NPD014s-AD344 (SEQ ID NO.703 and SEQ ID NO.944) NPD014s-AD345 (SEQ ID NO.704 and SEQ ID NO.945) NPD014s-AD346 (SEQ ID NO.705 and SEQ ID NO.946) NPD014s-AD347 (SEQ ID NO.706 and SEQ ID NO.947) NPD014s-AD348 (SEQ ID NO.707 and SEQ ID NO.948) NPD014s-AD349 (SEQ ID NO.708 and SEQ ID NO.949) NPD014s-AD350 (SEQ ID NO.709 and SEQ ID NO.950) NPD014s-AD351 (SEQ ID NO.710 and SEQ ID NO. NO.951) NPD014s-AD352 (SEQ ID NO.711 and SEQ ID NO.952) NPD014s-AD353 (SEQ ID NO.712 and SEQ ID NO.953) NPD014s-AD354 (SEQ ID NO.713 and SEQ ID NO.954) NPD014s-AD355 (SEQ ID NO.714 and SEQ ID NO.955) NPD014s-AD356 (SEQ ID NO.715 and SEQ ID NO.956) NPD014s-AD357 (SEQ ID NO.716 and SEQ ID NO.957) NPD014s-AD358 (SEQ ID NO.717 and SEQ ID NO.958) NPD014s-AD359 (SEQ ID NO.718 and SEQ ID NO.959) NPD014s-AD360 (SEQ ID NO.719 and SEQ ID NO.960) NPD014s-AD361 (SEQ ID NO.720 and SEQ ID NO.961) NPD014s-AD362 (SEQ ID NO.721 and SEQ ID NO.962) NPD014s-AD363 (SEQID NO.722 and SEQ ID NO.963) NPD014s-AD364 (SEQ ID NO.723 and SEQ ID NO.964) NPD014s-AD365 (SEQ ID NO.724 and SEQ ID NO.965) NPD014s-AD366 (SEQ ID NO.725 and SEQ ID NO.966) NPD014s-AD367 (SEQ ID NO.728 and SEQ ID NO.969) NO.726 and SEQ ID NO.967) NPD014s-AD368 (SEQ ID NO.727 and SEQ ID NO.968) NPD014s-AD369 (SEQ ID NO.728 and SEQ ID NO.969) NPD014s-AD370 (SEQ ID NO.729 and SEQ ID NO.970) NPD014s-AD371 (SEQ ID NO.730 and SEQ ID NO.971) NPD014s-AD372 (SEQ ID NO.731 and SEQ ID NO.972) NPD014s-AD373 (SEQ ID NO.732 and SEQ ID NO.973) NPD014s-AD374 (SEQ ID NO.733 and SEQ ID NO.974) NPD014s-AD375 (SEQ ID NO.734 and SEQ ID NO.976) NO.975) NPD014s-AD376 (SEQ ID NO.735 and SEQ ID NO.976) NPD014s-AD377 (SEQ ID NO.736 and SEQ ID NO.977) NPD014s-AD378 (SEQ ID NO.737 and SEQ ID NO.978) NPD014s-AD379 (SEQ ID NO.738 and SEQ ID NO.979) NPD014s-AD380 (SEQ ID NO.739 and SEQ ID NO.980) NPD014s-AD381 (SEQ ID NO.740 and SEQ ID NO.981) NPD014s-AD382 (SEQ ID NO.741 and SEQ ID NO.982) NPD014s-AD383 (SEQ ID NO.742 and SEQ ID NO.983) NPD014s-AD384 (SEQ ID NO.743 and SEQ ID NO.984) NPD014s-AD385 (SEQ ID NO.744 and SEQ ID NO.985) NPD014s-AD386 (SEQ ID NO.745 and SEQ ID NO.986) NPD014s-AD387 (SEQ ID NO.746 and SEQ ID NO.987) NPD014s-AD388 (SEQ ID NO.747 and SEQ ID NO.988) NPD014s-AD389 (SEQ ID NO.748 and SEQ ID NO.989) NPD014s-AD390 (SEQ ID NO.749 and SEQ ID NO.990) NPD014s-AD391 (SEQ ID NO.742 and SEQ ID NO.982) NPD014s-AD383 (SEQ ID NO.742 and SEQ ID NO.983) NPD014s-AD384 (SEQ ID NO.743 and SEQ ID NO.984) NPD014s-AD385 (SEQ ID NO.744 and SEQ ID NO.985) NPD014s-AD386 (SEQ ID NO.745 and SEQ ID NO.986) NPD014s-AD387 (SEQ ID NO.746 and SEQ ID NO.987) NPD014s-AD388 (SEQ ID NO.747 and SEQ ID NO.988) NPD014s-AD389 (SEQ ID NO.748 and SEQ ID NO.989) NPD014s-AD390 (SEQ ID NO.749 and SEQ ID NO.990) NO.750 and SEQ ID NO.991) NPD014s-AD392 (SEQ ID NO.751 and SEQ ID NO.992) NPD014s-AD393 (SEQ ID NO.752 and SEQ ID NO.993) NPD014s-AD394 (SEQ ID NO.753 and SEQ ID NO.994) NPD014s-AD395 (SEQ ID NO.754 and SEQ ID NO.995) NPD014s-AD396 (SEQ ID NO.755 and SEQ ID NO.996) NPD014s-AD397 (SEQ ID NO.756 and SEQ ID NO.997) NPD014s-AD398 (SEQ ID NO.757 and SEQ ID NO.998) NPD014s-AD399 (SEQ ID NO.758 and SEQ ID NO.999) NO.999)NPD014s-AD400 (SEQ ID NO.759 and SEQ ID NO.1000)NPD014s-AD401 (SEQ ID NO.760 and SEQ ID NO.1001)NPD014s-AD402 (SEQ ID NO.761 and SEQ ID NO.1002)NPD014s-AD403 (SEQ ID NO.762 and SEQ ID NO.1003) NPD014s-AD404 (SEQ ID NO.763 and SEQ ID NO.1004) NPD014s-AD405 (SEQ ID NO.764 and SEQ ID NO.1005) NPD014s-AD406 (SEQ ID NO.765 and SEQ ID NO.1006) NPD014s-AD407 (SEQ ID NO.766 and SEQ ID NO.1007) NPD014s-AD408 (SEQ ID NO.767 and SEQ ID NO.1008) NPD014s-AD409 (SEQ ID NO.768 and SEQ ID NO.1009) NPD014s-AD410 (SEQ ID NO.769 and SEQ ID NO.1010) NPD014s-AD411 (SEQ ID NO.770 and SEQ ID NO.1011) NPD014s-AD412 (SEQ ID NO.771 and SEQ ID NO.1012) NPD014s-AD413 (SEQ ID NO.772 and SEQ ID NO.1013) NPD014s-AD414 (SEQ ID NO.773 and SEQ ID NO.1014) NO.1014) NPD014s-AD415 (SEQ ID NO.774 and SEQ ID NO.1015) NPD014s-AD416 (SEQ ID NO.775 and SEQ ID NO.1016) NPD014s-AD417 (SEQ ID NO.776 and SEQ ID NO.1017) NPD014s-AD418 (SEQ ID NO.777 and SEQ ID NO.1018) NPD014s-AD419 (SEQ ID NO.778 and SEQ ID NO.1019) NPD014s-AD420 (SEQ ID NO.779 and SEQ ID NO.1020) NPD014s-AD421 (SEQ ID NO.780 and SEQ ID NO.1021) NPD014s-AD422 (SEQ ID NO.781 and SEQ ID NO.1023) NO.1022) NPD014s-AD423 (SEQ ID NO.782 and SEQ ID NO.1023) NPD014s-AD424 (SEQ ID NO.783 and SEQ ID NO.1024) NPD014s-AD425 (SEQ ID NO.784 and SEQ ID NO.1025) NPD014s-AD426 (SEQ ID NO.785 and SEQ ID NO.1026) NPD014s-AD427 (SEQ ID NO.786 and SEQ ID NO.1027) NPD014s-AD428 (SEQ ID NO.787 and SEQ ID NO.1028) NPD014s-AD429 (SEQ ID NO.788 and SEQ ID NO.1029) NPD014s-AD430 (SEQ ID NO.789 and SEQ ID NO.1030) NPD014s-AD431 (SEQ ID NO.790 and SEQ ID NO.1031) NPD014s-AD432 (SEQ ID NO.791 and SEQ ID NO.1032) NPD014s-AD433 (SEQ ID NO.792 and SEQ ID NO.1033) NPD014s-AD434 (SEQ ID NO.793 and SEQ ID NO.1034) NPD014s-AD435 (SEQ ID NO.794 and SEQ ID NO.1035) NPD014s-AD436 (SEQ ID NO.795 and SEQ ID NO.1036) NPD014s-AD437 (SEQ ID NO.796 and SEQ ID NO.1037) NO.1037) NPD014s-AD438 (SEQ ID NO.797 and SEQ ID NO.1038) NPD014s-AD439 (SEQ ID NO.798 and SEQ ID NO.1039) NPD014s-AD440 (SEQ ID NO.799 and SEQ ID NO.1040) NPD014s-AD441 (SEQ ID NO.800 and SEQ ID NO.1041) NPD014s-AD442 (SEQ ID NO.801 and SEQ ID