Sirna for inhibiting LPA expression and use thereof

Abstract

An siRNA duplex molecule for inhibiting LPA (apo(a)) gene expression, an siRNA-GalNAc delivery vector conjugate, and an application thereof. By means of forming a silencing complex, complementarily pairing with an LPA (apo(a)) mRNA sequence, and causing mRNA degradation, the siRNA inhibits LPA (apo(a)) expression; the siRNA can specifically reduce liver cell synthesis of LPA, providing treatment of a cardiovascular-related disease.

Description

siRNA for inhibiting LPA expression and its use

[0001] The present invention claims priority to Chinese patent application No. 2023115376242, filed with the Patent Office of China on November 17, 2023, entitled “siRNA for inhibiting LPA expression and its use”, the entire contents of which are incorporated by reference into the application. Technical Field

[0002] The present invention belongs to the field of biopharmaceutical technology. Specifically, the present invention relates to an siRNA targeting LPA mRNA and its uses. More specifically, the present invention relates to an siRNA duplex, an siRNA-delivery vector conjugate (GalNAc-siRNA), a pharmaceutical composition, and its uses. Background Art

[0003] Lipoprotein(a) is a heterogeneous low-density lipoprotein (LDL)-like particle containing a lipid core and apolipoprotein B (apoB-100) and a unique component, apolipoprotein(a) (apo(a)) attached to apoB-100 by a disulfide bond.

[0004] The apo(a) gene (LPA) is primarily expressed in the liver, and expression is limited to humans and non-human primates. Lp(a) levels in humans are genetically determined and do not significantly change with diet, exercise, or other lifestyle changes. The length of LPA varies depending on the number of Kringle KIV2 domains present, and its expression is inversely correlated with the number of domains present. Normal Lp(a) levels range from 0.1 to 25 mg / dL.

[0005] Analysis of Lp(a) levels in multiple studies has suggested that high Lp(a) levels are an independent risk factor for cardiovascular disease, stroke, and other related conditions, including atherosclerotic stenosis. Furthermore, genome-wide association studies have also implicated LPA as a genetic risk factor for diseases such as atherosclerotic stenosis.

[0006] When therapeutic lipoprotein apheresis is used to lower both Lp(a) and LDL levels in hyperlipidemic patients, a significant reduction in cardiovascular events is observed.

[0007] SiRNA is a short RNA molecule that can specifically inhibit the expression of mRNA genes. Through the RNA interference mechanism, siRNA binds to the target gene's mRNA and guides RNA nucleases to cleave the corresponding mRNA molecules, thereby preventing mRNA translation and protein synthesis. Compared with other gene silencing technologies, siRNA technology offers advantages such as high efficiency, selectivity, and reproducibility.

[0008] In recent years, siRNAs targeting LPA (apo(a)) mRNA have attracted considerable research attention as a novel strategy for treating diseases associated with abnormal LPA expression. The human LPA gene sequence is well-characterized, and the structure and function of its mRNA are well understood. Therefore, by studying the LPA mRNA sequence, it is possible to design LPA-targeting siRNA duplexes.

[0009] Furthermore, due to its targeted and reversible properties, siRNA can reduce side effects during treatment and restore normal gene expression levels in patients after treatment. SiRNA technology also offers greater flexibility in drug design and is expected to become a key technology for the future treatment of diseases associated with abnormal LPA expression. Summary of the Invention

[0010] The present invention aims to, at least to some extent, address at least one of the technical problems existing in the prior art. To this end, the present invention provides an siRNA for inhibiting LPA expression and its use. The siRNA of the present invention can inhibit LPA expression and is effective in treating cardiovascular diseases such as atherosclerosis.

[0011] The present invention provides an siRNA duplex. According to an embodiment of the present invention, the siRNA comprises a sense strand and an antisense strand. The antisense strand comprises a complementary region that pairs with 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:57 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:58 to SEQ ID NO:114 by no more than 2 nucleotides. Through experimental design, the inventors have discovered that the above-mentioned suitable small interfering RNA (siRNA) can specifically reduce the synthesis of LPA (apo(a)) in hepatocytes while avoiding off-target effects. siRNA forms an RNA-induced silencing complex (RISC) and pairs complementary to the sequence of the target gene LPA mRNA, thereby degrading LPA (apo(a)) mRNA, inhibiting the expression of apo(a), and reducing LPA in the body, thereby effectively preventing or treating related diseases, such as Buerger's disease, peripheral artery disease, coronary artery disease, metabolic syndrome, acute coronary syndrome, aortic stenosis, aortic regurgitation, aortic dissection, retinal artery occlusion, cardiovascular and cerebrovascular diseases, mesenteric ischemia, superior mesenteric artery occlusion, renal artery stenosis, stable / unstable angina, acute coronary syndrome, heterozygous or homozygous familial hypercholesterolemia, hyperlipoprotein-β lipoproteinemia, atherosclerosis, and venous thrombosis.

[0012] In the present invention, the "difference of 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 nucleotide deletion, nucleotide insertion (which can be inserted into the 3'-end, 5'-end or between any two nucleotides of the nucleotide sequence), nucleotide substitution, etc.

[0013] According to an embodiment of the present invention, the above siRNA may further include at least one of the following additional technical features:

[0014] According to an embodiment of the present invention, the sense strand includes at least one of SEQ ID NO: 1 to SEQ ID NO: 57 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.

[0015] According to an embodiment of the present invention, the antisense strand includes at least one of SEQ ID NO: 58 to SEQ ID NO: 114 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.

[0016] For example, NDS-015-31 5'-CAGAGUUAUCAAGGCACAUAA-3' (SEQ ID NO: 31) and 5'-AGAGUUAUCAAGGCACAUUU-3', 5'-UAGAGUUAUCAAGGCACAUAA-3' and 5'-IAGAGUUAUCAAGGCACAUAA-3' should be considered as the same nucleotide sequence.

[0017] Table 1: Nucleotide sequences of siRNA

[0018] According to an embodiment of the present invention, the sense strand comprises 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:11, SEQ ID NO:16 and SEQ ID NO:27, SEQ ID NO:29, SEQ ID NO:31, SEQ ID NO:40 and / or SEQ ID NO:56; the antisense strand comprises one of the following nucleotide sequences, or a nucleotide sequence that differs therefrom by no more than 2 nucleotides: SEQ ID NO:61, SEQ ID NO:64, SEQ ID NO:68, SEQ ID NO:73, SEQ ID NO:84, SEQ ID NO:86, SEQ ID NO:88, SEQ ID NO:97 and / or SEQ ID NO:113.

[0019] According to an embodiment of the present invention, the antisense strand comprises at least 19 consecutive nucleotides of any one antisense strand nucleotide sequence of the following duplexes:

[0020] NDS-015-2 (SEQ ID NO.: 2 and SEQ ID NO.: 59)

[0021] NDS-015-4 (SEQ ID NO.: 4 and SEQ ID NO.: 61)

[0022] NDS-015-6 (SEQ ID NO.: 6 and SEQ ID NO.: 63)

[0023] NDS-015-7 (SEQ ID NO.: 7 and SEQ ID NO.: 64)

[0024] NDS-015-11 (SEQ ID NO.: 11 and SEQ ID NO.: 68)

[0025] NDS-015-16 (SEQ ID NO.: 16 and SEQ ID NO.: 73)

[0026] NDS-015-17 (SEQ ID NO.: 17 and SEQ ID NO.: 74)

[0027] NDS-015-20 (SEQ ID NO.: 20 and SEQ ID NO.: 77)

[0028] NDS-015-26 (SEQ ID NO.: 26 and SEQ ID NO.: 83)

[0029] NDS-015-27 (SEQ ID NO.: 27 and SEQ ID NO.: 84)

[0030] NDS-015-29 (SEQ ID NO.: 29 and SEQ ID NO.: 86)

[0031] NDS-015-31 (SEQ ID NO.: 31 and SEQ ID NO.: 88)

[0032] NDS-015-37 (SEQ ID NO.: 37 and SEQ ID NO.: 94)

[0033] NDS-015-40 (SEQ ID NO.: 40 and SEQ ID NO.: 97)

[0034] NDS-015-45 (SEQ ID NO.: 45 and SEQ ID NO.: 102)

[0035] NDS-015-56 (SEQ ID NO.: 56 and SEQ ID NO.: 113)

[0036] According to an embodiment of the present invention, the sense strand comprises at least 17 consecutive nucleotides of any sense strand nucleotide sequence selected from the following duplexes:

[0037] NDS-015-2 (SEQ ID NO.: 2 and SEQ ID NO.: 59)

[0038] NDS-015-4 (SEQ ID NO.: 4 and SEQ ID NO.: 61)

[0039] NDS-015-6 (SEQ ID NO.: 6 and SEQ ID NO.: 63)

[0040] NDS-015-7 (SEQ ID NO.: 7 and SEQ ID NO.: 64)

[0041] NDS-015-11 (SEQ ID NO.: 11 and SEQ ID NO.: 68)

[0042] NDS-015-16 (SEQ ID NO.: 16 and SEQ ID NO.: 73)

[0043] NDS-015-17 (SEQ ID NO.: 17 and SEQ ID NO.: 74)

[0044] NDS-015-20 (SEQ ID NO.: 20 and SEQ ID NO.: 77)

[0045] NDS-015-26 (SEQ ID NO.: 26 and SEQ ID NO.: 83)

[0046] NDS-015-27 (SEQ ID NO.: 27 and SEQ ID NO.: 84)

[0047] NDS-015-29 (SEQ ID NO.: 29 and SEQ ID NO.: 86)

[0048] NDS-015-31 (SEQ ID NO.: 31 and SEQ ID NO.: 88)

[0049] NDS-015-37 (SEQ ID NO.: 37 and SEQ ID NO.: 94)

[0050] NDS-015-40 (SEQ ID NO.: 40 and SEQ ID NO.: 97)

[0051] NDS-015-45 (SEQ ID NO.: 45 and SEQ ID NO.: 102)

[0052] NDS-015-56 (SEQ ID NO.: 56 and SEQ ID NO.: 113)

[0053] According to an embodiment of the present invention, the sense and antisense strands comprise duplex nucleotide sequences selected from the group consisting of:

[0054] NDS-015-2 (SEQ ID NO.: 2 and SEQ ID NO.: 59)

[0055] NDS-015-4 (SEQ ID NO.: 4 and SEQ ID NO.: 61)

[0056] NDS-015-6 (SEQ ID NO.: 6 and SEQ ID NO.: 63)

[0057] NDS-015-7 (SEQ ID NO.: 7 and SEQ ID NO.: 64)

[0058] NDS-015-11 (SEQ ID NO.: 11 and SEQ ID NO.: 68)

[0059] NDS-015-16 (SEQ ID NO.: 16 and SEQ ID NO.: 73)

[0060] NDS-015-17 (SEQ ID NO.: 17 and SEQ ID NO.: 74)

[0061] NDS-015-20 (SEQ ID NO.: 20 and SEQ ID NO.: 77)

[0062] NDS-015-26 (SEQ ID NO.: 26 and SEQ ID NO.: 83)

[0063] NDS-015-27 (SEQ ID NO.: 27 and SEQ ID NO.: 84)

[0064] NDS-015-29 (SEQ ID NO.: 29 and SEQ ID NO.: 86)

[0065] NDS-015-31 (SEQ ID NO.: 31 and SEQ ID NO.: 88)

[0066] NDS-015-37 (SEQ ID NO.: 37 and SEQ ID NO.: 94)

[0067] NDS-015-40 (SEQ ID NO.: 40 and SEQ ID NO.: 97)

[0068] NDS-015-45 (SEQ ID NO.: 45 and SEQ ID NO.: 102)

[0069] NDS-015-56 (SEQ ID NO.: 56 and SEQ ID NO.: 113)

[0070] According to an embodiment of the present invention, the antisense strand comprises at least 19 consecutive nucleotides of the nucleotide sequence (5'-UUAUGUGCCUUGAUAACUCUGUU-3', SEQ ID NO: 88) of the antisense strand of NDS-015-31 (SEQ ID NO.: 31 and SEQ ID NO.: 88). In certain embodiments, the sense strand comprises at least 19 consecutive nucleotides of the nucleotide sequence (5'-CAGAGUUAUCAAGGCACAUAA-3', SEQ ID NO: 31) of the sense strand of NDS-015-31. In certain embodiments, the sense and antisense strands comprise the sense and antisense strand nucleotide sequences of NDS-015-31 (5'-CAGAGUUAUCAAGGCACAUAA-3', SEQ ID NO: 31) and (5'-UUAUGUGCCUUGAUAACUCUGUU-3', SEQ ID NO: 88).

[0071] According to an embodiment of the present invention, the length of the complementary region is at least 19 bases.

[0072] According to an embodiment of the present invention, the length of the complementary region is 19 to 23 bases.

[0073] 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.

[0074] According to an embodiment of the present invention, the siRNA includes at least one modified nucleotide.

[0075] 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.

[0076] According to an embodiment of the present invention, the modified nucleotide is selected from at least one of the following:

[0077] 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;

[0078] 2'-Fluoro-modified nucleotides: aF, gF, cF, and uF are 2'-fluoro A, 2'-fluoro G, 2'-fluoro C, and 2'-fluoro U, respectively;

[0079] 2'-deoxy modified nucleotides: 2'-deoxycytidine-3'-phosphate, 2'-deoxyguanosine-3'-phosphate, 2'-deoxyadenosine-3'-phosphate, 2'-deoxyuridine-3'-phosphate;

[0080] 5'-(1,2,4)-triazole-modified nucleotides: cTA4, gTA4, aTA4, and 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, and 2'-O-methyl-5'-deoxy-(1-(1,2,4-triazole))-uridine-3'-phosphate, respectively;

[0081] 5'-Thiomorpholinoline-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;

[0082] 3'-Fluoro-modified nucleotides: cRF, gRF, aRF, and uRF are 3'-fluoro-3'-deoxycytidine-2'-phosphate, 3'-fluoro-3'-deoxyguanosine-2'-phosphate, 3'-fluoro-3'-deoxyadenosine-2'-phosphate, and 3'-fluoro-3'-deoxyuridine-2'-phosphate, respectively;

[0083] 3'-deoxy modified nucleotides: 3'-deoxycytidine-2'-phosphate, 3'-deoxyguanosine-2'-phosphate, 3'-deoxyadenosine-2'-phosphate, 3'-deoxyuridine-2'-phosphate;

[0084] 5'-phosphorothioate diester linkages and / or methylphosphonate nucleotides;

[0085] Nucleotides with unconventional bases;

[0086] 5'-trans-vinylphosphonate (E-VP) modified nucleotides.

[0087] 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.

[0088] As is known to those skilled in the art, a ribonucleotide molecule is composed of phosphate, ribose, and a base. As used herein, a "modified nucleotide" refers to a conventional nucleotide other than A, U, C, or G, or an unconventional nucleotide such as inosine (I) or pseudouridine (ψ), in which the group attached to the ribose sugar is altered, the phosphodiester linker group is altered, or a base is deleted or replaced.

[0089] 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 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'-thiophosphorodiester modified nucleotides and 5'-VP phosphonate modified nucleotides.

[0090] According to an embodiment of the present invention, in the sense chain and / or the antisense chain, the 2'-fluoro-modified nucleotides are present in the following positions: the nucleotides at the 5'-terminus of the sense chain 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 chain 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.

[0091] For example, the nucleotide at the 5'-terminus of the sense strand is the first nucleotide from the starting point and is a 2'-O-methyl modified nucleotide.

[0092] Illustratively, the 5'-terminal nucleotide of the antisense strand is the first nucleotide at the starting point, and the 3'-terminal nucleotide of the antisense strand is the first and second nucleotides at the starting point, which are both 2'-O-methyl modified nucleotides and 5'-phosphorothioate diester modified nucleotides.

[0093] According to an embodiment of the present invention, the 5'-modified nucleotide at position 1 of the nucleotide starting point at the 5'-end of the siRNA sense strand may be optionally a 5'-(1,2,4)-triazole-modified nucleotide: cTA4, gTA4, aTA4, and 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, and 2'-O-methyl-5'-deoxy-(1-(1,2,4-triazole))-uridine-3'-phosphate, respectively; or

[0094] 5'-Thiomorpholinoline-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.

[0095] 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.

[0096] According to an embodiment of the present invention, the nucleotide starting point at position 1 of the 5'-terminus of the antisense strand of the siRNA is a 5'-unmodified or 5'-trans vinylphosphonate (E-VP) modified nucleotide.

[0097] For example, the nucleotide at the 5'-terminus 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.

[0098] 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.

[0099] For example, the nucleotide at position 7 of the starting point of the 5'-terminus of the antisense strand may be 3'-fluoro-3'-deoxyadenosine-2'-phosphate.

[0100] According to embodiments of the present invention, siRNA double-stranded molecules, wherein the siRNA double-stranded molecules may further comprise at least one phosphorothioate or methylphosphonate internucleotide connection. In certain embodiments, the phosphorothioate or methylphosphonate internucleotide is connected at 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 at 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 at the 5'-end and 3'-end of a chain, wherein the chain is an antisense strand.

[0101] According to an embodiment of the present invention, in a double-stranded siRNA molecule, the base pair at position 1 of the 5′-end of the antisense strand of the duplex is an A:U base pair or an A:I base pair, wherein I is inosine.

[0102] According to an embodiment of the present invention, the siRNA antisense strand comprises any chemically modified antisense strand nucleotide sequence selected from the duplexes of SEQ ID NO.: 312 to SEQ ID NO.: 508.

