SiRNA for inhibiting LPA expression and application thereof

Abstract

The invention relates to a siRNA double-chain molecule for inhibiting LPA (apo (a)) gene expression, a siRNA-GalNAc delivery carrier conjugate and application of the siRNA double-chain molecule and the siRNA-GalNAc delivery carrier conjugate. The siRNA provided by the invention can be used for degrading mRNA by forming a silent complex and complementarily pairing with the mRNA sequence of LPA (apo (a)), so that the expression of the LPA (apo (a)) is inhibited, the synthesis of the LPA by liver cells can be specifically reduced, and the treatment on cardiovascular related diseases is provided.

Description

Technical Field

[0001] The present invention belongs to the field of biomedical technologies. Specifically, the present invention relates to an siRNA targeting LPA mRNA and its use. More specifically, the present invention relates to an siRNA duplex, an siRNA-delivery vector conjugate (GalNAc-siRNA), a pharmaceutical composition and their uses. Background Art

[0002] Lipoprotein(a) [Lp(a)] is a heterogeneous low-density lipoprotein (LDL)-like particle that contains a lipid core and apolipoprotein B (apoB-100) and a unique component, i.e., apolipoprotein(a) (apo(a)) attached to apoB-100 by a disulfide bond.

[0003] The Apo(a) gene (LPA) is mainly expressed in the liver and the expression is limited to humans and non-human primates. The Lp(a) level in humans is genetically determined and does not change significantly with diet, exercise or other lifestyle changes. The length of LPA varies according to the number of Kringle KIV2 domains present, and its expression is negatively correlated with the number of domains present. The normal range of Lp(a) level is 0.1 - 25 mg / dL.

[0004] Analysis of Lp(a) levels in multiple studies suggests that high Lp(a) levels are an independent risk factor for cardiovascular diseases, stroke and other related conditions including atherosclerotic stenosis. In addition, genome-wide association analysis also implicates LPA as a genetic risk factor for diseases such as atherosclerotic stenosis.

[0005] When using therapeutic lipoprotein apheresis to reduce both Lp(a) and LDL levels in patients with hyperlipidemia, a significant reduction in cardiovascular events was observed.

[0006] SiRNA is a short RNA molecule that can targetedly inhibit the expression of mRNA genes. Through the RNA interference mechanism, siRNA binds to the mRNA of the target gene and guides RNA nuclease to cleave the corresponding mRNA molecule, thereby preventing the translation of mRNA and the synthesis of proteins. Compared with other gene silencing technologies, the siRNA technology has advantages such as high efficiency, selectivity and repeatability.

[0007] In recent years, siRNA drugs targeting LPA (apo(a)) mRNA have attracted much attention from researchers as a new strategy for treating diseases related to abnormal LPA expression. The LPA gene sequence in humans has been fully studied and the structure and function of its mRNA have been deeply understood. Therefore, by studying the LPA mRNA sequence, siRNA duplexes targeting LPA can be designed.

[0008] In addition, because siRNA is targeted and reversible, it can reduce side effects during treatment and restore the patient's normal gene expression level after treatment. SiRNA technology can also provide more flexibility for drug design and is expected to become one of the important technical means for treating diseases related to abnormal LPA expression in the future. SUMMARY OF THE INVENTION

[0009] The present invention aims to solve at least one of the technical problems existing in the prior art to a certain extent. To this end, the present invention provides an siRNA for inhibiting the expression of LPA and its use. The siRNA of the present invention can inhibit the expression of LPA and can effectively treat cardiovascular diseases such as atherosclerosis.

[0010] The present invention proposes a siRNA duplex. According to an embodiment of the present invention, the siRNA includes a sense strand and an antisense strand. The antisense strand includes a complementary region that is complementary to the sense strand. The sense strand is selected from a nucleotide sequence that differs from the nucleotide sequence of each strand in SEQ ID NO:1 to SEQ ID NO: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. The inventors obtained the above-mentioned suitable small interfering RNA (siRNA) through experimental design, which can specifically reduce the synthesis of LPA (apo (a)) by hepatocytes, while avoiding off-target effects. siRNA forms a silencing complex (RNA-induced silencing complex, RISC), and complements the sequence of the target gene LPA mRNA, thereby degrading the mRNA of LPA (apo (a)), 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 valve stenosis, aortic valve 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.

[0011] In the present invention, the "difference of no more than 2 nucleotides" means that there may be 1 or 2 nucleotide differences compared with the target nucleotide sequence, 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.

[0012] According to an embodiment of the present invention, the above siRNA may further include at least one of the following additional technical features:

[0013] According to an embodiment of the present invention, in addition to including at least one of SEQ ID NO:1 to SEQ ID NO:57 shown in Table 1, the sense strand further includes a continuous nucleotide sequence that differs from the sense strand shown in Table 1 by 1 or 2 nucleotides.

[0014] According to an embodiment of the present invention, in addition to including at least one of SEQ ID NO:58 to SEQ ID NO:114 shown in Table 1, the antisense strand further includes a continuous nucleotide sequence that differs from the antisense strand (excluding the 3'-overhanging end bases) shown in Table 1 by 1 or 2 nucleotides.

[0015] Exemplarily, NDS-015-3 15'-CAGAGUUAUCAAGGCACAUAA-3' (SEQ ID NO:31) and 5'-AGAGUUAUCAAGGCACAUUU-3', 5'-UAGAGUUAUCAAGGCACAUAA-3' and 5'-IAGAGUUAUCAAGGCACAUAA-3' etc. should be regarded as the same nucleotide sequence.

[0016] Table 1: Nucleotide sequences of siRNA

[0017]

[0018]

[0019] According to an embodiment of the present invention, the sense strand includes one of the following nucleotide sequences, or a nucleotide sequence that differs from it by no more than 2 nucleotides: SEQ ID NO:4, SEQ ID NO:7, SEQ ID NO:11, SEQ ID NO:16, 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 includes one of the following nucleotide sequences, or a nucleotide sequence that differs from it 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.

[0020] According to an embodiment of the present invention, the antisense strand comprises at least 19 consecutive nucleotides of the antisense strand nucleotide sequence of any of the double-stranded bodies selected from the following:

[0021] NDS-015-2 (SEQ ID NO.: 2 and SEQ ID NO.: 59)

[0022] NDS-015-4 (SEQ ID NO.: 4 and SEQ ID NO.: 61)

[0023] NDS-015-6 (SEQ ID NO.: 6 and SEQ ID NO.: 63)

[0024] NDS-015-7 (SEQ ID NO.: 7 and SEQ ID NO.: 64)

[0025] NDS-015-11 (SEQ ID NO.: 11 and SEQ ID NO.: 68)

[0026] NDS-015-16 (SEQ ID NO.: 16 and SEQ ID NO.: 73)

[0027] NDS-015-17 (SEQ ID NO.: 17 and SEQ ID NO.: 74)

[0028] NDS-015-20 (SEQ ID NO.: 20 and SEQ ID NO.: 77)

[0029] NDS-015-26 (SEQ ID NO.: 26 and SEQ ID NO.: 83)

[0030] NDS-015-27 (SEQ ID NO.: 27 and SEQ ID NO.: 84)

[0031] NDS-015-29 (SEQ ID NO.: 29 and SEQ ID NO.: 86)

[0032] NDS-015-31 (SEQ ID NO.: 31 and SEQ ID NO.: 88)

[0033] NDS-015-37 (SEQ ID NO.: 37 and SEQ ID NO.: 94)

[0034] NDS-015-40 (SEQ ID NO.: 40 and SEQ ID NO.: 97)

[0035] NDS-015-45 (SEQ ID NO.: 45 and SEQ ID NO.: 102)

[0036] NDS-015-56 (SEQ ID NO.: 56 and SEQ ID NO.: 113)

[0037] According to an embodiment of the present invention, the sense strand comprises at least 17 consecutive nucleotides of the sense strand nucleotide sequence of any of the duplexes selected from the following:

[0038] NDS-015-2 (SEQ ID NO.: 2 and SEQ ID NO.: 59)

[0039] NDS-015-4 (SEQ ID NO.: 4 and SEQ ID NO.: 61)

[0040] NDS-015-6 (SEQ ID NO.: 6 and SEQ ID NO.: 63)

[0041] NDS-015-7 (SEQ ID NO.: 7 and SEQ ID NO.: 64)

[0042] NDS-015-11 (SEQ ID NO.: 11 and SEQ ID NO.: 68)

[0043] NDS-015-16 (SEQ ID NO.: 16 and SEQ ID NO.: 73)

[0044] NDS-015-17 (SEQ ID NO.: 17 and SEQ ID NO.: 74)

[0045] NDS-015-20 (SEQ ID NO.: 20 and SEQ ID NO.: 77)

[0046] NDS-015-26 (SEQ ID NO.: 26 and SEQ ID NO.: 83)

[0047] NDS-015-27 (SEQ ID NO.: 27 and SEQ ID NO.: 84)

[0048] NDS-015-29 (SEQ ID NO.: 29 and SEQ ID NO.: 86)

[0049] NDS-015-31 (SEQ ID NO.: 31 and SEQ ID NO.: 88)

[0050] NDS-015-37 (SEQ ID NO.: 37 and SEQ ID NO.: 94)

[0051] NDS-015-40 (SEQ ID NO.: 40 and SEQ ID NO.: 97)

[0052] NDS-015-45 (SEQ ID NO.: 45 and SEQ ID NO.: 102)

[0053] NDS-015-56 (SEQ ID NO.: 56 and SEQ ID NO.: 113)

[0054] According to an embodiment of the present invention, the sense and antisense strands comprise a nucleotide sequence of a duplex selected from the following:

[0055] NDS-015-2 (SEQ ID NO.: 2 and SEQ ID NO.: 59)

[0056] NDS-015-4 (SEQ ID NO.: 4 and SEQ ID NO.: 61)

[0057] NDS-015-6 (SEQ ID NO.: 6 and SEQ ID NO.: 63)

[0058] NDS-015-7 (SEQ ID NO.: 7 and SEQ ID NO.: 64)

[0059] NDS-015-11 (SEQ ID NO.: 11 and SEQ ID NO.: 68)

[0060] NDS-015-16 (SEQ ID NO.: 16 and SEQ ID NO.: 73)

[0061] NDS-015-17 (SEQ ID NO.: 17 and SEQ ID NO.: 74)

[0062] NDS-015-20 (SEQ ID NO.: 20 and SEQ ID NO.: 77)

[0063] NDS-015-26 (SEQ ID NO.: 26 and SEQ ID NO.: 83)

[0064] NDS-015-27 (SEQ ID NO.: 27 and SEQ ID NO.: 84)

[0065] NDS-015-29 (SEQ ID NO.: 29 and SEQ ID NO.: 86)

[0066] NDS-015-31 (SEQ ID NO.: 31 and SEQ ID NO.: 88)

[0067] NDS-015-37 (SEQ ID NO.: 37 and SEQ ID NO.: 94)

[0068] NDS-015-40 (SEQ ID NO.: 40 and SEQ ID NO.: 97)

[0069] NDS-015-45 (SEQ ID NO.: 45 and SEQ ID NO.: 102)

[0070] NDS-015-56 (SEQ ID NO.: 56 and SEQ ID NO.: 113)

[0071] According to an embodiment of the present invention, the antisense strand comprises at least 19 consecutive nucleotides of the nucleotide sequence of the antisense strand of NDS-015-31 (SEQ ID NO.: 31 and SEQ ID NO.: 88) (5'-UUAUGUGCCUUGAUAACUCUGUU-3', SEQ ID NO: 88). In certain embodiments, the sense strand comprises at least 19 consecutive nucleotides of the nucleotide sequence of the sense strand of NDS-015-31 (5'-CAGAGUUAUCAAGGCACAUAA-3', SEQ ID NO: 31). In certain embodiments, the sense and antisense strands comprise the nucleotide sequences of the sense and antisense strands of NDS-015-31 (5'-CAGAGUUAUCAAGGCACAUAA-3', SEQ ID NO: 31) and (5'-UUAUGUGCCUUGAUAACUCUGUU-3', SEQ ID NO: 88).

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

[0073] According to an embodiment of the present invention, the length of the complementary region is 19 to 23 bases.

[0074] 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 overhangs.

[0075] According to an embodiment of the present invention, the siRNA comprises at least one modified nucleotide.

[0076] 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.

[0077] According to an embodiment of the present invention, the modified nucleotide is selected from at least one of the following:

[0078] 2'-O-methyl modified nucleotide : aM, gM, cM, and uM are 2'-O-Me A, 2'-O-Me G, 2'-O-Me C, and 2'-O-Me U, respectively;

[0079] 2'-fluoro modified nucleotide : aF, gF, cF, and uF are 2'-fluoro A, 2'-fluoro G, 2'-fluoro C, and 2'-fluoro U, respectively;

[0080] 2'-deoxy modified nucleotide : 2'-deoxycytidine-3'-phosphate, 2'-deoxyguanosine-3'-phosphate, 2'-deoxyadenosine-3'-phosphate, 2'-deoxyuridine-3'-phosphate;

[0081] 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, 2'-O-methyl-5'-deoxy-(1-(1,2,4-triazole))-uridine-3'-phosphate, respectively;

[0082] 5'-thiomorpholine modified nucleotide : 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, 2'-O-methyl-5'-N-(thiomorpholine)-uridine-3'-phosphate, respectively;

[0083] 3'-fluoro modified nucleotide : cRF, gRF, aRF, and uRF are 3'-fluoro-3'-deoxycytidine-2'-phosphate, 3'-fluoro-3'-deoxyguanosine-2'-phosphate, 3'-fluoro-3'-deoxyadenosine-2'-phosphate, 3'-fluoro-3'-deoxyuridine-2'-phosphate, respectively;

[0084] 3'-deoxy modified nucleotide: 3'-deoxycytidine-2'-phosphate, 3'-deoxyguanosine-2'-phosphate, 3'-deoxyadenosine-2'-phosphate, 3'-deoxyuridine-2'-phosphate;

[0085] 5'-thiophosphate diester linkage and / or methylphosphonate nucleotide ;

[0086] nucleotide with unconventional base ;

[0087] 5'-trans-vinylphosphonate (E-VP) modified nucleotide 。

[0088] It should be noted that when a modified nucleotide is selected from 2'-modified nucleotides and 5'-thiophosphorodiamidate-modified nucleotides, that is, the modified nucleotide has both 2'-modification and 5'-thiophosphorodiamidate chain modification.