NO.1042) NPD014s-AD443 (SEQ ID NO.802 and SEQ ID NO.1043) NPD014s-AD444 (SEQ ID NO.803 and SEQ ID NO.1044) NPD014s-AD445 (SEQ ID NO.804 and SEQ ID NO.1046) NO.1045) NPD014s-AD446 (SEQ ID NO.805 and SEQ ID NO.1046) NPD014s-AD447 (SEQ ID NO.806 and SEQ ID NO.1047) NPD014s-AD448 (SEQ ID NO.807 and SEQ ID NO.1048) NPD014s-AD449 (SEQ ID NO.808 and SEQ ID NO.1049) NPD014s-AD450 (SEQ ID NO.809 and SEQ ID NO.1050) NPD014s-AD451 (SEQ ID NO.810 and SEQ ID NO.1051) NPD014s-AD452 (SEQ ID NO.811 and SEQ ID NO.1052) NPD014s-AD453 (SEQ ID NO.812 and SEQ ID NO.1053) NPD014s-AD454 (SEQ ID NO.813 and SEQ ID NO.1054) NPD014s-AD455 (SEQ ID NO.814 and SEQ ID NO.1055) NPD014s-AD456 (SEQ ID NO.815 and SEQ ID NO.1056) NPD014s-AD457 (SEQ ID NO.816 and SEQ ID NO.1057) NPD014s-AD458 (SEQ ID NO.817 and SEQ ID NO.1058). NPD014s-AD459 (SEQ ID NO.818 and SEQ ID NO.1059) NPD014s-AD460 (SEQ ID NO.819 and SEQ ID NO.1060) NPD014s-AD461 (SEQ ID NO.820 and SEQ ID NO.1061) NPD014s-AD462 (SEQ ID NO.821 and SEQ ID NO.1062) NPD014s-AD463 (SEQ ID NO.822 and SEQ ID NO.1063) NPD014s-AD464 (SEQ ID NO.823 and SEQ ID NO.1064) NPD014s-AD465 (SEQ ID NO.824 and SEQ ID NO.1065) NPD014s-AD466 (SEQ ID NO.825 and SEQ ID NO.1066) NPD014s-AD467 (SEQ ID NO.826 and SEQ ID NO.1067) NPD014s-AD468 (SEQ ID NO.827 and SEQ ID NO.1068) NPD014s-AD469 (SEQ ID NO.828 and SEQ ID NO.1069) NPD014s-AD470 (SEQ ID NO.829 and SEQ ID NO.1070) NPD014s-AD471 (SEQ ID NO.830 and SEQ ID NO.1071) NPD014s-AD472 (SEQ ID NO.831 and SEQ ID NO.1072) NPD014s-AD473 (SEQ ID NO.832 and SEQ ID NO.1073) NPD014s-AD474 (SEQ ID NO.833 and SEQ ID NO.1074) NPD014s-AD475 (SEQ ID NO.834 and SEQ ID NO.1075) NPD014s-AD476 (SEQ ID NO.835 and SEQ ID NO.1076) NPD014s-AD477 (SEQ ID NO.836 and SEQ ID NO.1077) NPD014s-AD478 (SEQ ID NO.837 and SEQ ID NO.1078) NPD014s-AD479 (SEQ ID NO.838 and SEQ ID NO.1079) NPD014s-AD480 (SEQ ID NO.839 and SEQ ID NO.1080) NPD014s-AD481 (SEQ ID NO.840 and SEQ ID NO.1081) NPD014s-AD482 (SEQ ID NO. 841 and SEQ ID NO. 1082).
46. A cell comprising CFB mRNA targeted by the siRNA duplex of any one of claims 1 to 45.
47. A pharmaceutical composition for inhibiting the expression of a gene encoding CFB, comprising the siRNA duplex according to any one of claims 1 to 45.
48. A pharmaceutical composition comprising the siRNA duplex of any one of claims 1 to 45 and a lipid formulation.
49. A method for inhibiting the expression of CFB gene in a cell, the method comprising allowing the cell to act with the siRNA duplex according to any one of claims 1 to 45 or the pharmaceutical composition according to claim 47 or 48, thereby inhibiting the expression of CFB gene in the cell.