[0103] According to an embodiment of the present invention, the siRNA antisense strand comprises any one of the chemically modified antisense strand nucleotide sequences selected from the following duplexes:

[0104] NPD015s-AD002 (SEQ ID NO.: 116 and SEQ ID NO.: 313)

[0105] NPD015s-AD004 (SEQ ID NO.: 118 and SEQ ID NO.: 315)

[0106] NPD015s-AD006 (SEQ ID NO.: 120 and SEQ ID NO.: 317)

[0107] NPD015s-AD007 (SEQ ID NO.: 121 and SEQ ID NO.: 318)

[0108] NPD015s-AD011 (SEQ ID NO.: 125 and SEQ ID NO.: 322)

[0109] NPD015s-AD016 (SEQ ID NO.: 130 and SEQ ID NO.: 327)

[0110] NPD015s-AD017 (SEQ ID NO.: 131 and SEQ ID NO.: 328)

[0111] NPD015s-AD020 (SEQ ID NO.: 134 and SEQ ID NO.: 331)

[0112] NPD015s-AD026 (SEQ ID NO.: 140 and SEQ ID NO.: 337)

[0113] NPD015s-AD027 (SEQ ID NO.: 141 and SEQ ID NO.: 338)

[0114] NPD015s-AD029 (SEQ ID NO.: 143 and SEQ ID NO.: 340)

[0115] NPD015s-AD031 (SEQ ID NO.: 145 and SEQ ID NO.: 342)

[0116] NPD015s-AD037 (SEQ ID NO.: 151 and SEQ ID NO.: 348)

[0117] NPD015s-AD040 (SEQ ID NO.: 154 and SEQ ID NO.: 351)

[0118] NPD015s-AD045 (SEQ ID NO.: 159 and SEQ ID NO.: 356)

[0119] NPD015s-AD056 (SEQ ID NO.: 170 and SEQ ID NO.: 367)

[0120] NPD015s-AD058 (SEQ ID NO.: 172 and SEQ ID NO.: 369)

[0121] NPD015s-AD059 (SEQ ID NO.: 173 and SEQ ID NO.: 370)

[0122] NPD015s-AD060 (SEQ ID NO.: 174 and SEQ ID NO.: 371)

[0123] NPD015s-AD061 (SEQ ID NO.: 175 and SEQ ID NO.: 372)

[0124] NPD015s-AD062 (SEQ ID NO.: 176 and SEQ ID NO.: 373)

[0125] NPD015s-AD063 (SEQ ID NO.: 177 and SEQ ID NO.: 374)

[0126] NPD015s-AD064 (SEQ ID NO.: 178 and SEQ ID NO.: 375)

[0127] NPD015s-AD065 (SEQ ID NO.: 179 and SEQ ID NO.: 376)

[0128] NPD015s-AD066 (SEQ ID NO.: 180 and SEQ ID NO.: 377)

[0129] NPD015s-AD067 (SEQ ID NO.: 181 and SEQ ID NO.: 378)

[0130] NPD015s-AD078 (SEQ ID NO.: 192 and SEQ ID NO.: 389)

[0131] NPD015s-AD079 (SEQ ID NO.: 193 and SEQ ID NO.: 390)

[0132] NPD015s-AD080 (SEQ ID NO.: 194 and SEQ ID NO.: 391)

[0133] NPD015s-AD081 (SEQ ID NO.: 195 and SEQ ID NO.: 392)

[0134] NPD015s-AD082 (SEQ ID NO.: 196 and SEQ ID NO.: 393)

[0135] NPD015s-AD083 (SEQ ID NO.: 197 and SEQ ID NO.: 394)

[0136] NPD015s-AD084 (SEQ ID NO.: 198 and SEQ ID NO.: 395)

[0137] NPD015s-AD085 (SEQ ID NO.: 199 and SEQ ID NO.: 396)

[0138] NPD015s-AD086 (SEQ ID NO.: 200 and SEQ ID NO.: 397)

[0139] NPD015s-AD087 (SEQ ID NO.: 201 and SEQ ID NO.: 398)

[0140] NPD015s-AD098 (SEQ ID NO.: 212 and SEQ ID NO.: 409)

[0141] NPD015s-AD099 (SEQ ID NO.: 213 and SEQ ID NO.: 410)

[0142] NPD015s-AD100 (SEQ ID NO.: 214 and SEQ ID NO.: 411)

[0143] NPD015s-AD101 (SEQ ID NO.: 215 and SEQ ID NO.: 412)

[0144] NPD015s-AD102 (SEQ ID NO.: 216 and SEQ ID NO.: 413)

[0145] NPD015s-AD103 (SEQ ID NO.: 217 and SEQ ID NO.: 414)

[0146] NPD015s-AD104 (SEQ ID NO.: 218 and SEQ ID NO.: 415)

[0147] NPD015s-AD105 (SEQ ID NO.: 219 and SEQ ID NO.: 416)

[0148] NPD015s-AD106 (SEQ ID NO.: 220 and SEQ ID NO.: 417)

[0149] NPD015s-AD107 (SEQ ID NO.: 221 and SEQ ID NO.: 418)

[0150] NPD015s-AD108 (SEQ ID NO.: 222 and SEQ ID NO.: 419)

[0151] NPD015s-AD109 (SEQ ID NO.: 223 and SEQ ID NO.: 420)

[0152] NPD015s-AD110 (SEQ ID NO.: 224 and SEQ ID NO.: 421)

[0153] NPD015s-AD111 (SEQ ID NO.: 225 and SEQ ID NO.: 422)

[0154] NPD015s-AD112 (SEQ ID NO.: 226 and SEQ ID NO.: 423)

[0155] NPD015s-AD113 (SEQ ID NO.: 227 and SEQ ID NO.: 424)

[0156] NPD015s-AD114 (SEQ ID NO.: 228 and SEQ ID NO.: 425)

[0157] NPD015s-AD115 (SEQ ID NO.: 229 and SEQ ID NO.: 426)

[0158] NPD015s-AD116 (SEQ ID NO.: 230 and SEQ ID NO.: 427)

[0159] NPD015s-AD117 (SEQ ID NO.: 231 and SEQ ID NO.: 428)

[0160] NPD015s-AD138 (SEQ ID NO.: 252 and SEQ ID NO.: 449)

[0161] NPD015s-AD139 (SEQ ID NO.: 253 and SEQ ID NO.: 450)

[0162] NPD015s-AD140 (SEQ ID NO.: 254 and SEQ ID NO.: 451)

[0163] NPD015s-AD141 (SEQ ID NO.: 255 and SEQ ID NO.: 452)

[0164] NPD015s-AD142 (SEQ ID NO.: 256 and SEQ ID NO.: 453)

[0165] NPD015s-AD143 (SEQ ID NO.: 257 and SEQ ID NO.: 454)

[0166] NPD015s-AD144 (SEQ ID NO.: 258 and SEQ ID NO.: 455)

[0167] NPD015s-AD145 (SEQ ID NO.: 259 and SEQ ID NO.: 456)

[0168] NPD015s-AD146 (SEQ ID NO.: 260 and SEQ ID NO.: 457)

[0169] NPD015s-AD147 (SEQ ID NO.: 261 and SEQ ID NO.: 458)

[0170] NPD015s-AD148 (SEQ ID NO.: 262 and SEQ ID NO.: 459)

[0171] NPD015s-AD149 (SEQ ID NO.: 263 and SEQ ID NO.: 460)

[0172] NPD015s-AD150 (SEQ ID NO.: 264 and SEQ ID NO.: 461)

[0173] NPD015s-AD151 (SEQ ID NO.: 265 and SEQ ID NO.: 462)

[0174] NPD015s-AD152 (SEQ ID NO.: 266 and SEQ ID NO.: 463)

[0175] NPD015s-AD153 (SEQ ID NO.: 267 and SEQ ID NO.: 464)

[0176] NPD015s-AD154 (SEQ ID NO.: 268 and SEQ ID NO.: 465)

[0177] NPD015s-AD155 (SEQ ID NO.: 269 and SEQ ID NO.: 466)

[0178] NPD015s-AD156 (SEQ ID NO.: 270 and SEQ ID NO.: 467)

[0179] NPD015s-AD157 (SEQ ID NO.: 271 and SEQ ID NO.: 468)

[0180] NPD015s-AD168 (SEQ ID NO.: 282 and SEQ ID NO.: 479)

[0181] NPD015s-AD169 (SEQ ID NO.:283 and SEQ ID NO.:480)

[0182] NPD015s-AD170 (SEQ ID NO.: 284 and SEQ ID NO.: 481)

[0183] NPD015s-AD171 (SEQ ID NO.: 285 and SEQ ID NO.: 482)

[0184] NPD015s-AD172 (SEQ ID NO.: 286 and SEQ ID NO.: 483)

[0185] NPD015s-AD173 (SEQ ID NO.: 287 and SEQ ID NO.: 484)

[0186] NPD015s-AD174 (SEQ ID NO.: 288 and SEQ ID NO.: 485)

[0187] NPD015s-AD175 (SEQ ID NO.: 289 and SEQ ID NO.: 486)

[0188] NPD015s-AD176 (SEQ ID NO.: 290 and SEQ ID NO.: 487)

[0189] NPD015s-AD177 (SEQ ID NO.: 291 and SEQ ID NO.: 488)

[0190] NPD015s-AD178 (SEQ ID NO.: 292 and SEQ ID NO.: 489)

[0191] NPD015s-AD179 (SEQ ID NO.: 293 and SEQ ID NO.: 490)

[0192] NPD015s-AD180 (SEQ ID NO.: 294 and SEQ ID NO.: 491)

[0193] NPD015s-AD181 (SEQ ID NO.: 295 and SEQ ID NO.: 492)

[0194] NPD015s-AD182 (SEQ ID NO.: 296 and SEQ ID NO.: 493)

[0195] NPD015s-AD183 (SEQ ID NO.: 297 and SEQ ID NO.: 494)

[0196] NPD015s-AD184 (SEQ ID NO.: 298 and SEQ ID NO.: 495)

[0197] NPD015s-AD185 (SEQ ID NO.: 299 and SEQ ID NO.: 496)

[0198] NPD015s-AD186 (SEQ ID NO.: 300 and SEQ ID NO.: 497)

[0199] NPD015s-AD187 (SEQ ID NO.: 301 and SEQ ID NO.: 498)

[0200] According to an embodiment of the present invention, the siRNA sense strand comprises any chemically modified sense strand nucleotide sequence selected from the duplexes of SEQ ID NO.: 115 to SEQ ID NO.: 311.

[0201] According to an embodiment of the present invention, the siRNA sense strand comprises any one of the chemically modified sense strand nucleotide sequences selected from the following duplexes:

[0202] NPD015s-AD002 (SEQ ID NO.: 116 and SEQ ID NO.: 313)

[0203] NPD015s-AD004 (SEQ ID NO.: 118 and SEQ ID NO.: 315)

[0204] NPD015s-AD006 (SEQ ID NO.: 120 and SEQ ID NO.: 317)

[0205] NPD015s-AD007 (SEQ ID NO.: 121 and SEQ ID NO.: 318)

[0206] NPD015s-AD011 (SEQ ID NO.: 125 and SEQ ID NO.: 322)

[0207] NPD015s-AD016 (SEQ ID NO.: 130 and SEQ ID NO.: 327)

[0208] NPD015s-AD017 (SEQ ID NO.: 131 and SEQ ID NO.: 328)

[0209] NPD015s-AD020 (SEQ ID NO.: 134 and SEQ ID NO.: 331)

[0210] NPD015s-AD026 (SEQ ID NO.: 140 and SEQ ID NO.: 337)

[0211] NPD015s-AD027 (SEQ ID NO.: 141 and SEQ ID NO.: 338)

[0212] NPD015s-AD029 (SEQ ID NO.: 143 and SEQ ID NO.: 340)

[0213] NPD015s-AD031 (SEQ ID NO.: 145 and SEQ ID NO.: 342)

[0214] NPD015s-AD037 (SEQ ID NO.: 151 and SEQ ID NO.: 348)

[0215] NPD015s-AD040 (SEQ ID NO.: 154 and SEQ ID NO.: 351)

[0216] NPD015s-AD045 (SEQ ID NO.: 159 and SEQ ID NO.: 356)

[0217] NPD015s-AD056 (SEQ ID NO.: 170 and SEQ ID NO.: 367)

[0218] NPD015s-AD058 (SEQ ID NO.: 172 and SEQ ID NO.: 369)

[0219] NPD015s-AD059 (SEQ ID NO.: 173 and SEQ ID NO.: 370)

[0220] NPD015s-AD060 (SEQ ID NO.: 174 and SEQ ID NO.: 371)

[0221] NPD015s-AD061 (SEQ ID NO.: 175 and SEQ ID NO.: 372)

[0222] NPD015s-AD062 (SEQ ID NO.: 176 and SEQ ID NO.: 373)

[0223] NPD015s-AD063 (SEQ ID NO.: 177 and SEQ ID NO.: 374)

[0224] NPD015s-AD064 (SEQ ID NO.: 178 and SEQ ID NO.: 375)

[0225] NPD015s-AD065 (SEQ ID NO.: 179 and SEQ ID NO.: 376)

[0226] NPD015s-AD066 (SEQ ID NO.: 180 and SEQ ID NO.: 377)

[0227] NPD015s-AD067 (SEQ ID NO.: 181 and SEQ ID NO.: 378)

[0228] NPD015s-AD078 (SEQ ID NO.: 192 and SEQ ID NO.: 389)

[0229] NPD015s-AD079 (SEQ ID NO.: 193 and SEQ ID NO.: 390)

[0230] NPD015s-AD080 (SEQ ID NO.: 194 and SEQ ID NO.: 391)

[0231] NPD015s-AD081 (SEQ ID NO.: 195 and SEQ ID NO.: 392)

[0232] NPD015s-AD082 (SEQ ID NO.: 196 and SEQ ID NO.: 393)

[0233] NPD015s-AD083 (SEQ ID NO.: 197 and SEQ ID NO.: 394)

[0234] NPD015s-AD084 (SEQ ID NO.: 198 and SEQ ID NO.: 395)

[0235] NPD015s-AD085 (SEQ ID NO.: 199 and SEQ ID NO.: 396)

[0236] NPD015s-AD086 (SEQ ID NO.: 200 and SEQ ID NO.: 397)

[0237] NPD015s-AD087 (SEQ ID NO.: 201 and SEQ ID NO.: 398)

[0238] NPD015s-AD098 (SEQ ID NO.: 212 and SEQ ID NO.: 409)

[0239] NPD015s-AD099 (SEQ ID NO.: 213 and SEQ ID NO.: 410)

[0240] NPD015s-AD100 (SEQ ID NO.: 214 and SEQ ID NO.: 411)

[0241] NPD015s-AD101 (SEQ ID NO.: 215 and SEQ ID NO.: 412)

[0242] NPD015s-AD102 (SEQ ID NO.: 216 and SEQ ID NO.: 413)

[0243] NPD015s-AD103 (SEQ ID NO.: 217 and SEQ ID NO.: 414)

[0244] NPD015s-AD104 (SEQ ID NO.: 218 and SEQ ID NO.: 415)

[0245] NPD015s-AD105 (SEQ ID NO.: 219 and SEQ ID NO.: 416)

[0246] NPD015s-AD106 (SEQ ID NO.: 220 and SEQ ID NO.: 417)

[0247] NPD015s-AD107 (SEQ ID NO.: 221 and SEQ ID NO.: 418)

[0248] NPD015s-AD108 (SEQ ID NO.: 222 and SEQ ID NO.: 419)

[0249] NPD015s-AD109 (SEQ ID NO.: 223 and SEQ ID NO.: 420)

[0250] NPD015s-AD110 (SEQ ID NO.: 224 and SEQ ID NO.: 421)

[0251] NPD015s-AD111 (SEQ ID NO.: 225 and SEQ ID NO.: 422)

[0252] NPD015s-AD112 (SEQ ID NO.: 226 and SEQ ID NO.: 423)

[0253] NPD015s-AD113 (SEQ ID NO.: 227 and SEQ ID NO.: 424)

[0254] NPD015s-AD114 (SEQ ID NO.: 228 and SEQ ID NO.: 425)

[0255] NPD015s-AD115 (SEQ ID NO.: 229 and SEQ ID NO.: 426)

[0256] NPD015s-AD116 (SEQ ID NO.: 230 and SEQ ID NO.: 427)

[0257] NPD015s-AD117 (SEQ ID NO.: 231 and SEQ ID NO.: 428)

[0258] NPD015s-AD138 (SEQ ID NO.: 252 and SEQ ID NO.: 449)

[0259] NPD015s-AD139 (SEQ ID NO.: 253 and SEQ ID NO.: 450)

[0260] NPD015s-AD140 (SEQ ID NO.: 254 and SEQ ID NO.: 451)

[0261] NPD015s-AD141 (SEQ ID NO.: 255 and SEQ ID NO.: 452)

[0262] NPD015s-AD142 (SEQ ID NO.: 256 and SEQ ID NO.: 453)

[0263] NPD015s-AD143 (SEQ ID NO.: 257 and SEQ ID NO.: 454)

[0264] NPD015s-AD144 (SEQ ID NO.: 258 and SEQ ID NO.: 455)

[0265] NPD015s-AD145 (SEQ ID NO.: 259 and SEQ ID NO.: 456)

[0266] NPD015s-AD146 (SEQ ID NO.: 260 and SEQ ID NO.: 457)

[0267] NPD015s-AD147 (SEQ ID NO.: 261 and SEQ ID NO.: 458)

[0268] NPD015s-AD148 (SEQ ID NO.: 262 and SEQ ID NO.: 459)

[0269] NPD015s-AD149 (SEQ ID NO.: 263 and SEQ ID NO.: 460)

[0270] NPD015s-AD150 (SEQ ID NO.: 264 and SEQ ID NO.: 461)

[0271] NPD015s-AD151 (SEQ ID NO.: 265 and SEQ ID NO.: 462)

[0272] NPD015s-AD152 (SEQ ID NO.: 266 and SEQ ID NO.: 463)

[0273] NPD015s-AD153 (SEQ ID NO.: 267 and SEQ ID NO.: 464)

[0274] NPD015s-AD154 (SEQ ID NO.: 268 and SEQ ID NO.: 465)

[0275] NPD015s-AD155 (SEQ ID NO.: 269 and SEQ ID NO.: 466)

[0276] NPD015s-AD156 (SEQ ID NO.: 270 and SEQ ID NO.: 467)

[0277] NPD015s-AD157 (SEQ ID NO.: 271 and SEQ ID NO.: 468)

[0278] NPD015s-AD168 (SEQ ID NO.: 282 and SEQ ID NO.: 479)

[0279] NPD015s-AD169 (SEQ ID NO.:283 and SEQ ID NO.:480)

[0280] NPD015s-AD170 (SEQ ID NO.: 284 and SEQ ID NO.: 481)

[0281] NPD015s-AD171 (SEQ ID NO.: 285 and SEQ ID NO.: 482)

[0282] NPD015s-AD172 (SEQ ID NO.: 286 and SEQ ID NO.: 483)

[0283] NPD015s-AD173 (SEQ ID NO.: 287 and SEQ ID NO.: 484)

[0284] NPD015s-AD174 (SEQ ID NO.: 288 and SEQ ID NO.: 485)

[0285] NPD015s-AD175 (SEQ ID NO.: 289 and SEQ ID NO.: 486)

[0286] NPD015s-AD176 (SEQ ID NO.: 290 and SEQ ID NO.: 487)

[0287] NPD015s-AD177 (SEQ ID NO.: 291 and SEQ ID NO.: 488)

[0288] NPD015s-AD178 (SEQ ID NO.: 292 and SEQ ID NO.: 489)

[0289] NPD015s-AD179 (SEQ ID NO.: 293 and SEQ ID NO.: 490)

[0290] NPD015s-AD180 (SEQ ID NO.: 294 and SEQ ID NO.: 491)

[0291] NPD015s-AD181 (SEQ ID NO.: 295 and SEQ ID NO.: 492)

[0292] NPD015s-AD182 (SEQ ID NO.: 296 and SEQ ID NO.: 493)

[0293] NPD015s-AD183 (SEQ ID NO.: 297 and SEQ ID NO.: 494)

[0294] NPD015s-AD184 (SEQ ID NO.: 298 and SEQ ID NO.: 495)

[0295] NPD015s-AD185 (SEQ ID NO.: 299 and SEQ ID NO.: 496)

[0296] NPD015s-AD186 (SEQ ID NO.: 300 and SEQ ID NO.: 497)

[0297] NPD015s-AD187 (SEQ ID NO.: 301 and SEQ ID NO.: 498).

[0298] According to an embodiment of the present invention, the siRNA antisense strand comprises a chemically modified nucleotide sequence selected from SEQ ID NO.: 312 to SEQ ID NO.: 508, and the sense strand comprises a duplex chemically modified nucleotide sequence selected from SEQ ID NO.: 115 to SEQ ID NO.: 311.

