siRNA for inhibiting LPA gene expression, a composition containing the same, and uses thereof

Abstract

The present invention relates to siRNA for inhibiting LPA gene expression, a composition containing the same, and the use thereof, wherein the siRNA comprises a sense strand and an antisense strand, the antisense strand comprises a sequence complementary to the LPA mRNA sequence, and the sequence of the antisense strand comprises the sequence of any one of the antisense strands in Table 1.

Description

Technology Field

[0001] The present application relates to the field of biopharmaceuticals, and specifically, to siRNA for inhibiting LPA gene expression, a composition containing the same, and the use thereof. Background Technology

[0002] LPA is the name of the gene encoding apolipoprotein(a), apo(a) which is primarily expressed in the liver and is limited to humans and non-primates. Apolipoprotein(a) is linked to apo(B)-100 via disulfide bonds and, together with a lipid core, forms lipoprotein(a) (Lp(a)) particles. Lp(a) particles are specialized macromolecules of cholesterol-rich lipoproteins, with cholesterol and phospholipids coated on their surfaces, and embedded within them are hydrophilic apolipoprotein components, namely apolipoprotein(a) and apo(B)-100. Lp(a) can penetrate and deposit within the inner walls of blood vessels, thereby promoting atherosclerosis. Lp(a) is structurally homologous to plasminogen (PLG) and can inhibit the hydrolysis of fibrinogen and promote thrombus formation by binding to fibrin sites in competition with plasminogen. Therefore, Lp(a) is closely associated with atherosclerosis and thrombus formation. According to studies, blood Lp(a) levels are an independent risk factor for cardiovascular disease, stroke, and atherosclerotic stenosis.

[0003] Analysis of Lp(a) levels in several studies has shown that high Lp(a) levels are an independent risk factor for cardiovascular disease, stroke, and other related conditions (including atherosclerotic stenosis). Additionally, through genome-wide association analysis, LPA has been identified as a genetic risk factor for conditions such as atherosclerotic stenosis.

[0004] Therefore, there is currently a need for methods to effectively treat and prevent the following diseases and related conditions, and to reduce the risk of developing the following diseases and related conditions: stroke, atherosclerosis, thrombosis, and cardiovascular diseases including coronary artery atherosclerosis and aortic valve stenosis, and other related conditions, pathologies, or syndromes that have not yet been identified. The present invention has addressed this unmet medical need. The problem to be solved

[0005] The object of the present invention is to provide siRNA (referred to as LPA siRNA herein) for inhibiting the expression of an LPA gene, or a pharmaceutically acceptable salt thereof. The siRNA described herein is delivered to a cell expressing an LPA gene and subsequently inhibits and / or knocks down LPA expression in vitro and / or in vivo through the biological process of RNA interference (RNAi).

[0006] Another object of the present invention is to provide a drug composition comprising the siRNA or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0007] Another objective of the present invention is to provide the use of the siRNA, its pharmaceutically acceptable salt, or the drug composition in the prevention or treatment of diseases or pathologies associated with LPA expression. means of solving the problem

[0008] To achieve the above objective, the present invention provides siRNA or a pharmaceutically acceptable salt thereof, wherein the siRNA comprises a sense strand and an antisense strand, wherein the antisense strand comprises a sequence complementary to an LPA mRNA sequence, and the sequence of the antisense strand comprises the sequence of any one of the antisense strands in Table 1.

[0009] siRNA knockdown 센스 가닥(5'-3') SEQ ID NO. 안티센스 가닥(3'-5') SEQ ID NO. 190024001 GUGGCACUUAUUGUU 1 CACCGUCAGGAAUAACAA 128 190024002 GCACCUCUAUUGUUAUA 2 CGUCGAGAUAACAAUAU 129 190024003 GGCACUUAUUGUUAU 3 CCGUCGAGAUAACAAUA 130 190024004 GCAAUGCUCACAGACGCAA 4 CHOUSEHOLD 131 190024005 STORAGESTORAGE 5 CHOUSEHOLD 132 190024006 WATERHOUSEHOUSE 6 GGAUCCCAGGRAW 133 190024007 CHICKWATERAGAGGCUUU 7 CONCLUSIONCONCLUSIONAA 134 190024008 WORKWORKWORK 8 HOUSEHOLDAGCGGGAA 135 190024009 GCACCUCCACCUGU 9 CGUGGGGGGGGGGGGG 136 190024010 ACTIVITIES 10 CUUAGGUACCUCUA 137 190024011 UGGCACUUAUUGUUA 11 ACCGUCGAGAUAACAAU 138 190024012 AGAGUUAUCGAGCCAUUU 12 UCUCAAUAGCUCCGAGUA 139 190024013 CHARGEHEAT 13 CONNECTED 140 190024014 ACUGUACUACUU 14 LET’S STOP 141 190024015 CCGAACACCGACUGA 15 GGHOLDING 142 190024016 CCUAGHGCUUUUUUGA 16 GGAUCCCGAAAAAAACU 143 190024017 CLIMATECAAAA 17 STORAGE 144 190024018 GACCUCCACCESSION 18 CCUGGACGCUGGACCAG 145 190024019 ACCAUUAGGAGAGUUA 19 UGGUAAUACCUCUCAAU 146 190024020 EXPERIMENTACACA 20 HOLDING UP 147 190024021 HOLDER 21 UCCUGACGAUGAUGGUAU 148 190024022 GSTORAGECAGCA 22 CCGAGGAGAKEY 149 190024023 AUCCACTION 23 UUAGQUAKAU 150 190024024 STORMING 24 HOLDING 151 190024025 CHANGECHANGECAAA 25 STORAGE 152 190024026 GGCACCUCCACCACUG 26 CCGUGAGGUGGUGAC 153 190024027 HOLD 27 CGACUAAGCGGGAACCA 154 190024028 GGCCUUCCACAAGCA 28 CCGAGGAAGGSTOP 155 190024029 REVIEWREACHAAAAC 29 HOLD UP 156 190024030 CCARGEGACCAA 30 HOLD UP 157 190024031 UGUGGCACUUAUUGU 31 ACACCGUCAGAAUAACA 158 190024032 GAGUUAUCGAGGCUCAUUC 32 CUCAAUAGCUCCGAGUAAG 159 190024033 GAGGCUUUUUUUUUGACAAG 33 CUCKAAAAAAAAAAAAAC 160 190024034 WATERWATERWATERWATER 34 CGGAUCUCCGAGGAGACU 161 190024035 AAGAAGAGAAAAAA 35 HOW TO BE 162 190024036 INJURIES 36 REPLACEMENT 163 190024037 STORAGECAGCA 37 CCGACAAKEEP 164 190024038 CGGUGGUCCAG 38 GCCACCAGGGCAAGGUUC 165 190024039 CONNECT HOLD 39 UCCUGGACGRECOVERY 166 190024040 CUGCUCCCURRY 40 CAGCGAGGGCUGACAGU 167 190024041 CAGGACUGQUACCAUU 41 HOLD ON 168 190024042 GCAUCAWEATHER 42 CHEARING 169 190024043 BACKGROUNDWEATHER 43 ACCWATERWATER 170 190024044 HEATHEATHEAT 44 HOLDING 171 190024045 WATERWATERWATER 45 UCGGAUCUCCGAGGAAGAC 172 190024046 GCSEARCH 46 CREPARATION 173 190024047 EXPERIENCES 47 WEARING CLOTHES 174 190024048 ACUAUCACAGGAGAACAU 48 UGAUAGUAQUE 175 190024049 RAINBOW 49 UPDATE 176 190024050 CUACCAUUAGGACAGAGU 50 GAUGGUAAUACCURACY 177 190024051 GCCUAGGCUUUUUUGA 51 CGGAUCUCCGAAAAAAACU 178 190024052 CCGCCAGGACUGAAUGUUA 52 GGCGGUCCUGACUUACAAU 179 190024053 CAAGCACCAACGGAGCAAA 53 GUUCGUGGUUGCCUCGUUU 180 190024054 CCCUUGGUGUUACACCAUG 54 GGGAACCACAAUGUGGUAC 181 190024055 CUGCUACUACCAUUAUGGA 55 GACGAUGAUGGUAAUACCU 182 190024056 ACAAGCACCACCACCUGAGAAA 56 UGUUCGUGGUGGACUCUUUU 183 190024057 CAAUGCCUGGUGGACAGAAU 57 GUUACGGACCACUGUCUUA 184 190024058 AAGCACCGACUGAGCAAAG 58 UUCGUGGCUGACUCGUUUC 185 190024059 CACAGAGGCUUCUUCUGAA 59 GUGUCUCCGAAGAAGACUU 186 190024060 GUGUCCUUGCAACUCUCAC 60 CACAGGAAACGUUGAGAGUG 187 190024061 CAGCUCCUUAUUGUUAUC 61 GUCGAGGAAUAACAAUAUG 188 190024062 GCUCCUUCCGAACAAGCAC 62 CGAGGAAGGCUUGUUCGUG 189 190024063 GGCAUCAGAGGGACAACAGA 63 CCGUAGUCUCCUGUUGUCU 190 190024064 GCACCAACUGAAAACAGCA 64 CGUGGUUGACUUUUGUCGU 191 190024065 UGCUGAGAUUCGCCCCUUGG 65 ACGACUCUAAGCGGAACC 192 190024066 UUCCGAACAAGCACCGAC 66 AAGGCUUGUUCGUGGCUGA 193 190024067 GCUACUACCAUUAUGGACA 67 CGAUGAUGGUAAUACCUGU 194 190024068 GCACCAACUGAGCAAAGGC 68 CGUGGUUGACUCGUUUCCG 195 190024069 CAGGAAGAACAUGUCAGUC 69 GUCCUUCUUGUACAGUCAG 196 190024070 AAGCACCAACGGAGCAAAG 70 UUCGUGGUUGCCUCGUUUC 197 190024071 GACACCACACCAGCAUAGU 71 CUGUGGUGUGGUCGUAUCA 198 190024072 CUGUCACAGGAAGAACUUG 72 GACAGUGUCUUCCUUGAAC 199 190024073 CAGAGGACAACAGAAUUU 73 GUCUCCUGUUGUCUUAUAA 200 190024074 CUGGCAUCAGAGGACAACA 74 GACCGUAGUCUCCUGUUGU 201 190024075 UACCAUUAUGGACAGAGUU 75 AUGGUAAUACCUGUCUCAA 202 190024076 UCAGAGGACAACAGAAUAU 76 AGUCUCUCUGUUGUCUUAUA 203 190024077 CAUGGAUCCCAAUGUCAGA 77 GUACQUAQUE 204 190024078 CCAUUAGGACAGAGUUAC 78 GGUAAUACCUCUCAAUG 205 190024079 WATER WATER 79 UAUGWATERWATER 206 190024080 GCUSTORAGEAC 80 CONGRATULATIONS 207 190024081 GCACCGACUGAGCAAAGGC 81 CGUGGCUCUCUUCG 208 190024082 UCCAACCWATER 82 HOLD ON 209 190024083 UGACACCACACCAGCAUAG 83 CUSTOMER 210 190024084 CCCACHAGAGAGG 84 GGPRESENTATION 211 190024085 CACCACCAWATERCG 85 HOLDINGHOUSECAGC 212 190024086 REVIEW 86 CACCAGGTAX 213 190024087 EXERCISEACTIVITY 87 HOLD UP 214 190024088 AAGCAGEGGLOCATION 88 REVISION 215 190024089 GGUGGUCCAGC 89 CCACCAGGCAGGUUCG 216 190024090 ACACCACCAGCAUAGUC 90 RECOVERY 217 190024091 AGCACCGACCAAAGG 91 UCCUGGQUEQUE 218 190024092 PLAYING THROUGH 92 EQUIPMENT 219 190024093 GAUUCCCCUUGGUGUUAC 93 WATERAGCGGGAACCACAAUG 220 190024094 CHACKAUGGAUCCCU 94 GUGGUAGUAGUCAG 221 190024095 CCWATERAGAGGCUUUUU 95 STOPTAKEAAAA 222 190024096 BACKGROUND 96 REPLACEMENT 223 190024097 CGGKEEPCAAAGC 97 GCCGACARRY 224 190024098 GUGCCAUCCAAGCA 98 CACCAGGKEEP 225 190024099 CCAGUGAGUGAGUG 99 TAKE CARE 226 190024100 AUCACTIVITY 100 WAAGHOUSEHOUSE 227 190024101 AAGHEATCOURSEAAG 101 RECOVERY 228 190024102 INSTALLATION 102 HOLDING UP 229 190024103 AAGACACAGAAACAG 103 UUCGUGGUUGACUUUUGUC 230 190024104 AGGCUCCUUCUGAACAAGC 104 UCCGAGGAAGACUUGUUCG 231 190024105 AGCACCAACUGAGCAAAGG 105 UCGUGGUUGACUCGUUUCC 232 190024106 UCCCACGGUGGUCCCAGUU 106 AGGGUGCCACCAGGGUCAA 233 190024107 UCCGAACAAGCACCGACUG 107 AGGCUUGUUCGUGGCUGAC 234 190024108 UCCACGGCUGUUUCUGAAC 108 AGGUGCCGACAAAGACUUG 235 190024109 GAAUCGAGUGUCCUCACAA 109 CUUAGCUCACAGGAGUGUU 236 190024110 CCUGACACGAUGUCCAGUG 110 GGACUGUGCUACAGGUCAC 237 190024111 UCCUCACAACUCCCACGGU 111 AGGAGUGUUGAGGGUGCCA 238 190024112 UGGCAUCAGAGGACAACAG 112 ACCGUAGUCUCCUGUUGUC 239 190024113 GGACAACAGAAUAUUAUCC 113 CCUGUUGUCUUAUAAUAGG 240 190024114 GGUGGUCCCAGAUCCAAGC 114 CCACCAGGGUCUAGGUUCG 241 190024115 AGGCUUCUUCUGAAGAAGC 115 UCCGAAGAAGACUUCUUCG 242 190024116 UCUCACGGUGGUCCCAGAU 116 AGAGUGCCACCAGGGUCUA 243 190024117 ACUGGCAUCAGAGGACAAC 117 UGACCGUAGUCUCCUGUUG 244 190024118 GGUGUUAUACCAUGGAUCC 118 CCACAAUAUGGUACCUAGG 245 190024119 ACACCAUGGAUCCCAGUGU 119 UGUGGUACCUAGGGUCACA 246 190024120 CUCACGGUGGUCCCAGAUC 120 GAGUGCCACCAGGGUCUAG 247 190024121 CCGGUUCCAAGCACAGAGG 121 GGCCAAGGUUCGUGUCUCC 248 190024122 CAAGCACAGAGGCUUCUUC 122 GUUCGUGUCUCCGAAGAAG 249 190024123 CCCUUGGUGUUAUACCAUG 123 GGGAACCACAAUAUGGUAC 250 190024124 UUGGUGUUAUACCAUGGAU 124 AACCACAAUAUGGUACCUA 251 190024125 GGCUUCUUCUGAAGAAGCA 125 CCGAAGAAGACUUCUUCGU 252 190024126 ACAGAGUUAUCGAGGCUCAUU 126 UGUCUCAAUAGCUCCGAGUAA 253 190024127 CAGAUGCUGAGAUUCGCCCUU 127 GUCUACGACUCUAAGCGGGAA 254