[0089] As is known to those skilled in the art, ribonucleotide molecules are composed of phosphoric acid, ribose and bases. In this article, "modified nucleotide" refers to a nucleotide that is different from the conventional nucleotides of A, U, C or G, or an unconventional nucleotide, such as inosine (I) or pseudouridine (ψ), in which there are changes in the groups attached to different carbon atoms on the ribose, changes in the phosphodiester linker groups, or deletions or substitutions of bases.

[0090] According to an embodiment of the present invention, all nucleotides in the sense strand and / or the antisense strand are modified nucleotides, and the modified nucleotides are each independently selected from at least one of 2'-O-methyl-modified nucleotides, 2'-fluoro-modified nucleotides, 2'-deoxy-modified nucleotides, 3'-O-methyl-modified nucleotides, 3'-fluoro-modified nucleotides, 3'-deoxy-modified nucleotides, 5'-(1,2,4)-triazole-modified nucleotides, 5'-thiomorpholine-modified nucleotides, 5'-thiophosphorodiamidate-modified nucleotides and 5'-VP phosphonate-modified nucleotides.

[0091] According to an embodiment of the present invention, in the sense strand and / or the antisense strand, 2'-fluoro-modified nucleotides are present in the following positions: 2'-fluoro-modified nucleotides at the 9th, 10th and 11th positions starting from the nucleotide at the 5'-end of the sense strand, and the remaining positions are 2'-O-methyl-modified nucleotides; and / or, 2'-fluoro-modified nucleotides at the 2nd, 6th, 14th and 16th positions starting from the nucleotide at the 5'-end of the antisense strand, and the remaining positions are 2'-O-methyl-modified nucleotides.

[0092] Exemplarily, the nucleotide at the 5'-end of the sense strand, which is the nucleotide at the 1st position starting from the starting point, is a 2'-O-methyl-modified nucleotide.

[0093] Exemplarily, the nucleotide at the 1st position starting from the nucleotide at the 5'-end of the antisense strand, the nucleotides at the 1st and 2nd positions starting from the nucleotide at the 3'-end of the antisense strand are all 2'-O-methyl modified nucleotides and 5'-thiophosphorothioate modified nucleotides.

[0094] According to an embodiment of the present invention, the 5'-modified nucleotide at the 1st position starting from the nucleotide at the 5'-end of the siRNA sense strand can optionally be 5'-(1,2,4)-triazole modified nucleotide : cTA4, gTA4, aTA4, uTA4 are 2'-O-methyl-5'-deoxy-(1-(1,2,4-triazole))-cytidine-3'-phosphate, 2'-O-methyl-5'-deoxy-(1-(1,2,4-triazole))-guanosine-3'-phosphate, 2'-O-methyl-5'-deoxy-(1-(1,2,4-triazole))-adenosine-3'-phosphate, 2'-O-methyl-5'-deoxy-(1-(1,2,4-triazole))-uridine-3'-phosphate; or

[0095] 5'-thiomorpholine modified nucleotide : cSMP, gSMP, aSMP, 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, 2'-O-methyl-5'-N-(thiomorpholine)-uridine-3'-phosphate.

[0096] Exemplarily, the nucleotide at the 5'-end of the sense strand can be the nucleotide at the 1st position starting from the nucleotide at the 5'-end is 2'-O-methyl-5'-deoxy-(1-(1,2,4-triazole))-cytidine-3'-phosphate.

[0097] According to an embodiment of the present invention, the 5'-unmodified or 5'-trans-vinylphosphonate (E-VP) modified nucleotide at the 1st position starting from the nucleotide at the 5'-end of the siRNA antisense strand.

[0098] Exemplarily, the nucleotide at the 1st position starting from the nucleotide at the 5'-end of the antisense strand can be 2'-O-methyl-5'-deoxy-(E)-vinyl phosphate-inosine-3'-phosphate.

[0099] According to an embodiment of the present invention, the nucleotides at the 5th to 8th positions starting from the nucleotide at the 5'-end of the siRNA antisense strand can optionally be 3'-O-methyl or 3'-fluoro modified nucleotides.

[0100] Exemplarily, the nucleotide at the 7th position starting from the nucleotide at the 5'-end of the antisense strand can be 3'-fluoro-3'-deoxyadenosine-2'-phosphate.

[0101] According to an embodiment of the present invention, an siRNA double-stranded molecule, wherein the siRNA double-stranded molecule may further comprise at least one phosphorothioate or methylphosphonate internucleotide linkage. In certain embodiments, the phosphorothioate or methylphosphonate internucleotide linkage is at the 3'-end of one strand, wherein the strand is an antisense strand and / or a sense strand. In certain embodiments, the phosphorothioate or methylphosphonate internucleotide linkage is at the 5'-end of one strand, wherein the strand is an antisense strand and / or a sense strand. In certain embodiments, the phosphorothioate or methylphosphonate internucleotide linkage is at the 5'-end and 3'-end of one strand, wherein the strand is an antisense strand.

[0102] According to an embodiment of the present invention, an siRNA double-stranded molecule, wherein the base pair at position 1 at 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.

[0103] According to an embodiment of the present invention, the antisense strand of the siRNA comprises any antisense strand nucleotide sequence of a chemically modified duplex selected from SEQ ID NO.: 312 to SEQ ID NO.: 508.

[0104] According to an embodiment of the present invention, the antisense strand of the siRNA comprises any antisense strand nucleotide sequence of a chemically modified duplex selected from the following:

[0105] NPD015s-AD002 (SEQ ID NO.: 116 and SEQ ID NO.: 313)

[0106] NPD015s-AD004 (SEQ ID NO.: 118 and SEQ ID NO.: 315)

[0107] NPD015s-AD006 (SEQ ID NO.: 120 and SEQ ID NO.: 317)

[0108] NPD015s-AD007 (SEQ ID NO.: 121 and SEQ ID NO.: 318)

[0109] NPD015s-AD011 (SEQ ID NO.: 125 and SEQ ID NO.: 322)

[0110] NPD015s-AD016 (SEQ ID NO.: 130 and SEQ ID NO.: 327)

[0111] NPD015s-AD017 (SEQ ID NO.: 131 and SEQ ID NO.: 328)

[0112] NPD015s-AD020 (SEQ ID NO.: 134 and SEQ ID NO.: 331)

[0113] NPD015s-AD026 (SEQ ID NO.: 140 and SEQ ID NO.: 337)

[0114] NPD015s-AD027 (SEQ ID NO.: 141 and SEQ ID NO.: 338)

[0115] NPD015s-AD029 (SEQ ID NO.: 143 and SEQ ID NO.: 340)

[0116] NPD015s-AD031 (SEQ ID NO.: 145 and SEQ ID NO.: 342)

[0117] NPD015s-AD037 (SEQ ID NO.: 151 and SEQ ID NO.: 348)

[0118] NPD015s-AD040 (SEQ ID NO.: 154 and SEQ ID NO.: 351)

[0119] NPD015s-AD045 (SEQ ID NO.: 159 and SEQ ID NO.: 356)

[0120] NPD015s-AD056 (SEQ ID NO.: 170 and SEQ ID NO.: 367)

[0121] NPD015s-AD058 (SEQ ID NO.: 172 and SEQ ID NO.: 369)

[0122] NPD015s-AD059 (SEQ ID NO.: 173 and SEQ ID NO.: 370)

[0123] NPD015s-AD060 (SEQ ID NO.: 174 and SEQ ID NO.: 371)

[0124] NPD015s-AD061 (SEQ ID NO.: 175 and SEQ ID NO.: 372)

[0125] NPD015s-AD062 (SEQ ID NO.: 176 and SEQ ID NO.: 373)

[0126] NPD015s-AD063 (SEQ ID NO.: 177 and SEQ ID NO.: 374)

[0127] NPD015s-AD064 (SEQ ID NO.: 178 and SEQ ID NO.: 375)

[0128] NPD015s-AD065 (SEQ ID NO.: 179 and SEQ ID NO.: 376)

[0129] NPD015s-AD066 (SEQ ID NO.: 180 and SEQ ID NO.: 377)

[0130] NPD015s-AD067 (SEQ ID NO.: 181 and SEQ ID NO.: 378)

[0131] NPD015s-AD078 (SEQ ID NO.: 192 and SEQ ID NO.: 389)

[0132] NPD015s-AD079 (SEQ ID NO.: 193 and SEQ ID NO.: 390)

[0133] NPD015s-AD080 (SEQ ID NO.: 194 and SEQ ID NO.: 391)

[0134] NPD015s-AD081 (SEQ ID NO.: 195 and SEQ ID NO.: 392)

[0135] NPD015s-AD082 (SEQ ID NO.: 196 and SEQ ID NO.: 393)

[0136] NPD015s-AD083 (SEQ ID NO.: 197 and SEQ ID NO.: 394)

[0137] NPD015s-AD084 (SEQ ID NO.: 198 and SEQ ID NO.: 395)

[0138] NPD015s-AD085 (SEQ ID NO.: 199 and SEQ ID NO.: 396)

[0139] NPD015s-AD086 (SEQ ID NO.: 200 and SEQ ID NO.: 397)

[0140] NPD015s-AD087 (SEQ ID NO.: 201 and SEQ ID NO.: 398)

[0141] NPD015s-AD098 (SEQ ID NO.: 212 and SEQ ID NO.: 409)

[0142] NPD015s-AD099 (SEQ ID NO.: 213 and SEQ ID NO.: 410)

[0143] NPD015s-AD100 (SEQ ID NO.: 214 and SEQ ID NO.: 411)

[0144] NPD015s-AD101 (SEQ ID NO.: 215 and SEQ ID NO.: 412)

[0145] NPD015s-AD102 (SEQ ID NO.: 216 and SEQ ID NO.: 413)

[0146] NPD015s-AD103 (SEQ ID NO.: 217 and SEQ ID NO.: 414)

[0147] NPD015s-AD104 (SEQ ID NO.: 218 and SEQ ID NO.: 415)

[0148] NPD015s-AD105 (SEQ ID NO.: 219 and SEQ ID NO.: 416)

[0149] NPD015s-AD106 (SEQ ID NO.: 220 and SEQ ID NO.: 417)

[0150] NPD015s-AD107 (SEQ ID NO.: 221 and SEQ ID NO.: 418)

[0151] NPD015s-AD108 (SEQ ID NO.: 222 and SEQ ID NO.: 419)

[0152] NPD015s-AD109 (SEQ ID NO.: 223 and SEQ ID NO.: 420)

[0153] NPD015s-AD110 (SEQ ID NO.: 224 and SEQ ID NO.: 421)

[0154] NPD015s-AD111 (SEQ ID NO.: 225 and SEQ ID NO.: 422)

[0155] NPD015s-AD112 (SEQ ID NO.: 226 and SEQ ID NO.: 423)

[0156] NPD015s-AD113 (SEQ ID NO.: 227 and SEQ ID NO.: 424)

[0157] NPD015s-AD114 (SEQ ID NO.: 228 and SEQ ID NO.: 425)

[0158] NPD015s-AD115 (SEQ ID NO.: 229 and SEQ ID NO.: 426)

[0159] NPD015s-AD116 (SEQ ID NO.: 230 and SEQ ID NO.: 427)

[0160] NPD015s-AD117 (SEQ ID NO.: 231 and SEQ ID NO.: 428)

[0161] NPD015s-AD138 (SEQ ID NO.: 252 and SEQ ID NO.: 449)

[0162] NPD015s-AD139 (SEQ ID NO.: 253 and SEQ ID NO.: 450)

[0163] NPD015s-AD140 (SEQ ID NO.: 254 and SEQ ID NO.: 451)

[0164] NPD015s-AD141 (SEQ ID NO.: 255 and SEQ ID NO.: 452)

[0165] NPD015s-AD142 (SEQ ID NO.: 256 and SEQ ID NO.: 453)

[0166] NPD015s-AD143 (SEQ ID NO.: 257 and SEQ ID NO.: 454)

[0167] NPD015s-AD144 (SEQ ID NO.: 258 and SEQ ID NO.: 455)

[0168] NPD015s-AD145 (SEQ ID NO.: 259 and SEQ ID NO.: 456)

[0169] NPD015s-AD146 (SEQ ID NO.: 260 and SEQ ID NO.: 457)

[0170] NPD015s-AD147 (SEQ ID NO.: 261 and SEQ ID NO.: 458)

[0171] NPD015s-AD148 (SEQ ID NO.: 262 and SEQ ID NO.: 459)

[0172] NPD015s-AD149 (SEQ ID NO.: 263 and SEQ ID NO.: 460)

[0173] NPD015s-AD150 (SEQ ID NO.: 264 and SEQ ID NO.: 461)

[0174] NPD015s-AD151 (SEQ ID NO.: 265 and SEQ ID NO.: 462)

[0175] NPD015s-AD152 (SEQ ID NO.: 266 and SEQ ID NO.: 463)

[0176] NPD015s-AD153 (SEQ ID NO.: 267 and SEQ ID NO.: 464)

[0177] NPD015s-AD154 (SEQ ID NO.: 268 and SEQ ID NO.: 465)

[0178] NPD015s-AD155 (SEQ ID NO.: 269 and SEQ ID NO.: 466)

[0179] NPD015s-AD156 (SEQ ID NO.: 270 and SEQ ID NO.: 467)