[0299] 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 group consisting of:

[0300] NPD015s-AD002 (SEQ ID NO.: 116 and SEQ ID NO.: 313)

[0301] NPD015s-AD004 (SEQ ID NO.: 118 and SEQ ID NO.: 315)

[0302] NPD015s-AD006 (SEQ ID NO.: 120 and SEQ ID NO.: 317)

[0303] NPD015s-AD007 (SEQ ID NO.: 121 and SEQ ID NO.: 318)

[0304] NPD015s-AD011 (SEQ ID NO.: 125 and SEQ ID NO.: 322)

[0305] NPD015s-AD016 (SEQ ID NO.: 130 and SEQ ID NO.: 327)

[0306] NPD015s-AD017 (SEQ ID NO.: 131 and SEQ ID NO.: 328)

[0307] NPD015s-AD020 (SEQ ID NO.: 134 and SEQ ID NO.: 331)

[0308] NPD015s-AD026 (SEQ ID NO.: 140 and SEQ ID NO.: 337)

[0309] NPD015s-AD027 (SEQ ID NO.: 141 and SEQ ID NO.: 338)

[0310] NPD015s-AD029 (SEQ ID NO.: 143 and SEQ ID NO.: 340)

[0311] NPD015s-AD031 (SEQ ID NO.: 145 and SEQ ID NO.: 342)

[0312] NPD015s-AD037 (SEQ ID NO.: 151 and SEQ ID NO.: 348)

[0313] NPD015s-AD040 (SEQ ID NO.: 154 and SEQ ID NO.: 351)

[0314] NPD015s-AD045 (SEQ ID NO.: 159 and SEQ ID NO.: 356)

[0315] NPD015s-AD056 (SEQ ID NO.: 170 and SEQ ID NO.: 367)

[0316] NPD015s-AD058 (SEQ ID NO.: 172 and SEQ ID NO.: 369)

[0317] NPD015s-AD059 (SEQ ID NO.: 173 and SEQ ID NO.: 370)

[0318] NPD015s-AD060 (SEQ ID NO.: 174 and SEQ ID NO.: 371)

[0319] NPD015s-AD061 (SEQ ID NO.: 175 and SEQ ID NO.: 372)

[0320] NPD015s-AD062 (SEQ ID NO.: 176 and SEQ ID NO.: 373)

[0321] NPD015s-AD063 (SEQ ID NO.: 177 and SEQ ID NO.: 374)

[0322] NPD015s-AD064 (SEQ ID NO.: 178 and SEQ ID NO.: 375)

[0323] NPD015s-AD065 (SEQ ID NO.: 179 and SEQ ID NO.: 376)

[0324] NPD015s-AD066 (SEQ ID NO.: 180 and SEQ ID NO.: 377)

[0325] NPD015s-AD067 (SEQ ID NO.: 181 and SEQ ID NO.: 378)

[0326] NPD015s-AD078 (SEQ ID NO.: 192 and SEQ ID NO.: 389)

[0327] NPD015s-AD079 (SEQ ID NO.: 193 and SEQ ID NO.: 390)

[0328] NPD015s-AD080 (SEQ ID NO.: 194 and SEQ ID NO.: 391)

[0329] NPD015s-AD081 (SEQ ID NO.: 195 and SEQ ID NO.: 392)

[0330] NPD015s-AD082 (SEQ ID NO.: 196 and SEQ ID NO.: 393)

[0331] NPD015s-AD083 (SEQ ID NO.: 197 and SEQ ID NO.: 394)

[0332] NPD015s-AD084 (SEQ ID NO.: 198 and SEQ ID NO.: 395)

[0333] NPD015s-AD085 (SEQ ID NO.: 199 and SEQ ID NO.: 396)

[0334] NPD015s-AD086 (SEQ ID NO.: 200 and SEQ ID NO.: 397)

[0335] NPD015s-AD087 (SEQ ID NO.: 201 and SEQ ID NO.: 398)

[0336] NPD015s-AD098 (SEQ ID NO.: 212 and SEQ ID NO.: 409)

[0337] NPD015s-AD099 (SEQ ID NO.: 213 and SEQ ID NO.: 410)

[0338] NPD015s-AD100 (SEQ ID NO.: 214 and SEQ ID NO.: 411)

[0339] NPD015s-AD101 (SEQ ID NO.: 215 and SEQ ID NO.: 412)

[0340] NPD015s-AD102 (SEQ ID NO.: 216 and SEQ ID NO.: 413)

[0341] NPD015s-AD103 (SEQ ID NO.: 217 and SEQ ID NO.: 414)

[0342] NPD015s-AD104 (SEQ ID NO.: 218 and SEQ ID NO.: 415)

[0343] NPD015s-AD105 (SEQ ID NO.: 219 and SEQ ID NO.: 416)

[0344] NPD015s-AD106 (SEQ ID NO.: 220 and SEQ ID NO.: 417)

[0345] NPD015s-AD107 (SEQ ID NO.: 221 and SEQ ID NO.: 418)

[0346] NPD015s-AD108 (SEQ ID NO.: 222 and SEQ ID NO.: 419)

[0347] NPD015s-AD109 (SEQ ID NO.: 223 and SEQ ID NO.: 420)

[0348] NPD015s-AD110 (SEQ ID NO.: 224 and SEQ ID NO.: 421)

[0349] NPD015s-AD111 (SEQ ID NO.: 225 and SEQ ID NO.: 422)

[0350] NPD015s-AD112 (SEQ ID NO.: 226 and SEQ ID NO.: 423)

[0351] NPD015s-AD113 (SEQ ID NO.: 227 and SEQ ID NO.: 424)

[0352] NPD015s-AD114 (SEQ ID NO.: 228 and SEQ ID NO.: 425)

[0353] NPD015s-AD115 (SEQ ID NO.: 229 and SEQ ID NO.: 426)

[0354] NPD015s-AD116 (SEQ ID NO.: 230 and SEQ ID NO.: 427)

[0355] NPD015s-AD117 (SEQ ID NO.: 231 and SEQ ID NO.: 428)

[0356] NPD015s-AD138 (SEQ ID NO.: 252 and SEQ ID NO.: 449)

[0357] NPD015s-AD139 (SEQ ID NO.: 253 and SEQ ID NO.: 450)

[0358] NPD015s-AD140 (SEQ ID NO.: 254 and SEQ ID NO.: 451)

[0359] NPD015s-AD141 (SEQ ID NO.: 255 and SEQ ID NO.: 452)

[0360] NPD015s-AD142 (SEQ ID NO.: 256 and SEQ ID NO.: 453)

[0361] NPD015s-AD143 (SEQ ID NO.: 257 and SEQ ID NO.: 454)

[0362] NPD015s-AD144 (SEQ ID NO.: 258 and SEQ ID NO.: 455)

[0363] NPD015s-AD145 (SEQ ID NO.: 259 and SEQ ID NO.: 456)

[0364] NPD015s-AD146 (SEQ ID NO.: 260 and SEQ ID NO.: 457)

[0365] NPD015s-AD147 (SEQ ID NO.: 261 and SEQ ID NO.: 458)

[0366] NPD015s-AD148 (SEQ ID NO.: 262 and SEQ ID NO.: 459)

[0367] NPD015s-AD149 (SEQ ID NO.: 263 and SEQ ID NO.: 460)

[0368] NPD015s-AD150 (SEQ ID NO.: 264 and SEQ ID NO.: 461)

[0369] NPD015s-AD151 (SEQ ID NO.: 265 and SEQ ID NO.: 462)

[0370] NPD015s-AD152 (SEQ ID NO.: 266 and SEQ ID NO.: 463)

[0371] NPD015s-AD153 (SEQ ID NO.: 267 and SEQ ID NO.: 464)

[0372] NPD015s-AD154 (SEQ ID NO.: 268 and SEQ ID NO.: 465)

[0373] NPD015s-AD155 (SEQ ID NO.: 269 and SEQ ID NO.: 466)

[0374] NPD015s-AD156 (SEQ ID NO.: 270 and SEQ ID NO.: 467)

[0375] NPD015s-AD157 (SEQ ID NO.: 271 and SEQ ID NO.: 468)

[0376] NPD015s-AD168 (SEQ ID NO.: 282 and SEQ ID NO.: 479)

[0377] NPD015s-AD169 (SEQ ID NO.:283 and SEQ ID NO.:480)

[0378] NPD015s-AD170 (SEQ ID NO.: 284 and SEQ ID NO.: 481)

[0379] NPD015s-AD171 (SEQ ID NO.: 285 and SEQ ID NO.: 482)

[0380] NPD015s-AD172 (SEQ ID NO.: 286 and SEQ ID NO.: 483)

[0381] NPD015s-AD173 (SEQ ID NO.: 287 and SEQ ID NO.: 484)

[0382] NPD015s-AD174 (SEQ ID NO.: 288 and SEQ ID NO.: 485)

[0383] NPD015s-AD175 (SEQ ID NO.: 289 and SEQ ID NO.: 486)

[0384] NPD015s-AD176 (SEQ ID NO.: 290 and SEQ ID NO.: 487)

[0385] NPD015s-AD177 (SEQ ID NO.: 291 and SEQ ID NO.: 488)

[0386] NPD015s-AD178 (SEQ ID NO.: 292 and SEQ ID NO.: 489)

[0387] NPD015s-AD179 (SEQ ID NO.: 293 and SEQ ID NO.: 490)

[0388] NPD015s-AD180 (SEQ ID NO.: 294 and SEQ ID NO.: 491)

[0389] NPD015s-AD181 (SEQ ID NO.: 295 and SEQ ID NO.: 492)

[0390] NPD015s-AD182 (SEQ ID NO.: 296 and SEQ ID NO.: 493)

[0391] NPD015s-AD183 (SEQ ID NO.: 297 and SEQ ID NO.: 494)

[0392] NPD015s-AD184 (SEQ ID NO.: 298 and SEQ ID NO.: 495)

[0393] NPD015s-AD185 (SEQ ID NO.: 299 and SEQ ID NO.: 496)

[0394] NPD015s-AD186 (SEQ ID NO.: 300 and SEQ ID NO.: 497)

[0395] NPD015s-AD187 (SEQ ID NO.: 301 and SEQ ID NO.: 498)

[0396] In another aspect of the present invention, an siRNA conjugate is provided. 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 experimentally discovered that the addition of a delivery vector to the above-mentioned siRNA conjugate can further enhance the degradation of LPA mRNA, specifically reduce the synthesis of Apo(a) by hepatocytes, and thereby reduce LPA in the body, thereby effectively preventing or treating related diseases, such as Buerger's disease, peripheral artery disease, coronary artery disease, metabolic syndrome, acute coronary syndrome, aortic stenosis, aortic regurgitation, aortic dissection, retinal artery occlusion, cardiovascular and cerebrovascular diseases, mesenteric ischemia, superior mesenteric artery occlusion, renal artery stenosis, stable / unstable angina, acute coronary syndrome, heterozygous or homozygous familial hypercholesterolemia, hyperlipoprotein betalipoproteinemia, atherosclerosis, and venous thrombosis.

[0397] In the present invention, the "difference of 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 nucleotide deletion, nucleotide insertion (which can be inserted into the 3'-end, 5'-end or between any two nucleotides of the nucleotide sequence), nucleotide substitution, etc.

[0398] A delivery vector refers to a class of substances that can alter the tissue distribution of siRNA and target specific tissues, for example, compared to species in which the delivery vector is not present, the delivery vector provides enhanced affinity for a selected target (e.g., a molecule, a cell or cell type, a compartment (e.g., a cell or organ compartment, a body tissue, an organ, or a region). The delivery vector can be a natural protein (e.g., human serum albumin (HSA)), a carbohydrate (e.g., dextran and chitosan), 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 and antisense chains in the siRNA.

[0399] According to an embodiment of the present invention, the delivery vector is connected to the sense strand of the siRNA.

[0400] 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.

[0401] According to an embodiment of the present invention, the delivery vector is a GalNAc-derived compound;

[0402] According to an embodiment of the present invention, the GalNAc derivative compound includes at least one selected from 1043, 1046, 1048, 1059 and 1060:

[0403] According to an embodiment of the present invention, the antisense strand of the siRNA conjugate comprises a chemically modified nucleotide sequence selected from the duplex of SEQ ID NO.: 706 to SEQ ID NO.: 902.

[0404] According to an embodiment of the present invention, the antisense strand of the siRNA conjugate comprises a chemically modified nucleotide sequence selected from the following duplexes:

[0405] NPD015s-AD199 (SEQ ID NO.:510 and SEQ ID NO.:707)

[0406] NPD015s-AD201 (SEQ ID NO.: 512 and SEQ ID NO.: 709)

[0407] NPD015s-AD203 (SEQ ID NO.: 514 and SEQ ID NO.: 711)

[0408] NPD015s-AD204 (SEQ ID NO.: 515 and SEQ ID NO.: 712)

[0409] NPD015s-AD208 (SEQ ID NO.: 519 and SEQ ID NO.: 716)

[0410] NPD015s-AD213 (SEQ ID NO.: 524 and SEQ ID NO.: 721)

[0411] NPD015s-AD214 (SEQ ID NO.: 525 and SEQ ID NO.: 722)

[0412] NPD015s-AD217 (SEQ ID NO.: 528 and SEQ ID NO.: 725)

[0413] NPD015s-AD223 (SEQ ID NO.: 534 and SEQ ID NO.: 731)

[0414] NPD015s-AD224 (SEQ ID NO.: 535 and SEQ ID NO.: 732)

[0415] NPD015s-AD226 (SEQ ID NO.: 537 and SEQ ID NO.: 734)

[0416] NPD015s-AD228 (SEQ ID NO.: 539 and SEQ ID NO.: 736)

[0417] NPD015s-AD234 (SEQ ID NO.: 545 and SEQ ID NO.: 742)

[0418] NPD015s-AD237 (SEQ ID NO.: 548 and SEQ ID NO.: 745)

[0419] NPD015s-AD242 (SEQ ID NO.: 553 and SEQ ID NO.: 750)

[0420] NPD015s-AD253 (SEQ ID NO.: 564 and SEQ ID NO.: 761)

[0421] NPD015s-AD255 (SEQ ID NO.: 566 and SEQ ID NO.: 763)

[0422] NPD015s-AD256 (SEQ ID NO.: 567 and SEQ ID NO.: 764)

[0423] NPD015s-AD257 (SEQ ID NO.: 568 and SEQ ID NO.: 765)

[0424] NPD015s-AD258 (SEQ ID NO.: 569 and SEQ ID NO.: 766)

[0425] NPD015s-AD259 (SEQ ID NO.: 570 and SEQ ID NO.: 767)

[0426] NPD015s-AD260 (SEQ ID NO.: 571 and SEQ ID NO.: 768)

[0427] NPD015s-AD261 (SEQ ID NO.: 572 and SEQ ID NO.: 769)

[0428] NPD015s-AD262 (SEQ ID NO.: 573 and SEQ ID NO.: 770)

[0429] NPD015s-AD263 (SEQ ID NO.: 574 and SEQ ID NO.: 771)

[0430] NPD015s-AD264 (SEQ ID NO.: 575 and SEQ ID NO.: 772)

[0431] NPD015s-AD275 (SEQ ID NO.: 586 and SEQ ID NO.: 783)

[0432] NPD015s-AD276 (SEQ ID NO.: 587 and SEQ ID NO.: 784)

[0433] NPD015s-AD277 (SEQ ID NO.: 588 and SEQ ID NO.: 785)

[0434] NPD015s-AD278 (SEQ ID NO.: 589 and SEQ ID NO.: 786)

[0435] NPD015s-AD279 (SEQ ID NO.: 590 and SEQ ID NO.: 787)

[0436] NPD015s-AD280 (SEQ ID NO.: 591 and SEQ ID NO.: 788)

[0437] NPD015s-AD281 (SEQ ID NO.: 592 and SEQ ID NO.: 789)

[0438] NPD015s-AD282 (SEQ ID NO.: 593 and SEQ ID NO.: 790)

[0439] NPD015s-AD283 (SEQ ID NO.: 594 and SEQ ID NO.: 791)

[0440] NPD015s-AD284 (SEQ ID NO.: 595 and SEQ ID NO.: 792)

[0441] NPD015s-AD295 (SEQ ID NO.: 596 and SEQ ID NO.: 803)

[0442] NPD015s-AD296 (SEQ ID NO.: 597 and SEQ ID NO.: 804)

[0443] NPD015s-AD297 (SEQ ID NO.: 598 and SEQ ID NO.: 805)

[0444] NPD015s-AD298 (SEQ ID NO.: 599 and SEQ ID NO.: 806)

[0445] NPD015s-AD299 (SEQ ID NO.: 600 and SEQ ID NO.: 807)

[0446] NPD015s-AD300 (SEQ ID NO.: 601 and SEQ ID NO.: 808)

[0447] NPD015s-AD301 (SEQ ID NO.: 602 and SEQ ID NO.: 809)

[0448] NPD015s-AD302 (SEQ ID NO.: 603 and SEQ ID NO.: 810)

[0449] NPD015s-AD303 (SEQ ID NO.: 604 and SEQ ID NO.: 811)

[0450] NPD015s-AD304 (SEQ ID NO.: 605 and SEQ ID NO.: 812)

[0451] NPD015s-AD305 (SEQ ID NO.: 606 and SEQ ID NO.: 813)

[0452] NPD015s-AD306 (SEQ ID NO.: 607 and SEQ ID NO.: 814)

[0453] NPD015s-AD307 (SEQ ID NO.: 608 and SEQ ID NO.: 815)

[0454] NPD015s-AD308 (SEQ ID NO.: 609 and SEQ ID NO.: 816)

[0455] NPD015s-AD309 (SEQ ID NO.: 610 and SEQ ID NO.: 817)

[0456] NPD015s-AD310 (SEQ ID NO.: 611 and SEQ ID NO.: 818)

[0457] NPD015s-AD311 (SEQ ID NO.: 612 and SEQ ID NO.: 819)

[0458] NPD015s-AD312 (SEQ ID NO.: 613 and SEQ ID NO.: 820)

[0459] NPD015s-AD313 (SEQ ID NO.: 614 and SEQ ID NO.: 821)

[0460] NPD015s-AD314 (SEQ ID NO.: 615 and SEQ ID NO.: 822)

[0461] NPD015s-AD335 (SEQ ID NO.: 646 and SEQ ID NO.: 843)

[0462] NPD015s-AD336 (SEQ ID NO.: 647 and SEQ ID NO.: 844)

[0463] NPD015s-AD337 (SEQ ID NO.: 648 and SEQ ID NO.: 845)

[0464] NPD015s-AD338 (SEQ ID NO.: 649 and SEQ ID NO.: 846)

[0465] NPD015s-AD339 (SEQ ID NO.:650 and SEQ ID NO.:847)

[0466] NPD015s-AD340 (SEQ ID NO.: 651 and SEQ ID NO.: 848)

[0467] NPD015s-AD341 (SEQ ID NO.: 652 and SEQ ID NO.: 849)

[0468] NPD015s-AD342 (SEQ ID NO.: 653 and SEQ ID NO.: 850)

[0469] NPD015s-AD343 (SEQ ID NO.: 654 and SEQ ID NO.: 851)

[0470] NPD015s-AD344 (SEQ ID NO.: 655 and SEQ ID NO.: 852)

[0471] NPD015s-AD345 (SEQ ID NO.: 656 and SEQ ID NO.: 853)

[0472] NPD015s-AD346 (SEQ ID NO.: 657 and SEQ ID NO.: 854)

[0473] NPD015s-AD347 (SEQ ID NO.: 658 and SEQ ID NO.: 855)

[0474] NPD015s-AD348 (SEQ ID NO.: 659 and SEQ ID NO.: 856)

[0475] NPD015s-AD349 (SEQ ID NO.: 660 and SEQ ID NO.: 857)

[0476] NPD015s-AD350 (SEQ ID NO.: 661 and SEQ ID NO.: 858)

[0477] NPD015s-AD351 (SEQ ID NO.: 662 and SEQ ID NO.: 859)

[0478] NPD015s-AD352 (SEQ ID NO.: 663 and SEQ ID NO.: 860)

[0479] NPD015s-AD353 (SEQ ID NO.:664 and SEQ ID NO.:861)

[0480] NPD015s-AD354 (SEQ ID NO.: 665 and SEQ ID NO.: 862)

[0481] NPD015s-AD365 (SEQ ID NO.: 676 and SEQ ID NO.: 873)

[0482] NPD015s-AD366 (SEQ ID NO.: 677 and SEQ ID NO.: 874)

[0483] NPD015s-AD367 (SEQ ID NO.: 678 and SEQ ID NO.: 875)

[0484] NPD015s-AD368 (SEQ ID NO.: 679 and SEQ ID NO.: 876)

[0485] NPD015s-AD369 (SEQ ID NO.: 680 and SEQ ID NO.: 877)

[0486] NPD015s-AD370 (SEQ ID NO.: 681 and SEQ ID NO.: 878)

[0487] NPD015s-AD371 (SEQ ID NO.: 682 and SEQ ID NO.: 879)

[0488] NPD015s-AD372 (SEQ ID NO.: 683 and SEQ ID NO.: 880)

[0489] NPD015s-AD373 (SEQ ID NO.: 684 and SEQ ID NO.: 881)

[0490] NPD015s-AD374 (SEQ ID NO.: 685 and SEQ ID NO.: 882)

[0491] NPD015s-AD375 (SEQ ID NO.: 686 and SEQ ID NO.: 883)

[0492] NPD015s-AD376 (SEQ ID NO.: 687 and SEQ ID NO.: 884)

[0493] NPD015s-AD377 (SEQ ID NO.: 688 and SEQ ID NO.: 885)

[0494] NPD015s-AD378 (SEQ ID NO.: 689 and SEQ ID NO.: 886)

[0495] NPD015s-AD379 (SEQ ID NO.: 690 and SEQ ID NO.: 887)

[0496] NPD015s-AD380 (SEQ ID NO.: 691 and SEQ ID NO.: 888)

[0497] NPD015s-AD381 (SEQ ID NO.: 692 and SEQ ID NO.: 889)

[0498] NPD015s-AD382 (SEQ ID NO.: 693 and SEQ ID NO.: 890)

[0499] NPD015s-AD383 (SEQ ID NO.: 694 and SEQ ID NO.: 891)

[0500] NPD015s-AD384 (SEQ ID NO.: 695 and SEQ ID NO.: 892)

[0501] According to an embodiment of the present invention, the sense strand of the siRNA conjugate comprises a chemically modified nucleotide sequence selected from the duplex of SEQ ID NO.: 509 to SEQ ID NO.: 705.