[0010] In some embodiments, the length of the antisense strand is 19-26 nucleobases long.

[0011] In some embodiments, the length of the antisense strand is 19-21 nucleotide lengths.

[0012] In some embodiments, the sense strand comprises a sequence that is basically complementary to the antisense strand and forms a duplex complementary region of 15 to 26 consecutive base pairs.

[0013] In some embodiments, the length of the duplex complementary region is 18 to 23 consecutive base pairs.

[0014] In some embodiments, the length of the duplex complementary region is 19 to 21 consecutive base pairs.

[0015] In some embodiments, the length of the sense strand is 19-26 nucleotide lengths.

[0016] In some embodiments, the length of the sense strand is 19-21 nucleotide lengths.

[0017] In some embodiments, the sequence of the sense strand comprises the sequence of any one of the sense strands in Table 1.

[0018] In some embodiments, the antisense strand comprises any one of the sequences SEQ ID NO.128-150, 253-254.

[0019] In some embodiments, the sense strand comprises any one of the sequences SEQ ID NO.1-23, 126-127.

[0020] In some embodiments, the siRNA comprises any one of the siRNAs in Table 1.

[0021] In some embodiments, among the siRNAs:

[0022] The above antisense strand includes SEQ ID NO. 128, and the above sense strand includes SEQ ID NO. 1;

[0023] The above antisense strand includes SEQ ID NO. 129, and the above sense strand includes SEQ ID NO. 2;

[0024] The antisense strand comprises SEQ ID NO. 130, and the sense strand comprises SEQ ID NO. 3;

[0025] The antisense strand comprises SEQ ID NO. 131, and the sense strand comprises SEQ ID NO. 4;

[0026] The antisense strand comprises SEQ ID NO. 132, and the sense strand comprises SEQ ID NO. 5;

[0027] The antisense strand comprises SEQ ID NO. 133, and the sense strand comprises SEQ ID NO. 6;

[0028] The antisense strand comprises SEQ ID NO. 134, and the sense strand comprises SEQ ID NO. 7;

[0029] The antisense strand comprises SEQ ID NO. 135, and the sense strand comprises SEQ ID NO. 8;

[0030] The above antisense strand includes SEQ ID NO. 136, and the above sense strand includes SEQ ID NO. 9;

[0031] The antisense strand comprises SEQ ID NO. 137, and the sense strand comprises SEQ ID NO. 10;

[0032] The antisense strand comprises SEQ ID NO. 138, and the sense strand comprises SEQ ID NO. 11;

[0033] The antisense strand comprises SEQ ID NO. 139, and the sense strand comprises SEQ ID NO. 12;

[0034] The antisense strand comprises SEQ ID NO. 140, and the sense strand comprises SEQ ID NO. 13;

[0035] The antisense strand comprises SEQ ID NO. 141, and the sense strand comprises SEQ ID NO. 14;

[0036] The antisense strand comprises SEQ ID NO. 142, and the sense strand comprises SEQ ID NO. 15;

[0037] The antisense strand comprises SEQ ID NO. 143, and the sense strand comprises SEQ ID NO. 16;

[0038] The antisense strand comprises SEQ ID NO. 144, and the sense strand comprises SEQ ID NO. 17;

[0039] The antisense strand comprises SEQ ID NO. 145, and the sense strand comprises SEQ ID NO. 18;

[0040] The antisense strand comprises SEQ ID NO. 146, and the sense strand comprises SEQ ID NO. 19;

[0041] The antisense strand comprises SEQ ID NO. 147, and the sense strand comprises SEQ ID NO. 20;

[0042] The antisense strand comprises SEQ ID NO. 148, and the sense strand comprises SEQ ID NO. 21;

[0043] The antisense strand comprises SEQ ID NO. 149, and the sense strand comprises SEQ ID NO. 22;

[0044] The above antisense strand includes SEQ ID NO. 150, and the above sense strand includes SEQ ID NO. 23;

[0045] The antisense strand comprises SEQ ID NO. 253, and the sense strand comprises SEQ ID NO. 126; or

[0046] The antisense strand includes SEQ ID NO.254, and the sense strand includes SEQ ID NO.127.

[0047] In some embodiments, the antisense strand or sense strand contains 1, 2, 3, 4, 5, or 6 extensions.

[0048] In some embodiments, the extension of the antisense strand or sense strand is dT.

[0049] In some embodiments, the antisense strand or sense strand contains two dT extensions.

[0050] In some embodiments, the 3' end of the antisense strand contains two dT extensions, and the sense strand does not contain dT.

[0051] In some embodiments, the antisense strand comprises the sequence of any one of the antisense strands in Table 2.