[0180] NPD015s-AD157 (SEQ ID NO.: 271 and SEQ ID NO.: 468)

[0181] NPD015s-AD168 (SEQ ID NO.: 282 and SEQ ID NO.: 479)

[0182] NPD015s-AD169 (SEQ ID NO.: 283 and SEQ ID NO.: 480)

[0183] NPD015s-AD170 (SEQ ID NO.: 284 and SEQ ID NO.: 481)

[0184] NPD015s-AD171 (SEQ ID NO.: 285 and SEQ ID NO.: 482)

[0185] NPD015s-AD172 (SEQ ID NO.: 286 and SEQ ID NO.: 483)

[0186] NPD015s-AD173 (SEQ ID NO.: 287 and SEQ ID NO.: 484)

[0187] NPD015s-AD174 (SEQ ID NO.: 288 and SEQ ID NO.: 485)

[0188] NPD015s-AD175 (SEQ ID NO.: 289 and SEQ ID NO.: 486)

[0189] NPD015s-AD176 (SEQ ID NO.: 290 and SEQ ID NO.: 487)

[0190] NPD015s-AD177 (SEQ ID NO.: 291 and SEQ ID NO.: 488)

[0191] NPD015s-AD178 (SEQ ID NO.: 292 and SEQ ID NO.: 489)

[0192] NPD015s-AD179 (SEQ ID NO.: 293 and SEQ ID NO.: 490)

[0193] NPD015s-AD180 (SEQ ID NO.: 294 and SEQ ID NO.: 491)

[0194] NPD015s-AD181 (SEQ ID NO.: 295 and SEQ ID NO.: 492)

[0195] NPD015s-AD182 (SEQ ID NO.: 296 and SEQ ID NO.: 493)

[0196] NPD015s-AD183 (SEQ ID NO.: 297 and SEQ ID NO.: 494)

[0197] NPD015s-AD184 (SEQ ID NO.: 298 and SEQ ID NO.: 495)

[0198] NPD015s-AD185 (SEQ ID NO.: 299 and SEQ ID NO.: 496)

[0199] NPD015s-AD186 (SEQ ID NO.: 300 and SEQ ID NO.: 497)

[0200] NPD015s-AD187 (SEQ ID NO.: 301 and SEQ ID NO.: 498)

[0201] According to an embodiment of the present invention, the sense strand of the siRNA comprises any chemically modified sense strand nucleotide sequence of the duplexes selected from SEQ ID NO.: 115 to SEQ ID NO.: 311.

[0202] According to an embodiment of the present invention, the sense strand of the siRNA comprises any chemically modified sense strand nucleotide sequence of the duplexes selected from the following:

[0203] NPD015s-AD002 (SEQ ID NO.: 116 and SEQ ID NO.: 313)

[0204] NPD015s-AD004 (SEQ ID NO.: 118 and SEQ ID NO.: 315)

[0205] NPD015s-AD006 (SEQ ID NO.: 120 and SEQ ID NO.: 317)

[0206] NPD015s-AD007 (SEQ ID NO.: 121 and SEQ ID NO.: 318)

[0207] NPD015s-AD011 (SEQ ID NO.: 125 and SEQ ID NO.: 322)

[0208] NPD015s-AD016 (SEQ ID NO.: 130 and SEQ ID NO.: 327)

[0209] NPD015s-AD017 (SEQ ID NO.: 131 and SEQ ID NO.: 328)

[0210] NPD015s-AD020 (SEQ ID NO.: 134 and SEQ ID NO.: 331)

[0211] NPD015s-AD026 (SEQ ID NO.: 140 and SEQ ID NO.: 337)

[0212] NPD015s-AD027 (SEQ ID NO.: 141 and SEQ ID NO.: 338)

[0213] NPD015s-AD029 (SEQ ID NO.: 143 and SEQ ID NO.: 340)

[0214] NPD015s-AD031 (SEQ ID NO.: 145 and SEQ ID NO.: 342)

[0215] NPD015s-AD037 (SEQ ID NO.: 151 and SEQ ID NO.: 348)

[0216] NPD015s-AD040 (SEQ ID NO.: 154 and SEQ ID NO.: 351)

[0217] NPD015s-AD045 (SEQ ID NO.: 159 and SEQ ID NO.: 356)

[0218] NPD015s-AD056 (SEQ ID NO.: 170 and SEQ ID NO.: 367)

[0219] NPD015s-AD058 (SEQ ID NO.: 172 and SEQ ID NO.: 369)

[0220] NPD015s-AD059 (SEQ ID NO.: 173 and SEQ ID NO.: 370)

[0221] NPD015s-AD060 (SEQ ID NO.: 174 and SEQ ID NO.: 371)

[0222] NPD015s-AD061 (SEQ ID NO.: 175 and SEQ ID NO.: 372)

[0223] NPD015s-AD062 (SEQ ID NO.: 176 and SEQ ID NO.: 373)

[0224] NPD015s-AD063 (SEQ ID NO.: 177 and SEQ ID NO.: 374)

[0225] NPD015s-AD064 (SEQ ID NO.: 178 and SEQ ID NO.: 375)

[0226] NPD015s-AD065 (SEQ ID NO.: 179 and SEQ ID NO.: 376)

[0227] NPD015s-AD066 (SEQ ID NO.: 180 and SEQ ID NO.: 377)

[0228] NPD015s-AD067 (SEQ ID NO.: 181 and SEQ ID NO.: 378)

[0229] NPD015s-AD078 (SEQ ID NO.: 192 and SEQ ID NO.: 389)

[0230] NPD015s-AD079 (SEQ ID NO.: 193 and SEQ ID NO.: 390)

[0231] NPD015s-AD080 (SEQ ID NO.: 194 and SEQ ID NO.: 391)

[0232] NPD015s-AD081 (SEQ ID NO.: 195 and SEQ ID NO.: 392)

[0233] NPD015s-AD082 (SEQ ID NO.: 196 and SEQ ID NO.: 393)

[0234] NPD015s-AD083 (SEQ ID NO.: 197 and SEQ ID NO.: 394)

[0235] NPD015s-AD084 (SEQ ID NO.: 198 and SEQ ID NO.: 395)

[0236] NPD015s-AD085 (SEQ ID NO.: 199 and SEQ ID NO.: 396)

[0237] NPD015s-AD086 (SEQ ID NO.: 200 and SEQ ID NO.: 397)

[0238] NPD015s-AD087 (SEQ ID NO.: 201 and SEQ ID NO.: 398)

[0239] NPD015s-AD098 (SEQ ID NO.: 212 and SEQ ID NO.: 409)

[0240] NPD015s-AD099 (SEQ ID NO.: 213 and SEQ ID NO.: 410)

[0241] NPD015s-AD100 (SEQ ID NO.: 214 and SEQ ID NO.: 411)

[0242] NPD015s-AD101 (SEQ ID NO.: 215 and SEQ ID NO.: 412)

[0243] NPD015s-AD102 (SEQ ID NO.: 216 and SEQ ID NO.: 413)

[0244] NPD015s-AD103 (SEQ ID NO.: 217 and SEQ ID NO.: 414)

[0245] NPD015s-AD104 (SEQ ID NO.: 218 and SEQ ID NO.: 415)

[0246] NPD015s-AD105 (SEQ ID NO.: 219 and SEQ ID NO.: 416)

[0247] NPD015s-AD106 (SEQ ID NO.: 220 and SEQ ID NO.: 417)

[0248] NPD015s-AD107 (SEQ ID NO.: 221 and SEQ ID NO.: 418)

[0249] NPD015s-AD108 (SEQ ID NO.: 222 and SEQ ID NO.: 419)

[0250] NPD015s-AD109 (SEQ ID NO.: 223 and SEQ ID NO.: 420)

[0251] NPD015s-AD110 (SEQ ID NO.: 224 and SEQ ID NO.: 421)

[0252] NPD015s-AD111 (SEQ ID NO.: 225 and SEQ ID NO.: 422)

[0253] NPD015s-AD112 (SEQ ID NO.: 226 and SEQ ID NO.: 423)

[0254] NPD015s-AD113 (SEQ ID NO.: 227 and SEQ ID NO.: 424)

[0255] NPD015s-AD114 (SEQ ID NO.: 228 and SEQ ID NO.: 425)

[0256] NPD015s-AD115 (SEQ ID NO.: 229 and SEQ ID NO.: 426)

[0257] NPD015s-AD116 (SEQ ID NO.: 230 and SEQ ID NO.: 427)

[0258] NPD015s-AD117 (SEQ ID NO.: 231 and SEQ ID NO.: 428)

[0259] NPD015s-AD138 (SEQ ID NO.: 252 and SEQ ID NO.: 449)

[0260] NPD015s-AD139 (SEQ ID NO.: 253 and SEQ ID NO.: 450)

[0261] NPD015s-AD140 (SEQ ID NO.: 254 and SEQ ID NO.: 451)

[0262] NPD015s-AD141 (SEQ ID NO.: 255 and SEQ ID NO.: 452)

[0263] NPD015s-AD142 (SEQ ID NO.: 256 and SEQ ID NO.: 453)

[0264] NPD015s-AD143 (SEQ ID NO.: 257 and SEQ ID NO.: 454)

[0265] NPD015s-AD144 (SEQ ID NO.: 258 and SEQ ID NO.: 455)

[0266] NPD015s-AD145 (SEQ ID NO.: 259 and SEQ ID NO.: 456)

[0267] NPD015s-AD146 (SEQ ID NO.: 260 and SEQ ID NO.: 457)

[0268] NPD015s-AD147 (SEQ ID NO.: 261 and SEQ ID NO.: 458)

[0269] NPD015s-AD148 (SEQ ID NO.: 262 and SEQ ID NO.: 459)

[0270] NPD015s-AD149 (SEQ ID NO.: 263 and SEQ ID NO.: 460)

[0271] NPD015s-AD150 (SEQ ID NO.: 264 and SEQ ID NO.: 461)

[0272] NPD015s-AD151 (SEQ ID NO.: 265 and SEQ ID NO.: 462)

[0273] NPD015s-AD152 (SEQ ID NO.: 266 and SEQ ID NO.: 463)

[0274] NPD015s-AD153 (SEQ ID NO.: 267 and SEQ ID NO.: 464)

[0275] NPD015s-AD154 (SEQ ID NO.: 268 and SEQ ID NO.: 465)

[0276] NPD015s-AD155 (SEQ ID NO.: 269 and SEQ ID NO.: 466)

[0277] NPD015s-AD156 (SEQ ID NO.: 270 and SEQ ID NO.: 467)

[0278] NPD015s-AD157 (SEQ ID NO.: 271 and SEQ ID NO.: 468)

[0279] NPD015s-AD168 (SEQ ID NO.: 282 and SEQ ID NO.: 479)

[0280] NPD015s-AD169 (SEQ ID NO.: 283 and SEQ ID NO.: 480)

[0281] NPD015s-AD170 (SEQ ID NO.: 284 and SEQ ID NO.: 481)

[0282] NPD015s-AD171 (SEQ ID NO.: 285 and SEQ ID NO.: 482)

[0283] NPD015s-AD172 (SEQ ID NO.: 286 and SEQ ID NO.: 483)

[0284] NPD015s-AD173 (SEQ ID NO.: 287 and SEQ ID NO.: 484)

[0285] NPD015s-AD174 (SEQ ID NO.: 288 and SEQ ID NO.: 485)

[0286] NPD015s-AD175 (SEQ ID NO.: 289 and SEQ ID NO.: 486)

[0287] NPD015s-AD176 (SEQ ID NO.: 290 and SEQ ID NO.: 487)

[0288] NPD015s-AD177 (SEQ ID NO.: 291 and SEQ ID NO.: 488)

[0289] NPD015s-AD178 (SEQ ID NO.: 292 and SEQ ID NO.: 489)

[0290] NPD015s-AD179 (SEQ ID NO.: 293 and SEQ ID NO.: 490)

[0291] NPD015s-AD180 (SEQ ID NO.: 294 and SEQ ID NO.: 491)

[0292] NPD015s-AD181 (SEQ ID NO.: 295 and SEQ ID NO.: 492)

[0293] NPD015s-AD182 (SEQ ID NO.: 296 and SEQ ID NO.: 493)

[0294] NPD015s-AD183 (SEQ ID NO.: 297 and SEQ ID NO.: 494)

[0295] NPD015s-AD184 (SEQ ID NO.: 298 and SEQ ID NO.: 495)

[0296] NPD015s-AD185 (SEQ ID NO.: 299 and SEQ ID NO.: 496)

[0297] NPD015s-AD186 (SEQ ID NO.: 300 and SEQ ID NO.: 497)

[0298] NPD015s-AD187 (SEQ ID NO.: 301 and SEQ ID NO.: 498).

[0299] According to an embodiment of the present invention, the siRNA antisense strand comprises a chemically modified nucleotide sequence of a duplex selected from SEQ ID NO.: 312 to SEQ ID NO.: 508, and the sense strand comprises a chemically modified nucleotide sequence of a duplex selected from SEQ ID NO.: 115 to SEQ ID NO.: 311.