[0502] According to an embodiment of the present invention, the sense strand of the siRNA conjugate comprises a chemically modified nucleotide sequence selected from the following duplexes:

[0503] NPD015s-AD199 (SEQ ID NO.:510 and SEQ ID NO.:707)

[0504] NPD015s-AD201 (SEQ ID NO.: 512 and SEQ ID NO.: 709)

[0505] NPD015s-AD203 (SEQ ID NO.: 514 and SEQ ID NO.: 711)

[0506] NPD015s-AD204 (SEQ ID NO.: 515 and SEQ ID NO.: 712)

[0507] NPD015s-AD208 (SEQ ID NO.: 519 and SEQ ID NO.: 716)

[0508] NPD015s-AD213 (SEQ ID NO.: 524 and SEQ ID NO.: 721)

[0509] NPD015s-AD214 (SEQ ID NO.: 525 and SEQ ID NO.: 722)

[0510] NPD015s-AD217 (SEQ ID NO.: 528 and SEQ ID NO.: 725)

[0511] NPD015s-AD223 (SEQ ID NO.: 534 and SEQ ID NO.: 731)

[0512] NPD015s-AD224 (SEQ ID NO.: 535 and SEQ ID NO.: 732)

[0513] NPD015s-AD226 (SEQ ID NO.: 537 and SEQ ID NO.: 734)

[0514] NPD015s-AD228 (SEQ ID NO.: 539 and SEQ ID NO.: 736)

[0515] NPD015s-AD234 (SEQ ID NO.: 545 and SEQ ID NO.: 742)

[0516] NPD015s-AD237 (SEQ ID NO.: 548 and SEQ ID NO.: 745)

[0517] NPD015s-AD242 (SEQ ID NO.: 553 and SEQ ID NO.: 750)

[0518] NPD015s-AD253 (SEQ ID NO.: 564 and SEQ ID NO.: 761)

[0519] NPD015s-AD255 (SEQ ID NO.: 566 and SEQ ID NO.: 763)

[0520] NPD015s-AD256 (SEQ ID NO.: 567 and SEQ ID NO.: 764)

[0521] NPD015s-AD257 (SEQ ID NO.: 568 and SEQ ID NO.: 765)

[0522] NPD015s-AD258 (SEQ ID NO.: 569 and SEQ ID NO.: 766)

[0523] NPD015s-AD259 (SEQ ID NO.: 570 and SEQ ID NO.: 767)

[0524] NPD015s-AD260 (SEQ ID NO.: 571 and SEQ ID NO.: 768)

[0525] NPD015s-AD261 (SEQ ID NO.: 572 and SEQ ID NO.: 769)

[0526] NPD015s-AD262 (SEQ ID NO.: 573 and SEQ ID NO.: 770)

[0527] NPD015s-AD263 (SEQ ID NO.: 574 and SEQ ID NO.: 771)

[0528] NPD015s-AD264 (SEQ ID NO.: 575 and SEQ ID NO.: 772)

[0529] NPD015s-AD275 (SEQ ID NO.: 586 and SEQ ID NO.: 783)

[0530] NPD015s-AD276 (SEQ ID NO.: 587 and SEQ ID NO.: 784)

[0531] NPD015s-AD277 (SEQ ID NO.: 588 and SEQ ID NO.: 785)

[0532] NPD015s-AD278 (SEQ ID NO.: 589 and SEQ ID NO.: 786)

[0533] NPD015s-AD279 (SEQ ID NO.: 590 and SEQ ID NO.: 787)

[0534] NPD015s-AD280 (SEQ ID NO.: 591 and SEQ ID NO.: 788)

[0535] NPD015s-AD281 (SEQ ID NO.: 592 and SEQ ID NO.: 789)

[0536] NPD015s-AD282 (SEQ ID NO.: 593 and SEQ ID NO.: 790)

[0537] NPD015s-AD283 (SEQ ID NO.: 594 and SEQ ID NO.: 791)

[0538] NPD015s-AD284 (SEQ ID NO.: 595 and SEQ ID NO.: 792)

[0539] NPD015s-AD295 (SEQ ID NO.: 596 and SEQ ID NO.: 803)

[0540] NPD015s-AD296 (SEQ ID NO.: 597 and SEQ ID NO.: 804)

[0541] NPD015s-AD297 (SEQ ID NO.: 598 and SEQ ID NO.: 805)

[0542] NPD015s-AD298 (SEQ ID NO.: 599 and SEQ ID NO.: 806)

[0543] NPD015s-AD299 (SEQ ID NO.: 600 and SEQ ID NO.: 807)

[0544] NPD015s-AD300 (SEQ ID NO.: 601 and SEQ ID NO.: 808)

[0545] NPD015s-AD301 (SEQ ID NO.: 602 and SEQ ID NO.: 809)

[0546] NPD015s-AD302 (SEQ ID NO.: 603 and SEQ ID NO.: 810)

[0547] NPD015s-AD303 (SEQ ID NO.: 604 and SEQ ID NO.: 811)

[0548] NPD015s-AD304 (SEQ ID NO.: 605 and SEQ ID NO.: 812)

[0549] NPD015s-AD305 (SEQ ID NO.: 606 and SEQ ID NO.: 813)

[0550] NPD015s-AD306 (SEQ ID NO.: 607 and SEQ ID NO.: 814)

[0551] NPD015s-AD307 (SEQ ID NO.: 608 and SEQ ID NO.: 815)

[0552] NPD015s-AD308 (SEQ ID NO.: 609 and SEQ ID NO.: 816)

[0553] NPD015s-AD309 (SEQ ID NO.: 610 and SEQ ID NO.: 817)

[0554] NPD015s-AD310 (SEQ ID NO.: 611 and SEQ ID NO.: 818)

[0555] NPD015s-AD311 (SEQ ID NO.: 612 and SEQ ID NO.: 819)

[0556] NPD015s-AD312 (SEQ ID NO.: 613 and SEQ ID NO.: 820)

[0557] NPD015s-AD313 (SEQ ID NO.: 614 and SEQ ID NO.: 821)

[0558] NPD015s-AD314 (SEQ ID NO.: 615 and SEQ ID NO.: 822)

[0559] NPD015s-AD335 (SEQ ID NO.: 646 and SEQ ID NO.: 843)

[0560] NPD015s-AD336 (SEQ ID NO.: 647 and SEQ ID NO.: 844)

[0561] NPD015s-AD337 (SEQ ID NO.: 648 and SEQ ID NO.: 845)

[0562] NPD015s-AD338 (SEQ ID NO.: 649 and SEQ ID NO.: 846)

[0563] NPD015s-AD339 (SEQ ID NO.:650 and SEQ ID NO.:847)

[0564] NPD015s-AD340 (SEQ ID NO.: 651 and SEQ ID NO.: 848)

[0565] NPD015s-AD341 (SEQ ID NO.: 652 and SEQ ID NO.: 849)

[0566] NPD015s-AD342 (SEQ ID NO.: 653 and SEQ ID NO.: 850)

[0567] NPD015s-AD343 (SEQ ID NO.: 654 and SEQ ID NO.: 851)

[0568] NPD015s-AD344 (SEQ ID NO.: 655 and SEQ ID NO.: 852)

[0569] NPD015s-AD345 (SEQ ID NO.: 656 and SEQ ID NO.: 853)

[0570] NPD015s-AD346 (SEQ ID NO.: 657 and SEQ ID NO.: 854)

[0571] NPD015s-AD347 (SEQ ID NO.: 658 and SEQ ID NO.: 855)

[0572] NPD015s-AD348 (SEQ ID NO.: 659 and SEQ ID NO.: 856)

[0573] NPD015s-AD349 (SEQ ID NO.: 660 and SEQ ID NO.: 857)

[0574] NPD015s-AD350 (SEQ ID NO.: 661 and SEQ ID NO.: 858)

[0575] NPD015s-AD351 (SEQ ID NO.: 662 and SEQ ID NO.: 859)

[0576] NPD015s-AD352 (SEQ ID NO.: 663 and SEQ ID NO.: 860)

[0577] NPD015s-AD353 (SEQ ID NO.:664 and SEQ ID NO.:861)

[0578] NPD015s-AD354 (SEQ ID NO.: 665 and SEQ ID NO.: 862)

[0579] NPD015s-AD365 (SEQ ID NO.: 676 and SEQ ID NO.: 873)

[0580] NPD015s-AD366 (SEQ ID NO.: 677 and SEQ ID NO.: 874)

[0581] NPD015s-AD367 (SEQ ID NO.: 678 and SEQ ID NO.: 875)

[0582] NPD015s-AD368 (SEQ ID NO.: 679 and SEQ ID NO.: 876)

[0583] NPD015s-AD369 (SEQ ID NO.: 680 and SEQ ID NO.: 877)

[0584] NPD015s-AD370 (SEQ ID NO.: 681 and SEQ ID NO.: 878)

[0585] NPD015s-AD371 (SEQ ID NO.: 682 and SEQ ID NO.: 879)

[0586] NPD015s-AD372 (SEQ ID NO.: 683 and SEQ ID NO.: 880)

[0587] NPD015s-AD373 (SEQ ID NO.: 684 and SEQ ID NO.: 881)

[0588] NPD015s-AD374 (SEQ ID NO.: 685 and SEQ ID NO.: 882)

[0589] NPD015s-AD375 (SEQ ID NO.: 686 and SEQ ID NO.: 883)

[0590] NPD015s-AD376 (SEQ ID NO.: 687 and SEQ ID NO.: 884)

[0591] NPD015s-AD377 (SEQ ID NO.: 688 and SEQ ID NO.: 885)

[0592] NPD015s-AD378 (SEQ ID NO.: 689 and SEQ ID NO.: 886)

[0593] NPD015s-AD379 (SEQ ID NO.: 690 and SEQ ID NO.: 887)

[0594] NPD015s-AD380 (SEQ ID NO.: 691 and SEQ ID NO.: 888)

[0595] NPD015s-AD381 (SEQ ID NO.: 692 and SEQ ID NO.: 889)

[0596] NPD015s-AD382 (SEQ ID NO.: 693 and SEQ ID NO.: 890)

[0597] NPD015s-AD383 (SEQ ID NO.: 694 and SEQ ID NO.: 891)

[0598] NPD015s-AD384 (SEQ ID NO.: 695 and SEQ ID NO.: 892)

[0599] 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 SEQ ID NO.: 706 to SEQ ID NO.: 902, and the sense strand comprises a chemically modified nucleotide sequence of a duplex selected from SEQ ID NO.: 509 to SEQ ID NO.: 705.

[0600] 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 group consisting of:

[0601] NPD015s-AD199 (SEQ ID NO.:510 and SEQ ID NO.:707)

[0602] NPD015s-AD201 (SEQ ID NO.: 512 and SEQ ID NO.: 709)

[0603] NPD015s-AD203 (SEQ ID NO.: 514 and SEQ ID NO.: 711)

[0604] NPD015s-AD204 (SEQ ID NO.: 515 and SEQ ID NO.: 712)

[0605] NPD015s-AD208 (SEQ ID NO.: 519 and SEQ ID NO.: 716)

[0606] NPD015s-AD213 (SEQ ID NO.: 524 and SEQ ID NO.: 721)

[0607] NPD015s-AD214 (SEQ ID NO.: 525 and SEQ ID NO.: 722)

[0608] NPD015s-AD217 (SEQ ID NO.: 528 and SEQ ID NO.: 725)

[0609] NPD015s-AD223 (SEQ ID NO.: 534 and SEQ ID NO.: 731)

[0610] NPD015s-AD224 (SEQ ID NO.: 535 and SEQ ID NO.: 732)

[0611] NPD015s-AD226 (SEQ ID NO.: 537 and SEQ ID NO.: 734)

[0612] NPD015s-AD228 (SEQ ID NO.: 539 and SEQ ID NO.: 736)

[0613] NPD015s-AD234 (SEQ ID NO.: 545 and SEQ ID NO.: 742)

[0614] NPD015s-AD237 (SEQ ID NO.: 548 and SEQ ID NO.: 745)

[0615] NPD015s-AD242 (SEQ ID NO.: 553 and SEQ ID NO.: 750)

[0616] NPD015s-AD253 (SEQ ID NO.: 564 and SEQ ID NO.: 761)

[0617] NPD015s-AD255 (SEQ ID NO.: 566 and SEQ ID NO.: 763)

[0618] NPD015s-AD256 (SEQ ID NO.: 567 and SEQ ID NO.: 764)

[0619] NPD015s-AD257 (SEQ ID NO.: 568 and SEQ ID NO.: 765)

[0620] NPD015s-AD258 (SEQ ID NO.: 569 and SEQ ID NO.: 766)

[0621] NPD015s-AD259 (SEQ ID NO.: 570 and SEQ ID NO.: 767)

[0622] NPD015s-AD260 (SEQ ID NO.: 571 and SEQ ID NO.: 768)

[0623] NPD015s-AD261 (SEQ ID NO.: 572 and SEQ ID NO.: 769)

[0624] NPD015s-AD262 (SEQ ID NO.: 573 and SEQ ID NO.: 770)

[0625] NPD015s-AD263 (SEQ ID NO.: 574 and SEQ ID NO.: 771)

[0626] NPD015s-AD264 (SEQ ID NO.: 575 and SEQ ID NO.: 772)

[0627] NPD015s-AD275 (SEQ ID NO.: 586 and SEQ ID NO.: 783)

[0628] NPD015s-AD276 (SEQ ID NO.: 587 and SEQ ID NO.: 784)

[0629] NPD015s-AD277 (SEQ ID NO.: 588 and SEQ ID NO.: 785)

[0630] NPD015s-AD278 (SEQ ID NO.: 589 and SEQ ID NO.: 786)

[0631] NPD015s-AD279 (SEQ ID NO.: 590 and SEQ ID NO.: 787)

[0632] NPD015s-AD280 (SEQ ID NO.: 591 and SEQ ID NO.: 788)

[0633] NPD015s-AD281 (SEQ ID NO.: 592 and SEQ ID NO.: 789)

[0634] NPD015s-AD282 (SEQ ID NO.: 593 and SEQ ID NO.: 790)

[0635] NPD015s-AD283 (SEQ ID NO.: 594 and SEQ ID NO.: 791)

[0636] NPD015s-AD284 (SEQ ID NO.: 595 and SEQ ID NO.: 792)

[0637] NPD015s-AD295 (SEQ ID NO.: 596 and SEQ ID NO.: 803)

[0638] NPD015s-AD296 (SEQ ID NO.: 597 and SEQ ID NO.: 804)

[0639] NPD015s-AD297 (SEQ ID NO.: 598 and SEQ ID NO.: 805)

[0640] NPD015s-AD298 (SEQ ID NO.: 599 and SEQ ID NO.: 806)

[0641] NPD015s-AD299 (SEQ ID NO.: 600 and SEQ ID NO.: 807)

[0642] NPD015s-AD300 (SEQ ID NO.: 601 and SEQ ID NO.: 808)

[0643] NPD015s-AD301 (SEQ ID NO.: 602 and SEQ ID NO.: 809)

[0644] NPD015s-AD302 (SEQ ID NO.: 603 and SEQ ID NO.: 810)

[0645] NPD015s-AD303 (SEQ ID NO.: 604 and SEQ ID NO.: 811)

[0646] NPD015s-AD304 (SEQ ID NO.: 605 and SEQ ID NO.: 812)

[0647] NPD015s-AD305 (SEQ ID NO.: 606 and SEQ ID NO.: 813)

[0648] NPD015s-AD306 (SEQ ID NO.: 607 and SEQ ID NO.: 814)

[0649] NPD015s-AD307 (SEQ ID NO.: 608 and SEQ ID NO.: 815)

[0650] NPD015s-AD308 (SEQ ID NO.: 609 and SEQ ID NO.: 816)

[0651] NPD015s-AD309 (SEQ ID NO.: 610 and SEQ ID NO.: 817)

[0652] NPD015s-AD310 (SEQ ID NO.: 611 and SEQ ID NO.: 818)

[0653] NPD015s-AD311 (SEQ ID NO.: 612 and SEQ ID NO.: 819)

[0654] NPD015s-AD312 (SEQ ID NO.: 613 and SEQ ID NO.: 820)

[0655] NPD015s-AD313 (SEQ ID NO.: 614 and SEQ ID NO.: 821)

[0656] NPD015s-AD314 (SEQ ID NO.: 615 and SEQ ID NO.: 822)

[0657] NPD015s-AD335 (SEQ ID NO.: 646 and SEQ ID NO.: 843)

[0658] NPD015s-AD336 (SEQ ID NO.: 647 and SEQ ID NO.: 844)

[0659] NPD015s-AD337 (SEQ ID NO.: 648 and SEQ ID NO.: 845)

[0660] NPD015s-AD338 (SEQ ID NO.: 649 and SEQ ID NO.: 846)

[0661] NPD015s-AD339 (SEQ ID NO.:650 and SEQ ID NO.:847)

[0662] NPD015s-AD340 (SEQ ID NO.: 651 and SEQ ID NO.: 848)

[0663] NPD015s-AD341 (SEQ ID NO.: 652 and SEQ ID NO.: 849)

[0664] NPD015s-AD342 (SEQ ID NO.: 653 and SEQ ID NO.: 850)

[0665] NPD015s-AD343 (SEQ ID NO.: 654 and SEQ ID NO.: 851)

[0666] NPD015s-AD344 (SEQ ID NO.: 655 and SEQ ID NO.: 852)

[0667] NPD015s-AD345 (SEQ ID NO.: 656 and SEQ ID NO.: 853)

[0668] NPD015s-AD346 (SEQ ID NO.: 657 and SEQ ID NO.: 854)

[0669] NPD015s-AD347 (SEQ ID NO.: 658 and SEQ ID NO.: 855)

[0670] NPD015s-AD348 (SEQ ID NO.: 659 and SEQ ID NO.: 856)

[0671] NPD015s-AD349 (SEQ ID NO.: 660 and SEQ ID NO.: 857)

[0672] NPD015s-AD350 (SEQ ID NO.: 661 and SEQ ID NO.: 858)