[0052] siRNA 명칭 센스 가닥(5'-3') SEQ ID NO. 안티센스 가닥(3'-5') SEQ ID NO. 190024001dt GUGGCAGCUUAUUGUUdTdT 255 dTdTCACCGUCGAGGAAUAACAA 380 190024002dt GCACCUCUAUUGUUAuAdTdT 256 dTdTCGUCGAGGAAUAACAAUAU 381 190024003dt GGCACCUUAUUGUUAUdTdT 257 dTdTCCGUCGAGGAAUAACAAUA 382 190024004dt GCAAUGCUCAGACGCAGAAdTdT 258 dTdTCHOUSEHOLD 383 190024005dt ACUACUGdTdT 259 dTdTCGAWATER 384 190024006dt CCUAGUACCucuccAdTdT 260 dTdTGGAUCUCCGAGGAGACUU 385 190024007dt CUCCAACCAUAGGCUUUdTdT 261 dTdTGAGGUCCGAUCCCGAAA 386 190024008dt GAUGCUGAAUUCCCCUUdTdT 262 dTdTCCUACQUAAGCGGGAA 387 190024009dt GCACCUCCACCUGUdTdT 263 dTdTCWGGGGGGGGGGGGGGGG 388 190024010dt GAAUCCAGAUGCUGAUdTdT 264 dTdTCUUAGCUACUA 389 190024011dt UGGCACCUUAUUGUUAdTdT 265 dTdTACCGUCGAGGAAUAACAAU 390 190024012dt AGAGUUAUCGAGGCAUUdTdT 266 dTdTUCUCAAUAGCUCCGAGUAA 391 190024013dt CCHARGEACCAAdTdT 267 dTdTGGAKEWORD 392 190024014dt ACUCAQGAGACUUdTdT 268 dTdCONVERSION 393 190024015dt CCGAACAAGCACCGACUGAdTdT 269 dTdTGGGGGGGG 394 190024016dt CCUAAGGCUUUUUUUGAadTdT 270 dTdTGGAUCCCGAAAAAAACUU 395 190024017dt CLIMATECAAAdTdT 271 dTdTWOODENERGY 396 190024018dt GGACCUGCCAAGCUUGGUCdTdT 272 dTdTCCUGGACGGUUCGAACCAG 397 190024019dt ACCAUUAUGGACAGAGUUAdTdT 273 dTdTUGGUAAUACCUGUCUCAAU 398 190024020dt GAAGCACCAACUGAAAACAdTdT 274 dTdTCUUCGUGGUUGACUUUUGU 399 190024021dt AGGACUGCUACUACCAUUAdTdT 275 dTdTUCCUGACGAUGAUGGUAAU 400 190024022dt GGCUCCUUCUGAACAAGCAdTdT 276 dTdTCCGAGGAAGACUUGUUCGU 401 190024023dt AAUCCAGAUGCUGAGAUUAdTdT 277 dTdTUUAGGUCUACGACUCUAAU 402 190024024dt CACUAUCACAGGAAGAACAdTdT 278 dTdTGUGAUAGUGUCCUUCUUGU 403 190024025dt CAAGCACCGACUGAGCAAAdTdT 279 dTdTGUUCGUGGCUGACUCGUUU 404 190024026dt GGCACGUACUCCACCACUGdTdT 280 dTdTCCGUGCAUGAGGUGGUGAC 405 190024027dt GCUGAGAUUCGCCCUUGGUdTdT 281 dTdTCGACUCUAAGCGGGAACCA 406 190024028dt GGCUCCUUCCGAACAAGCAdTdT 282 dTdTCCGAGGAAGGCUUGUUCGU 407 190024029dt AGAAGCACCAACUGAAAACdTdT 283 dTdTUCUUCGUGGUUGACUUUUG 408 190024030dt CCUUCUGAAGAAGCACCAAdTdT 284 dTdTGGAAGACUUCUUCGUGGUU 409 190024031dt UGUGGCAGCUCCUUAUUGUdTdT 285 dTdTACACCGUCGAGGAAUAACA 410 190024032dt GAGUUAUCGAGGCUCAUUCdTdT 286 dTdTCUCAAUAGCUCCGAGUAAG 411 190024033dt GAGGCUUUUUUUGAACAAGdTdT 287 dTdTCUCCGAAAAAAACUUGUUC 412 190024034dt GCCUAGAGGCUCCUUCUGAdTdT 288 dTdTCGGAUCUCCGAGGAAGACU 413 190024035dt AAGAAGCACCAACUGAAAAdTdT 289 dTdTUUCUUCGUGGUUGACUUUU 414 190024036dt ACAGGAAGAACAUGUCAGUdTdT 290 dTdTUGUCCUUCUUGUACAGUCA 415 190024037dt GGCUGUUUCUGAACAAGCAdTdT 291 dTdTCCGACAAAGACUUGUUCGU 416 190024038dt CGGUGGUCCCAGUUCCAAGdTdT 292 dTdTGCCACCAGGGUCAAGGUUC 417 190024039dt AGGACCUGCCAAGCUUGGUdTdT 293 dTdTUCCUGGACGGUUCGAACCA 418 190024040dt GUCGCUCCUCCGACUGUCAdTdT 294 dTdTCAGCGAGGAGGCUGACAGU 419 190024041dt CAGGACUGCUACUACCAUUdTdT 295 dTdTGUCCUGACGAUGAUGGUAA 420 190024042dt GCAUCAGAGGACAACAGAAdTdT 296 dTdTCGUAGUCUCCUGUUGUCUU 421 190024043dt UGGCUUGAUCAAGAACUACdTdT 297 dTdTACCGAACUAGUUCUUGAUG 422 190024044dt CACUGGCAUCAGAGGACAAdTdT 298 dTdTGUGACCGUAGUCUCCUGUU 423 190024045dt AGCCUAGAGGCUCCUUCUGdTdT 299 dTdTUCGGAUCUCCGAGGAAGAC 424 190024046dt GCACAGAGGCUUCUUCUGAdTdT 300 dTdTCGUGUCUCCGAAGAAGACU 425 190024047dt CAGAAUCAGGUGUCCUAGAdTdT 301 dTdTGUCUUAGUCCACAGGAUCU 426 190024048dt ACUAUCACAGGAAGAACAUdTdT 302 dTdTUGAUAGUGUCCUUCUUGUA 427 190024049dt ACAGGACUGCUACUACCAUdTdT 303 dTdTUGUCCUGACGAUGAUGGUA 428 190024050dt CUACCAUUAUGGACAGAGUdTdT 304 dTdTGAUGGUAAUACCUGUCUCA 429 190024051dt GCCUAGAGGCUUUUUUUGAdTdT 305 dTdTCGGAUCUCCGAAAAAAACU 430 190024052dt CCGCCAGGACUGAAUGUUAdTdT 306 dTdTGGCGGUCCUGACUUACAAU 431 190024053dt CAAGCACCAACGGAGCAAAdTdT 307 dTdTGUUCGUGGUUGCCUCGUUU 432 190024054dt CCCUUGGUGUUACACCAUGdTdT 308 dTdTGGGAACCCAAUGUGGUAC 433 190024055dt CUGCUACUACCAUUAUGGAdTdT 309 dTdTGACGAUGAUGGUAAUACCU 434 190024056dt ACAAGCACCACCACCUGAGAAAdTdT 310 dTdTUGUUCGUGGUGGACUCUUUU 435 190024057dt CAAUGCCUGGUGACAGAAAUdTdT 311 dTdTGUUACGGACCACUGUCUUA 436 190024058dt AAGCACCGACUGAGCAAAGdTdT 312 dTdTUUCGUGGCUGACUCGUUUC 437 190024059dt CACAGAGGCUUCUUCUGAAdTdT 313 dTdTGUGUCUCCGAAGAAGACUU 438 190024060dt GUGUCCUUGCAACUCUCACdTdT 314 dTdTCACAGGAACGUUGAGAGUG 439 190024061dt CAGCUCCUUAUUGUUAUACdTdT 315 dTdTGUCGAGGAAUAACAAUAUG 440 190024062dt GCUCCUUCCGAACAAGCACdTdT 316 dTdTCGAGGAAGGCUUGUUCGUG 441 190024063dt GGCAUCAGAGGACAACAGAdTdT 317 dTdTCCGUAGUCUCCUGUGUCU 442 190024064dt GCACCAACUGAAAACAGCAdTdT 318 dTdTCGUGGUUGACUUUUGUCGU 443 190024065dt UGCUGAGAUUCGCCCCUUGGdTdT 319 dTdTACGACUCUAAGCGGGAACC 444 190024066dt UUCCGAACAAGCACCGACUdTdT 320 dTdTAAGGCUUGUUCGUGGCUGA 445 190024067dt GCUACUACCAUUAUGGACAdTdT 321 dTdTCGAUGAUGGUAAUACCUGU 446 190024068dt GCACCAACUGAGCAAAGGCdTdT 322 dTdTCGUGGUUGACUCGUUUCCG 447 190024069dt CAGGAAGAACAUGUCAGUCAGUCdTdT 323 dTdTGUCCUUCUUGUACAGUCAG 448 190024070dt AAGCACCAACGGAGCAAAGdTdT 324 dTdTUUCGUGGUUGCCUCGUUUC 449 190024071dt GACACCACACCAGCAUAGUdTdT 325 dTdTCUGUGGUGGUCGUAUCA 450 190024072dt CUGUCACAGGAAGAACUUGdTdT 326 dTdTGACAGUGUCCUUCUUGAAC 451 190024073dt CAGAGGACAACAGAAUAUUdTdT 327 dTdTGUCUCCUGUUGUCUUAUAA 452 190024074dt CUGGCAUCAGAGGACAACAdTdT 328 dTdTGACCGUAGUCUCUGUUGU 453 190024075dt UACCAUUAUGGACAGAGUUdTdT 329 dTdTAUGGUAAUACCUGUCUCAA 454 190024076dt UCAGAGGACAACAGAAUAUdTdT 330 dTdTAGUCUCCUGUUGUCUUAUA 455 190024077dt CAUGGAUCCCAAUGUCAGAdTdT 331 dTdTGUACCUAGGGUUACAGUCU 456 190024078dt CCAUUAUGGACAGAGUUACdTdT 332 dTdTGGUAAUACCUGUCUCAAUG 457 190024079dt AUACCAUGGAUCCCAAUGUdTdT 333 dTdTUAUGGUACCUAGGGUUACA 458 190024080dt GCUCCUUCUGAACAAGCACdTdT 334 dTdTCGAGGAAGACUUGUUCGUG 459 190024081dt GCACCGACUGAGCAAAGGCdTdT 335 dTdTCGUGGCUGACUCGUUUCCG 460 190024082dt UCCAAGCCUAGGGCUUUUuDtD 336 dTdTAGGUUCGGAUCUCCGAAA 461 190024083dt UGACACCACACCAGCAUAGdTdT 337 dTdTACUGUGGUGUGUGGUCGUAUC 462 190024084dt CCCAGUUCCAAGCACAGAGdTdT 338 dTdTGGGUCAAGGUUCGUCUC 463 190024085dt CACCACACCAGCAUAGUCGdTdT 339 dTdTGUGGUGUGGUCGUAUCAGC 464 190024086dt GUGGUCCCAGUUCCAAGCAdTdT 340 dTdTCACCAGGGUUAGGUUCGU 465 190024087dt CAUCAGAGGACAACAGAAUdTdT 341 dTdTWARKER 466 190024088dt AAGCAGAGGSTROUCUdTdT 342 dTdCONNECTION 467 190024089dt GGUGGUCCAAGCdTdT 343 dTdTCCACCAGGGCUCAGCUCC 468 190024090dt ACACCACCAGCAUAGUCdTdT 344 dTdTUGGGGGGG 469 190024091dt AGCCACCAAAGGdTdT 345 dTdTUCCUGGCUCUUCC 470 190024092dt CUGACAGOCUGAdTdT 346 dTdTHOLDER 471 190024093dt GAUUCCCCUUGGUUACdTdT 347 dTdTCUAAGCGGGAACCACAAUG 472 190024094dt CACCAUGGAUCCCAGUUCdTdT 348 dTdTGUGWATERAGGGGUCAG 473 190024095dt CCAACCWAGGCUUUUUdTdT 349 dTdTGGCCGAAAAAAA 474 190024096dt AXAGGGSTROGGdTdT 350 dTdCUCCAGAGAC 475 190024097dt CGGCUSTACAGCdTdT 351 dTdTGCCGACAAACUUCG 476 190024098dt GUGGUCCAUCCAAGCAdTdT 352 dTdTCACCAGGKEEPER 477 190024099dt CCAGUGACAGAAUCGAGUGdTdT 353 dTdTGQUEQUEQUE 478 190024100dt AUCAGGACAGAAUAdTdT 354 dTdHOWHOWHOW 479 190024101dt AAGCAACACAAAGdTdT 355 dTdEVERYONE 480 190024102dt STATEMENTGdTdT 356 dTdTCUCUUOWNING 481 190024103dt AAGCAACAGAAACAGdTdT 357 dTdSOMEWHERE 482 190024104dt AGGCACAAGCdTdT 358 dTdTUCCGAGGAGACUUCG 483 190024105dt AGCACCAACUGAGCAAAGGdTdT 359 dTdTUCGUGGUUGACUCGUUUCC 484 190024106dt UCCCACGGUGGUCCCAGUUdTdT 360 dTdTAGGGUGCCACCAGGGUCAA 485 190024107dt UCCGAACAAGCACCGACUGdTdT 361 dTdTAGGCUUGUUCGUGGCUGAC 486 190024108dt UCCACGGCUGUUUCUGAACdTdT 362 dTdTAGGUGCCGACAAAGACUUG 487 190024109dt GAAUCGAGUGUCCUCACAAdTdT 363 dTdTCUUAGCUCACAGGAGUGUU 488 190024110dt CCUGACACGAUGUCCAGUGdTdT 364 dTdTGGACUGUGCUACAGGUCAC 489 190024111dt UCCUCACAACUCCCACGGUdTdT 365 dTdTAGGAGUGUUGAGGGUGCCA 490 190024112dt UGGCAUCAGAGGACAACAGdTdT 366 dTdTACCGUAGUCUCCUGUUGUC 491 190024113dt GGACAACAGAAUAUUAUCCdTdT 367 dTdTCCUGUUGUCUUAUAAUAGG 492 190024114dt GGUGGUCCCAGAUCCAAGCdTdT 368 dTdTCCACCAGGGUCUAGGUUCG 493 190024115dt AGGCUUCUUCUGAAGAAGCdTdT 369 dTdTUCCGAAGAAGACUUCUUCG 494 190024116dt UCUCACGGUGGUCCCAGAUdTdT 370 dTdTAGAGUGCCACCAGGGUCUA 495 190024117dt ACUGGCAUCAGAGGACAACdTdT 371 dTdTUGACCGUAGUCUCCUGUUG 496 190024118dt GGUGUUAUACCAUGGAUCCdTdT 372 dTdTCCACAAUAUGGUACCUAGG 497 190024119dt ACACCAUGGAUCCCAGUGUdTdT 373 dTdTUGUGGUACCUAGGGUCACA 498 190024120dt CUCACGGUGGUCCCAGAUCdTdT 374 dTdTGAGUGCCACCAGGGUCUAG 499 190024121dt CCGGUUCCAAGCACAGAGGdTdT 375 dTdTGGCCAAGGUUCGUGUCUCC 500 190024122dt CAAGCACAGAGGCUUCUUCdTdT 376 dTdTGUUCGUGUCUCCGAAGAAG 501 190024123dt CCCUUGGUGUUAUACCAUGdTdT 377 dTdTGGGAACCACAAUAUGGUAC 502 190024124dt UUGGUGUUAUACCAUGGAUdTdT 378 dTdTAACCACAAUAUGGUACCUA 503 190024125dt GGCUUCUUCUGAAGAAGCAdTdT 379 dTdTCCGAAGAAGACUUCUUCGU 504 190024001dt1 GUGGCAGCUCCUUAUUGUU 541 dTdTCACCGUCGAGGAAUAACAA 544 190024002dt1 GCAGCUCCUUAUUGUUAUA 542 dTdTCGUCGAGGAAUAACAAUAU 545 190024005dt1 GCUUGAUCAAGAACUACUG 543 dTdTCGAACUAGUUCUUGAUGAC 546