50. The method of claim 49, wherein: The cell is in a subject.
51. The method of claim 50, wherein: The subject is a human being.
52. The method of claim 51, wherein: The subject suffers from a complement component-associated disease.
53. The method of claim 52, wherein: The CFB-related clinical symptoms are selected from the group consisting of paroxysmal nocturnal hemoglobinuria (PNH), asthma, rheumatoid arthritis, systemic lupus erythematosus, glomerulonephritis, psoriasis, dermatomyositis bullous pemphigoid, atypical hemolytic uremic syndrome, Shiga toxin-producing Escherichia coli-associated hemolytic uremic syndrome, myasthenia gravis, neuromyelitis optica, dense deposit disease, C3 neuropathy, age-related macular degeneration, cold agglutinin disease, anti-neutrophil cytoplasmic antibody-associated vasculitis, humoral and vascular transplant rejection, graft dysfunction, myocardial infarction, sensitized receptors of transplants, immunoglobulin a nephropathy, and sepsis.
54. The use of claim 53, wherein the complement component-related disease is paroxysmal nocturnal hemoglobinuria (PNH), glomerulonephritis, immunoglobulin a nephropathy, age-related macular degeneration or rheumatoid arthritis.
55. The use of claim 54, wherein the complement component-related disease is paroxysmal nocturnal hemoglobinuria (PNH), IgA nephropathy, or age-related macular degeneration.
56. The method of claim 55, wherein the complement component-related disease is immunoglobulin a nephropathy or age-related macular degeneration.
57. The method according to any one of claims 46 to 49, characterized in that The siRNA duplex inhibits the expression of CFB by at least 50%, 60%, 70%, 80%, 90%, or 95% on the cells.
58. The method according to any one of claims 50 to 56, characterized in that The inhibition of CFB expression reduces the CFB protein level in the serum of the subject by at least 50%, 60%, 70%, 80%, 90% or 95%.
59. A method of treating a CFB-related clinical symptom in a subject, comprising administering to the subject an siRNA duplex as described in any one of claims 1 to 45 or a pharmaceutical composition as described in claim 47 or 48, for use in the preparation of a medicament for treating a subject suffering from a disorder that would benefit from reduced expression of complement factor B (CFB).
60. The use of claim 59, wherein the disorder is a complement component-associated disease.
61. The use of claim 59, wherein the complement component-related disease is selected from the group consisting of: Paroxysmal nocturnal hemoglobinuria (PNH), asthma, rheumatoid arthritis, systemic lupus erythematosus, glomerulonephritis, immunoglobulin A nephropathy, psoriasis, dermatomyositis bullous pemphigoid, atypical hemolytic uremic syndrome, Shiga toxin-producing Escherichia coli-associated hemolytic uremic syndrome, myasthenia gravis, neuromyelitis optica, dense deposit disease, C3 neuropathy, age-related macular degeneration, cold agglutinin disease, antineutrophil cytoplasmic antibody-associated vasculitis, humoral and vascular transplant rejection, graft dysfunction, myocardial infarction, sensitized receptors of the transplant, and sepsis.
62. The method of claim 59, wherein: The subject is a human being.
63. The method of claim 59, wherein: Wherein administration of the siRNA to the subject results in a decrease in hemolysis and / or a decrease in CFB protein accumulation.
64. The method according to any one of claims 52 to 63, characterized in that The siRNA duplex is administered to the subject at a dose of about 0.01 mg / kg to about 50 mg / kg.
65. The method according to any one of claims 52 to 63, characterized in that The siRNA-GalNAc conjugate is subcutaneously injected into the subject.
66. The method according to any one of claims 52 to 65, characterized in that Further comprising determining the level of CFB protein in a sample from the subject.
67. The method of claim 66, wherein: The CFB protein expression level in the subject sample is derived from the test of a blood sample, a serum sample or a urine sample.
68. The method according to any one of claims 52 to 67, characterized in that Further comprising administering to the subject an additional therapeutic agent for treating a complement component-associated disease.
69. The method of claim 68, wherein: The additional therapeutic agent is selected from: an antibody or a small molecule complement inhibitor.
70. The method of claim 68, wherein: The additional therapeutic agent includes eculizumab.
71. Use of the siRNA duplex of any one of claims 1 to 45 or the pharmaceutical composition of claim 46 or 47 for treating clinical symptoms associated with CFB.
72. The use as claimed in claim 71, for use in a method as claimed in any one of claims 50 to 71.
Citation Information
Patent Citations
Targeting ligand and application thereof in therapeutic nucleic acid conjugate
CN114716489A