[0300] According to an embodiment of the present invention, the siRNA antisense strand and the sense strand comprise a chemically modified nucleotide sequence of a duplex selected from the following:

[0301] NPD015s-AD002 (SEQ ID NO.: 116 and SEQ ID NO.: 313)

[0302] NPD015s-AD004 (SEQ ID NO.: 118 and SEQ ID NO.: 315)

[0303] NPD015s-AD006 (SEQ ID NO.: 120 and SEQ ID NO.: 317)

[0304] NPD015s-AD007 (SEQ ID NO.: 121 and SEQ ID NO.: 318)

[0305] NPD015s-AD011 (SEQ ID NO.: 125 and SEQ ID NO.: 322)

[0306] NPD015s-AD016 (SEQ ID NO.: 130 and SEQ ID NO.: 327)

[0307] NPD015s-AD017 (SEQ ID NO.: 131 and SEQ ID NO.: 328)

[0308] NPD015s-AD020 (SEQ ID NO.: 134 and SEQ ID NO.: 331)

[0309] NPD015s-AD026 (SEQ ID NO.: 140 and SEQ ID NO.: 337)

[0310] NPD015s-AD027 (SEQ ID NO.: 141 and SEQ ID NO.: 338)

[0311] NPD015s-AD029 (SEQ ID NO.: 143 and SEQ ID NO.: 340)

[0312] NPD015s-AD031 (SEQ ID NO.: 145 and SEQ ID NO.: 342)

[0313] NPD015s-AD037 (SEQ ID NO.: 151 and SEQ ID NO.: 348)

[0314] NPD015s-AD040 (SEQ ID NO.: 154 and SEQ ID NO.: 351)

[0315] NPD015s-AD045 (SEQ ID NO.: 159 and SEQ ID NO.: 356)

[0316] NPD015s-AD056 (SEQ ID NO.: 170 and SEQ ID NO.: 367)

[0317] NPD015s-AD058 (SEQ ID NO.: 172 and SEQ ID NO.: 369)

[0318] NPD015s-AD059 (SEQ ID NO.: 173 and SEQ ID NO.: 370)

[0319] NPD015s-AD060 (SEQ ID NO.: 174 and SEQ ID NO.: 371)

[0320] NPD015s-AD061 (SEQ ID NO.: 175 and SEQ ID NO.: 372)

[0321] NPD015s-AD062 (SEQ ID NO.: 176 and SEQ ID NO.: 373)

[0322] NPD015s-AD063 (SEQ ID NO.: 177 and SEQ ID NO.: 374)

[0323] NPD015s-AD064 (SEQ ID NO.: 178 and SEQ ID NO.: 375)

[0324] NPD015s-AD065 (SEQ ID NO.: 179 and SEQ ID NO.: 376)

[0325] NPD015s-AD066 (SEQ ID NO.: 180 and SEQ ID NO.: 377)

[0326] NPD015s-AD067 (SEQ ID NO.: 181 and SEQ ID NO.: 378)

[0327] NPD015s-AD078 (SEQ ID NO.: 192 and SEQ ID NO.: 389)

[0328] NPD015s-AD079 (SEQ ID NO.: 193 and SEQ ID NO.: 390)

[0329] NPD015s-AD080 (SEQ ID NO.: 194 and SEQ ID NO.: 391)

[0330] NPD015s-AD081 (SEQ ID NO.: 195 and SEQ ID NO.: 392)

[0331] NPD015s-AD082 (SEQ ID NO.: 196 and SEQ ID NO.: 393)

[0332] NPD015s-AD083 (SEQ ID NO.: 197 and SEQ ID NO.: 394)

[0333] NPD015s-AD084 (SEQ ID NO.: 198 and SEQ ID NO.: 395)

[0334] NPD015s-AD085 (SEQ ID NO.: 199 and SEQ ID NO.: 396)

[0335] NPD015s-AD086 (SEQ ID NO.: 200 and SEQ ID NO.: 397)

[0336] NPD015s-AD087 (SEQ ID NO.: 201 and SEQ ID NO.: 398)

[0337] NPD015s-AD098 (SEQ ID NO.: 212 and SEQ ID NO.: 409)

[0338] NPD015s-AD099 (SEQ ID NO.: 213 and SEQ ID NO.: 410)

[0339] NPD015s-AD100 (SEQ ID NO.: 214 and SEQ ID NO.: 411)

[0340] NPD015s-AD101 (SEQ ID NO.: 215 and SEQ ID NO.: 412)

[0341] NPD015s-AD102 (SEQ ID NO.: 216 and SEQ ID NO.: 413)

[0342] NPD015s-AD103 (SEQ ID NO.: 217 and SEQ ID NO.: 414)

[0343] NPD015s-AD104 (SEQ ID NO.: 218 and SEQ ID NO.: 415)

[0344] NPD015s-AD105 (SEQ ID NO.: 219 and SEQ ID NO.: 416)

[0345] NPD015s-AD106 (SEQ ID NO.: 220 and SEQ ID NO.: 417)

[0346] NPD015s-AD107 (SEQ ID NO.: 221 and SEQ ID NO.: 418)

[0347] NPD015s-AD108 (SEQ ID NO.: 222 and SEQ ID NO.: 419)

[0348] NPD015s-AD109 (SEQ ID NO.: 223 and SEQ ID NO.: 420)

[0349] NPD015s-AD110 (SEQ ID NO.: 224 and SEQ ID NO.: 421)

[0350] NPD015s-AD111 (SEQ ID NO.: 225 and SEQ ID NO.: 422)

[0351] NPD015s-AD112 (SEQ ID NO.: 226 and SEQ ID NO.: 423)

[0352] NPD015s-AD113 (SEQ ID NO.: 227 and SEQ ID NO.: 424)

[0353] NPD015s-AD114 (SEQ ID NO.: 228 and SEQ ID NO.: 425)

[0354] NPD015s-AD115 (SEQ ID NO.: 229 and SEQ ID NO.: 426)

[0355] NPD015s-AD116 (SEQ ID NO.: 230 and SEQ ID NO.: 427)

[0356] NPD015s-AD117 (SEQ ID NO.: 231 and SEQ ID NO.: 428)

[0357] NPD015s-AD138 (SEQ ID NO.: 252 and SEQ ID NO.: 449)

[0358] NPD015s-AD139 (SEQ ID NO.: 253 and SEQ ID NO.: 450)

[0359] NPD015s-AD140 (SEQ ID NO.: 254 and SEQ ID NO.: 451)

[0360] NPD015s-AD141 (SEQ ID NO.: 255 and SEQ ID NO.: 452)

[0361] NPD015s-AD142 (SEQ ID NO.: 256 and SEQ ID NO.: 453)

[0362] NPD015s-AD143 (SEQ ID NO.: 257 and SEQ ID NO.: 454)

[0363] NPD015s-AD144 (SEQ ID NO.: 258 and SEQ ID NO.: 455)

[0364] NPD015s-AD145 (SEQ ID NO.: 259 and SEQ ID NO.: 456)

[0365] NPD015s-AD146 (SEQ ID NO.: 260 and SEQ ID NO.: 457)

[0366] NPD015s-AD147 (SEQ ID NO.: 261 and SEQ ID NO.: 458)

[0367] NPD015s-AD148 (SEQ ID NO.: 262 and SEQ ID NO.: 459)

[0368] NPD015s-AD149 (SEQ ID NO.: 263 and SEQ ID NO.: 460)

[0369] NPD015s-AD150 (SEQ ID NO.: 264 and SEQ ID NO.: 461)

[0370] NPD015s-AD151 (SEQ ID NO.: 265 and SEQ ID NO.: 462)

[0371] NPD015s-AD152 (SEQ ID NO.: 266 and SEQ ID NO.: 463)

[0372] NPD015s-AD153 (SEQ ID NO.: 267 and SEQ ID NO.: 464)

[0373] NPD015s-AD154 (SEQ ID NO.: 268 and SEQ ID NO.: 465)

[0374] NPD015s-AD155 (SEQ ID NO.: 269 and SEQ ID NO.: 466)

[0375] NPD015s-AD156 (SEQ ID NO.: 270 and SEQ ID NO.: 467)

[0376] NPD015s-AD157 (SEQ ID NO.: 271 and SEQ ID NO.: 468)

[0377] NPD015s-AD168 (SEQ ID NO.: 282 and SEQ ID NO.: 479)

[0378] NPD015s-AD169 (SEQ ID NO.: 283 and SEQ ID NO.: 480)

[0379] NPD015s-AD170 (SEQ ID NO.: 284 and SEQ ID NO.: 481)

[0380] NPD015s-AD171 (SEQ ID NO.: 285 and SEQ ID NO.: 482)

[0381] NPD015s-AD172 (SEQ ID NO.: 286 and SEQ ID NO.: 483)

[0382] NPD015s-AD173 (SEQ ID NO.: 287 and SEQ ID NO.: 484)

[0383] NPD015s-AD174 (SEQ ID NO.: 288 and SEQ ID NO.: 485)

[0384] NPD015s-AD175 (SEQ ID NO.: 289 and SEQ ID NO.: 486)

[0385] NPD015s-AD176 (SEQ ID NO.: 290 and SEQ ID NO.: 487)

[0386] NPD015s-AD177 (SEQ ID NO.: 291 and SEQ ID NO.: 488)

[0387] NPD015s-AD178 (SEQ ID NO.: 292 and SEQ ID NO.: 489)

[0388] NPD015s-AD179 (SEQ ID NO.: 293 and SEQ ID NO.: 490)

[0389] NPD015s-AD180 (SEQ ID NO.: 294 and SEQ ID NO.: 491)

[0390] NPD015s-AD181 (SEQ ID NO.: 295 and SEQ ID NO.: 492)

[0391] NPD015s-AD182 (SEQ ID NO.:296 and SEQ ID NO.:493)

[0392] NPD015s-AD183(SEQ ID NO.:297 and SEQ ID NO.:494)

[0393] NPD015s-AD184(SEQ ID NO.:298 and SEQ ID NO.:495)

[0394] NPD015s-AD185(SEQ ID NO.:299 and SEQ ID NO.:496)

[0395] NPD015s-AD186(SEQ ID NO.:300 and SEQ ID NO.:497)

[0396] NPD015s-AD187(SEQ ID NO.:301 and SEQ ID NO.:498)

[0397] In another aspect of the present invention, the present invention proposes an siRNA conjugate. According to an embodiment of the present invention, the siRNA conjugate comprises: the aforementioned siRNA and a delivery vector, wherein the siRNA is covalently linked to the delivery vector. The inventors have found through experiments that in the above-mentioned siRNA conjugate, by adding a delivery vector, the degradation of LPA mRNA can be further improved, and the synthesis of Apo (a) by hepatocytes can be specifically reduced, so that LPA in the body is reduced, and then the related diseases such as Buerger's disease, peripheral artery disease, coronary artery disease, metabolic syndrome, acute coronary syndrome, aortic valve stenosis, aortic valve 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 can be effectively prevented or treated.

[0398] In the present invention, the "difference of no more than 2 nucleotides" means that there may be 1 or 2 nucleotide differences compared with the target nucleotide sequence, 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.

[0399] A delivery vehicle refers to a class of substances that can alter the tissue distribution of siRNA and target specific tissues. For example, compared to a species without a delivery vehicle, the delivery vehicle provides enhanced affinity for a selected target (such as a molecule, cell or cell type, compartment (such as a cellular or organ compartment, body tissue, organ or region)). The delivery vehicle can be a natural protein (such as human serum albumin (HSA), etc.), carbohydrate (such as dextran and chitosan, etc.) or lipid; it can also be a recombinant or synthetic molecule, such as a synthetic polymer. Preferably, the delivery vehicle does not participate in the pairing of the sense strand and the antisense strand in siRNA.

[0400] According to an embodiment of the present invention, the delivery vehicle is linked to the sense strand in the siRNA.

[0401] 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 through a phosphodiester bond or a phosphorothioate bond.

[0402] According to an embodiment of the present invention, the delivery vehicle is a GalNAc-derived compound;

[0403] According to an embodiment of the present invention, the GalNAc-derived compound includes at least one selected from 1043, 1046, 1048, 1059 and 1060:

[0404]

[0405]

[0406]

[0407] According to an embodiment of the present invention, the antisense strand of the siRNA conjugate contains a chemically modified nucleotide sequence of a duplex selected from SEQ ID NO.: 706 to SEQ ID NO.: 902.

[0408] According to an embodiment of the present invention, the antisense strand of the siRNA conjugate contains a chemically modified nucleotide sequence of a duplex selected from the following:

[0409] NPD015s-AD199 (SEQ ID NO.: 510 and SEQ ID NO.: 707)

[0410] NPD015s-AD201 (SEQ ID NO.: 512 and SEQ ID NO.: 709)

[0411] NPD015s-AD203 (SEQ ID NO.: 514 and SEQ ID NO.: 711)

[0412] NPD015s-AD204 (SEQ ID NO.: 515 and SEQ ID NO.: 712)

[0413] NPD015s-AD208 (SEQ ID NO.: 519 and SEQ ID NO.: 716)

[0414] NPD015s-AD213 (SEQ ID NO.: 524 and SEQ ID NO.: 721)

[0415] NPD015s-AD214 (SEQ ID NO.: 525 and SEQ ID NO.: 722)

[0416] NPD015s-AD217 (SEQ ID NO.: 528 and SEQ ID NO.: 725)

[0417] NPD015s-AD223 (SEQ ID NO.: 534 and SEQ ID NO.: 731)

[0418] NPD015s-AD224 (SEQ ID NO.: 535 and SEQ ID NO.: 732)

[0419] NPD015s-AD226 (SEQ ID NO.: 537 and SEQ ID NO.: 734)

[0420] NPD015s-AD228 (SEQ ID NO.: 539 and SEQ ID NO.: 736)

[0421] NPD015s-AD234 (SEQ ID NO.: 545 and SEQ ID NO.: 742)

[0422] NPD015s-AD237 (SEQ ID NO.: 548 and SEQ ID NO.: 745)

[0423] NPD015s-AD242 (SEQ ID NO.: 553 and SEQ ID NO.: 750)

[0424] NPD015s-AD253 (SEQ ID NO.: 564 and SEQ ID NO.: 761)

[0425] NPD015s-AD255 (SEQ ID NO.: 566 and SEQ ID NO.: 763)

[0426] NPD015s-AD256 (SEQ ID NO.: 567 and SEQ ID NO.: 764)

[0427] NPD015s-AD257 (SEQ ID NO.: 568 and SEQ ID NO.: 765)

[0428] NPD015s-AD258 (SEQ ID NO.: 569 and SEQ ID NO.: 766)

[0429] NPD015s-AD259 (SEQ ID NO.: 570 and SEQ ID NO.: 767)