[0673] NPD015s-AD351 (SEQ ID NO.: 662 and SEQ ID NO.: 859)

[0674] NPD015s-AD352 (SEQ ID NO.: 663 and SEQ ID NO.: 860)

[0675] NPD015s-AD353 (SEQ ID NO.:664 and SEQ ID NO.:861)

[0676] NPD015s-AD354 (SEQ ID NO.: 665 and SEQ ID NO.: 862)

[0677] NPD015s-AD365 (SEQ ID NO.: 676 and SEQ ID NO.: 873)

[0678] NPD015s-AD366 (SEQ ID NO.: 677 and SEQ ID NO.: 874)

[0679] NPD015s-AD367 (SEQ ID NO.: 678 and SEQ ID NO.: 875)

[0680] NPD015s-AD368 (SEQ ID NO.: 679 and SEQ ID NO.: 876)

[0681] NPD015s-AD369 (SEQ ID NO.: 680 and SEQ ID NO.: 877)

[0682] NPD015s-AD370 (SEQ ID NO.: 681 and SEQ ID NO.: 878)

[0683] NPD015s-AD371 (SEQ ID NO.: 682 and SEQ ID NO.: 879)

[0684] NPD015s-AD372 (SEQ ID NO.: 683 and SEQ ID NO.: 880)

[0685] NPD015s-AD373 (SEQ ID NO.: 684 and SEQ ID NO.: 881)

[0686] NPD015s-AD374 (SEQ ID NO.: 685 and SEQ ID NO.: 882)

[0687] NPD015s-AD375 (SEQ ID NO.: 686 and SEQ ID NO.: 883)

[0688] NPD015s-AD376 (SEQ ID NO.: 687 and SEQ ID NO.: 884)

[0689] NPD015s-AD377 (SEQ ID NO.: 688 and SEQ ID NO.: 885)

[0690] NPD015s-AD378 (SEQ ID NO.: 689 and SEQ ID NO.: 886)

[0691] NPD015s-AD379 (SEQ ID NO.: 690 and SEQ ID NO.: 887)

[0692] NPD015s-AD380 (SEQ ID NO.: 691 and SEQ ID NO.: 888)

[0693] NPD015s-AD381 (SEQ ID NO.: 692 and SEQ ID NO.: 889)

[0694] NPD015s-AD382 (SEQ ID NO.: 693 and SEQ ID NO.: 890)

[0695] NPD015s-AD383 (SEQ ID NO.: 694 and SEQ ID NO.: 891)

[0696] NPD015s-AD384 (SEQ ID NO.: 695 and SEQ ID NO.: 892)

[0697] 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 apo(a) by hepatocytes, thereby reducing Lp(a) in the body, and then effectively preventing or treating related diseases, such as Buerger's disease, peripheral artery disease, coronary artery disease, metabolic syndrome, acute coronary syndrome, aortic stenosis, aortic regurgitation, aortic dissection, retinal artery occlusion, cardiovascular and cerebrovascular diseases, mesenteric ischemia, superior mesenteric artery occlusion, renal artery stenosis, stable / unstable angina, acute coronary syndrome, heterozygous or homozygous familial hypercholesterolemia, hyperlipoprotein betalipoproteinemia, atherosclerosis and venous thrombosis.

[0698] It should be noted that the pharmaceutical composition herein may include one or more of the aforementioned siRNAs or siRNA conjugates.

[0699] According to an embodiment of the present invention, the pharmaceutical composition further comprises: a pharmaceutically acceptable excipient.

[0700] 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 LPA.

[0701] 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 for treating diseases related to abnormal LPA expression.

[0702] According to an embodiment of the present invention, the diseases associated with abnormal LPA expression are coronary artery disease, metabolic syndrome, cardiovascular and cerebrovascular diseases, heterozygous or homozygous familial hypercholesterolemia, hyperlipoprotein betalipoproteinemia and atherosclerosis.

[0703] In another aspect, the present invention provides a method for treating diseases associated with abnormal LPA expression. According to an embodiment of the present invention, the method comprises administering a pharmaceutically acceptable amount of the aforementioned siRNA, siRNA conjugate, or pharmaceutical composition to a subject. According to embodiments of the present invention, this method can effectively prevent and / or treat diseases associated with abnormal LPA expression.

[0704] 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). Such 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, the patient's weight, the patient's immune status, the route of administration, etc. For example, depending on the urgency of the treatment condition, several divided doses may be administered daily, for example, once every several days, several weeks, or several months.

[0705] 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.

[0706] According to an embodiment of the present invention, the administration route of the method is subcutaneous injection.

[0707] According to an embodiment of the present invention, the diseases associated with abnormal LPA expression are coronary artery disease, metabolic syndrome, cardiovascular and cerebrovascular diseases, heterozygous or homozygous familial hypercholesterolemia, hyperlipoprotein betalipoproteinemia and atherosclerosis.

[0708] Additional aspects and advantages of the present invention will be set forth in part in the description which follows and, in part, will be obvious from the description which follows, or may be learned by practice of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0709] FIG1 shows the changes in relative hLPa content in plasma in Example 5. DETAILED DESCRIPTION

[0710] 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.

[0711] It should be noted that the terms "first" and "second" are used for descriptive purposes only and should not be understood to indicate or imply relative importance or implicitly specify the number of the technical features indicated. Therefore, features defined as "first" or "second" may explicitly or implicitly include one or more of such features. Furthermore, in the description of the present invention, unless otherwise specified, "plurality" means two or more.

[0712] 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.

[0713] 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.

[0714] As used herein, the term "small interfering RNA (siRNA)" refers to a double-stranded RNA (dsRNA) of 17 to 25 nucleotides in length, comprising both a sense and an antisense strand. siRNAs mediate the targeted cleavage of target mRNAs via the RNA-induced silencing complex (RISC) pathway by forming a silencing complex. Specifically, siRNAs direct the specific degradation of mRNA sequences through a process known as RNA interference (RNAi), inhibiting the translation of mRNA into protein. For example, siRNAs can modulate (e.g., inhibit) LPA expression in cells.

[0715] As used herein, the term "antisense strand (or guide strand)" includes a region that is substantially complementary to a target sequence, such as LPA mRNA. The "sense strand (or follower strand)" refers to the RNAi strand that contains a region 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 occur within the interior or terminal regions of the molecule, with the most tolerated mismatches occurring within the terminal regions, for example, within 5, 4, 3, or 2 nucleotides of the 5' and / or 3' ends of the RNAi.

[0716] It should be noted that the antisense strand is "at least partially complementary to" an mRNA, meaning that the antisense strand comprises a polynucleotide that is substantially complementary to a continuous portion of an mRNA of interest (e.g., an mRNA encoding LPA). Alternatively, if a polynucleotide is substantially non-interruptedly complementary to a portion of an mRNA encoding LPA, the antisense strand is complementary to at least a portion of an LPA mRNA.

[0717] Herein, the term "target sequence" refers to a continuous portion of the nucleotide sequence of an mRNA molecule formed during transcription of the LPA gene, including mRNA that is a product of RNA processing of the primary transcript.

[0718] As used herein, the term "inhibiting LPA gene expression" includes any level of LPA gene inhibition, for example, at least partial inhibition of LPA 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%. LPA gene expression can be assessed based on the level of any variable associated with LPA gene expression, for example, LPA mRNA levels, Apo(a) protein, or Lp(a) levels. Inhibition can be assessed 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 determined from a similar subject, cell, or sample that has not been treated or has been treated with a control (e.g., a buffer-only control or a no active agent control).

[0719] As used herein, the term "LPA" includes LPA mRNA or its complete coding sequence, such as human LPA, which can be found, for example, in GenBank accession search (NM_005577.4). Other examples of LPA mRNA sequences can be obtained using publicly available databases, such as GenBank and genome project websites such as UniProt. The term "LPA" can also refer to naturally occurring DNA sequence variations of the LPA gene, such as single nucleotide polymorphisms (SNPs) in the LPA gene.

[0720] 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.

[0721] As used herein, "pharmaceutical composition" may refer to a composition for use in treating a disease or in vitro cell culture experiments. When used in treating a disease, the term "pharmaceutical composition" generally refers to a unit dosage form and can be prepared by any of the methods well known in the pharmaceutical art. All methods include the step of combining the active ingredient with an excipient that constitutes one or more adjunct ingredients. Typically, the composition is prepared by uniformly and thoroughly combining the active siRNA or siRNA conjugate with a liquid excipient, a finely divided solid excipient, or both.

[0722] As used herein, 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 mammal to be treated therewith. Preferably, the term "pharmaceutically acceptable" as used herein means approved by federal regulatory agencies or national governments or listed in the U.S. Pharmacopoeia or other generally recognized pharmacopeia for use in animals, particularly humans.

[0723] 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. Such excipients include liquid or solid fillers, diluents, excipients, solvents, or encapsulating materials that participate in carrying the subject substance or transferring it from one organ or part of the body to another. 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 gum 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.

[0724] 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.

[0725] The pharmaceutical compositions of the present disclosure include formulations suitable for oral, nasal, topical, buccal, sublingual, rectal and / or parenteral administration. The formulations 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 excipients to prepare a single dose form is generally the amount of siRNA or siRNA conjugate that produces a therapeutic effect. Generally speaking, in percent units, this amount is from about 1% to about 99% active ingredient, preferably from about 5% to about 70%, and most preferably from about 10% to about 30%.

[0726] As used herein, the term "treatment" refers to any process used 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 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 arresting the progression of the disease; or (c) alleviating the disease, such as alleviating the 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.

[0727] Below, the scheme of the present invention will be explained in conjunction with embodiment.It will be understood by those skilled in the art that the following examples are only used to illustrate the present invention and should not be regarded as limiting the scope of the present invention.In the embodiment, if specific techniques or conditions are not specified, they are carried out according to the techniques or conditions described in the literature in this area or according to the product instructions.If the manufacturer of the reagents or instruments used is not specified, they are all conventional products that can be purchased commercially.

[0728] Example 1: Design of siRNA

[0729] siRNA technology is an innovative gene knockout method with advantages such as high efficiency, specificity and reliability. It has received widespread attention in the fields of disease treatment and genetic research. The 57 siRNAs designed by the custom Python script proposed in this example for the human LPA gene (NCBI refseqID NM_005577.4) are an important advance in this technology. Unlike traditional siRNA design methods, the siRNA design method of this example relies on an independently developed Python script, which can quickly and accurately determine suitable siRNA sequences. In this experiment, 57 unmodified siRNA duplexes were prepared, named NDS-015-1 to NDS-015-57. The nucleotide sequences of the sense and antisense chains of these siRNAs are given in Table 1.

[0730] Example 2: Synthesis of siRNA and conjugates

[0731] Table 2: Nucleotide monomer abbreviations used in nucleic acid sequences

[0732] 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 500 nmol or 4 μmol scale. A 50 mM RNA phosphoramidite solution and a 200 mM GalNAc monomer solution were prepared in acetonitrile. 0.3 M benzylthiotetrazolium (BTT) in acetonitrile was used as an activator to synthesize the sense and antisense strands in the 3'-to-5' direction. During synthesis, trivalent phosphorus was converted to pentavalent phosphorus using a 0.1 M oxidizing agent (I2:pyridine:THF:water) or a 0.2 M hydroxanthin / pyridine solution to stabilize the phosphate backbone. Following synthesis, aminolysis was performed using either an AMA solution (40% methylamine:ammonia solution = 1:1) at 55°C for 50 min or 28% ammonia solution at 65°C for 5 h. The AMA or ammonia solution was removed by vacuum centrifugation. Purification was performed using a PS-15Q ion purification column with a phosphate and sodium chloride solution as the mobile phase, or a C18 reverse-phase column with an aqueous triethylamine acetate solution and acetonitrile as the mobile phase. LCMS and HPLC were used for in-process control. The sense and antisense strands were mixed in a 1:1 molar ratio and annealed at 90°C to form double-stranded siRNA and siRNA conjugates. The inventors validated the resulting conjugates (compound 1048 linked to the 5' end of the sense strand; compounds 1059 and 1060 linked to the 3' end of the sense strand). The modified siRNA sequences are shown in Tables 3 and 4.

[0733] Table 3: Modified sense and antisense strand sequences of double-stranded RNAi agents

[0734] Table 4: Modified sense and antisense strand sequences of GalNAc-siRNA agents

[0735] 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, and 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, gTA4 represents 2'-O-methyl-5'-deoxy-(1-(1,2,4-triazole))-cytidine-3'-phosphate '-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, and uRF represents 3'-fluoro-3'-deoxyuridine-2'-phosphate. * indicates that two nucleotides (or compounds 1048, 1059, or 1060 and a nucleotide) are linked by a phosphorothioate diester bond. There is no symbol between directly adjacent nucleotides.

[0736] The raw materials (phosphoramidite monomers) and auxiliary materials required for the above nucleic acid chain synthesis were purchased from the following companies:

[0737] 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.

[0738] Example 3: In vitro testing of the activity of small interfering nucleic acids (siRNA)

[0739] For the test sequence, the human LPA cDNA sequence (accession number NM_005577.1) was subcloned from a commercially available mammalian expression vector (Origene, Rockville, MD) into the commercially available reporter-based screening plasmid psiCHECK TM -2 (Promega, Madison, WI), to produce Renilla luciferase / LPA fusion mRNA.

[0740] The silencing efficiency of the sequence on the target gene was evaluated in Hep3B cells using a fluorescent reporter enzyme system. Hep3B cells were cultured in DMEM (Gibco) medium supplemented with 10% FBS (Gibco). The cells were seeded in a 96-well plate at a density of 15,000 cells per well the day before transfection and transfected after adherence. The transfection process was carried out according to the standard procedure in the instructions of lipofectemine2000 (Thermofisher). The transfection system included 0.4 μL lipofectemine2000 / 50 ng plasmid / well and a selected dose of siRNA test substance. Three parallel wells were set up for each transfection condition. The final concentration of siRNA was 10 nM / 1 nM / 0.1 nM / 0.01 nM. 24 hours after transfection, the dual luciferase was detected using the Dual-Glo@Luciferase Assay System (Promega E2940) according to the standard procedure in the instructions. The test results were based on the single transfection of psiCHECK TM A control group containing a 2-LPA recombinant plasmid without siRNA was used, and the Renilla fluorescence / Firefly fluorescence ratio for this group was set at 100%. The Renilla fluorescence / Firefly fluorescence ratios for the other concentration groups were compared with the control group to obtain relative luminescence values. The activities of the siRNA sequences are shown in Table 5.

[0741] Table 5 In vitro silencing efficiency of siRNA duplexes (0.1 nM and 10 nM)

[0742] Example 4: Testing the activity of small interfering nucleic acids (siRNA) in primary monkey liver cells

[0743] Primary monkey liver cells were purchased from Miaoshun (Shanghai) Biotechnology Co., Ltd. and transported and stored in liquid nitrogen tanks. After recovery, the culture conditions were 37°C and 5% CO2 (il60, Thermos Fisher).

[0744] On the day of the transfection experiment, primary monkey liver cells frozen in liquid nitrogen were thawed and plated into 48-well cell culture plates pretreated with collagen coating medium (Coating Medium (Cat. No.: TIEP044)) according to the instructions for primary monkey liver thaw. The coating medium was washed off before plating, and plating medium (CM Seeding Medium (Cat. No.: CMIEP054)) was added. Then, the cell stock solution was added at a volume of 80,000 cells per well, and the cell suspension was gently mixed. Suspension transfection was performed using RNAiMAX (Thermos Fisher) as the vector according to standard transfection protocols. Final siRNA concentrations were 10 nM, 0.1 nM, and 0.01 nM. Each test substance was transfected in a single well at each dose. A control group containing only the transfection reagent without siRNA was used as the transfection system.

[0745] 24 hours after transfection, RNA was extracted from the 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 instructions, and a high-throughput QPCR instrument (Analytikjena qTOWER 384G) was used to quantify the changes in the expression level of the target gene. The experimental results were analyzed using the ΔΔCT method to analyze the relative changes in the expression of the target gene in the test sample and the control sample. The activity of the siRNA sequences is shown in Tables 6 and 7 below.

[0746] Table 6 In vitro silencing efficiency of duplex siRNA (10 nM and 0.1 nM)

[0747] Table 7 In vitro silencing efficiency of siRNA duplexes (10 nM, 0.1 nM and 0.01 nM)

[0748] Example 5: Activity test of GalNAc-siRNA in transgenic mice

[0749] The in vivo efficacy of the molecule was tested by subcutaneous administration in LPa humanized transgenic mice. The humanized mice used as experimental animals were purchased from Saiye (Suzhou) Biotechnology Co., Ltd. and are SPF-grade animals. Before administration, the mice were weighed and their conditions were observed, and animals with uniform weight and normal conditions were selected for subsequent experiments. The experimental animals were randomly divided into groups of 4, each group was given a subcutaneous injection of 1 mg / kg, and the day of administration was recorded as day 0. At selected time points after administration, blood was collected from the suborbital vein and plasma was separated. The Human Lipoprotein A ELISA Kit (ab212165) was used to detect the LPA expression level in animal plasma according to standard procedures.

[0750] The experimental results showed (Figure 1) that NPD015s-AD059 and NPD015s-AD062 had higher in vivo activity

[0751] In the description of this specification, the reference terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" mean 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 can be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art can combine and combine different embodiments or examples described in this specification and features of different embodiments or examples without contradiction.

[0752] Although the embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are illustrative and are not to be construed as limitations on the present invention. A person skilled in the art may change, modify, replace and modify the above embodiments within the scope of the present invention.

Claims

1. A siRNA double-stranded molecule for targeting LPA mRNA, characterized in that: The siRNA duplex is composed of a sense strand and an antisense strand through relevant 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:57 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:58 to SEQ ID NO:114 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 nucleotide sequence of SEQ ID NO: 1 to SEQ ID NO:

57.

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:58 to SEQ ID NO:

114.

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-015-2 (SEQ ID NO.: 2 and SEQ ID NO.: 59) NDS-015-4 (SEQ ID NO.: 4 and SEQ ID NO.: 61) NDS-015-6 (SEQ ID NO.: 6 and SEQ ID NO.: 63) NDS-015-7 (SEQ ID NO.: 7 and SEQ ID NO.: 64) NDS-015-11 (SEQ ID NO.: 11 and SEQ ID NO.: 68) NDS-015-16 (SEQ ID NO.: 16 and SEQ ID NO.: 73) NDS-015-17 (SEQ ID NO.: 17 and SEQ ID NO.: 74) NDS-015-20 (SEQ ID NO.: 20 and SEQ ID NO.: 77) NDS-015-26 (SEQ ID NO.: 26 and SEQ ID NO.: 83) NDS-015-27 (SEQ ID NO.: 27 and SEQ ID NO.: 84) NDS-015-29 (SEQ ID NO.: 29 and SEQ ID NO.: 86) NDS-015-31 (SEQ ID NO.: 31 and SEQ ID NO.: 88) NDS-015-37 (SEQ ID NO.: 37 and SEQ ID NO.: 94) NDS-015-40 (SEQ ID NO.: 40 and SEQ ID NO.: 97) NDS-015-45 (SEQ ID NO.: 45 and SEQ ID NO.: 102) NDS-015-56 (SEQ ID NO.: 56 and SEQ ID NO.: 113).