[0053] In some embodiments, the antisense strand comprises any one of the sequences SEQ ID NO.380-402, 544-546.

[0054] In some embodiments, the sense strand comprises the sequence of any one of the sense strands in Table 2.

[0055] In some embodiments, the sense strand comprises any one of the sequences SEQ ID NO.255-277, 541-543.

[0056] In some embodiments, the siRNA comprises any one of the siRNAs in Table 2.

[0057] In some embodiments, among the siRNAs:

[0058] The antisense strand comprises SEQ ID NO.380, and the sense strand comprises SEQ ID NO.255;

[0059] The antisense strand comprises SEQ ID NO. 381, and the sense strand comprises SEQ ID NO. 256;

[0060] The antisense strand comprises SEQ ID NO. 382, ​​and the sense strand comprises SEQ ID NO. 257;

[0061] The above antisense strand includes SEQ ID NO.383, and the above sense strand includes SEQ ID NO.258;

[0062] The antisense strand comprises SEQ ID NO.384, and the sense strand comprises SEQ ID NO.259;

[0063] The antisense strand comprises SEQ ID NO. 385, and the sense strand comprises SEQ ID NO. 260;

[0064] The antisense strand comprises SEQ ID NO. 386, and the sense strand comprises SEQ ID NO. 261;

[0065] The antisense strand comprises SEQ ID NO. 387, and the sense strand comprises SEQ ID NO. 262;

[0066] The antisense strand comprises SEQ ID NO. 388, and the sense strand comprises SEQ ID NO. 263;

[0067] The antisense strand comprises SEQ ID NO. 389, and the sense strand comprises SEQ ID NO. 264;

[0068] The antisense strand comprises SEQ ID NO.390, and the sense strand comprises SEQ ID NO.265;

[0069] The antisense strand comprises SEQ ID NO.391, and the sense strand comprises SEQ ID NO.266;

[0070] The antisense strand comprises SEQ ID NO.392, and the sense strand comprises SEQ ID NO.267;

[0071] The above antisense strand includes SEQ ID NO.393, and the above sense strand includes SEQ ID NO.268;

[0072] The antisense strand comprises SEQ ID NO.394, and the sense strand comprises SEQ ID NO.269;

[0073] The antisense strand comprises SEQ ID NO. 395, and the sense strand comprises SEQ ID NO. 270;

[0074] The antisense strand comprises SEQ ID NO. 396, and the sense strand comprises SEQ ID NO. 271;

[0075] The antisense strand comprises SEQ ID NO. 397, and the sense strand comprises SEQ ID NO. 272;

[0076] The antisense strand comprises SEQ ID NO.398, and the sense strand comprises SEQ ID NO.273;

[0077] The antisense strand comprises SEQ ID NO. 399, and the sense strand comprises SEQ ID NO. 274;

[0078] The antisense strand comprises SEQ ID NO. 400, and the sense strand comprises SEQ ID NO. 275;

[0079] The antisense strand comprises SEQ ID NO. 401, and the sense strand comprises SEQ ID NO. 276;

[0080] The antisense strand comprises SEQ ID NO. 402, and the sense strand comprises SEQ ID NO. 277;

[0081] The antisense strand comprises SEQ ID NO. 541, and the sense strand comprises SEQ ID NO. 544;

[0082] The antisense strand comprises SEQ ID NO. 542, and the sense strand comprises SEQ ID NO. 545; or

[0083] The antisense strand includes SEQ ID NO. 543, and the sense strand includes SEQ ID NO. 546.

[0084] In some embodiments, the sense strand and / or antisense strand independently comprise one or more modified nucleotides.

[0085] In some embodiments, the modified nucleotide is a 2'-modified nucleotide.

[0086] In some embodiments, the modified nucleotide is a 2'-O-methyl modified nucleotide (i.e., a ribonucleotide in which the 2'-OH on the ribose is substituted with 2'-OMe, denoted as mN in the text, where N denotes a nucleotide), a 2'-O-methoxyethyl modified nucleotide, a 2'-fluoro modified nucleotide (i.e., a ribonucleotide in which the 2'-OH on the ribose is substituted with 2'-F, denoted as fN in the text, where N denotes a ribonucleotide, also denoted as a 2'-deoxy-2'-fluoro modified nucleotide in the text), a 2'-deoxy modified nucleotide, a 2'-O-alkenyl modified nucleotide, a locked nucleotide, GNA, LNA, a baseless nucleotide, deoxythymidine, inverted deoxythymidine, deoxyadenosine, inverted deoxyadenosine, It includes 2'-amino-modified nucleotides, 2'-alkyl-modified nucleotides, morpholino nucleotides, nucleotides containing non-natural bases, 5'-(E)-vinylphosphonate modified nucleotides (indicated as VP in the text), or combinations thereof.

[0087] In some embodiments, the nucleotides are all modified nucleotides.

[0088] In some embodiments, the modified nucleotide comprises a 2'-O-methyl modified nucleotide, a 2'-fluoro modified nucleotide, a deoxythymidine and a 5'-(E)-vinylphosphonate modified nucleotide, or a combination thereof.

[0089] In some embodiments, the sense strand, antisense strand, or sense strand and antisense strand comprises one or more phosphorothioate or phosphorodithioate internucleoside linkages.

[0090] In some embodiments, the antisense strand comprises two consecutive phosphorothioate internucleoside bonds between the 3' and 5' terminal nucleotides.

[0091] In some embodiments, the sense strand comprises two consecutive phosphorothioate internucleoside bonds between the 3' and 5' terminal nucleotides.

[0092] In some embodiments, two consecutive phosphorothioate internucleoside bonds are included between the 5' end nucleotides of the sense strand, and one phosphorothioate internucleoside bond is included between the 3' end nucleotides of the sense strand.

[0093] In some embodiments, the sense strand comprises two consecutive phosphorothioate internucleoside bonds between the 5'-terminal nucleotides and one phosphorothioate internucleoside bond between the 3'-terminal nucleotides of the sense strand; and the antisense strand comprises two consecutive phosphorothioate internucleoside bonds between the 3'-terminal and 5'-terminal nucleotides.

[0094] In some embodiments:

[0095] 1) The sense strand comprises 21 nucleotides, the antisense strand comprises 23 nucleotides, the length of the duplex complementary region is 21 base pairs, the nucleotides at positions 9, 10, and 11 from the 5' end of the sense strand are all 2'-fluoro-modified nucleotides, and the remaining nucleotides of the sense strand are all 2'-O-methyl-modified nucleotides; the nucleotides at positions 8, 10, 18, and 22 from the 3' end of the antisense strand are all 2'-fluoro-modified nucleotides, and the remaining nucleotides of the antisense strand are all 2'-O-methyl-modified nucleotides; The nucleotides between the 5' end of the sense strand and positions 1 through 3, the nucleotides between the 3' end of the sense strand and positions 1 through 3, the nucleotides between the 5' end of the antisense strand and positions 1 through 3, and the nucleotides between the 3' end of the antisense strand and positions 1 through 3 are all connected via phosphothioate bonds, and the remaining nucleotides of the sense strand and the antisense strand are all connected via phosphodiester bonds;

[0096] 2) The sense strand comprises 19 nucleotides, the antisense strand comprises 21 nucleotides, the length of the duplex complementary region is 19 base pairs, the nucleotides at positions 7, 8, and 9 from the 5' end of the sense strand are all 2'-fluoro-modified nucleotides, and the remaining nucleotides of the sense strand are all 2'-O-methyl-modified nucleotides; the first and second positions from the 3' end of the antisense strand are two dTs, the nucleotides at positions 6, 8, 14, 16, and 20 from the 3' end of the antisense strand are all 2'-fluoro-modified nucleotides, and the remaining nucleotides of the antisense strand are all 2'-O-methyl-modified nucleotides; The nucleotides between the 5' end of the sense strand and positions 1 through 3, the nucleotides between the 3' end of the sense strand and positions 1 through 3, the nucleotides between the 5' end of the antisense strand and positions 1 through 3, and the nucleotides between the 3' end of the antisense strand and positions 1 through 3 are all connected via phosphothioate bonds, and the remaining nucleotides of the sense strand and the antisense strand are all connected via phosphodiester bonds;

[0097] 3) The sense strand comprises 19 nucleotides, the antisense strand comprises 21 nucleotides, the length of the duplex complementary region is 19 base pairs, the nucleotides at positions 7, 8, and 9 from the 5' end of the sense strand are all 2'-fluoro-modified nucleotides, and the remaining nucleotides of the sense strand are all 2'-O-methyl-modified nucleotides; the first and second positions from the 3' end of the antisense strand are two dTs, the nucleotides at positions 4, 6, 8, 16, and 20 from the 3' end of the antisense strand are all 2'-fluoro-modified nucleotides, and the remaining nucleotides of the antisense strand are all 2'-O-methyl-modified nucleotides; The nucleotides between the 5' end of the sense strand and positions 1 through 3, the nucleotides between the 3' end of the sense strand and positions 1 through 3, the nucleotides between the 5' end of the antisense strand and positions 1 through 3, and the nucleotides between the 3' end of the antisense strand and positions 1 through 3 are all connected via phosphothioate bonds, and the remaining nucleotides of the sense strand and the antisense strand are all connected via phosphodiester bonds;