[0430] NPD015s-AD260 (SEQ ID NO.: 571 and SEQ ID NO.: 768)

[0431] NPD015s-AD261 (SEQ ID NO.: 572 and SEQ ID NO.: 769)

[0432] NPD015s-AD262 (SEQ ID NO.: 573 and SEQ ID NO.: 770)

[0433] NPD015s-AD263 (SEQ ID NO.: 574 and SEQ ID NO.: 771)

[0434] NPD015s-AD264 (SEQ ID NO.: 575 and SEQ ID NO.: 772)

[0435] NPD015s-AD275 (SEQ ID NO.: 586 and SEQ ID NO.: 783)

[0436] NPD015s-AD276 (SEQ ID NO.: 587 and SEQ ID NO.: 784)

[0437] NPD015s-AD277 (SEQ ID NO.: 588 and SEQ ID NO.: 785)

[0438] NPD015s-AD278 (SEQ ID NO.: 589 and SEQ ID NO.: 786)

[0439] NPD015s-AD279 (SEQ ID NO.: 590 and SEQ ID NO.: 787)

[0440] NPD015s-AD280 (SEQ ID NO.: 591 and SEQ ID NO.: 788)

[0441] NPD015s-AD281 (SEQ ID NO.: 592 and SEQ ID NO.: 789)

[0442] NPD015s-AD282 (SEQ ID NO.: 593 and SEQ ID NO.: 790)

[0443] NPD015s-AD283 (SEQ ID NO.: 594 and SEQ ID NO.: 791)

[0444] NPD015s-AD284 (SEQ ID NO.: 595 and SEQ ID NO.: 792)

[0445] NPD015s-AD295 (SEQ ID NO.: 596 and SEQ ID NO.: 803)

[0446] NPD015s-AD296 (SEQ ID NO.: 597 and SEQ ID NO.: 804)

[0447] NPD015s-AD297 (SEQ ID NO.: 598 and SEQ ID NO.: 805)

[0448] NPD015s-AD298 (SEQ ID NO.: 599 and SEQ ID NO.: 806)

[0449] NPD015s-AD299 (SEQ ID NO.: 600 and SEQ ID NO.: 807)

[0450] NPD015s-AD300 (SEQ ID NO.: 601 and SEQ ID NO.: 808)

[0451] NPD015s-AD301 (SEQ ID NO.: 602 and SEQ ID NO.: 809)

[0452] NPD015s-AD302 (SEQ ID NO.: 603 and SEQ ID NO.: 810)

[0453] NPD015s-AD303 (SEQ ID NO.: 604 and SEQ ID NO.: 811)

[0454] NPD015s-AD304 (SEQ ID NO.: 605 and SEQ ID NO.: 812)

[0455] NPD015s-AD305 (SEQ ID NO.: 606 and SEQ ID NO.: 813)

[0456] NPD015s-AD306 (SEQ ID NO.: 607 and SEQ ID NO.: 814)

[0457] NPD015s-AD307 (SEQ ID NO.: 608 and SEQ ID NO.: 815)

[0458] NPD015s-AD308 (SEQ ID NO.: 609 and SEQ ID NO.: 816)

[0459] NPD015s-AD309 (SEQ ID NO.: 610 and SEQ ID NO.: 817)

[0460] NPD015s-AD310 (SEQ ID NO.: 611 and SEQ ID NO.: 818)

[0461] NPD015s-AD311 (SEQ ID NO.: 612 and SEQ ID NO.: 819)

[0462] NPD015s-AD312 (SEQ ID NO.: 613 and SEQ ID NO.: 820)

[0463] NPD015s-AD313 (SEQ ID NO.: 614 and SEQ ID NO.: 821)

[0464] NPD015s-AD314 (SEQ ID NO.: 615 and SEQ ID NO.: 822)

[0465] NPD015s-AD335 (SEQ ID NO.: 646 and SEQ ID NO.: 843)

[0466] NPD015s-AD336 (SEQ ID NO.: 647 and SEQ ID NO.: 844)

[0467] NPD015s-AD337 (SEQ ID NO.: 648 and SEQ ID NO.: 845)

[0468] NPD015s-AD338 (SEQ ID NO.: 649 and SEQ ID NO.: 846), NPD015s-AD339 (SEQ ID NO.: 650 and SEQ ID NO.: 847)

[0469] NPD015s-AD340 (SEQ ID NO.: 651 and SEQ ID NO.: 848)

[0470] NPD015s-AD341 (SEQ ID NO.: 652 and SEQ ID NO.: 849)

[0471] NPD015s-AD342 (SEQ ID NO.: 653 and SEQ ID NO.: 850)

[0472] NPD015s-AD343 (SEQ ID NO.: 654 and SEQ ID NO.: 851)

[0473] NPD015s-AD344 (SEQ ID NO.: 655 and SEQ ID NO.: 852)

[0474] NPD015s-AD345 (SEQ ID NO.: 656 and SEQ ID NO.: 853)

[0475] NPD015s-AD346 (SEQ ID NO.: 657 and SEQ ID NO.: 854)

[0476] NPD015s-AD347 (SEQ ID NO.: 658 and SEQ ID NO.: 855)

[0477] NPD015s-AD348 (SEQ ID NO.: 659 and SEQ ID NO.: 856)

[0478] NPD015s-AD349 (SEQ ID NO.: 660 and SEQ ID NO.: 857)

[0479] NPD015s-AD350 (SEQ ID NO.: 661 and SEQ ID NO.: 858)

[0480] NPD015s-AD351 (SEQ ID NO.: 662 and SEQ ID NO.: 859)

[0481] NPD015s-AD352 (SEQ ID NO.: 663 and SEQ ID NO.: 860)

[0482] NPD015s-AD353 (SEQ ID NO.: 664 and SEQ ID NO.: 861)

[0483] NPD015s-AD354 (SEQ ID NO.: 665 and SEQ ID NO.: 862)

[0484] NPD015s-AD365 (SEQ ID NO.: 676 and SEQ ID NO.: 873)

[0485] NPD015s-AD366 (SEQ ID NO.: 677 and SEQ ID NO.: 874)

[0486] NPD015s-AD367 (SEQ ID NO.: 678 and SEQ ID NO.: 875)

[0487] NPD015s-AD368 (SEQ ID NO.: 679 and SEQ ID NO.: 876)

[0488] NPD015s-AD369 (SEQ ID NO.: 680 and SEQ ID NO.: 877)

[0489] NPD015s-AD370 (SEQ ID NO.: 681 and SEQ ID NO.: 878)

[0490] NPD015s-AD371 (SEQ ID NO.: 682 and SEQ ID NO.: 879)

[0491] NPD015s-AD372 (SEQ ID NO.: 683 and SEQ ID NO.: 880)

[0492] NPD015s-AD373 (SEQ ID NO.: 684 and SEQ ID NO.: 881)

[0493] NPD015s-AD374 (SEQ ID NO.: 685 and SEQ ID NO.: 882)

[0494] NPD015s-AD375 (SEQ ID NO.: 686 and SEQ ID NO.: 883)

[0495] NPD015s-AD376 (SEQ ID NO.: 687 and SEQ ID NO.: 884)

[0496] NPD015s-AD377 (SEQ ID NO.: 688 and SEQ ID NO.: 885)

[0497] NPD015s-AD378 (SEQ ID NO.: 689 and SEQ ID NO.: 886)

[0498] NPD015s-AD379 (SEQ ID NO.: 690 and SEQ ID NO.: 887)

[0499] NPD015s-AD380 (SEQ ID NO.: 691 and SEQ ID NO.: 888)

[0500] NPD015s-AD381 (SEQ ID NO.: 692 and SEQ ID NO.: 889)

[0501] NPD015s-AD382 (SEQ ID NO.: 693 and SEQ ID NO.: 890)

[0502] NPD015s-AD383 (SEQ ID NO.: 694 and SEQ ID NO.: 891)

[0503] NPD015s-AD384 (SEQ ID NO.: 695 and SEQ ID NO.: 892)

[0504] According to an embodiment of the present invention, the sense strand of the siRNA conjugate comprises a chemically modified nucleotide sequence of a duplex selected from SEQ ID NO.: 509 to SEQ ID NO.: 705.

[0505] According to an embodiment of the present invention, the sense strand of the siRNA conjugate comprises a chemically modified nucleotide sequence of a duplex selected from the following:

[0506] NPD015s-AD199 (SEQ ID NO.: 510 and SEQ ID NO.: 707)

[0507] NPD015s-AD201 (SEQ ID NO.: 512 and SEQ ID NO.: 709)

[0508] NPD015s-AD203 (SEQ ID NO.: 514 and SEQ ID NO.: 711)

[0509] NPD015s-AD204 (SEQ ID NO.: 515 and SEQ ID NO.: 712)

[0510] NPD015s-AD208 (SEQ ID NO.: 519 and SEQ ID NO.: 716)

[0511] NPD015s-AD213 (SEQ ID NO.: 524 and SEQ ID NO.: 721)

[0512] NPD015s-AD214 (SEQ ID NO.: 525 and SEQ ID NO.: 722)

[0513] NPD015s-AD217 (SEQ ID NO.: 528 and SEQ ID NO.: 725)

[0514] NPD015s-AD223 (SEQ ID NO.: 534 and SEQ ID NO.: 731)

[0515] NPD015s-AD224 (SEQ ID NO.: 535 and SEQ ID NO.: 732)

[0516] NPD015s-AD226 (SEQ ID NO.: 537 and SEQ ID NO.: 734)

[0517] NPD015s-AD228 (SEQ ID NO.: 539 and SEQ ID NO.: 736)

[0518] NPD015s-AD234 (SEQ ID NO.: 545 and SEQ ID NO.: 742)

[0519] NPD015s-AD237 (SEQ ID NO.: 548 and SEQ ID NO.: 745)

[0520] NPD015s-AD242 (SEQ ID NO.: 553 and SEQ ID NO.: 750)

[0521] NPD015s-AD253 (SEQ ID NO.: 564 and SEQ ID NO.: 761)

[0522] NPD015s-AD255 (SEQ ID NO.: 566 and SEQ ID NO.: 763)

[0523] NPD015s-AD256 (SEQ ID NO.: 567 and SEQ ID NO.: 764)

[0524] NPD015s-AD257 (SEQ ID NO.: 568 and SEQ ID NO.: 765)

[0525] NPD015s-AD258 (SEQ ID NO.: 569 and SEQ ID NO.: 766)

[0526] NPD015s-AD259 (SEQ ID NO.: 570 and SEQ ID NO.: 767)

[0527] NPD015s-AD260 (SEQ ID NO.: 571 and SEQ ID NO.: 768)

[0528] NPD015s-AD261 (SEQ ID NO.: 572 and SEQ ID NO.: 769)

[0529] NPD015s-AD262 (SEQ ID NO.: 573 and SEQ ID NO.: 770)

[0530] NPD015s-AD263 (SEQ ID NO.: 574 and SEQ ID NO.: 771)

[0531] NPD015s-AD264 (SEQ ID NO.: 575 and SEQ ID NO.: 772)

[0532] NPD015s-AD275 (SEQ ID NO.: 586 and SEQ ID NO.: 783)

[0533] NPD015s-AD276 (SEQ ID NO.: 587 and SEQ ID NO.: 784)

[0534] NPD015s-AD277 (SEQ ID NO.: 588 and SEQ ID NO.: 785)

[0535] NPD015s-AD278 (SEQ ID NO.: 589 and SEQ ID NO.: 786)

[0536] NPD015s-AD279 (SEQ ID NO.: 590 and SEQ ID NO.: 787)

[0537] NPD015s-AD280 (SEQ ID NO.: 591 and SEQ ID NO.: 788)

[0538] NPD015s-AD281 (SEQ ID NO.: 592 and SEQ ID NO.: 789)

[0539] NPD015s-AD282 (SEQ ID NO.: 593 and SEQ ID NO.: 790)

[0540] NPD015s-AD283 (SEQ ID NO.: 594 and SEQ ID NO.: 791)

[0541] NPD015s-AD284 (SEQ ID NO.: 595 and SEQ ID NO.: 792)

[0542] NPD015s-AD295 (SEQ ID NO.: 596 and SEQ ID NO.: 803)

[0543] NPD015s-AD296 (SEQ ID NO.: 597 and SEQ ID NO.: 804)

[0544] NPD015s-AD297 (SEQ ID NO.: 598 and SEQ ID NO.: 805)

[0545] NPD015s-AD298 (SEQ ID NO.: 599 and SEQ ID NO.: 806)

[0546] NPD015s-AD299 (SEQ ID NO.: 600 and SEQ ID NO.: 807)

[0547] NPD015s-AD300 (SEQ ID NO.: 601 and SEQ ID NO.: 808)

[0548] NPD015s-AD301 (SEQ ID NO.: 602 and SEQ ID NO.: 809)

[0549] NPD015s-AD302 (SEQ ID NO.: 603 and SEQ ID NO.: 810)

[0550] NPD015s-AD303 (SEQ ID NO.: 604 and SEQ ID NO.: 811)

[0551] NPD015s-AD304 (SEQ ID NO.: 605 and SEQ ID NO.: 812)

[0552] NPD015s-AD305 (SEQ ID NO.: 606 and SEQ ID NO.: 813)

[0553] NPD015s-AD306 (SEQ ID NO.: 607 and SEQ ID NO.: 814)

[0554] NPD015s-AD307 (SEQ ID NO.: 608 and SEQ ID NO.: 815)

[0555] NPD015s-AD308 (SEQ ID NO.: 609 and SEQ ID NO.: 816)

[0556] NPD015s-AD309 (SEQ ID NO.: 610 and SEQ ID NO.: 817)

[0557] NPD015s-AD310 (SEQ ID NO.: 611 and SEQ ID NO.: 818)

[0558] NPD015s-AD311 (SEQ ID NO.: 612 and SEQ ID NO.: 819)