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-015-2 (SEQ ID NO.: 2 and SEQ ID NO.: 59) NDS-015-4 (SEQ ID NO.: 4 and SEQ ID NO.: 61) NDS-015-6 (SEQ ID NO.: 6 and SEQ ID NO.: 63) NDS-015-7 (SEQ ID NO.: 7 and SEQ ID NO.: 64) NDS-015-11 (SEQ ID NO.: 11 and SEQ ID NO.: 68) NDS-015-16 (SEQ ID NO.: 16 and SEQ ID NO.: 73) NDS-015-17 (SEQ ID NO.: 17 and SEQ ID NO.: 74) NDS-015-20 (SEQ ID NO.: 20 and SEQ ID NO.: 77) NDS-015-26 (SEQ ID NO.: 26 and SEQ ID NO.: 83) NDS-015-27 (SEQ ID NO.: 27 and SEQ ID NO.: 84) NDS-015-29 (SEQ ID NO.: 29 and SEQ ID NO.: 86) NDS-015-31 (SEQ ID NO.: 31 and SEQ ID NO.: 88) NDS-015-37 (SEQ ID NO.: 37 and SEQ ID NO.: 94) NDS-015-40 (SEQ ID NO.: 40 and SEQ ID NO.: 97) NDS-015-45 (SEQ ID NO.: 45 and SEQ ID NO.: 102) NDS-015-56 (SEQ ID NO.: 56 and SEQ ID NO.: 113).

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-015-2 (SEQ ID NO.: 2 and SEQ ID NO.: 59) NDS-015-4 (SEQ ID NO.: 4 and SEQ ID NO.: 61) NDS-015-6 (SEQ ID NO.: 6 and SEQ ID NO.: 63) NDS-015-7 (SEQ ID NO.: 7 and SEQ ID NO.: 64) NDS-015-11 (SEQ ID NO.: 11 and SEQ ID NO.: 68) NDS-015-16 (SEQ ID NO.: 16 and SEQ ID NO.: 73) NDS-015-17 (SEQ ID NO.: 17 and SEQ ID NO.: 74) NDS-015-20 (SEQ ID NO.: 20 and SEQ ID NO.: 77) NDS-015-26 (SEQ ID NO.: 26 and SEQ ID NO.: 83) NDS-015-27 (SEQ ID NO.: 27 and SEQ ID NO.: 84) NDS-015-29 (SEQ ID NO.: 29 and SEQ ID NO.: 86) NDS-015-31 (SEQ ID NO.: 31 and SEQ ID NO.: 88) NDS-015-37 (SEQ ID NO.: 37 and SEQ ID NO.: 94) NDS-015-40 (SEQ ID NO.: 40 and SEQ ID NO.: 97) NDS-015-45 (SEQ ID NO.: 45 and SEQ ID NO.: 102) NDS-015-56 (SEQ ID NO.: 56 and SEQ ID NO.: 113).

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.

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 claimed in claim 11, preferably a phosphodiester linker or a thiophosphodiester 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, wherein 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, and the unconventional bases are preferably selected from one of the following nitrogen-containing heterocyclic bases:

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 modification, preferably the nucleotide at position 7 is modified. 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 G, 2'-Fluoro C 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, and 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, and 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-(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; 3'-Fluoro-modified nucleotides: cRF, gRF, aRF, and uRF are 3'-fluoro-3'-deoxycytidine-2'-phosphate, 3'-fluoro-3'-deoxyguanosine-2'-phosphate, 3'-fluoro-3'-deoxyadenosine-2'-phosphate, and 3'-fluoro-3'-deoxyuridine-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: NPD015s-AD002 (SEQ ID NO.: 116 and SEQ ID NO.: 313) NPD015s-AD004 (SEQ ID NO.: 118 and SEQ ID NO.: 315) NPD015s-AD006 (SEQ ID NO.: 120 and SEQ ID NO.: 317) NPD015s-AD007 (SEQ ID NO.: 121 and SEQ ID NO.: 318) NPD015s-AD011 (SEQ ID NO.: 125 and SEQ ID NO.: 322) NPD015s-AD016 (SEQ ID NO.: 130 and SEQ ID NO.: 327) NPD015s-AD017 (SEQ ID NO.: 131 and SEQ ID NO.: 328) NPD015s-AD020 (SEQ ID NO.: 134 and SEQ ID NO.: 331) NPD015s-AD026 (SEQ ID NO.: 140 and SEQ ID NO.: 337) NPD015s-AD027 (SEQ ID NO.: 141 and SEQ ID NO.: 338) NPD015s-AD029 (SEQ ID NO.: 143 and SEQ ID NO.: 340) NPD015s-AD031 (SEQ ID NO.: 145 and SEQ ID NO.: 342) NPD015s-AD037 (SEQ ID NO.: 151 and SEQ ID NO.: 348) NPD015s-AD040 (SEQ ID NO.: 154 and SEQ ID NO.: 351) NPD015s-AD045 (SEQ ID NO.: 159 and SEQ ID NO.: 356) NPD015s-AD056 (SEQ ID NO.: 170 and SEQ ID NO.: 367) NPD015s-AD058 (SEQ ID NO.: 172 and SEQ ID NO.: 369) NPD015s-AD059 (SEQ ID NO.: 173 and SEQ ID NO.: 370) NPD015s-AD060 (SEQ ID NO.: 174 and SEQ ID NO.: 371) NPD015s-AD061 (SEQ ID NO.: 175 and SEQ ID NO.: 372) NPD015s-AD062 (SEQ ID NO.: 176 and SEQ ID NO.: 373) NPD015s-AD063 (SEQ ID NO.: 177 and SEQ ID NO.: 374) NPD015s-AD064 (SEQ ID NO.: 178 and SEQ ID NO.: 375) NPD015s-AD065 (SEQ ID NO.: 179 and SEQ ID NO.: 376) NPD015s-AD066 (SEQ ID NO.: 180 and SEQ ID NO.: 377) NPD015s-AD067 (SEQ ID NO.: 181 and SEQ ID NO.: 378) NPD015s-AD078 (SEQ ID NO.: 192 and SEQ ID NO.: 389) NPD015s-AD079 (SEQ ID NO.: 193 and SEQ ID NO.: 390) NPD015s-AD080 (SEQ ID NO.: 194 and SEQ ID NO.: 391) NPD015s-AD081 (SEQ ID NO.: 195 and SEQ ID NO.: 392) NPD015s-AD082 (SEQ ID NO.: 196 and SEQ ID NO.: 393) NPD015s-AD083 (SEQ ID NO.: 197 and SEQ ID NO.: 394) NPD015s-AD084 (SEQ ID NO.: 198 and SEQ ID NO.: 395) NPD015s-AD085 (SEQ ID NO.: 199 and SEQ ID NO.: 396) NPD015s-AD086 (SEQ ID NO.: 200 and SEQ ID NO.: 397) NPD015s-AD087 (SEQ ID NO.: 201 and SEQ ID NO.: 398) NPD015s-AD098 (SEQ ID NO.: 212 and SEQ ID NO.: 409) NPD015s-AD099 (SEQ ID NO.: 213 and SEQ ID NO.: 410) NPD015s-AD100 (SEQ ID NO.: 214 and SEQ ID NO.: 411) NPD015s-AD101 (SEQ ID NO.: 215 and SEQ ID NO.: 412) NPD015s-AD102 (SEQ ID NO.: 216 and SEQ ID NO.: 413) NPD015s-AD103 (SEQ ID NO.: 217 and SEQ ID NO.: 414) NPD015s-AD104 (SEQ ID NO.: 218 and SEQ ID NO.: 415) NPD015s-AD105 (SEQ ID NO.: 219 and SEQ ID NO.: 416) NPD015s-AD106 (SEQ ID NO.: 220 and SEQ ID NO.: 417) NPD015s-AD107 (SEQ ID NO.: 221 and SEQ ID NO.: 418) NPD015s-AD108 (SEQ ID NO.: 222 and SEQ ID NO.: 419) NPD015s-AD109 (SEQ ID NO.: 223 and SEQ ID NO.: 420) NPD015s-AD110 (SEQ ID NO.: 224 and SEQ ID NO.: 421) NPD015s-AD111 (SEQ ID NO.: 225 and SEQ ID NO.: 422) NPD015s-AD112 (SEQ ID NO.: 226 and SEQ ID NO.: 423) NPD015s-AD113 (SEQ ID NO.: 227 and SEQ ID NO.: 424) NPD015s-AD114 (SEQ ID NO.: 228 and SEQ ID NO.: 425) NPD015s-AD115 (SEQ ID NO.: 229 and SEQ ID NO.: 426) NPD015s-AD116 (SEQ ID NO.: 230 and SEQ ID NO.: 427) NPD015s-AD117 (SEQ ID NO.: 231 and SEQ ID NO.: 428) NPD015s-AD138 (SEQ ID NO.: 252 and SEQ ID NO.: 449) NPD015s-AD139 (SEQ ID NO.: 253 and SEQ ID NO.: 450) NPD015s-AD140 (SEQ ID NO.: 254 and SEQ ID NO.: 451) NPD015s-AD141 (SEQ ID NO.: 255 and SEQ ID NO.: 452) NPD015s-AD142 (SEQ ID NO.: 256 and SEQ ID NO.: 453) NPD015s-AD143 (SEQ ID NO.: 257 and SEQ ID NO.: 454) NPD015s-AD144 (SEQ ID NO.: 258 and SEQ ID NO.: 455) NPD015s-AD145 (SEQ ID NO.: 259 and SEQ ID NO.: 456) NPD015s-AD146 (SEQ ID NO.: 260 and SEQ ID NO.: 457) NPD015s-AD147 (SEQ ID NO.: 261 and SEQ ID NO.: 458) NPD015s-AD148 (SEQ ID NO.: 262 and SEQ ID NO.: 459) NPD015s-AD149 (SEQ ID NO.: 263 and SEQ ID NO.: 460) NPD015s-AD150 (SEQ ID NO.: 264 and SEQ ID NO.: 461) NPD015s-AD151 (SEQ ID NO.: 265 and SEQ ID NO.: 462) NPD015s-AD152 (SEQ ID NO.: 266 and SEQ ID NO.: 463) NPD015s-AD153 (SEQ ID NO.: 267 and SEQ ID NO.: 464) NPD015s-AD154 (SEQ ID NO.: 268 and SEQ ID NO.: 465) NPD015s-AD155 (SEQ ID NO.: 269 and SEQ ID NO.: 466) NPD015s-AD156 (SEQ ID NO.: 270 and SEQ ID NO.: 467) NPD015s-AD157 (SEQ ID NO.: 271 and SEQ ID NO.: 468) NPD015s-AD168 (SEQ ID NO.: 282 and SEQ ID NO.: 479) NPD015s-AD169 (SEQ ID NO.:283 and SEQ ID NO.:480) NPD015s-AD170 (SEQ ID NO.: 284 and SEQ ID NO.: 481) NPD015s-AD171 (SEQ ID NO.: 285 and SEQ ID NO.: 482) NPD015s-AD172 (SEQ ID NO.: 286 and SEQ ID NO.: 483) NPD015s-AD173 (SEQ ID NO.: 287 and SEQ ID NO.: 484) NPD015s-AD174 (SEQ ID NO.: 288 and SEQ ID NO.: 485) NPD015s-AD175 (SEQ ID NO.: 289 and SEQ ID NO.: 486) NPD015s-AD176 (SEQ ID NO.: 290 and SEQ ID NO.: 487) NPD015s-AD177 (SEQ ID NO.: 291 and SEQ ID NO.: 488) NPD015s-AD178 (SEQ ID NO.: 292 and SEQ ID NO.: 489) NPD015s-AD179 (SEQ ID NO.: 293 and SEQ ID NO.: 490) NPD015s-AD180 (SEQ ID NO.: 294 and SEQ ID NO.: 491) NPD015s-AD181 (SEQ ID NO.: 295 and SEQ ID NO.: 492) NPD015s-AD182 (SEQ ID NO.: 296 and SEQ ID NO.: 493) NPD015s-AD183 (SEQ ID NO.: 297 and SEQ ID NO.: 494) NPD015s-AD184 (SEQ ID NO.: 298 and SEQ ID NO.: 495) NPD015s-AD185 (SEQ ID NO.: 299 and SEQ ID NO.: 496) NPD015s-AD186 (SEQ ID NO.: 300 and SEQ ID NO.: 497) NPD015s-AD187 (SEQ ID NO.: 301 and SEQ ID NO.: 498).

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: NPD015s-AD002 (SEQ ID NO.: 116 and SEQ ID NO.: 313) NPD015s-AD004 (SEQ ID NO.: 118 and SEQ ID NO.: 315) NPD015s-AD006 (SEQ ID NO.: 120 and SEQ ID NO.: 317) NPD015s-AD007 (SEQ ID NO.: 121 and SEQ ID NO.: 318) NPD015s-AD011 (SEQ ID NO.: 125 and SEQ ID NO.: 322) NPD015s-AD016 (SEQ ID NO.: 130 and SEQ ID NO.: 327) NPD015s-AD017 (SEQ ID NO.: 131 and SEQ ID NO.: 328) NPD015s-AD020 (SEQ ID NO.: 134 and SEQ ID NO.: 331) NPD015s-AD026 (SEQ ID NO.: 140 and SEQ ID NO.: 337) NPD015s-AD027 (SEQ ID NO.: 141 and SEQ ID NO.: 338) NPD015s-AD029 (SEQ ID NO.: 143 and SEQ ID NO.: 340) NPD015s-AD031 (SEQ ID NO.: 145 and SEQ ID NO.: 342) NPD015s-AD037 (SEQ ID NO.: 151 and SEQ ID NO.: 348) NPD015s-AD040 (SEQ ID NO.: 154 and SEQ ID NO.: 351) NPD015s-AD045 (SEQ ID NO.: 159 and SEQ ID NO.: 356) NPD015s-AD056 (SEQ ID NO.: 170 and SEQ ID NO.: 367) NPD015s-AD058 (SEQ ID NO.: 172 and SEQ ID NO.: 369) NPD015s-AD059 (SEQ ID NO.: 173 and SEQ ID NO.: 370) NPD015s-AD060 (SEQ ID NO.: 174 and SEQ ID NO.: 371) NPD015s-AD061 (SEQ ID NO.: 175 and SEQ ID NO.: 372) NPD015s-AD062 (SEQ ID NO.: 176 and SEQ ID NO.: 373) NPD015s-AD063 (SEQ ID NO.: 177 and SEQ ID NO.: 374) NPD015s-AD064 (SEQ ID NO.: 178 and SEQ ID NO.: 375) NPD015s-AD065 (SEQ ID NO.: 179 and SEQ ID NO.: 376) NPD015s-AD066 (SEQ ID NO.: 180 and SEQ ID NO.: 377) NPD015s-AD067 (SEQ ID NO.: 181 and SEQ ID NO.: 378) NPD015s-AD078 (SEQ ID NO.: 192 and SEQ ID NO.: 389) NPD015s-AD079 (SEQ ID NO.: 193 and SEQ ID NO.: 390) NPD015s-AD080 (SEQ ID NO.: 194 and SEQ ID NO.: 391) NPD015s-AD081 (SEQ ID NO.: 195 and SEQ ID NO.: 392) NPD015s-AD082 (SEQ ID NO.: 196 and SEQ ID NO.: 393) NPD015s-AD083 (SEQ ID NO.: 197 and SEQ ID NO.: 394) NPD015s-AD084 (SEQ ID NO.: 198 and SEQ ID NO.: 395) NPD015s-AD085 (SEQ ID NO.: 199 and SEQ ID NO.: 396) NPD015s-AD086 (SEQ ID NO.: 200 and SEQ ID NO.: 397) NPD015s-AD087 (SEQ ID NO.: 201 and SEQ ID NO.: 398) NPD015s-AD098 (SEQ ID NO.: 212 and SEQ ID NO.: 409) NPD015s-AD099 (SEQ ID NO.: 213 and SEQ ID NO.: 410) NPD015s-AD100 (SEQ ID NO.: 214 and SEQ ID NO.: 411) NPD015s-AD101 (SEQ ID NO.: 215 and SEQ ID NO.: 412) NPD015s-AD102 (SEQ ID NO.: 216 and SEQ ID NO.: 413) NPD015s-AD103 (SEQ ID NO.: 217 and SEQ ID NO.: 414) NPD015s-AD104 (SEQ ID NO.: 218 and SEQ ID NO.: 415) NPD015s-AD105 (SEQ ID NO.: 219 and SEQ ID NO.: 416) NPD015s-AD106 (SEQ ID NO.: 220 and SEQ ID NO.: 417) NPD015s-AD107 (SEQ ID NO.: 221 and SEQ ID NO.: 418) NPD015s-AD108 (SEQ ID NO.: 222 and SEQ ID NO.: 419) NPD015s-AD109 (SEQ ID NO.: 223 and SEQ ID NO.: 420) NPD015s-AD110 (SEQ ID NO.: 224 and SEQ ID NO.: 421) NPD015s-AD111 (SEQ ID NO.: 225 and SEQ ID NO.: 422) NPD015s-AD112 (SEQ ID NO.: 226 and SEQ ID NO.: 423) NPD015s-AD113 (SEQ ID NO.: 227 and SEQ ID NO.: 424) NPD015s-AD114 (SEQ ID NO.: 228 and SEQ ID NO.: 425) NPD015s-AD115 (SEQ ID NO.: 229 and SEQ ID NO.: 426) NPD015s-AD116 (SEQ ID NO.: 230 and SEQ ID NO.: 427) NPD015s-AD117 (SEQ ID NO.: 231 and SEQ ID NO.: 428) NPD015s-AD138 (SEQ ID NO.: 252 and SEQ ID NO.: 449) NPD015s-AD139 (SEQ ID NO.: 253 and SEQ ID NO.: 450) NPD015s-AD140 (SEQ ID NO.: 254 and SEQ ID NO.: 451) NPD015s-AD141 (SEQ ID NO.: 255 and SEQ ID NO.: 452) NPD015s-AD142 (SEQ ID NO.: 256 and SEQ ID NO.: 453) NPD015s-AD143 (SEQ ID NO.: 257 and SEQ ID NO.: 454) NPD015s-AD144 (SEQ ID NO.: 258 and SEQ ID NO.: 455) NPD015s-AD145 (SEQ ID NO.: 259 and SEQ ID NO.: 456) NPD015s-AD146 (SEQ ID NO.: 260 and SEQ ID NO.: 457) NPD015s-AD147 (SEQ ID NO.: 261 and SEQ ID NO.: 458) NPD015s-AD148 (SEQ ID NO.: 262 and SEQ ID NO.: 459) NPD015s-AD149 (SEQ ID NO.: 263 and SEQ ID NO.: 460) NPD015s-AD150 (SEQ ID NO.: 264 and SEQ ID NO.: 461) NPD015s-AD151 (SEQ ID NO.: 265 and SEQ ID NO.: 462) NPD015s-AD152 (SEQ ID NO.: 266 and SEQ ID NO.: 463) NPD015s-AD153 (SEQ ID NO.: 267 and SEQ ID NO.: 464) NPD015s-AD154 (SEQ ID NO.: 268 and SEQ ID NO.: 465) NPD015s-AD155 (SEQ ID NO.: 269 and SEQ ID NO.: 466) NPD015s-AD156 (SEQ ID NO.: 270 and SEQ ID NO.: 467) NPD015s-AD157 (SEQ ID NO.: 271 and SEQ ID NO.: 468) NPD015s-AD168 (SEQ ID NO.: 282 and SEQ ID NO.: 479) NPD015s-AD169 (SEQ ID NO.:283 and SEQ ID NO.:480) NPD015s-AD170 (SEQ ID NO.: 284 and SEQ ID NO.: 481) NPD015s-AD171 (SEQ ID NO.: 285 and SEQ ID NO.: 482) NPD015s-AD172 (SEQ ID NO.: 286 and SEQ ID NO.: 483) NPD015s-AD173 (SEQ ID NO.: 287 and SEQ ID NO.: 484) NPD015s-AD174 (SEQ ID NO.: 288 and SEQ ID NO.: 485) NPD015s-AD175 (SEQ ID NO.: 289 and SEQ ID NO.: 486) NPD015s-AD176 (SEQ ID NO.: 290 and SEQ ID NO.: 487) NPD015s-AD177 (SEQ ID NO.: 291 and SEQ ID NO.: 488) NPD015s-AD178 (SEQ ID NO.: 292 and SEQ ID NO.: 489) NPD015s-AD179 (SEQ ID NO.: 293 and SEQ ID NO.: 490) NPD015s-AD180 (SEQ ID NO.: 294 and SEQ ID NO.: 491) NPD015s-AD181 (SEQ ID NO.: 295 and SEQ ID NO.: 492) NPD015s-AD182 (SEQ ID NO.: 296 and SEQ ID NO.: 493) NPD015s-AD183 (SEQ ID NO.: 297 and SEQ ID NO.: 494) NPD015s-AD184 (SEQ ID NO.: 298 and SEQ ID NO.: 495) NPD015s-AD185 (SEQ ID NO.: 299 and SEQ ID NO.: 496) NPD015s-AD186 (SEQ ID NO.: 300 and SEQ ID NO.: 497) NPD015s-AD187 (SEQ ID NO.: 301 and SEQ ID NO.: 498).