[0098] 4) The sense strand comprises 21 nucleotides, the antisense strand comprises 21 nucleotides, the length of the duplex complementary region is 21 base pairs, the nucleotides at positions 9, 10, and 11 from the 5' end of the sense strand are all 2'-fluoro-modified nucleotides, and the remaining nucleotides of the sense strand are all 2'-O-methyl-modified nucleotides; the nucleotides at positions 3 through 4, 6, 8, 10, 16, 18, and 20 from the 3' end of the antisense strand are all 2'-fluoro-modified nucleotides, and the remaining nucleotides of the antisense strand are all 2'-O-methyl-modified nucleotides; The nucleotides between the 5' end of the sense strand and positions 1 through 3, the nucleotides between the 3' end of the sense strand and positions 1 through 3, the nucleotides between the 5' end of the antisense strand and positions 1 through 3, and the nucleotides between the 3' end of the antisense strand and positions 1 through 3 are all connected via phosphothioate bonds, and the remaining nucleotides of the sense strand and the antisense strand are all connected via phosphodiester bonds;

[0099] 5) The sense strand comprises 21 nucleotides, the antisense strand comprises 21 nucleotides, the length of the duplex complementary region is 21 base pairs, the nucleotides at positions 9, 10, and 11 from the 5' end of the sense strand are all 2'-fluoro-modified nucleotides, and the remaining nucleotides of the sense strand are all 2'-O-methyl-modified nucleotides; the nucleotides at positions 3 through 4, 6, 8, 10, 16, 18, and 20 from the 3' end of the antisense strand are all 2'-fluoro-modified nucleotides, the remaining nucleotides of the antisense strand are all 2'-O-methyl-modified nucleotides, and the nucleotide at position 1 of the 5' end of the antisense strand is VP modified; The nucleotides between the 5' end of the sense strand and positions 1 through 3, the nucleotides between the 3' end of the sense strand and positions 1 through 3, the nucleotides between the 5' end of the antisense strand and positions 1 through 3, and the nucleotides between the 3' end of the antisense strand and positions 1 through 3 are all connected via phosphothioate bonds, and the remaining nucleotides of the sense strand and the antisense strand are all connected via phosphodiester bonds;

[0100] 6) The sense strand comprises 19 nucleotides, the antisense strand comprises 21 nucleotides, the length of the duplex complementary region is 19 base pairs, the nucleotides at positions 7, 8, and 9 from the 5' end of the sense strand are all 2'-fluoro-modified nucleotides, and the remaining nucleotides of the sense strand are all 2'-O-methyl-modified nucleotides; the first and second positions from the 3' end of the antisense strand are two dTs, the nucleotides at positions 6, 8, 14, 16, and 20 from the 3' end of the antisense strand are all 2'-fluoro-modified nucleotides, the remaining nucleotides of the antisense strand are all 2'-O-methyl-modified nucleotides, and the nucleotide at position 1 of the 5' end of the antisense strand is VP-modified; The nucleotides between the 5' end of the sense strand and positions 1 through 3, the nucleotides between the 3' end of the sense strand and positions 1 through 3, the nucleotides between the 5' end of the antisense strand and positions 1 through 3, and the nucleotides between the 3' end of the antisense strand and positions 1 through 3 are all connected via phosphothioate bonds, and the remaining nucleotides of the sense strand and the antisense strand are all connected via phosphodiester bonds;

[0101] 7) The sense strand comprises 19 nucleotides, the antisense strand comprises 21 nucleotides, the length of the duplex complementary region is 19 base pairs, the nucleotides at positions 7, 8, and 9 from the 5' end of the sense strand are all 2'-fluoro-modified nucleotides, and the remaining nucleotides of the sense strand are all 2'-O-methyl-modified nucleotides; the first and second positions from the 3' end of the antisense strand are two dTs, the nucleotides at positions 6, 8, 14, 16, and 20 from the 3' end of the antisense strand are all 2'-fluoro-modified nucleotides, and the remaining nucleotides of the antisense strand are all 2'-O-methyl-modified nucleotides; The nucleotides between the 5' end of the sense strand and positions 1 through 3, the nucleotides between the 3' end of the sense strand and positions 1 through 2, the nucleotides between the 5' end of the antisense strand and positions 1 through 3, and the nucleotides between the 3' end of the antisense strand and positions 1 through 3 are all connected via phosphothioate bonds, and the remaining nucleotides of the sense strand and the antisense strand are all connected via phosphodiester bonds; or

[0102] 8) The sense strand comprises 19 nucleotides, the antisense strand comprises 21 nucleotides, the length of the duplex complementary region is 19 base pairs, the nucleotides at positions 7, 8, and 9 from the 5' end of the sense strand are all 2'-fluoro-modified nucleotides, and the remaining nucleotides of the sense strand are all 2'-O-methyl-modified nucleotides; the first and second positions from the 3' end of the antisense strand are two dTs, the nucleotides at positions 6, 8, 14, 16, and 20 from the 3' end of the antisense strand are all 2'-fluoro-modified nucleotides, the remaining nucleotides of the antisense strand are all 2'-O-methyl-modified nucleotides, and the nucleotide at position 1 of the 5' end of the antisense strand is VP-modified; The nucleotides between the 5' end of the sense strand and the nucleotides at positions 1 through 3, the nucleotides between the 3' end of the sense strand and the nucleotides at positions 1 through 2, the nucleotides between the 5' end of the antisense strand and the nucleotides at positions 1 through 3, and the nucleotides between the 3' end of the antisense strand and the nucleotides at positions 1 through 3 are all connected through phosphothioate bonds, and the remaining nucleotides of the sense strand and the antisense strand are all connected through phosphodiester bonds.

[0103] In some embodiments, the antisense strand comprises any one of the antisense strands in Table 3.

[0104] siRNA names single strand order SEQ ID NO. 190024-M1 Antisense strand (5'-3') mU*fA*mUmAmAfCmAmAmUmAmAmGmGfAmGfCmUmGmCmCmA*mC*mA 505 Sense strand (5'-3') mU*mG*mGmCmAmGmCmUfCfCfUmUmAmUmUmGmUmUmA*mU*mA 506 190024-M2 Antisense strand (3'-5') dT*dT*mCmGmUfCmGfAmGmGmAmAmUfAmAfCmAmAmU*fA*mU 507 Sense strand (5'-3') mG*mC*mAmGmCmUfCfCfUmUmAmUmUmGmUmUmA*mU*mA 508 190024-M3 Antisense strand (3'-5') dT*dT*mCmGmUfCmGfAmGmGmAmAmUfAmAfCmAmAmU*fA*mU 509 Sense strand (5'-3') mG*mC*mAmGmCmUfCfCfUmUmAmUmUmGmUmUmAmU*mA 510 190024-M4 Antisense strand (3'-5') dT*dT*mCmGmUfCmGfAmGmGmAmAmUfAmAfCmAmAmU*fA*mUVP 511 Sense strand (5'-3') mG*mC*mAmGmCmUfCfCfUmUmAmUmUmGmUmUmAmU*mA 512 190024-M5 Antisense strand (3'-5') dT*dT*mCmGmUfCmGfAmGmGmAmAmUfAmAfCmAmAmU*fA*mUVP 513 Sense strand (5'-3') mG*mC*mAmGmCmUfCfCfUmUmAmUmUmGmUmUmA*mU*mA 514 190024-M6 Antisense strand (3'-5') dT*dT*mCmGmAfAmCfUmAmGmUmUmCfUmUfGmAmUmG*fA*mC 515 Sense strand (5'-3') mG*mC*mUmUmGmAfUfCfAmAmGmAmAmCmUmAmC*mU*mG 516 190024-M7 Antisense strand (3'-5') dT*dT*mCmAmCfCmGfUmCmGmAmGmGfAmAfUmAmAmC*fA*mA 517 Sense strand (5'-3') mG*mU*mGmGmCmAfGfCfUmCmCmUmUmAmUmUmG*mU*mU 518 190024-M8 Antisense strand (3'-5') dT*dT*mCfGmUfCmGfAmGmGmAmAmUmAmAfCmAmAmU*fA*mU 519 Sense strand (5'-3') mG*mC*mAmGmCmUfCfCfUmUmAmUmUmGmUmUmA*mU*mA 520 190024-M9 Antisense strand (3'-5') mU*mG*mUfCmUfCmAfAmUfAmGmCmUmCmCfGmAfGmU*fA*mA 521 Sense strand (5'-3') mA*mC*mAmGmAmGmUmUfAfUfCmGmAmGmGmCmUmCmA*mU*mU 522 190024-M10 Antisense strand (3'-5') mG*mU*mCfUmAfCmGfAmCfUmCmUmAmAmGfCmGfGmG*fA*mA 523 Sense strand (5'-3') mC*mA*mGmAmUmGmCmUfGfAfGmAmUmUmCmGmCmCmC*mU*mU 524 190024-M11 Antisense strand (3'-5') mG*mU*mCfUmAfCmGfAmCfUmCmUmAmAmGfCmGfGmG*fA*mAVP 525 Sense strand (5'-3') mC*mA*mGmAmUmGmCmUfGfAfGmAmUmUmCmGmCmCmC*mU*mU 526 190024-M12 Antisense strand (3'-5') mU*mG*mUfCmUfCmAfAmUfAmGmCmUmCmCfGmAfGmU*fA*mAVP 527 Sense strand (5'-3') mA*mC*mAmGmAmGmUmUfAfUfCmGmAmGmGmCmUmCmA*mU*mU 528

[0105] In Table 3, fA, fC, fU, and fG represent 2'-fluoro modified A, C, U, and G ribonucleoside-3'-phosphate, respectively, and mA, mC, mU, and mG represent 2'-O-methyl modified A, C, U, and G ribonucleoside-3'-phosphate, respectively; * represents a phosphorothioate bond, dT represents a thymidine deoxyribonucleoside-3'-phosphate, and VP represents a 5'-(E)-vinyl phosphate modified ribonucleotide.

[0106] In some embodiments, the antisense strand comprises any one of SEQ ID NO. 505, 507, 509, 511, 513, 515, 517, 519, 521, 523, 525 and 527.

[0107] In some embodiments, the sense strand comprises any one of the sense strands in Table 3.

[0108] In some embodiments, the sense strand comprises any one of SEQ ID NO. 506, 508, 510, 512, 514, 516, 518, 520, 522, 524, 526 and 528.

[0109] In some embodiments, the siRNA comprises any one of the siRNAs in Table 3.

[0110] In some embodiments, among the siRNAs:

[0111] The antisense strand comprises SEQ ID NO. 505, and the sense strand comprises SEQ ID NO. 506;

[0112] The antisense strand comprises SEQ ID NO. 507, and the sense strand comprises SEQ ID NO. 508;

[0113] The antisense strand comprises SEQ ID NO. 509, and the sense strand comprises SEQ ID NO. 510;

[0114] The antisense strand comprises SEQ ID NO. 511, and the sense strand comprises SEQ ID NO. 512;

[0115] The antisense strand comprises SEQ ID NO. 513, and the sense strand comprises SEQ ID NO. 514;

[0116] The antisense strand comprises SEQ ID NO. 515, and the sense strand comprises SEQ ID NO. 516;

[0117] The antisense strand comprises SEQ ID NO. 517, and the sense strand comprises SEQ ID NO. 518;

[0118] The antisense strand comprises SEQ ID NO. 519, and the sense strand comprises SEQ ID NO. 520;

[0119] The antisense strand comprises SEQ ID NO. 521, and the sense strand comprises SEQ ID NO. 522;

[0120] The antisense strand comprises SEQ ID NO. 523, and the sense strand comprises SEQ ID NO. 524;

[0121] The above antisense strand comprises SEQ ID NO. 525, and the above sense strand comprises SEQ ID NO. 526; or

[0122] The antisense strand includes SEQ ID NO.527, and the sense strand includes SEQ ID NO.528.