[0559] NPD015s-AD312 (SEQ ID NO.: 613 and SEQ ID NO.: 820)

[0560] NPD015s-AD313 (SEQ ID NO.: 614 and SEQ ID NO.: 821)

[0561] NPD015s-AD314 (SEQ ID NO.: 615 and SEQ ID NO.: 822)

[0562] NPD015s-AD335 (SEQ ID NO.: 646 and SEQ ID NO.: 843)

[0563] NPD015s-AD336 (SEQ ID NO.: 647 and SEQ ID NO.: 844)

[0564] NPD015s-AD337 (SEQ ID NO.: 648 and SEQ ID NO.: 845)

[0565] NPD015s-AD338 (SEQ ID NO.: 649 and SEQ ID NO.: 846)

[0566] NPD015s-AD339 (SEQ ID NO.: 650 and SEQ ID NO.: 847)

[0567] NPD015s-AD340 (SEQ ID NO.: 651 and SEQ ID NO.: 848)

[0568] NPD015s-AD341 (SEQ ID NO.: 652 and SEQ ID NO.: 849)

[0569] NPD015s-AD342 (SEQ ID NO.: 653 and SEQ ID NO.: 850)

[0570] NPD015s-AD343 (SEQ ID NO.: 654 and SEQ ID NO.: 851)

[0571] NPD015s-AD344 (SEQ ID NO.: 655 and SEQ ID NO.: 852)

[0572] NPD015s-AD345 (SEQ ID NO.: 656 and SEQ ID NO.: 853)

[0573] NPD015s-AD346 (SEQ ID NO.: 657 and SEQ ID NO.: 854)

[0574] NPD015s-AD347 (SEQ ID NO.: 658 and SEQ ID NO.: 855)

[0575] NPD015s-AD348 (SEQ ID NO.: 659 and SEQ ID NO.: 856)

[0576] NPD015s-AD349 (SEQ ID NO.: 660 and SEQ ID NO.: 857)

[0577] NPD015s-AD350 (SEQ ID NO.: 661 and SEQ ID NO.: 858)

[0578] NPD015s-AD351 (SEQ ID NO.: 662 and SEQ ID NO.: 859)

[0579] NPD015s-AD352 (SEQ ID NO.: 663 and SEQ ID NO.: 860)

[0580] NPD015s-AD353 (SEQ ID NO.: 664 and SEQ ID NO.: 861)

[0581] NPD015s-AD354 (SEQ ID NO.: 665 and SEQ ID NO.: 862)

[0582] NPD015s-AD365 (SEQ ID NO.: 676 and SEQ ID NO.: 873)

[0583] NPD015s-AD366 (SEQ ID NO.: 677 and SEQ ID NO.: 874)

[0584] NPD015s-AD367 (SEQ ID NO.: 678 and SEQ ID NO.: 875)

[0585] NPD015s-AD368 (SEQ ID NO.: 679 and SEQ ID NO.: 876)

[0586] NPD015s-AD369 (SEQ ID NO.: 680 and SEQ ID NO.: 877)

[0587] NPD015s-AD370 (SEQ ID NO.: 681 and SEQ ID NO.: 878)

[0588] NPD015s-AD371 (SEQ ID NO.: 682 and SEQ ID NO.: 879)

[0589] NPD015s-AD372 (SEQ ID NO.: 683 and SEQ ID NO.: 880)

[0590] NPD015s-AD373 (SEQ ID NO.: 684 and SEQ ID NO.: 881)

[0591] NPD015s-AD374 (SEQ ID NO.: 685 and SEQ ID NO.: 882)

[0592] NPD015s-AD375 (SEQ ID NO.: 686 and SEQ ID NO.: 883)

[0593] NPD015s-AD376 (SEQ ID NO.: 687 and SEQ ID NO.: 884)

[0594] NPD015s-AD377 (SEQ ID NO.: 688 and SEQ ID NO.: 885)

[0595] NPD015s-AD378 (SEQ ID NO.: 689 and SEQ ID NO.: 886)

[0596] NPD015s-AD379 (SEQ ID NO.: 690 and SEQ ID NO.: 887)

[0597] NPD015s-AD380 (SEQ ID NO.: 691 and SEQ ID NO.: 888)

[0598] NPD015s-AD381 (SEQ ID NO.: 692 and SEQ ID NO.: 889)

[0599] NPD015s-AD382 (SEQ ID NO.: 693 and SEQ ID NO.: 890)

[0600] NPD015s-AD383 (SEQ ID NO.: 694 and SEQ ID NO.: 891)

[0601] NPD015s-AD384 (SEQ ID NO.: 695 and SEQ ID NO.: 892)

[0602] 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.

[0603] According to an embodiment of the present invention, the sense strand and the antisense strand of the siRNA conjugate comprise a chemically modified nucleotide sequence of a duplex selected from the following:

[0604] NPD015s-AD199 (SEQ ID NO.: 510 and SEQ ID NO.: 707)

[0605] NPD015s-AD201 (SEQ ID NO.: 512 and SEQ ID NO.: 709)

[0606] NPD015s-AD203 (SEQ ID NO.: 514 and SEQ ID NO.: 711)

[0607] NPD015s-AD204 (SEQ ID NO.: 515 and SEQ ID NO.: 712)

[0608] NPD015s-AD208 (SEQ ID NO.: 519 and SEQ ID NO.: 716)

[0609] NPD015s-AD213 (SEQ ID NO.: 524 and SEQ ID NO.: 721)

[0610] NPD015s-AD214 (SEQ ID NO.: 525 and SEQ ID NO.: 722)

[0611] NPD015s-AD217 (SEQ ID NO.: 528 and SEQ ID NO.: 725)

[0612] NPD015s-AD223 (SEQ ID NO.: 534 and SEQ ID NO.: 731)

[0613] NPD015s-AD224 (SEQ ID NO.: 535 and SEQ ID NO.: 732)

[0614] NPD015s-AD226 (SEQ ID NO.: 537 and SEQ ID NO.: 734)

[0615] NPD015s-AD228 (SEQ ID NO.: 539 and SEQ ID NO.: 736)

[0616] NPD015s-AD234 (SEQ ID NO.: 545 and SEQ ID NO.: 742)

[0617] NPD015s-AD237 (SEQ ID NO.: 548 and SEQ ID NO.: 745)

[0618] NPD015s-AD242 (SEQ ID NO.: 553 and SEQ ID NO.: 750)

[0619] NPD015s-AD253 (SEQ ID NO.: 564 and SEQ ID NO.: 761)

[0620] NPD015s-AD255 (SEQ ID NO.: 566 and SEQ ID NO.: 763)

[0621] NPD015s-AD256 (SEQ ID NO.: 567 and SEQ ID NO.: 764)

[0622] NPD015s-AD257 (SEQ ID NO.: 568 and SEQ ID NO.: 765)

[0623] NPD015s-AD258 (SEQ ID NO.: 569 and SEQ ID NO.: 766)

[0624] NPD015s-AD259 (SEQ ID NO.: 570 and SEQ ID NO.: 767)

[0625] NPD015s-AD260 (SEQ ID NO.: 571 and SEQ ID NO.: 768)

[0626] NPD015s-AD261 (SEQ ID NO.: 572 and SEQ ID NO.: 769)

[0627] NPD015s-AD262 (SEQ ID NO.: 573 and SEQ ID NO.: 770)

[0628] NPD015s-AD263 (SEQ ID NO.: 574 and SEQ ID NO.: 771)

[0629] NPD015s-AD264 (SEQ ID NO.: 575 and SEQ ID NO.: 772)

[0630] NPD015s-AD275 (SEQ ID NO.: 586 and SEQ ID NO.: 783)

[0631] NPD015s-AD276 (SEQ ID NO.: 587 and SEQ ID NO.: 784)

[0632] NPD015s-AD277 (SEQ ID NO.: 588 and SEQ ID NO.: 785)

[0633] NPD015s-AD278 (SEQ ID NO.: 589 and SEQ ID NO.: 786)

[0634] NPD015s-AD279 (SEQ ID NO.: 590 and SEQ ID NO.: 787)

[0635] NPD015s-AD280 (SEQ ID NO.: 591 and SEQ ID NO.: 788)

[0636] NPD015s-AD281 (SEQ ID NO.: 592 and SEQ ID NO.: 789)

[0637] NPD015s-AD282 (SEQ ID NO.: 593 and SEQ ID NO.: 790)

[0638] NPD015s-AD283 (SEQ ID NO.: 594 and SEQ ID NO.: 791)

[0639] NPD015s-AD284 (SEQ ID NO.: 595 and SEQ ID NO.: 792)

[0640] NPD015s-AD295 (SEQ ID NO.: 596 and SEQ ID NO.: 803)

[0641] NPD015s-AD296 (SEQ ID NO.: 597 and SEQ ID NO.: 804)

[0642] NPD015s-AD297 (SEQ ID NO.: 598 and SEQ ID NO.: 805)

[0643] NPD015s-AD298 (SEQ ID NO.: 599 and SEQ ID NO.: 806)

[0644] NPD015s-AD299 (SEQ ID NO.: 600 and SEQ ID NO.: 807)

[0645] NPD015s-AD300 (SEQ ID NO.: 601 and SEQ ID NO.: 808)

[0646] NPD015s-AD301 (SEQ ID NO.: 602 and SEQ ID NO.: 809)

[0647] NPD015s-AD302 (SEQ ID NO.: 603 and SEQ ID NO.: 810)

[0648] NPD015s-AD303 (SEQ ID NO.: 604 and SEQ ID NO.: 811)

[0649] NPD015s-AD304 (SEQ ID NO.: 605 and SEQ ID NO.: 812)

[0650] NPD015s-AD305 (SEQ ID NO.: 606 and SEQ ID NO.: 813)

[0651] NPD015s-AD306 (SEQ ID NO.: 607 and SEQ ID NO.: 814)

[0652] NPD015s-AD307 (SEQ ID NO.: 608 and SEQ ID NO.: 815)

[0653] NPD015s-AD308 (SEQ ID NO.: 609 and SEQ ID NO.: 816)

[0654] NPD015s-AD309 (SEQ ID NO.: 610 and SEQ ID NO.: 817)

[0655] NPD015s-AD310 (SEQ ID NO.: 611 and SEQ ID NO.: 818)

[0656] NPD015s-AD311 (SEQ ID NO.: 612 and SEQ ID NO.: 819)

[0657] NPD015s-AD312 (SEQ ID NO.: 613 and SEQ ID NO.: 820)

[0658] NPD015s-AD313 (SEQ ID NO.: 614 and SEQ ID NO.: 821)

[0659] NPD015s-AD314 (SEQ ID NO.: 615 and SEQ ID NO.: 822)

[0660] NPD015s-AD335 (SEQ ID NO.: 646 and SEQ ID NO.: 843)

[0661] NPD015s-AD336 (SEQ ID NO.: 647 and SEQ ID NO.: 844)

[0662] NPD015s-AD337 (SEQ ID NO.: 648 and SEQ ID NO.: 845)

[0663] NPD015s-AD338 (SEQ ID NO.: 649 and SEQ ID NO.: 846)

[0664] NPD015s-AD339 (SEQ ID NO.: 650 and SEQ ID NO.: 847)

[0665] NPD015s-AD340 (SEQ ID NO.: 651 and SEQ ID NO.: 848)

[0666] NPD015s-AD341 (SEQ ID NO.: 652 and SEQ ID NO.: 849)

[0667] NPD015s-AD342 (SEQ ID NO.: 653 and SEQ ID NO.: 850)

[0668] NPD015s-AD343 (SEQ ID NO.: 654 and SEQ ID NO.: 851)

[0669] NPD015s-AD344 (SEQ ID NO.: 655 and SEQ ID NO.: 852)

[0670] NPD015s-AD345 (SEQ ID NO.: 656 and SEQ ID NO.: 853)

[0671] NPD015s-AD346 (SEQ ID NO.: 657 and SEQ ID NO.: 854)

[0672] NPD015s-AD347 (SEQ ID NO.: 658 and SEQ ID NO.: 855)

[0673] NPD015s-AD348 (SEQ ID NO.: 659 and SEQ ID NO.: 856)

[0674] NPD015s-AD349 (SEQ ID NO.: 660 and SEQ ID NO.: 857)

[0675] NPD015s-AD350 (SEQ ID NO.: 661 and SEQ ID NO.: 858)

[0676] NPD015s-AD351 (SEQ ID NO.: 662 and SEQ ID NO.: 859)

[0677] NPD015s-AD352 (SEQ ID NO.: 663 and SEQ ID NO.: 860)

[0678] NPD015s-AD353 (SEQ ID NO.: 664 and SEQ ID NO.: 861)

[0679] NPD015s-AD354 (SEQ ID NO.: 665 and SEQ ID NO.: 862)

[0680] NPD015s-AD365 (SEQ ID NO.: 676 and SEQ ID NO.: 873)

[0681] NPD015s-AD366 (SEQ ID NO.: 677 and SEQ ID NO.: 874)

[0682] NPD015s-AD367 (SEQ ID NO.: 678 and SEQ ID NO.: 875)

[0683] NPD015s-AD368 (SEQ ID NO.: 679 and SEQ ID NO.: 876)

[0684] NPD015s-AD369 (SEQ ID NO.: 680 and SEQ ID NO.: 877)

[0685] NPD015s-AD370 (SEQ ID NO.: 681 and SEQ ID NO.: 878)

[0686] NPD015s-AD371 (SEQ ID NO.: 682 and SEQ ID NO.: 879)

[0687] NPD015s-AD372 (SEQ ID NO.: 683 and SEQ ID NO.: 880)

[0688] NPD015s-AD373 (SEQ ID NO.: 684 and SEQ ID NO.: 881)

[0689] NPD015s-AD374 (SEQ ID NO.: 685 and SEQ ID NO.: 882)

[0690] NPD015s-AD375 (SEQ ID NO.: 686 and SEQ ID NO.: 883)

[0691] NPD015s-AD376 (SEQ ID NO.: 687 and SEQ ID NO.: 884)

[0692] NPD015s-AD377 (SEQ ID NO.: 688 and SEQ ID NO.: 885)

[0693] NPD015s-AD378 (SEQ ID NO.: 689 and SEQ ID NO.: 886)

[0694] NPD015s-AD379 (SEQ ID NO.: 690 and SEQ ID NO.: 887)

[0695] NPD015s-AD380 (SEQ ID NO.: 691 and SEQ ID NO.: 888)

[0696] NPD015s-AD381 (SEQ ID NO.: 692 and SEQ ID NO.: 889)

[0697] NPD015s-AD382 (SEQ ID NO.: 693 and SEQ ID NO.: 890)

[0698] NPD015s-AD383 (SEQ ID NO.: 694 and SEQ ID NO.: 891)

[0699] NPD015s-AD384 (SEQ ID NO.: 695 and SEQ ID NO.: 892)

[0700] In yet another aspect of the present invention, the present invention provides a pharmaceutical composition. According to an embodiment of the present invention, the pharmaceutical composition comprises: 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) in hepatocytes, thereby reducing Lp(a) in vivo, and then effectively preventing or treating related diseases, such as Burger's disease, peripheral artery disease, coronary artery disease, metabolic syndrome, acute coronary syndrome, aortic stenosis, aortic regurgitation, aortic dissection, retinal artery occlusion, cardio-cerebrovascular diseases, mesenteric ischemia, superior mesenteric artery occlusion, renal artery stenosis, stable / unstable angina pectoris, acute coronary syndrome, heterozygous or homozygous familial hypercholesterolemia, hyperapolipoprotein β-lipoproteinemia, atherosclerosis and venous thrombosis.