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: NPD015s-AD002 (SEQ ID NO.: 116 and SEQ ID NO.: 313) NPD015s-AD004 (SEQ ID NO.: 118 and SEQ ID NO.: 315) NPD015s-AD006 (SEQ ID NO.: 120 and SEQ ID NO.: 317) NPD015s-AD007 (SEQ ID NO.: 121 and SEQ ID NO.: 318) NPD015s-AD011 (SEQ ID NO.: 125 and SEQ ID NO.: 322) NPD015s-AD016 (SEQ ID NO.: 130 and SEQ ID NO.: 327) NPD015s-AD017 (SEQ ID NO.: 131 and SEQ ID NO.: 328) NPD015s-AD020 (SEQ ID NO.: 134 and SEQ ID NO.: 331) NPD015s-AD026 (SEQ ID NO.: 140 and SEQ ID NO.: 337) NPD015s-AD027 (SEQ ID NO.: 141 and SEQ ID NO.: 338) NPD015s-AD029 (SEQ ID NO.: 143 and SEQ ID NO.: 340) NPD015s-AD031 (SEQ ID NO.: 145 and SEQ ID NO.: 342) NPD015s-AD037 (SEQ ID NO.: 151 and SEQ ID NO.: 348) NPD015s-AD040 (SEQ ID NO.: 154 and SEQ ID NO.: 351) NPD015s-AD045 (SEQ ID NO.: 159 and SEQ ID NO.: 356) NPD015s-AD056 (SEQ ID NO.: 170 and SEQ ID NO.: 367) NPD015s-AD058 (SEQ ID NO.: 172 and SEQ ID NO.: 369) NPD015s-AD059 (SEQ ID NO.: 173 and SEQ ID NO.: 370) NPD015s-AD060 (SEQ ID NO.: 174 and SEQ ID NO.: 371) NPD015s-AD061 (SEQ ID NO.: 175 and SEQ ID NO.: 372) NPD015s-AD062 (SEQ ID NO.: 176 and SEQ ID NO.: 373) NPD015s-AD063 (SEQ ID NO.: 177 and SEQ ID NO.: 374) NPD015s-AD064 (SEQ ID NO.: 178 and SEQ ID NO.: 375) NPD015s-AD065 (SEQ ID NO.: 179 and SEQ ID NO.: 376) NPD015s-AD066 (SEQ ID NO.: 180 and SEQ ID NO.: 377) NPD015s-AD067 (SEQ ID NO.: 181 and SEQ ID NO.: 378) NPD015s-AD078 (SEQ ID NO.: 192 and SEQ ID NO.: 389) NPD015s-AD079 (SEQ ID NO.: 193 and SEQ ID NO.: 390) NPD015s-AD080 (SEQ ID NO.: 194 and SEQ ID NO.: 391) NPD015s-AD081 (SEQ ID NO.: 195 and SEQ ID NO.: 392) NPD015s-AD082 (SEQ ID NO.: 196 and SEQ ID NO.: 393) NPD015s-AD083 (SEQ ID NO.: 197 and SEQ ID NO.: 394) NPD015s-AD084 (SEQ ID NO.: 198 and SEQ ID NO.: 395) NPD015s-AD085 (SEQ ID NO.: 199 and SEQ ID NO.: 396) NPD015s-AD086 (SEQ ID NO.: 200 and SEQ ID NO.: 397) NPD015s-AD087 (SEQ ID NO.: 201 and SEQ ID NO.: 398) NPD015s-AD098 (SEQ ID NO.: 212 and SEQ ID NO.: 409) NPD015s-AD099 (SEQ ID NO.: 213 and SEQ ID NO.: 410) NPD015s-AD100 (SEQ ID NO.: 214 and SEQ ID NO.: 411) NPD015s-AD101 (SEQ ID NO.: 215 and SEQ ID NO.: 412) NPD015s-AD102 (SEQ ID NO.: 216 and SEQ ID NO.: 413) NPD015s-AD103 (SEQ ID NO.: 217 and SEQ ID NO.: 414) NPD015s-AD104 (SEQ ID NO.: 218 and SEQ ID NO.: 415) NPD015s-AD105 (SEQ ID NO.: 219 and SEQ ID NO.: 416) NPD015s-AD106 (SEQ ID NO.: 220 and SEQ ID NO.: 417) NPD015s-AD107 (SEQ ID NO.: 221 and SEQ ID NO.: 418) NPD015s-AD108 (SEQ ID NO.: 222 and SEQ ID NO.: 419) NPD015s-AD109 (SEQ ID NO.: 223 and SEQ ID NO.: 420) NPD015s-AD110 (SEQ ID NO.: 224 and SEQ ID NO.: 421) NPD015s-AD111 (SEQ ID NO.: 225 and SEQ ID NO.: 422) NPD015s-AD112 (SEQ ID NO.: 226 and SEQ ID NO.: 423) NPD015s-AD113 (SEQ ID NO.: 227 and SEQ ID NO.: 424) NPD015s-AD114 (SEQ ID NO.: 228 and SEQ ID NO.: 425) NPD015s-AD115 (SEQ ID NO.: 229 and SEQ ID NO.: 426) NPD015s-AD116 (SEQ ID NO.: 230 and SEQ ID NO.: 427) NPD015s-AD117 (SEQ ID NO.: 231 and SEQ ID NO.: 428) NPD015s-AD138 (SEQ ID NO.: 252 and SEQ ID NO.: 449) NPD015s-AD139 (SEQ ID NO.: 253 and SEQ ID NO.: 450) NPD015s-AD140 (SEQ ID NO.: 254 and SEQ ID NO.: 451) NPD015s-AD141 (SEQ ID NO.: 255 and SEQ ID NO.: 452) NPD015s-AD142 (SEQ ID NO.: 256 and SEQ ID NO.: 453) NPD015s-AD143 (SEQ ID NO.: 257 and SEQ ID NO.: 454) NPD015s-AD144 (SEQ ID NO.: 258 and SEQ ID NO.: 455) NPD015s-AD145 (SEQ ID NO.: 259 and SEQ ID NO.: 456) NPD015s-AD146 (SEQ ID NO.: 260 and SEQ ID NO.: 457) NPD015s-AD147 (SEQ ID NO.: 261 and SEQ ID NO.: 458) NPD015s-AD148 (SEQ ID NO.: 262 and SEQ ID NO.: 459) NPD015s-AD149 (SEQ ID NO.: 263 and SEQ ID NO.: 460) NPD015s-AD150 (SEQ ID NO.: 264 and SEQ ID NO.: 461) NPD015s-AD151 (SEQ ID NO.: 265 and SEQ ID NO.: 462) NPD015s-AD152 (SEQ ID NO.: 266 and SEQ ID NO.: 463) NPD015s-AD153 (SEQ ID NO.: 267 and SEQ ID NO.: 464) NPD015s-AD154 (SEQ ID NO.: 268 and SEQ ID NO.: 465) NPD015s-AD155 (SEQ ID NO.: 269 and SEQ ID NO.: 466) NPD015s-AD156 (SEQ ID NO.: 270 and SEQ ID NO.: 467) NPD015s-AD157 (SEQ ID NO.: 271 and SEQ ID NO.: 468) NPD015s-AD168 (SEQ ID NO.: 282 and SEQ ID NO.: 479) NPD015s-AD169 (SEQ ID NO.:283 and SEQ ID NO.:480) NPD015s-AD170 (SEQ ID NO.: 284 and SEQ ID NO.: 481) NPD015s-AD171 (SEQ ID NO.: 285 and SEQ ID NO.: 482) NPD015s-AD172 (SEQ ID NO.: 286 and SEQ ID NO.: 483) NPD015s-AD173 (SEQ ID NO.: 287 and SEQ ID NO.: 484) NPD015s-AD174 (SEQ ID NO.: 288 and SEQ ID NO.: 485) NPD015s-AD175 (SEQ ID NO.: 289 and SEQ ID NO.: 486) NPD015s-AD176 (SEQ ID NO.: 290 and SEQ ID NO.: 487) NPD015s-AD177 (SEQ ID NO.: 291 and SEQ ID NO.: 488) NPD015s-AD178 (SEQ ID NO.: 292 and SEQ ID NO.: 489) NPD015s-AD179 (SEQ ID NO.: 293 and SEQ ID NO.: 490) NPD015s-AD180 (SEQ ID NO.: 294 and SEQ ID NO.: 491) NPD015s-AD181 (SEQ ID NO.: 295 and SEQ ID NO.: 492) NPD015s-AD182 (SEQ ID NO.: 296 and SEQ ID NO.: 493) NPD015s-AD183 (SEQ ID NO.: 297 and SEQ ID NO.: 494) NPD015s-AD184 (SEQ ID NO.: 298 and SEQ ID NO.: 495) NPD015s-AD185 (SEQ ID NO.: 299 and SEQ ID NO.: 496) NPD015s-AD186 (SEQ ID NO.: 300 and SEQ ID NO.: 497) NPD015s-AD187 (SEQ ID NO.: 301 and SEQ ID NO.: 498).

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: NPD015s-AD199 (SEQ ID NO.:510 and SEQ ID NO.:707) NPD015s-AD201 (SEQ ID NO.: 512 and SEQ ID NO.: 709) NPD015s-AD203 (SEQ ID NO.: 514 and SEQ ID NO.: 711) NPD015s-AD204 (SEQ ID NO.: 515 and SEQ ID NO.: 712) NPD015s-AD208 (SEQ ID NO.: 519 and SEQ ID NO.: 716) NPD015s-AD213 (SEQ ID NO.: 524 and SEQ ID NO.: 721) NPD015s-AD214 (SEQ ID NO.: 525 and SEQ ID NO.: 722) NPD015s-AD217 (SEQ ID NO.: 528 and SEQ ID NO.: 725) NPD015s-AD223 (SEQ ID NO.: 534 and SEQ ID NO.: 731) NPD015s-AD224 (SEQ ID NO.: 535 and SEQ ID NO.: 732) NPD015s-AD226 (SEQ ID NO.: 537 and SEQ ID NO.: 734) NPD015s-AD228 (SEQ ID NO.: 539 and SEQ ID NO.: 736) NPD015s-AD234 (SEQ ID NO.: 545 and SEQ ID NO.: 742) NPD015s-AD237 (SEQ ID NO.: 548 and SEQ ID NO.: 745) NPD015s-AD242 (SEQ ID NO.: 553 and SEQ ID NO.: 750) NPD015s-AD253 (SEQ ID NO.: 564 and SEQ ID NO.: 761) NPD015s-AD255 (SEQ ID NO.: 566 and SEQ ID NO.: 763) NPD015s-AD256 (SEQ ID NO.: 567 and SEQ ID NO.: 764) NPD015s-AD257 (SEQ ID NO.: 568 and SEQ ID NO.: 765) NPD015s-AD258 (SEQ ID NO.: 569 and SEQ ID NO.: 766) NPD015s-AD259 (SEQ ID NO.: 570 and SEQ ID NO.: 767) NPD015s-AD260 (SEQ ID NO.: 571 and SEQ ID NO.: 768) NPD015s-AD261 (SEQ ID NO.: 572 and SEQ ID NO.: 769) NPD015s-AD262 (SEQ ID NO.: 573 and SEQ ID NO.: 770) NPD015s-AD263 (SEQ ID NO.: 574 and SEQ ID NO.: 771) NPD015s-AD264 (SEQ ID NO.: 575 and SEQ ID NO.: 772) NPD015s-AD275 (SEQ ID NO.: 586 and SEQ ID NO.: 783) NPD015s-AD276 (SEQ ID NO.: 587 and SEQ ID NO.: 784) NPD015s-AD277 (SEQ ID NO.: 588 and SEQ ID NO.: 785) NPD015s-AD278 (SEQ ID NO.: 589 and SEQ ID NO.: 786) NPD015s-AD279 (SEQ ID NO.: 590 and SEQ ID NO.: 787) NPD015s-AD280 (SEQ ID NO.: 591 and SEQ ID NO.: 788) NPD015s-AD281 (SEQ ID NO.: 592 and SEQ ID NO.: 789) NPD015s-AD282 (SEQ ID NO.: 593 and SEQ ID NO.: 790) NPD015s-AD283 (SEQ ID NO.: 594 and SEQ ID NO.: 791) NPD015s-AD284 (SEQ ID NO.: 595 and SEQ ID NO.: 792) NPD015s-AD295 (SEQ ID NO.: 596 and SEQ ID NO.: 803) NPD015s-AD296 (SEQ ID NO.: 597 and SEQ ID NO.: 804) NPD015s-AD297 (SEQ ID NO.: 598 and SEQ ID NO.: 805) NPD015s-AD298 (SEQ ID NO.: 599 and SEQ ID NO.: 806) NPD015s-AD299 (SEQ ID NO.: 600 and SEQ ID NO.: 807) NPD015s-AD300 (SEQ ID NO.: 601 and SEQ ID NO.: 808) NPD015s-AD301 (SEQ ID NO.: 602 and SEQ ID NO.: 809) NPD015s-AD302 (SEQ ID NO.: 603 and SEQ ID NO.: 810) NPD015s-AD303 (SEQ ID NO.: 604 and SEQ ID NO.: 811) NPD015s-AD304 (SEQ ID NO.: 605 and SEQ ID NO.: 812) NPD015s-AD305 (SEQ ID NO.: 606 and SEQ ID NO.: 813) NPD015s-AD306 (SEQ ID NO.: 607 and SEQ ID NO.: 814) NPD015s-AD307 (SEQ ID NO.: 608 and SEQ ID NO.: 815) NPD015s-AD308 (SEQ ID NO.: 609 and SEQ ID NO.: 816) NPD015s-AD309 (SEQ ID NO.: 610 and SEQ ID NO.: 817) NPD015s-AD310 (SEQ ID NO.: 611 and SEQ ID NO.: 818) NPD015s-AD311 (SEQ ID NO.: 612 and SEQ ID NO.: 819) NPD015s-AD312 (SEQ ID NO.: 613 and SEQ ID NO.: 820) NPD015s-AD313 (SEQ ID NO.: 614 and SEQ ID NO.: 821) NPD015s-AD314 (SEQ ID NO.: 615 and SEQ ID NO.: 822) NPD015s-AD335 (SEQ ID NO.: 646 and SEQ ID NO.: 843) NPD015s-AD336 (SEQ ID NO.: 647 and SEQ ID NO.: 844) NPD015s-AD337 (SEQ ID NO.: 648 and SEQ ID NO.: 845) NPD015s-AD338 (SEQ ID NO.: 649 and SEQ ID NO.: 846) NPD015s-AD339 (SEQ ID NO.:650 and SEQ ID NO.:847) NPD015s-AD340 (SEQ ID NO.: 651 and SEQ ID NO.: 848) NPD015s-AD341 (SEQ ID NO.: 652 and SEQ ID NO.: 849) NPD015s-AD342 (SEQ ID NO.: 653 and SEQ ID NO.: 850) NPD015s-AD343 (SEQ ID NO.: 654 and SEQ ID NO.: 851) NPD015s-AD344 (SEQ ID NO.: 655 and SEQ ID NO.: 852) NPD015s-AD345 (SEQ ID NO.: 656 and SEQ ID NO.: 853) NPD015s-AD346 (SEQ ID NO.: 657 and SEQ ID NO.: 854) NPD015s-AD347 (SEQ ID NO.: 658 and SEQ ID NO.: 855) NPD015s-AD348 (SEQ ID NO.: 659 and SEQ ID NO.: 856) NPD015s-AD349 (SEQ ID NO.: 660 and SEQ ID NO.: 857) NPD015s-AD350 (SEQ ID NO.: 661 and SEQ ID NO.: 858) NPD015s-AD351 (SEQ ID NO.: 662 and SEQ ID NO.: 859) NPD015s-AD352 (SEQ ID NO.: 663 and SEQ ID NO.: 860) NPD015s-AD353 (SEQ ID NO.:664 and SEQ ID NO.:861) NPD015s-AD354 (SEQ ID NO.: 665 and SEQ ID NO.: 862) NPD015s-AD365 (SEQ ID NO.: 676 and SEQ ID NO.: 873) NPD015s-AD366 (SEQ ID NO.: 677 and SEQ ID NO.: 874) NPD015s-AD367 (SEQ ID NO.: 678 and SEQ ID NO.: 875) NPD015s-AD368 (SEQ ID NO.: 679 and SEQ ID NO.: 876) NPD015s-AD369 (SEQ ID NO.: 680 and SEQ ID NO.: 877) NPD015s-AD370 (SEQ ID NO.: 681 and SEQ ID NO.: 878) NPD015s-AD371 (SEQ ID NO.: 682 and SEQ ID NO.: 879) NPD015s-AD372 (SEQ ID NO.: 683 and SEQ ID NO.: 880) NPD015s-AD373 (SEQ ID NO.: 684 and SEQ ID NO.: 881) NPD015s-AD374 (SEQ ID NO.: 685 and SEQ ID NO.: 882) NPD015s-AD375 (SEQ ID NO.: 686 and SEQ ID NO.: 883) NPD015s-AD376 (SEQ ID NO.: 687 and SEQ ID NO.: 884) NPD015s-AD377 (SEQ ID NO.: 688 and SEQ ID NO.: 885) NPD015s-AD378 (SEQ ID NO.: 689 and SEQ ID NO.: 886) NPD015s-AD379 (SEQ ID NO.: 690 and SEQ ID NO.: 887) NPD015s-AD380 (SEQ ID NO.: 691 and SEQ ID NO.: 888) NPD015s-AD381 (SEQ ID NO.: 692 and SEQ ID NO.: 889) NPD015s-AD382 (SEQ ID NO.: 693 and SEQ ID NO.: 890) NPD015s-AD383 (SEQ ID NO.: 694 and SEQ ID NO.: 891) NPD015s-AD384 (SEQ ID NO.: 695 and SEQ ID NO.: 892).