[0123] In some embodiments, the siRNA further comprises a targeting group.

[0124] In some embodiments, the targeting group comprises an asialoglycoprotein receptor ligand.

[0125] In some embodiments, the asialoglycoprotein receptor ligand comprises a galactose cluster.

[0126] In some embodiments, the galactose cluster is a monovalent, divalent, trivalent, or tetravalent galactose derivative.

[0127] In some embodiments, the galactose derivative is N-acetylgalactosamine (GalNAc).

[0128] In some embodiments, the galactose cluster is trivalent N-acetylgalactosamine.

[0129] In some embodiments, the galactose cluster is connected to a branch center through a linker, and the branch center is attached to a nucleotide of siRNA through a linker.

[0130] In some embodiments, the targeting device is connected to the 5' phase of the sense strand.

[0131] In some embodiments, the targeting device is connected to the 3' phase of the sense strand.

[0132] In some embodiments, the following fragment containing a targeting group is attached to the 5' end or 3' end of the sense strand (i.e., the following targeting group substitutes a hydroxyl group on the 5' end or 3' end).

[0133]

[0134]

[0135]

[0136]

[0137]

[0138]

[0139]

[0140]

[0141]

[0142] or

[0143] .

[0144] In some embodiments, the fragment including the targeting device is joined to the 5' end of the sense strand.

[0145] In some embodiments, the fragment including the targeting device is joined to the 3' end of the sense strand.

[0146] In some embodiments, the sense strand is any one of the sense strands in Table 4.

[0147] In some embodiments, the antisense strand is any one of the antisense strands in Table 4.

[0148] In some embodiments, the siRNA is any one of the siRNAs in Table 4.

[0149] siRNA names Sense strand (SS) and antisense strand (AS) order SEQ ID NO. JAB-190024-1 Antisense strand (3'-5') dT*dT*mCmGmUfCmGfAmGmGmAmAmUfAmAfCmAmAmU*fA*mU 529 Sense strand (5'-3') mG*mC*mAmGmCmUfCfCfUmUmAmUmUmGmUmUmAmU*mA*L96 530 JAB-190024-2 Antisense strand (3'-5') dT*dT*mCmGmUfCmGfAmGmGmAmAmUfAmAfCmAmAmU*fA*mUVP 531 Sense strand (5'-3') mG*mC*mAmGmCmUfCfCfUmUmAmUmUmGmUmUmAmU*mA*L96 532 JAB-190024-3 Antisense strand (3'-5') mG*mU*mCfUmAfCmGfAmCfUmCmUmAmAmGfCmGfGmG*fA*mA 533 Sense strand (5'-3') mC*mA*mGmAmUmGmCmUfGfAfGmAmUmUmCmGmCmCmCmU*mU*L96 534 JAB-190024-4 Antisense strand (3'-5') mG*mU*mCfUmAfCmGfAmCfUmCmUmAmAmGfCmGfGmG*fA*mAVP 535 Sense strand (5'-3') mC*mA*mGmAmUmGmCmUfGfAfGmAmUmUmCmGmCmCmCmU*mU*L96 536 JAB-190024-5 Antisense strand (3'-5') mU*mG*mUfCmUfCmAfAmUfAmGmCmUmCmCfGmAfGmU*fA*mA 537 Sense strand (5'-3') mA*mC*mAmGmAmGmUmUfAfUfCmGmAmGmGmCmUmCmAmU*mU*L96 538 JAB-190024-6 Antisense strand (3'-5') mU*mG*mUfCmUfCmAfAmUfAmGmCmUmCmCfGmAfGmU*fA*mAVP 539 Sense strand (5'-3') mA*mC*mAmGmAmGmUmUfAfUfCmGmAmGmGmCmUmCmAmU*mU*L96 540 Reference sequence 1 Sense strand (5'-3') mG*mC*mAmGmCmUfCmCfUfUfAmUmUmGmUmUmAmUmA*dT*dT 547 Antisense strand (5'-3') PmU*fA*mUfAmAfCmAfAmUfAmAfGmGfAmGfCmUfGmC*dT*dT 548 Reference sequence 2 Sense strand (5'-3') mU*mG*mGmCmAmGfCmUfCfCfUmUmAmUmUmGmUmUmAmUmA 549 Antisense strand (5'-3') mU*fA*mUmAmAfCmAmAmUmAmAmGmGfAmGfCmUmGmCmCmA*mC*mA 550 NAG25-AMG890 Sense strand (5'-3') NAG25*mC*mAmGmCmCmCmCmUfUfAfUmUmGmUmUmAmUmAmCmG*invdA 551 Antisense strand (5'-3') mU*fC*mGfUmAfUmAmAmCmAmAfUmAfAmGfGmGfGmC*fU*mG 552 GalNAC-SLN360 Sense strand (5'-3') [ST23*]3 / C6XLT*mCmGmGmUmAmAfUfGfGmAmCmAmGmAmGmUmU*mA*mU 553 Antisense strand (5'-3') mA*fU*mAfAmCfUmCfUmGfUmCfCmAfUmUfAmC*fC*mG 554

[0150] In Table 4, fA, fC, fU, and fG represent 2'-fluoro-modified A, C, U, and G ribonucleoside-3'-phosphate, respectively, and mA, mC, mU, and mG represent 2'-O-methyl-modified A, C, U, and G ribonucleoside-3'-phosphate, respectively; * represents a phosphorothioate bond, and if * is absent between two nucleotides, it indicates that they are connected via a normal phosphodiester bond; dT represents thymidine deoxyribonucleoside-3'-phosphate; P indicates that a single nucleotide adjacent to the right of the P is a 5'-phosphate modified nucleotide; invdA indicates an inverted deoxyribonucleotide (3'-3' linked nucleotide); NAG25-AMG890 is olpasiran and GalNAC-SLN360 is zerlasiran, among which NAG25 has a structure corresponding to [ST23*]3 / C6X; Reference Sequence 1 is modified via the method described in CN117327698A, Reference Sequence 2 is modified via the method described in CN116801886A, NAG25-AMG890 is modified via the method described in US9932586B, and GalNAC-SLN360 is modified via the method described in US11499153B. *L96 indicates the following:

[0151]

[0152] In some embodiments, all hydroxyl or thio groups on all phosphodiester or phosphorothioate bonds in the siRNA exist in the form of Na salts (i.e. , ).

[0153] In another aspect, the present invention provides a siRNA or a pharmaceutically acceptable salt thereof as described in the present invention, and a drug composition comprising the pharmaceutically acceptable salt.

[0154] In another aspect, the present invention provides a method for lowering the level of LPA expression in a subject, the method comprising administering to the subject the siRNA described in the present invention, a pharmaceutically acceptable salt thereof, or a drug composition described in the present invention.

[0155] In another aspect, the present invention provides the application of the siRNA described in the present invention, a pharmaceutically acceptable salt thereof, or the drug composition described in the present invention in the manufacture of a drug that prevents or treats diseases associated with LPA expression. In some embodiments, the diseases associated with LPA expression are cardiovascular diseases. In some embodiments, the cardiovascular diseases include stroke, atherosclerosis, thrombosis, coronary artery sclerosis or aortic valve stenosis, and other diseases or pathologies associated with elevated levels of Lp(a) particles.

[0156] In another aspect, the present invention provides a method for preventing or treating a disease associated with LPA expression, said method comprising administering to a subject the siRNA described in the present invention, a pharmaceutically acceptable salt thereof, or a drug composition described in the present invention. In some embodiments, the disease associated with LPA expression is a cardiovascular disease. In some embodiments, the cardiovascular disease includes stroke, atherosclerosis, thrombosis, coronary artery sclerosis or aortic valve stenosis, and other diseases or pathologies associated with elevated levels of Lp(a) particles.

[0157] In another aspect, the present invention provides the siRNA described in the present invention or a pharmaceutically acceptable salt thereof or a drug composition described in the present invention for preventing or treating diseases associated with LPA expression. In some embodiments, the diseases associated with LPA expression are cardiovascular diseases. In some embodiments, the cardiovascular diseases include stroke, atherosclerosis, thrombosis, coronary artery sclerosis or aortic valve stenosis, and other diseases or pathologies associated with elevated levels of Lp(a) particles.

[0158] Definition of Terms

[0159] The term siRNA (small interfering RNA) refers to short double-stranded RNA that mediates sequence-specific effective repression of gene expression (which may mean gene silencing).

[0160] The term "modified nucleotide" refers to a nucleotide excluding ribonucleotides (2'-hydroxynucleotides). In some embodiments, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% of the nucleotides are modified. Modified nucleotides include, but are not limited to, deoxynucleotides, nucleotide mimics, baseless nucleotides, 2'-modified nucleotides, 3'-to-3 linked (inverted) nucleotides, nucleotides containing non-natural bases, bridge nucleotides, peptide nucleic acids (PNA), 2',3'-seconucleotide mimics (unlocked nucleotide analogs), lock nucleotides, 3'-O-methoxy (2'-nucleotide linkage) nucleotides, 2'-F-arabinonucleotides, 5'-Me,2'-fluoronucleotides, morpholinonucleotides, deoxyribonucleotides containing vinylphosphonates, and nucleotides containing cyclopropylphosphonates (cPrpN). The 2'-modified nucleotides described in the present invention (i.e., nucleotides having a non-hydroxyl group at the 2' position of a pentagonal sugar ring) include, but are not limited to, 2'-O-methyl nucleotides, 2'-deoxy-2'-fluoronucleotides, 2'-deoxynucleotides, 2'-methoxyethyl(2'-O-2-methoxyethyl) nucleotides, 2'-amino nucleotides, and 2'-alkyl nucleotides. One or more modifications may be introduced within a single LPA siRNA or even within that single nucleotide. The sense strand and antisense strand of the LPA siRNA may be synthesized and / or modified through methods known in the art. In the present invention, the modification of one nucleotide is independent of the modification of another nucleotide. Modified nucleotides also include nucleotides having a modified nucleobase.

[0161] Locked nucleic acid (LNA) is a modified nucleotide in which a methylene bridge is inserted between the C4' and O2' of ribose.

[0162] Glycol nucleic acid (GNA) has a chiral acyclic 3-carbon main chain linked via phosphate and is the simplest phosphodiester-based nucleic acid analog.

[0163] The term “sequence” or “nucleotide sequence” refers to a series or a specific order of nucleobases, nucleotides, and / or nucleosides. Whether modified or not, they are described as a series of characters using standard nucleotide nomenclature and the symbol table for modified nucleotides described in the text.

[0164] The term "blunt end" refers to the end of a double-stranded siRNA in which the terminal nucleotides of the two annealed strands are complementary (forming complementary base pairs).