[0701] It should be noted that the pharmaceutical composition herein may comprise one or more of the aforementioned siRNA or siRNA conjugate.

[0702] According to an embodiment of the present invention, the pharmaceutical composition further comprises: a pharmaceutically acceptable excipient.

[0703] In yet another aspect of the present invention, there is provided the use of the foregoing siRNA, the foregoing siRNA conjugate or the foregoing pharmaceutical composition in the preparation of a medicament for inhibiting the expression of LPA.

[0704] In yet another aspect of the present invention, there is provided the use of the foregoing siRNA, the foregoing siRNA conjugate or the foregoing pharmaceutical composition in the preparation of a medicament for treating diseases associated with abnormal LPA expression.

[0705] 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, hyperapolipoprotein β lipoproteinemia, and atherosclerosis.

[0706] In yet another aspect of the present invention, there is provided a method for treating diseases associated with abnormal LPA expression. According to an embodiment of the present invention, the method comprises: administering to a subject a pharmaceutically acceptable amount of the foregoing siRNA, the foregoing siRNA conjugate or the foregoing pharmaceutical composition. According to an embodiment of the present invention, this method can effectively prevent and / or treat diseases associated with abnormal LPA expression.

[0707] 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, etc. The selection of a preferred effective amount can be determined by those of ordinary skill in the art according to various factors (such as through clinical trials). Such factors include, but are not limited to: the pharmacokinetic parameters of the active ingredient such as bioavailability, metabolism, half-life, etc.; the severity of the disease to be treated in the patient, the patient's weight, the patient's immune status, the route of administration, etc. For example, due to the urgency of the treatment situation, several separate doses may be administered daily, for example, administered at a dose once every several days, several weeks, or several months.

[0708] The subject can be administered by any suitable route known in the art, and such routes include, but are 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), and subcutaneous administration is preferred.

[0709] According to an embodiment of the present invention, the route of administration of the method is subcutaneous injection.

[0710] According to an embodiment of the present invention, the LPA abnormal expression-related diseases are coronary artery disease, metabolic syndrome, cardio-cerebrovascular diseases, heterozygous or homozygous familial hypercholesterolemia, hyperapolipoprotein β lipoproteinemia, and atherosclerosis.

[0711] Additional aspects and advantages of the present invention will be given in part in the following description, become apparent in part from the following description, or be learned through the practice of the present invention. Detailed implementation manners

[0712] Embodiments of the present invention will be described in detail below. The embodiments described below are exemplary and are only used to explain the present invention and should not be construed as a limitation of the present invention.

[0713] It should be noted that the terms "first" and "second" are only used for descriptive purposes and cannot be construed as indicating or implying relative importance or implicitly specifying the quantity of the indicated technical features. Thus, features defined with "first" and "second" may explicitly or implicitly include one or more of such features. Further, in the description of the present invention, unless otherwise specified, the meaning of "plurality" is two or more.

[0714] In this article, the term "comprising" or "including" is an open expression, that is, it includes the content specified by the present invention, but does not exclude other aspects of the content.

[0715] In this article, the terms "optionally", "optional" or "option" generally mean that the subsequent events or conditions may but do not necessarily occur, and this description includes the cases where such events or conditions occur, as well as the cases where such events or conditions do not occur.

[0716] In this article, the term "Small interfering RNA (siRNA)" is a double-stranded RNA with a length of 17 to 25 nucleotides, including a sense strand and an antisense strand. siRNA mediates the targeted cleavage of the target mRNA of the RISC pathway by forming an RNA-induced silencing complex (RISC). Specifically, siRNA guides the specific degradation of the mRNA sequence through the known RNA interference (RNAi) process and inhibits the translation of mRNA into proteins. For example, siRNA can regulate (e.g., inhibit) the expression of LPA in cells.

[0717] 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 lagging strand)" refers to an RNAi strand that contains a sequence that is substantially complementary to the antisense strand. The term "substantially complementary" means completely complementary or at least partially complementary, e.g., the antisense strand is completely or at least partially complementary to the target sequence. In the case of partial complementarity, mismatches can be present within the internal or terminal regions of the molecule, with the most tolerated mismatches being present within the terminal regions, e.g., within 5, 4, 3, or 2 nucleotides at the 5' end and / or 3' end of the RNAi.

[0718] It should be noted that "at least partially substantially complementary" between the antisense strand and the mRNA means that the antisense strand has a polynucleotide that is substantially complementary to a continuous portion of the mRNA of interest (e.g., the mRNA encoding LPA). Alternatively, if a polynucleotide is substantially non-discontinuously complementary to a portion of the mRNA encoding LPA, then the antisense strand is complementary to at least a portion of the LPA mRNA.

[0719] As used herein, the term "target sequence" refers to a continuous portion of the nucleotide sequence of an mRNA molecule formed during the transcription of the LPA gene, including the mRNA that is an RNA processing product of the primary transcript.

[0720] As used herein, the term "inhibiting the expression of the LPA gene" includes any level of inhibition of the LPA gene, e.g., 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%. The expression of the LPA gene can be evaluated based on the level of any variable associated with LPA gene expression, e.g., the mRNA level of LPA, the Apo(a) protein, or the Lp(a) level. Inhibition can be evaluated by a decrease in the absolute or relative level of one or more of these variables compared to a control level. The control level can be any type of control level utilized in the art, e.g., the baseline level prior to administration, or the level determined in similar subjects, cells, or samples that have not been treated or have been treated with a control (such as a control treated with only a buffer or a control without an active agent).

[0721] As used herein, the term "LPA" includes the mRNA of LPA or its complete coding sequence, such as human LPA, which can be found, for example, in the GenBank accession (NM_005577.4). Other examples of the mRNA sequence of LPA are obtained using publicly available databases, such as genomic project websites like GenBank and UniProt. The term "LPA" can also refer to naturally occurring DNA sequence variants of the LPA gene, such as single nucleotide polymorphisms (SNPs) in the LPA gene.

[0722] 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 gene or sequence in the host cell. Examples of vectors include, but are not limited to, viral vectors, plasmids, cosmids, or phage vectors.

[0723] As used herein, a "pharmaceutical composition" can refer to the treatment of diseases and can also be used in in vitro cell culture experiments. When used for the treatment of diseases, 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 excipients that make up one or more accessory ingredients. Generally, 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.

[0724] As used herein, the term "pharmaceutically acceptable" means that a substance or composition must be chemically and / or toxicologically compatible with the other ingredients of the formulation and / or the mammal being treated therewith. Preferably, "pharmaceutically acceptable" as used in the present invention refers to those approved by a federal regulatory agency or a national government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeias for use in animals, particularly in humans.

[0725] As used herein, the term "pharmaceutically acceptable excipient" is well recognized in the art and includes pharmaceutically acceptable materials, compositions or carriers suitable for administering the siRNA or siRNA conjugate of the present disclosure to a mammal. The excipients include liquid or solid fillers, diluents, excipients, solvents or encapsulating materials that participate in carrying the active substance or transferring it from one organ or part of the body to another organ or another part of the body. Each excipient must be "acceptable" in the sense of being compatible with the other ingredients in the formulation and harmless to the patient. Some examples of materials that can be used as pharmaceutically acceptable excipients include: saccharides such as lactose, glucose and sucrose; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose and cellulose acetate, powdered tragacanth, malt, gelatin, talc, excipients such as cocoa butter and suppository waxes; glycols such as propylene glycol; polyols such as glycerol, sorbitol, mannitol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; buffering agents such as magnesium hydroxide and aluminum hydroxide; ethanol; phosphate buffer; and other non-toxic and compatible substances used in pharmaceutical formulations.

[0726] In addition to any conventional excipients, the scope of incompatibility with the siRNA or siRNA conjugate of the present invention, such as any adverse biological effects produced or interactions with any other components of the pharmaceutically acceptable composition in a harmful manner, their uses are also within the scope contemplated by the present invention.

[0727] The pharmaceutical compositions of the present disclosure include formulations suitable for oral, nasal, topical, buccal, sublingual, rectal and / or parenteral administration. The formulations may conveniently be in unit dosage form and may be prepared by any method well known in the pharmaceutical art. The amount of the active ingredient that can be combined with the excipient substance to prepare a single dosage form is generally the amount of the siRNA or siRNA conjugate that produces a therapeutic effect. Generally, on a percentage basis, this amount is about 1% to about 99% of the active ingredient, preferably about 5% to about 70%, most preferably about 10% to about 30%.

[0728] As used herein, the term "treatment" refers to achieving a desired pharmacological and / or physiological effect. The effect can be prophylactic 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 adverse effects caused by the disease. "Treatment" as used herein covers diseases of mammals, particularly humans, including: (a) preventing the occurrence of a disease or disorder in an individual who is susceptible to the disease but has not been diagnosed with the disease; (b) inhibiting the disease, e.g., arresting the development of the disease; or (c) alleviating the disease, e.g., relieving symptoms associated with the disease. "Treatment" as used herein covers any administration of siRNA, siRNA conjugate, or drug to an individual to treat, cure, relieve, improve, mitigate, or inhibit a disease in the individual, including but not limited to administering a drug containing the siRNA or siRNA conjugate described herein to an individual in need thereof.

[0729] The solution of the present invention will be explained below in conjunction with embodiments. Those skilled in the art will understand that the following embodiments are only for illustrating the present invention and should not be construed as limiting the scope of the present invention. For those not specified in the embodiments regarding specific techniques or conditions, they shall be carried out according to the techniques or conditions described in the literature in the art or according to the product specifications. For reagents or instruments not specified by the manufacturer, they are all conventional products that can be commercially purchased.

[0730] Example 1: Design of siRNA

[0731] The siRNA technology is an innovative gene knockout method, which has advantages such as high efficiency, specificity, and reliability. It has received extensive attention in the fields of disease treatment, gene research, etc. The 57 siRNAs designed by a custom Python script targeting the human LPA gene (NCBI refseqID NM_005577.4) proposed in this example represent an important advancement in this technology. Different from traditional siRNA design methods, the siRNA design method in 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 and named NDS-015-1 to NDS-015-57 respectively. The nucleotide sequences of the sense and antisense strands of these siRNAs are given in Table 1.

[0732] Example 2: Synthesis of siRNA and Conjugates

[0733] Table 2: Abbreviations of Nucleotide Monomers Used in Nucleic Acid Sequences

[0734]

[0735]

[0736] Deprotect, condense, cap, oxidize or thiolate according to standard oligonucleotide solid-phase synthesis protocols, using commercially available 5'-DMT-2'-OMe-U phosphoramidite monomer, 5'-DMT-2'-OMe-A(Bz) phosphoramidite monomer, 5'-DMT-2'-OMe-C(Ac) phosphoramidite monomer, 5'-DMT-2'-OMe-G(ibu) phosphoramidite monomer, 5'-DMT-2'-F-dU phosphoramidite monomer, 5'-DMT-2'-F-Ac-dC phosphoramidite monomer, 5'-DMT-2'-F-ibu-dG phosphoramidite monomer, 5'-DMT-2'-F-Bz-dA phosphoramidite monomer and the synthesized GalNAc phosphoramidite monomer. Synthesize RNA on a scale of 500 nmol or 4 μmol. Prepare 50 mM RNA phosphoramidite solution and 200 mM GalNAc monomer solution with acetonitrile, and use 0.3 M benzylthiotetrazole (BTT) acetonitrile solution as an activator to synthesize the sense strand and the antisense strand in the 3'-to-5'-direction respectively. During the synthesis, use 0.1 M oxidation reagent (I 2 : pyridine: THF: water) or use 0.2 M xanthogenic acid / pyridine solution to convert trivalent phosphorus to pentavalent phosphorus to stabilize the phosphate backbone. After the synthesis is completed, perform ammonolysis with AMA solution (40% methylamine: ammonia water = 1:1) at 55 °C for 50 min or 28% ammonia water at 65 °C for 5 h, and remove AMA or ammonia water by vacuum centrifugation. Purify with a PS-15Q ion purification column under the condition that phosphate and sodium chloride solution are used as the mobile phase or purify with a C18 reverse-phase column under the condition that triethylamine acetate aqueous solution and acetonitrile are used as the mobile phase. Perform in-process control detection by LCMS and HPLC. Mix the sense strand and the antisense strand in a molar ratio of 1:1, and anneal at 90 °C to form double-stranded siRNA and siRNA conjugates. The inventors verified the prepared conjugates (compound 1048 is linked to the 5'-end of the sense strand; compounds 1059, 1060 are linked to the 3'-end of the sense strand), and the modified siRNA sequences are shown in Tables 3 and 4.