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: NPD015s-AD199 (SEQ ID NO.:510 and SEQ ID NO.:707) NPD015s-AD201 (SEQ ID NO.: 512 and SEQ ID NO.: 709) NPD015s-AD203 (SEQ ID NO.: 514 and SEQ ID NO.: 711) NPD015s-AD204 (SEQ ID NO.: 515 and SEQ ID NO.: 712) NPD015s-AD208 (SEQ ID NO.: 519 and SEQ ID NO.: 716) NPD015s-AD213 (SEQ ID NO.: 524 and SEQ ID NO.: 721) NPD015s-AD214 (SEQ ID NO.: 525 and SEQ ID NO.: 722) NPD015s-AD217 (SEQ ID NO.: 528 and SEQ ID NO.: 725) NPD015s-AD223 (SEQ ID NO.: 534 and SEQ ID NO.: 731) NPD015s-AD224 (SEQ ID NO.: 535 and SEQ ID NO.: 732) NPD015s-AD226 (SEQ ID NO.: 537 and SEQ ID NO.: 734) NPD015s-AD228 (SEQ ID NO.: 539 and SEQ ID NO.: 736) NPD015s-AD234 (SEQ ID NO.: 545 and SEQ ID NO.: 742) NPD015s-AD237 (SEQ ID NO.: 548 and SEQ ID NO.: 745) NPD015s-AD242 (SEQ ID NO.: 553 and SEQ ID NO.: 750) NPD015s-AD253 (SEQ ID NO.: 564 and SEQ ID NO.: 761) NPD015s-AD255 (SEQ ID NO.: 566 and SEQ ID NO.: 763) NPD015s-AD256 (SEQ ID NO.: 567 and SEQ ID NO.: 764) NPD015s-AD257 (SEQ ID NO.: 568 and SEQ ID NO.: 765) NPD015s-AD258 (SEQ ID NO.: 569 and SEQ ID NO.: 766) NPD015s-AD259 (SEQ ID NO.: 570 and SEQ ID NO.: 767) NPD015s-AD260 (SEQ ID NO.: 571 and SEQ ID NO.: 768) NPD015s-AD261 (SEQ ID NO.: 572 and SEQ ID NO.: 769) NPD015s-AD262 (SEQ ID NO.: 573 and SEQ ID NO.: 770) NPD015s-AD263 (SEQ ID NO.: 574 and SEQ ID NO.: 771) NPD015s-AD264 (SEQ ID NO.: 575 and SEQ ID NO.: 772) NPD015s-AD275 (SEQ ID NO.: 586 and SEQ ID NO.: 783) NPD015s-AD276 (SEQ ID NO.: 587 and SEQ ID NO.: 784) NPD015s-AD277 (SEQ ID NO.: 588 and SEQ ID NO.: 785) NPD015s-AD278 (SEQ ID NO.: 589 and SEQ ID NO.: 786) NPD015s-AD279 (SEQ ID NO.: 590 and SEQ ID NO.: 787) NPD015s-AD280 (SEQ ID NO.: 591 and SEQ ID NO.: 788) NPD015s-AD281 (SEQ ID NO.: 592 and SEQ ID NO.: 789) NPD015s-AD282 (SEQ ID NO.: 593 and SEQ ID NO.: 790) NPD015s-AD283 (SEQ ID NO.: 594 and SEQ ID NO.: 791) NPD015s-AD284 (SEQ ID NO.: 595 and SEQ ID NO.: 792) NPD015s-AD295 (SEQ ID NO.: 596 and SEQ ID NO.: 803) NPD015s-AD296 (SEQ ID NO.: 597 and SEQ ID NO.: 804) NPD015s-AD297 (SEQ ID NO.: 598 and SEQ ID NO.: 805) NPD015s-AD298 (SEQ ID NO.: 599 and SEQ ID NO.: 806) NPD015s-AD299 (SEQ ID NO.: 600 and SEQ ID NO.: 807) NPD015s-AD300 (SEQ ID NO.: 601 and SEQ ID NO.: 808) NPD015s-AD301 (SEQ ID NO.: 602 and SEQ ID NO.: 809) NPD015s-AD302 (SEQ ID NO.: 603 and SEQ ID NO.: 810) NPD015s-AD303 (SEQ ID NO.: 604 and SEQ ID NO.: 811) NPD015s-AD304 (SEQ ID NO.: 605 and SEQ ID NO.: 812) NPD015s-AD305 (SEQ ID NO.: 606 and SEQ ID NO.: 813) NPD015s-AD306 (SEQ ID NO.: 607 and SEQ ID NO.: 814) NPD015s-AD307 (SEQ ID NO.: 608 and SEQ ID NO.: 815) NPD015s-AD308 (SEQ ID NO.: 609 and SEQ ID NO.: 816) NPD015s-AD309 (SEQ ID NO.: 610 and SEQ ID NO.: 817) NPD015s-AD310 (SEQ ID NO.: 611 and SEQ ID NO.: 818) NPD015s-AD311 (SEQ ID NO.: 612 and SEQ ID NO.: 819) NPD015s-AD312 (SEQ ID NO.: 613 and SEQ ID NO.: 820) NPD015s-AD313 (SEQ ID NO.: 614 and SEQ ID NO.: 821) NPD015s-AD314 (SEQ ID NO.: 615 and SEQ ID NO.: 822) NPD015s-AD335 (SEQ ID NO.: 646 and SEQ ID NO.: 843) NPD015s-AD336 (SEQ ID NO.: 647 and SEQ ID NO.: 844) NPD015s-AD337 (SEQ ID NO.: 648 and SEQ ID NO.: 845) NPD015s-AD338 (SEQ ID NO.: 649 and SEQ ID NO.: 846) NPD015s-AD339 (SEQ ID NO.:650 and SEQ ID NO.:847) NPD015s-AD340 (SEQ ID NO.: 651 and SEQ ID NO.: 848) NPD015s-AD341 (SEQ ID NO.: 652 and SEQ ID NO.: 849) NPD015s-AD342 (SEQ ID NO.: 653 and SEQ ID NO.: 850) NPD015s-AD343 (SEQ ID NO.: 654 and SEQ ID NO.: 851) NPD015s-AD344 (SEQ ID NO.: 655 and SEQ ID NO.: 852) NPD015s-AD345 (SEQ ID NO.: 656 and SEQ ID NO.: 853) NPD015s-AD346 (SEQ ID NO.: 657 and SEQ ID NO.: 854) NPD015s-AD347 (SEQ ID NO.: 658 and SEQ ID NO.: 855) NPD015s-AD348 (SEQ ID NO.: 659 and SEQ ID NO.: 856) NPD015s-AD349 (SEQ ID NO.: 660 and SEQ ID NO.: 857) NPD015s-AD350 (SEQ ID NO.: 661 and SEQ ID NO.: 858) NPD015s-AD351 (SEQ ID NO.: 662 and SEQ ID NO.: 859) NPD015s-AD352 (SEQ ID NO.: 663 and SEQ ID NO.: 860) NPD015s-AD353 (SEQ ID NO.:664 and SEQ ID NO.:861) NPD015s-AD354 (SEQ ID NO.: 665 and SEQ ID NO.: 862) NPD015s-AD365 (SEQ ID NO.: 676 and SEQ ID NO.: 873) NPD015s-AD366 (SEQ ID NO.: 677 and SEQ ID NO.: 874) NPD015s-AD367 (SEQ ID NO.: 678 and SEQ ID NO.: 875) NPD015s-AD368 (SEQ ID NO.: 679 and SEQ ID NO.: 876) NPD015s-AD369 (SEQ ID NO.: 680 and SEQ ID NO.: 877) NPD015s-AD370 (SEQ ID NO.: 681 and SEQ ID NO.: 878) NPD015s-AD371 (SEQ ID NO.: 682 and SEQ ID NO.: 879) NPD015s-AD372 (SEQ ID NO.: 683 and SEQ ID NO.: 880) NPD015s-AD373 (SEQ ID NO.: 684 and SEQ ID NO.: 881) NPD015s-AD374 (SEQ ID NO.: 685 and SEQ ID NO.: 882) NPD015s-AD375 (SEQ ID NO.: 686 and SEQ ID NO.: 883) NPD015s-AD376 (SEQ ID NO.: 687 and SEQ ID NO.: 884) NPD015s-AD377 (SEQ ID NO.: 688 and SEQ ID NO.: 885) NPD015s-AD378 (SEQ ID NO.: 689 and SEQ ID NO.: 886) NPD015s-AD379 (SEQ ID NO.: 690 and SEQ ID NO.: 887) NPD015s-AD380 (SEQ ID NO.: 691 and SEQ ID NO.: 888) NPD015s-AD381 (SEQ ID NO.: 692 and SEQ ID NO.: 889) NPD015s-AD382 (SEQ ID NO.: 693 and SEQ ID NO.: 890) NPD015s-AD383 (SEQ ID NO.: 694 and SEQ ID NO.: 891) NPD015s-AD384 (SEQ ID NO.: 695 and SEQ ID NO.: 892).

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: NPD015s-AD199 (SEQ ID NO.:510 and SEQ ID NO.:707) NPD015s-AD201 (SEQ ID NO.: 512 and SEQ ID NO.: 709) NPD015s-AD203 (SEQ ID NO.: 514 and SEQ ID NO.: 711) NPD015s-AD204 (SEQ ID NO.: 515 and SEQ ID NO.: 712) NPD015s-AD208 (SEQ ID NO.: 519 and SEQ ID NO.: 716) NPD015s-AD213 (SEQ ID NO.: 524 and SEQ ID NO.: 721) NPD015s-AD214 (SEQ ID NO.: 525 and SEQ ID NO.: 722) NPD015s-AD217 (SEQ ID NO.: 528 and SEQ ID NO.: 725) NPD015s-AD223 (SEQ ID NO.: 534 and SEQ ID NO.: 731) NPD015s-AD224 (SEQ ID NO.: 535 and SEQ ID NO.: 732) NPD015s-AD226 (SEQ ID NO.: 537 and SEQ ID NO.: 734) NPD015s-AD228 (SEQ ID NO.: 539 and SEQ ID NO.: 736) NPD015s-AD234 (SEQ ID NO.: 545 and SEQ ID NO.: 742) NPD015s-AD237 (SEQ ID NO.: 548 and SEQ ID NO.: 745) NPD015s-AD242 (SEQ ID NO.: 553 and SEQ ID NO.: 750) NPD015s-AD253 (SEQ ID NO.: 564 and SEQ ID NO.: 761) NPD015s-AD255 (SEQ ID NO.: 566 and SEQ ID NO.: 763) NPD015s-AD256 (SEQ ID NO.: 567 and SEQ ID NO.: 764) NPD015s-AD257 (SEQ ID NO.: 568 and SEQ ID NO.: 765) NPD015s-AD258 (SEQ ID NO.: 569 and SEQ ID NO.: 766) NPD015s-AD259 (SEQ ID NO.: 570 and SEQ ID NO.: 767) NPD015s-AD260 (SEQ ID NO.: 571 and SEQ ID NO.: 768) NPD015s-AD261 (SEQ ID NO.: 572 and SEQ ID NO.: 769) NPD015s-AD262 (SEQ ID NO.: 573 and SEQ ID NO.: 770) NPD015s-AD263 (SEQ ID NO.: 574 and SEQ ID NO.: 771) NPD015s-AD264 (SEQ ID NO.: 575 and SEQ ID NO.: 772) NPD015s-AD275 (SEQ ID NO.: 586 and SEQ ID NO.: 783) NPD015s-AD276 (SEQ ID NO.: 587 and SEQ ID NO.: 784) NPD015s-AD277 (SEQ ID NO.: 588 and SEQ ID NO.: 785) NPD015s-AD278 (SEQ ID NO.: 589 and SEQ ID NO.: 786) NPD015s-AD279 (SEQ ID NO.: 590 and SEQ ID NO.: 787) NPD015s-AD280 (SEQ ID NO.: 591 and SEQ ID NO.: 788) NPD015s-AD281 (SEQ ID NO.: 592 and SEQ ID NO.: 789) NPD015s-AD282 (SEQ ID NO.: 593 and SEQ ID NO.: 790) NPD015s-AD283 (SEQ ID NO.: 594 and SEQ ID NO.: 791) NPD015s-AD284 (SEQ ID NO.: 595 and SEQ ID NO.: 792) NPD015s-AD295 (SEQ ID NO.: 596 and SEQ ID NO.: 803) NPD015s-AD296 (SEQ ID NO.: 597 and SEQ ID NO.: 804) NPD015s-AD297 (SEQ ID NO.: 598 and SEQ ID NO.: 805) NPD015s-AD298 (SEQ ID NO.: 599 and SEQ ID NO.: 806) NPD015s-AD299 (SEQ ID NO.: 600 and SEQ ID NO.: 807) NPD015s-AD300 (SEQ ID NO.: 601 and SEQ ID NO.: 808) NPD015s-AD301 (SEQ ID NO.: 602 and SEQ ID NO.: 809) NPD015s-AD302 (SEQ ID NO.: 603 and SEQ ID NO.: 810) NPD015s-AD303 (SEQ ID NO.: 604 and SEQ ID NO.: 811) NPD015s-AD304 (SEQ ID NO.: 605 and SEQ ID NO.: 812) NPD015s-AD305 (SEQ ID NO.: 606 and SEQ ID NO.: 813) NPD015s-AD306 (SEQ ID NO.: 607 and SEQ ID NO.: 814) NPD015s-AD307 (SEQ ID NO.: 608 and SEQ ID NO.: 815) NPD015s-AD308 (SEQ ID NO.: 609 and SEQ ID NO.: 816) NPD015s-AD309 (SEQ ID NO.: 610 and SEQ ID NO.: 817) NPD015s-AD310 (SEQ ID NO.: 611 and SEQ ID NO.: 818) NPD015s-AD311 (SEQ ID NO.: 612 and SEQ ID NO.: 819) NPD015s-AD312 (SEQ ID NO.: 613 and SEQ ID NO.: 820) NPD015s-AD313 (SEQ ID NO.: 614 and SEQ ID NO.: 821) NPD015s-AD314 (SEQ ID NO.: 615 and SEQ ID NO.: 822) NPD015s-AD335 (SEQ ID NO.: 646 and SEQ ID NO.: 843) NPD015s-AD336 (SEQ ID NO.: 647 and SEQ ID NO.: 844) NPD015s-AD337 (SEQ ID NO.: 648 and SEQ ID NO.: 845) NPD015s-AD338 (SEQ ID NO.: 649 and SEQ ID NO.: 846) NPD015s-AD339 (SEQ ID NO.:650 and SEQ ID NO.:847) NPD015s-AD340 (SEQ ID NO.: 651 and SEQ ID NO.: 848) NPD015s-AD341 (SEQ ID NO.: 652 and SEQ ID NO.: 849) NPD015s-AD342 (SEQ ID NO.: 653 and SEQ ID NO.: 850) NPD015s-AD343 (SEQ ID NO.: 654 and SEQ ID NO.: 851) NPD015s-AD344 (SEQ ID NO.: 655 and SEQ ID NO.: 852) NPD015s-AD345 (SEQ ID NO.: 656 and SEQ ID NO.: 853) NPD015s-AD346 (SEQ ID NO.: 657 and SEQ ID NO.: 854) NPD015s-AD347 (SEQ ID NO.: 658 and SEQ ID NO.: 855) NPD015s-AD348 (SEQ ID NO.: 659 and SEQ ID NO.: 856) NPD015s-AD349 (SEQ ID NO.: 660 and SEQ ID NO.: 857) NPD015s-AD350 (SEQ ID NO.: 661 and SEQ ID NO.: 858) NPD015s-AD351 (SEQ ID NO.: 662 and SEQ ID NO.: 859) NPD015s-AD352 (SEQ ID NO.: 663 and SEQ ID NO.: 860) NPD015s-AD353 (SEQ ID NO.:664 and SEQ ID NO.:861) NPD015s-AD354 (SEQ ID NO.: 665 and SEQ ID NO.: 862) NPD015s-AD365 (SEQ ID NO.: 676 and SEQ ID NO.: 873) NPD015s-AD366 (SEQ ID NO.: 677 and SEQ ID NO.: 874) NPD015s-AD367 (SEQ ID NO.: 678 and SEQ ID NO.: 875) NPD015s-AD368 (SEQ ID NO.: 679 and SEQ ID NO.: 876) NPD015s-AD369 (SEQ ID NO.: 680 and SEQ ID NO.: 877) NPD015s-AD370 (SEQ ID NO.: 681 and SEQ ID NO.: 878) NPD015s-AD371 (SEQ ID NO.: 682 and SEQ ID NO.: 879) NPD015s-AD372 (SEQ ID NO.: 683 and SEQ ID NO.: 880) NPD015s-AD373 (SEQ ID NO.: 684 and SEQ ID NO.: 881) NPD015s-AD374 (SEQ ID NO.: 685 and SEQ ID NO.: 882) NPD015s-AD375 (SEQ ID NO.: 686 and SEQ ID NO.: 883) NPD015s-AD376 (SEQ ID NO.: 687 and SEQ ID NO.: 884) NPD015s-AD377 (SEQ ID NO.: 688 and SEQ ID NO.: 885) NPD015s-AD378 (SEQ ID NO.: 689 and SEQ ID NO.: 886) NPD015s-AD379 (SEQ ID NO.: 690 and SEQ ID NO.: 887) NPD015s-AD380 (SEQ ID NO.: 691 and SEQ ID NO.: 888) NPD015s-AD381 (SEQ ID NO.: 692 and SEQ ID NO.: 889) NPD015s-AD382 (SEQ ID NO.: 693 and SEQ ID NO.: 890) NPD015s-AD383 (SEQ ID NO.: 694 and SEQ ID NO.: 891) NPD015s-AD384 (SEQ ID NO.: 695 and SEQ ID NO.: 892).

46. ​​A cell comprising LPA 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 LPA, 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 an LPA 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 the LPA 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 disease associated with abnormal LPA expression.

53. The method of claim 52, wherein: The clinical symptoms associated with abnormal LPA expression are selected from: Buerger's disease, peripheral artery disease, coronary artery disease, metabolic syndrome, acute coronary syndrome, aortic stenosis, aortic regurgitation, aortic dissection, retinal artery occlusion, cardiovascular and cerebrovascular diseases, mesenteric ischemia, superior mesenteric artery occlusion, renal artery stenosis, stable / unstable angina, acute coronary syndrome, heterozygous or homozygous familial hypercholesterolemia, hyperlipoprotein betalipoproteinemia, atherosclerosis and venous thrombosis.

54. The use as claimed in claim 53, wherein the disease associated with abnormal LPA expression is coronary artery disease, metabolic syndrome, cardiovascular and cerebrovascular diseases, heterozygous or homozygous familial hypercholesterolemia, hyperlipoprotein betalipoproteinemia and atherosclerosis.

55. The use according to claim 54, wherein the disease associated with abnormal LPA expression is coronary artery disease, cardiovascular and cerebrovascular disease and atherosclerosis.

56. The use according to claim 55, wherein the disease associated with abnormal LPA expression is atherosclerosis.

57. The method according to any one of claims 46 to 49, characterized in that The siRNA duplex inhibits the expression of LPA 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 LPA expression reduces the LPA level in the serum of the subject by at least 50%, 60%, 70%, 80%, 90% or 95%.

59. A method for treating clinical symptoms associated with abnormal LPA expression 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 LPA expression.

60. The use according to claim 59, wherein the disorder is a disease associated with abnormal expression of LPA.

61. The use according to claim 59, wherein the disease associated with abnormal LPA expression is selected from the group consisting of: Buerger's disease, peripheral artery disease, coronary artery disease, metabolic syndrome, acute coronary syndrome, aortic stenosis, aortic regurgitation, aortic dissection, retinal artery occlusion, cardiovascular and cerebrovascular diseases, mesenteric ischemia, superior mesenteric artery occlusion, renal artery stenosis, stable / unstable angina, acute coronary syndrome, heterozygous or homozygous familial hypercholesterolemia, hyperlipoprotein betalipoproteinemia, atherosclerosis and venous thrombosis.

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 LPA and / or a reduction in APO(a) 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 Lp(a) in a sample from the subject.

67. The method of claim 66, wherein: The Lp(a) level in the subject sample is derived from testing 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 dyslipidemia-related disease.

69. The method of claim 68, wherein: The additional therapeutic agent is selected from: antibodies, siRNA or small molecule complement inhibitors.

70. Use of the siRNA duplex according to any one of claims 1 to 45 or the pharmaceutical composition according to claim 46 or 47 for treating clinical symptoms related to abnormal expression of LPA.

71. The use as claimed in claim 70, for use in a method as claimed in any one of claims 50 to 70.

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