[0165] The term "frayed end" refers to the end of a double-stranded siRNA in which the terminal nucleotides of the two annealed strands form a pair (i.e., do not form an overhang) but are not complementary (i.e., form a non-complementary pair). In some embodiments, the sense strand 5' end and the antisense strand 3' end of the siRNA form a frayed end. In some embodiments, the sense strand 3' end and the antisense strand 5' end of the siRNA form a frayed end. In some embodiments, both ends of the siRNA form a frayed end. In some embodiments, neither end of the siRNA is a frayed end.

[0166] The term "overhang" refers to one or more unpaired nucleotide fragments located at one end of a double-stranded siRNA. Unpaired nucleotides may be on the sense strand or antisense strand to form a 3' or 5' overhang. In some embodiments, the siRNA comprises a smooth end and a phrased end, a smooth end and a 5' overhang end, a smooth end and a 3' overhang end, a phrased end and a 5' overhang end, a phrased end and a 3' overhang end, two 5' overhang ends, two 3' overhang ends, a 5' overhang end and a 3' overhang end, two phrased ends, or two smooth ends.

[0167] The term "extension" refers to 1, 2, 3, 4, 5, or 6 nucleotides at the 5' and / or 3' ends of the sense strand core sequence and / or the antisense strand core sequence. The nucleotide on the sense strand may or may not be complementary to the nucleotide (core sequence nucleotide or extended nucleotide) in the corresponding antisense strand. Conversely, the extended nucleotide on the antisense strand may or may not be complementary to the nucleotide (core sequence nucleotide or extended nucleotide) in the corresponding sense strand. In some embodiments, both the sense strand and the antisense strand of the siRNA comprise a 3' extension and a 5' extension. In some embodiments, the base of the 3' extension nucleotide of one strand is paired with the base of the 5' extension nucleotide of the other strand. In other embodiments, the bases of the 5' extended nucleotide of one strand are not paired with the bases of the 3' extended nucleotide of the other strand. In some embodiments, the LPA siRNA has a 3' extended antisense strand and a 5' extended sense strand.

[0168] The term “complementary” refers to the ability of a nucleotide containing the first nucleotide sequence to hybridize (form base pair hydrogen bonds) with a nucleotide containing the second nucleotide sequence under specific conditions to form a duplex or double helix structure when describing a first nucleotide sequence (e.g., siRNA antisense strand) to a second nucleotide sequence (e.g., siRNA sense strand or LPA mRNA). The complementary sequence may contain Watson-Crick base pairs or non-Watson-Crick base pairs, and may also contain natural or modified nucleotides or nucleotide mimics, provided that the requirement for the hybridization ability is satisfied.

[0169] The term "perfectly complementary" refers to the hybridization of all (100%) of the bases in the sequence of the first polynucleotide with the same number of bases in the sequence of the second polynucleotide.

[0170] The term “partially complementary” refers to a hybridized nucleobase sequence pair in which at least 70% (e.g., 70%, 75%, 80%, 85%, 90%, 95%, or 100%) of the sequence of the first polynucleotide is hybridized with the same number of bases in the sequence of the second polynucleotide.

[0171] The term “basically complementary” refers to a hybridized nucleobase sequence pair in which at least 85% (e.g., 85%, 90%, 95%, or 100%) of the sequence of the first polynucleotide is hybridized with the same number of bases in the sequence of the second polynucleotide.

[0172] The terms "complementary," "completely complementary," and "basically complementary" may be used in relation to base matching between the sense strand and antisense strand of siRNA or between the antisense strand of siRNA and the LPA mRNA sequence. Sequence identity or complementarity does not depend on modification. For the purpose of measuring identity or complementarity, for example, a and Af are complementary to U (or T) and identical to A.

[0173] The term "LPA" may refer to the LPA gene, LPA mRNA, or Lp(a) protein under appropriate circumstances.

[0174] The terms “silencing,” “reduction,” “inhibition,” “downregulation,” or “gene expression knockdown” in relation to the LPA gene refer to a reduction in gene expression (e.g., measured by the level of RNA transcribed from the gene or the level of a peptide, protein, or protein subunit translated from mRNA in the same cell, cell population, or tissue before administration of the LPA siRNA) when the cell, cell population, or tissue is treated with the LPA siRNA. In some embodiments, the LPA gene expression level and / or mRNA level of a subject administered the LPA siRNA is reduced by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 98% compared to a subject before administration of LPA siRNA or a subject not administered LPA siRNA. The gene expression level and / or mRNA level of the subject may be reduced in the subject's cells, cell populations, and / or tissues. In some embodiments, the LPA protein levels of subjects administered the LPA siRNA are reduced by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 98% compared to subjects prior to LPA siRNA administration or subjects not administered LPA siRNA. The protein levels of the subjects may be reduced in the subjects' cells, cell populations, tissues, blood, and / or other body fluids. A reduction in gene expression, mRNA, or protein levels may be evaluated by any method known in the art. A reduction or decrease in LPA mRNA levels and / or protein levels is collectively referred to herein as a reduction or decrease in LPA, or a suppression or reduction of LPA expression.

[0175] The term “targeting group” includes, but is not limited to, compounds having an affinity for cell surface molecules, cell receptor ligands, haptens, antibodies, monoclonal antibodies, antibody fragments, and antibody mimics having an affinity for cell surface molecules. The targeting group may have monovalent, divalent, trivalent, tetravalent, or more binding valencies. In some embodiments, the targeting group is linked to the siRNA using a linker such as a PEG linker or one, two, or three baseless and / or ribotol groups. In some embodiments, the targeting group comprises a galactose cluster. The LPA siRNA described herein having a reactive group (e.g., an amine group) at the 5’-terminus may be synthesized. The reactive group may subsequently be linked to the targeting site using methods conventional in the art. In some embodiments, the targeting group comprises an asialoglycoprotein receptor ligand. In some embodiments, the asialoglycoprotein receptor ligand comprises one or more galactose derivatives or galactose clusters, or is composed of one or more galactose derivatives or galactose clusters.

[0176] The term "galactose cluster" comprises a molecule having two to four terminal galactose derivatives. The terminal galactose derivatives are connected to the molecule through their C-1 carbon. In some embodiments, the galactose cluster is a galactose derivative trimer, a triantenary galactose derivative, or a trivalent galactose derivative. In some embodiments, the galactose cluster comprises N-acetylgalactosamine (GalNAc). In some embodiments, the galactose cluster comprises trivalent N-acetylgalactosamine. In some embodiments, the galactose cluster is a galactose derivative tetramer, a tetraantenary galactose derivative, or a tetravalent galactose derivative. In some embodiments, the galactose cluster comprises tetravalent N-acetylgalactosamine.

[0177] The term “galactose derivative” includes galactose and galactose derivatives having an affinity for asialoglycoprotein receptors (equal to or greater than the affinity of galactose). Galactose derivatives include, but are not limited to, galactose, galactosamine, N-formylgalactosamine, N-acetylgalactosamine, N-propionylgalactosamine, N-butyrylgalactosamine, and N-isobutyrylgalactosamine. Galactose derivatives and galactose clusters that can be used to target oligonucleotides and other molecules to the liver in the body are known in the art. Galactose derivatives have already been used to target molecules to hepatocytes by binding to asialoglycoprotein receptors (ASGPR) expressed on the surface of hepatocytes in the body. Binding of the ASGPR ligand to ASGPR promotes cell-specific targeting to hepatocytes and endocytizes the molecule into the hepatocytes. Galactose clusters can be attached to the 3' or 5' ends of siRNA polynucleotides using methods known in the art.

[0178] The term "galactose derivative trimer" comprises three galactose derivatives, each connected to a central branch point. In some embodiments, the galactose cluster is composed of a galactose derivative trimer, said galactose derivative trimer is an N-acetylgalactosamine trimer.

[0179] The term "galactose derivative tetramer" comprises four galactose derivatives each connected to a central branching point. In some embodiments, the galactose cluster is composed of a galactose derivative tetramer, said galactose derivative tetramer is an N-acetylgalactosamine tetramer.

[0180] The term "linker or spacer" refers to a group that connects a galactose derivative to a branching point or connects a branching point to siRNA.

[0181] The term "branching point" allows for the connection of several (e.g., three or four) galactose derivatives, and further allows the branching point to be connected to any small molecule of siRNA.

[0182] The term “linking group” refers to a linker or linking group that facilitates the covalent bonding of the LPA siRNA to a targeting group, a delivery polymer, or a delivery medium. The linking group may be connected to the 3’ or 5’ end of the sense strand or antisense strand of the siRNA. In some embodiments, the linking group is connected to the sense strand of the siRNA. In some embodiments, the linking group is attached to the 5’ or 3’ end of the siRNA sense strand. In some embodiments, the linking group is attached to the 5’ end of the siRNA sense strand.

[0183] Linkers or connecting groups are connections between two atoms that link one target chemical group (e.g., siRNA) or fragment to another target chemical group (e.g., targeting group or transfer polymer) or fragment through one or two covalent bonds. Unstable bonds include unstable bonds. Bonds may optionally include spacers that increase the distance between the two connecting atoms. Spacers may also increase the flexibility and / or length of the bond. Spacers include, but are not limited to, alkyl groups, alkenes, alkynes, aryl groups, arylalkyl groups, arylalkenes, and arylalkynes. Each of these may include one or more heteroatoms, heterocyclic groups, amino acids, nucleotides, and sugars. Spacer groups are well known in the art, and the foregoing list is not intended to limit the scope of this specification.

[0184] The term "delivery medium" refers to a substance that can be used to deliver siRNA to a cell or tissue. A delivery medium is a compound that improves the delivery of siRNA to a cell or tissue. In some embodiments, siRNA may be combined with lipids, nanoparticles, polymers, liposomes, micelles, or other delivery systems available in the art. Additionally, siRNA may be chemically bound to a targeting group, lipids (including but not limited to cholesterol and cholesterol derivatives), nanoparticles, polymers, liposomes, micelles, or other delivery systems available in the art. In some embodiments, LPA siRNA is linked to a targeting ligand comprising an asialoglycoprotein ligand. In some embodiments, LPA siRNA is linked to a targeting ligand comprising or composed of a galactose cluster.

[0185] The term “drug composition” comprises a pharmaceutically effective amount of at least one of the LPA siRNAs described in the present invention and one or more pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients are substances other than the active drug component (therapeutic substance such as API, LPA siRNA) intentionally included in the drug delivery system, which have undergone appropriate safety evaluation. The excipients do not exert or are not intended to exert a therapeutic effect at a given dose. The drug composition comprising the siRNA and the LPA siRNA disclosed herein may be packaged or contained in a kit, container, pack, or dispenser. The LPA siRNA and the drug composition comprising the LPA siRNA may be packaged in a pre-filled syringe or vial. Such drug compositions may be used to suppress the expression of LPA genes in cells, tissues, or organisms. In some embodiments, the drug composition is used to treat subjects suffering from diseases, disorders, or pathologies who may benefit from the reduction or suppression of LPA expression. In some embodiments, the drug composition is used to treat subjects at risk of developing a disease, condition, or pathology that may benefit from the reduction or inhibition of LPA expression. Diseases, conditions, or pathologies that may benefit from the reduction or inhibition of LPA expression include, but are not limited to, 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, cerebrovascular disease, mesenteric ischemia, suprasenteric artery occlusion, renal artery stenosis, stable / unstable angina pectoris, acute coronary syndrome, heterozygous or homozygous familial hypercholesterolemia, hyperlipoprotein β-lipoproteinemia, cerebrovascular atherosclerosis, cerebrovascular disease, and venous thrombosis. In some embodiments, the subjects are mammalian and include, but are not limited to, human patients.