[0737]

[0738]

[0739]

[0740]

[0741]

[0742]

[0743]

[0744]

[0745]

[0746]

[0747]

[0748]

[0749]

[0750] aM represents 2'-O-methyladenosine, uM represents 2'-O-methyluridine, gM represents 2'-O-methylguanosine, cM represents 2'-O-methylcytidine, aF represents 2'-fluoroadenosine, uF represents 2'-fluorouridine, gF represents 2'-fluoroguanosine, cF represents 2'-fluorocytidine, dA represents deoxyadenosine-3'-phosphate, dC represents deoxycytidine-3'-phosphate, dG represents deoxyguanosine-3'-phosphate, dT represents deoxythymidine-3'-phosphate, iVPM represents 2'-O-methyl-5'-deoxy-(E)-vinylphosphonate-inosine-3'-phosphate, uVPM represents 2'-O-methyl-5'-deoxy-(E)-vinylphosphate-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))-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-(thiomorpholine)-adenosine-3'-phosphate, cSMP represents 2'-O-methyl-5'-N-(thiomorpholine)-cytidine-3'-phosphate, gSMP represents 2'-O-methyl-5'-N-(thiomorpholine)-guanosine-3'-phosphate, uSMP represents 2'-O-methyl-5'-N-(thiomorpholine)-uridine-3'-phosphate, aRF represents 3'-fluoro-3'-deoxyadenosine-2'-phosphate, cRF represents 3'-fluoro-3'-deoxycytidine-2'-phosphate, gRF represents 3'-fluoro-3'-deoxyguanosine-2'-phosphate, uRF represents 3'-fluoro-3'-deoxyuridine-2'-phosphate, * represents a phosphorothioate diester bond between two nucleotides (or between compound 1048, 1059, 1060 and a nucleotide), and there is no symbol between directly adjacent nucleotides.

[0751] The raw materials (phosphoramidite monomers) and auxiliary materials required for the above nucleic acid chain synthesis were all purchased from the following companies:

[0752]

[0753] iVP was prepared by the method described in Patent CN202110008013.3; aTA4, cTA4, gTA4, uTA4, aSMP, cSMP, gSMP and uSMP were prepared by the method described in Patent CN202110008013.3; aRF, cRF, gRF and uRF were prepared by the method described in Patent CN202110008013.3; Compounds 1059 and 1060 were prepared by the method described in Patent CN202110008013.3; Compound 1048 was prepared by the method described in Patent CN202110008013.3.

[0754] Example 3: In vitro testing of the activity of small interfering nucleic acid (siRNA)

[0755] For the test sequences, the human LPA cDNA sequence (accession number NM_005577.1) was subcloned from a commercially available mammalian expression vector (Origene, Rockville, MD) into a commercially available reporter-based screening plasmid psiCHECK TM -2 (Promega, Madison, WI) to generate a Renilla luciferase / LPA fusion mRNA.

[0756] Using the fluorescence luciferase system, the silencing efficiency of the sequences on the target gene was evaluated in Hep3B cells. Hep3B cells were cultured in DMEM (Gibco) medium supplemented with 10% FBS (Gibco). One day before transfection, the cells were seeded in a 96-well plate at a density of 15,000 cells per well and transfected after attachment. The transfection process followed the standard protocol of lipofectemine2000 (Thermofisher). The transfection system included 0.4 μL lipofectemine2000 / 50 ng plasmid / well, and the selected dose of siRNA test substance. Three parallel wells were set for each transfection condition. The final concentration of siRNA was 10 nM / 1 nM / 0.1 nM / 0.01 nM. After 24 hours of transfection, the dual luciferase was detected using the Dual-Glo@Luciferase Assay System (Promega E2940) according to the standard protocol of the instruction manual. For the test results, the transfection of psiCHECK TM -2-LPA recombinant plasmid alone without the addition of siRNA was used as a control group, and the "Renilla fluorescence luminescence value / Firefly fluorescence luminescence value" of this group was set to 100%. The relative luminescence values of the "Renilla fluorescence luminescence value / Firefly fluorescence luminescence value" of other concentration groups were compared with the data of the control group. The activity of the siRNA sequences is shown in Table 5.

[0757] Table 5 In vitro silencing efficiency of siRNA duplexes (0.1 nM and 10 nM)

[0758]

[0759] Example 4: Activity testing of small interfering nucleic acid (siRNA) in primary monkey liver cells

[0760] Primary monkey liver cells were purchased from Miaoshun (Shanghai) Biotechnology Co., Ltd. and transported and stored in a liquid nitrogen tank. After resuscitation, the culture conditions were 37 °C and 5% CO2 (il60, Thermos Fisher).

[0761] On the day of the transfection experiment, the primary monkey liver cells frozen in the liquid nitrogen tank were resuscitated and plated in a 48-well cell culture plate pretreated with collagen coating solution (Coating Medium (product number: TIEP044)) according to the operation instructions of the primary monkey liver cell resuscitation manual. Before plating, the coating solution was washed away. First, the plating medium (CM Seeding Medium (product number: CMIEP054)) was added, and then the cell mother liquor was added at a cell density of 80,000 cells per well. The cell suspension was gently mixed immediately. For suspension transfection, RNAiMAX (Thermos Fisher) was used as the vector and transfected according to the standard configuration method. The final concentration of siRNA was 10 nM, 0.1 nM, and 0.01 nM, and each test substance was in a single well at each measured dose. An experimental group containing only the transfection reagent without siRNA in the transfection system was used as the control group.

[0762] At 24 hours after transfection, RNA in the cells was extracted using Trizol (Solarbio R1100). Subsequently, a one-step SYBR green qPCR kit (HiScript II One Step qRT-PCR SYBR Green Kit, VAZYME Q221-01) was used to configure the QPCR reaction system according to the standard method in the instruction manual, and a high-throughput QPCR instrument (Analytikjena qTOWER384G) was used to quantitatively analyze the change in the expression level of the target gene. For the experimental results, the relative change in the expression of the target gene in the test sample and the control sample was analyzed using the ΔΔCT method. The activities of the siRNA sequences are shown in Tables 6 and 7 below.

[0763] Table 6 In vitro silencing efficiency of siRNA duplexes (10 nM and 0.1 nM)

[0764]

[0765] Table 7 In vitro silencing efficiency of siRNA duplexes (10 nM, 0.1 nM, and 0.01 nM)

[0766]

[0767]

[0768] In the description of this specification, the description referring to the terms "one embodiment", "some embodiments", "example", "specific example", or "some examples", etc. means that the specific features, structures, materials, or characteristics described in connection with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials, or characteristics described may be combined in any one or more embodiments or examples in a suitable manner. In addition, without contradiction, those skilled in the art may combine and combine the different embodiments or examples described in this specification and the features of different embodiments or examples.

[0769] Although the embodiments of the present invention have been shown and described above, it can be understood that the above embodiments are exemplary and should not be construed as limiting the present invention. Those of ordinary skill in the art can make changes, modifications, substitutions, and variations to 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 related base pairing, wherein the sense strand is selected from a nucleotide sequence that differs from the nucleotide sequence of each strand in SEQ ID NO:1 to SEQ ID NO: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 is used.

12. The siRNA duplex according to claim 10, characterized in that The ribose modification in the modified nucleotide is selected from one of the following general formula II and general formula III: Wherein, X=O or S, preferably O Y is optionally H, OH, F, OCH3, OCH2OCH2CH3, OCH2SCH3, OCH2CH2CONHR 3 (R 3 is H, or a C1-C3 alkyl), etc.; preferably H, F, or OMe. PA is the general formula I as described in claim 11, preferably a phosphodiester linker or a thiophosphate diester linker. Bx is a base.

13. The siRNA duplex according to claim 10, characterized in that In the modified nucleotide, Bx is a conventional base or an unconventional base. The conventional nucleoside bases are adenine, guanine, cytosine, uracil and thymine; the unconventional bases are unconventional purine, pyrimidine or nitrogen-containing heterocyclic bases other than conventional nucleoside bases. The unconventional bases are preferably selected from one of the following nitrogen-containing heterocyclics:

14. The siRNA duplex according to any one of claims 10 to 13, characterized in that All nucleotides in the sense strand and / or the antisense strand are independently optionally modified nucleotides.

15. The siRNA duplex according to any one of claims 10 to 14, characterized in that The ribose modification of the modified nucleotide is independently selected from position 2 or position 3 of the ribose group: 2'-O-methyl modified nucleotide, 3'-O-methyl modified nucleotide, 2'-fluoro modified nucleotide, 3'-fluoro modified nucleotide, 2'-deoxy nucleotide, 3'-deoxy nucleotide; optionally, the phosphodiester linker modification of the modified nucleotide can be independently a 5'-phosphothioate diester linker.

16. The siRNA duplex according to claim 15, wherein The modification of the ribose group of the modified nucleotide is 2'-O-methyl or 2'-fluoro modification or 2'-deoxy modification.

17. The siRNA duplex according to claim 16, wherein The nucleotides at the 5'-end of the sense strand are 2'-fluoro-modified nucleotides at positions 9, 10 and 11 of the starting point, and the remaining positions are 2'-O-methyl-modified nucleotides; and / or The nucleotides at the 5'-end of the antisense strand are 2'-fluoro-modified nucleotides at the 2nd, 6th, 14th and 16th positions at the starting point, and the remaining positions are 2'-O-methyl-modified nucleotides.

18. The siRNA duplex according to claim 15, wherein The ribose modification of the nucleotides at positions 5 to 8 starting from the 5'-end of the siRNA antisense strand can be 3'-methoxy or 3'-fluoro or 3'-deoxy, preferably nucleotide modification at position 7. For this purpose, the phosphodiester linkage is a 2',5'-phosphodiester linkage as shown in general formula (III).

19. The siRNA duplex according to any one of claims 10 to 18, characterized in that The 5'-modified nucleotide at the first nucleotide starting point of the 5'-terminal nucleotide of the siRNA sense strand can be optionally one of the general formula (IV): Wherein, X=O or S, preferably O; Y is optionally H, OH, F, OCH3, OCH2OCH2CH3, OCH2SCH3, OCH2CH2CONHR 3 (R 3 is H, or a C1-C3 alkyl), etc.; preferably H, F or OMe; PA is the general formula (I) according to claim 11, preferably a phosphodiester linker or a thiophosphodiester linker, Bx is the base according to claim 13; R 4 is hydroxyl or one of the following optional groups: Among them, R 5 is H, F, Cl, Br, or a C1-C3 alkyl or alkoxy substituent; Preferably:

20. The siRNA duplex according to any one of claims 10 to 19, characterized in that The first nucleotide at the 5'-terminus of the antisense strand of the siRNA can be optionally 5'-unmodified, or a nucleotide (VP) modified as follows: Preferably: More preferably: Wherein, X=O or S, preferably O; Y is optionally H, OH, F, OCH3, OCH2OCH2CH3, OCH2SCH3, OCH2CH2CONHR 3 (R 3 is H, or a C1-C3 alkyl), etc.; preferably H, F or OMe.

21. The siRNA duplex according to any one of claims 10 to 20, characterized in that The siRNA duplex sense strand and antisense strand include the following optional combinations of one or more groups of different types of modifications: 2'-O-methyl modified nucleotides : aM, gM, cM and uM are 2'-O-Me A, 2'-O-Me G, 2'-O-Me C and 2'-O-Me U, respectively; 2'-Fluoro-modified nucleotides : aF, gF, cF and uF are 2'-fluoro A, 2'-fluoro 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, uTA4 are 2'-O-methyl-5'-deoxy-(1-(1,2,4-triazole))-cytidine-3'-phosphate, 2'-O-methyl-5'-deoxy-(1-(1,2,4-triazole))-guanosine-3'-phosphate, 2'-O-methyl-5'-deoxy-(1-(1,2,4-triazole))-adenosine-3'-phosphate, 2'-O-methyl-5'-deoxy-(1-(1,2,4-triazole))-uridine-3'-phosphate, respectively; 5'-Thiomorpholine-modified nucleotides : cSMP, gSMP, aSMP, and uSMP are 2'-O-methyl-5'-N-(thiomorpholino)-cytidine-3'-phosphate, 2'-O-methyl-5'-N-(thiomorpholino)-guanosine-3'-phosphate, 2'-O-methyl-5'-N-(thiomorpholino)-adenosine-3'-phosphate, and 2'-O-methyl-5'-N-(thiomorpholino)-uridine-3'-phosphate, respectively; 3'-Fluoro-modified nucleotides : cRF, gRF, aRF, 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.: 417) : 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.: 425) 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): 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.: 460) 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) : 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.: 381) 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.: 398): 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.: 216 and SEQ ID NO.: 417) : 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.: 230 and SEQ ID NO.: 431) NPD015s-AD101 (SEQ ID NO.: 231 and SEQ ID NO.: 432) 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-AD10 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.:458) 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.: 466) 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.: 269 and SEQ ID NO.: 466): 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 : 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.: 414) 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.:217 and SEQ ID NO.:417): 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.: 429) : 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.: 457) 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.:471) 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.: 489) 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.: 296 and SEQ ID NO.: 497):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.: 769) 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.: 768) 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.: 789): 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) : 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.: 810) 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.:844) 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.: 854) 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.: 879): 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.: 789) 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.: 800) 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.: 817): 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) 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.: 729) 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.: 765) 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.: 768): 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.: 791) 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.: 809) 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) 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.: 851) 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.: 858): 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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