[0186] siRNA is delivered to a cell, tissue, human organism, or non-human organism by any method available in the art. In some embodiments, the cell is a mammalian cell and includes, but is not limited to, a human cell. The cell, tissue, or non-human organism may be used for research or as a research tool (e.g., drug testing or diagnosis).

[0187] The LPA siRNA described in the text may be used to treat subjects who have a disease, condition, or pathology, or who are at risk of having such disease, condition, or pathology, who may benefit from the reduction or suppression of LPA expression. Treatment for subjects who may benefit from the reduction and / or suppression of LPA gene expression includes therapeutic and / or prophylactic treatment. Examples of diseases, conditions, or pathologies include, but are not limited to, 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, cerebrovascular disease, mesenteric ischemia, suprasenteric artery occlusion, renal artery stenosis, stable / unstable angina pectoris, acute coronary syndrome, heterozygous or homozygous familial hypercholesterolemia, hyperlipoprotein β-lipoproteinemia, cerebrovascular atherosclerosis, cerebrovascular disease, and venous thrombosis. In some embodiments, the present method comprises administering a composition, such as the drug composition containing LPA siRNA described in the text, to a mammal to be treated.

[0188] In some embodiments, a therapeutically effective amount of one or more of the above-mentioned LPA siRNAs is administered to a subject to suppress the expression of LPA in the subject (e.g., an amount that effectively suppresses LPA expression in the subject). In some embodiments, one or more of the above-mentioned LPA siRNAs described herein are used to treat a subject suffering from a disease or pathology who may benefit from the reduction or suppression of LPA expression. In some embodiments, the above-mentioned LPA siRNAs are used to treat or prevent at least one symptom of a subject suffering from a disease or pathology who may benefit from the reduction or suppression of LPA expression. The symptom is treated by administering any one or more of the above-mentioned siRNAs to the subject in a therapeutically effective amount. In some embodiments, at least one symptom is prevented by administering any one or more of the above-mentioned siRNAs to the subject in a preventively effective amount.

[0189] In some embodiments, LPA siRNA is used to treat or manage clinical symptoms, in which case one or more of the LPA siRNAs described herein or a composition containing LPA siRNA is administered to a subject requiring such treatment, prevention, or management in an effective amount for treatment or prevention. In some embodiments, the method comprises administering a composition containing LPA siRNA described herein to a mammal subject to treatment.

[0190] The route of administration is the route of contact of LPA siRNA with the body. In general, methods of administering drugs and nucleic acids to treat subjects are well known in the art and may be applied to the administration of the compositions described herein. The compounds described herein are formulations customized for specific routes and may be administered via any suitable route. Accordingly, the compounds described herein may be administered via injection, e.g., intravenous, intramuscular, intradermal, subcutaneous, or intraperitoneal administration. Brief explanation of the drawing

[0191] The features and advantages of the invention to which the present invention relates can be better understood by referring to the exemplary embodiments and drawings described in detail below. A brief description of the drawings is as follows: Figure 1 is a process diagram for synthesizing the LPA siRNA formulation of the present invention using solid-phase phosphoramide technology. Figure 2 is a diagram showing the effect of the RNA inhibitor of Table 7 prepared in Example 4 of the present invention on reducing Lp(a) levels in the serum of transgenic mice at various concentrations. Figure 3 is a diagram showing the effect of the RNA inhibitor of Table 8 prepared in Example 5 of the present invention on reducing Lp(a) levels in the serum of transgenic mice at various concentrations. Figure 4 is a diagram showing the effect of the RNA inhibitor of Table 9 prepared in Example 6 of the present invention on reducing the Lp(a) level in the serum of synomolgus monkeys. Specific details for implementing the invention

[0192] The present invention will be explained in more detail below through examples.

[0193] Example 1: Design and Synthesis of LPA siRNA

[0194] For the lipoprotein gene (transcript information: NM005577.4), the present invention designed a small interfering RNA (siRNA) as shown in Table 1. Here, the transcript information of the corresponding protein gene is listed in the NCBI database. The names in Table 1 represent the siRNA sequences targeting LPA mRNA and the sequences of their sense strands and antisense strands. Based on Table 1, Table 2 represents the siRNA and its sense strands and antisense strands with two dTs added to the 3' end of the sense strand and antisense strand. Subsequently, the present invention modified the above sequences, and the modified siRNA, its sense strand, and antisense strands are listed in Table 3. The modified siRNA, its sense strand, and antisense strands having a targeting group are listed in Table 4. The siRNA and its sense strand and antisense strand disclosed in the prior art are also listed in Table 4.

[0195] The LPA siRNA formulation of the present invention can be synthesized by adopting the conventional solid-phase phosphoramid technique shown in Fig. 1, and all reagents are commercially available. Briefly, the DMT protecting group is first removed using TCA, followed by washing with ACN, coupling, capping, oxidation / sulfurization, and ACN washing, and then cyclic coupling is performed. After synthesizing the target sequence, aminolysis is performed; the aminolysis conditions involve aminolysis using ammonia water at 40°C for 16 hours, followed by centrifugation and drying. Subsequently, the product is obtained through desalination or HPLC purification. For UPLC / TOF-MS detection and UV quantitative concentration measurement, 196 μL of water is added to 4 μL of the sample and placed in a UV plate. The concentration is measured using a microplate reader, and the nmol concentration is calculated. Annealing: Antisense strand:Sense strand = 1.05:1 molar ratio is mixed and annealed, then dispensed into 2.5 nmol x 2 (suitable centrifuge tubes), freeze-dried per tube to ensure a small solution volume, and sealed with aluminum foil during the freeze-drying period to obtain the final siRNA.

[0196] Example 2: Detection of LPA expression levels

[0197] The expression level of LPA was evaluated through a dual luciferase reporter gene experiment. First, to construct the psiCHECK2-LPA dual luciferase reporter gene plasmid, the full-length LPA sequence was inserted into the psiCHECK2-LPA vector. The LPA sequence was derived from Origene, and the psiCHECK2 vector from Promega. HUH7 cells were selected as the primary experimental material, seeded into 96-well plates, and incubated in a 37°C incubator for 2 hours to allow the cells to adhere to the walls. Subsequently, the LPA dual reporter gene plasmid was transduced into HUH7 cells using Fugene HD, and 5% CO₂ The cells were cultured overnight in a 37°C incubator. After culturing the cells for 16 hours, LPA-siRNA was transduced into HUH7 cells using RNAiMAX, and the cells were cultured for 24 hours. RNAiMAX is derived from Invitrogen. HUH7 cells were cultured under 5% CO2. After incubating for 24 hours in a 37°C incubator, the expression of Firefly luciferase and Renilla luciferase was measured using the Dual-Glo luciferase Assay System. The formulas for calculating the absolute and relative inhibition rates of LPA are as follows. Here, the sample refers to the group added with the target 0.3 nM siRNA, the internal control refers to the group without siRNA, and the control refers to the group added with 0.3 nM control siRNA.

[0198] LPA inhibition rate (%) = { 1 - [(average value of sample's Renilla lum. - background Renilla lum.) / (average value of sample's Firefly lum. - background Firefly lum.)] / [(average value of internal reference's Renilla lum. - background Renilla lum.) / (average value of internal reference's Firefly lum. - background Firefly lum.)]} Х 100%. At this time, the LPA inhibition rate of the control siRNA was 60.38%.

[0199] LPA Relative Inhibition Rate (%) = (LPA Inhibition Rate of Sample / LPA Inhibition Rate of Control) Х 100%.

[0200]

[0201] The results are as shown in Table 5.

[0202] siRNA names Relative inhibition rate siRNA names Relative inhibition rate 190024001dt 120% 190024064dt 48% 190024002dt 114% 190024065dt 48% 190024003dt 113% 190024066dt 47% 190024004dt 112% 190024067dt 47% 190024005dt 110% 190024068dt 47% 190024006dt 108% 190024069dt 47% 190024007dt 108% 190024070dt 46% 190024008dt 107% 190024071dt 45% 190024009dt 106% 190024072dt 45% 190024010dt 103% 190024073dt 45% 190024011dt 102% 190024074dt 44% 190024012dt 100% 190024075dt 42% 190024013dt 98% 190024076dt 42% 190024014dt 97% 190024077dt 41% 190024015dt 97% 190024078dt 41% 190024016dt 95% 190024079dt 39% 190024017dt 93% 190024080dt 39% 190024018dt 88% 190024081dt 39% 190024019dt 86% 190024082dt 39% 190024020dt 86% 190024083dt 38% 190024021dt 83% 190024084dt 38% 190024022dt 82% 190024085dt 38% 190024023dt 81% 190024086dt 37% 190024024dt 79% 190024087dt 37% 190024025dt 78% 190024088dt 37% 190024026dt 77% 190024089dt 36% 190024027dt 76% 190024090dt 34% 190024028dt 75% 190024091dt 33% 190024029dt 75% 190024092dt 33% 190024030dt 74% 190024093dt 33% 190024031dt 74% 190024094dt 33% 190024032dt 73% 190024095dt 33% 190024033dt 73% 190024096dt 32% 190024034dt 72% 190024097dt 31% 190024035dt 72% 190024098dt 31% 190024036dt 72% 190024099dt 30% 190024037dt 72% 190024100dt 28% 190024038dt 71% 190024101dt 28% 190024039dt 69% 190024102dt 27% 190024040dt 69% 190024103dt 26% 190024041dt 67% 190024104dt 25% 190024042dt 64% 190024105dt 24% 190024043dt 62% 190024106dt 24% 190024044dt 61% 190024107dt 23% 190024045dt 60% 190024108dt 23% 190024046dt 60% 190024109dt 23% 190024047dt 60% 190024110dt 22% 190024048dt 59% 190024111dt 20% 190024049dt 59% 190024112dt 19% 190024050dt 59% 190024113dt 18% 190024051dt 58% 190024114dt 17% 190024052dt 57% 190024115dt 16% 190024053dt 56% 190024116dt 14% 190024054dt 55% 190024117dt 14% 190024055dt 54% 190024118dt 14% 190024056dt 52% 190024119dt 14% 190024057dt 52% 190024120dt 14% 190024058dt 51% 190024121dt 13% 190024059dt 51% 190024122dt 13% 190024060dt 50% 190024123dt 7% 190024061dt 49% 190024124dt 1% 190024062dt 49% 190024125dt 0% 190024063dt 49%

[0203] Example 3: In vitro experiment of LPA RNAi preparations

[0204] The expression level of LPA was evaluated using a dual luciferase reporter gene assay. First, the psiCHECK2-LPA dual luciferase reporter gene plasmid was constructed, and the full-length human LPA sequence was inserted into the psiCHECK2 vector. The LPA sequence was derived from Origene, and the psiCHECK2 vector from Promega. 10,000 Hep3B cells were seeded into each well of a 96-well plate and incubated overnight in a 37°C incubator to allow the cells to adhere to the walls. The LPA reporter gene plasmid was transduced into the cells using 0.2 μL of FUGENEHD (Promega, E2311) per well. After incubating the cells for 6 hours, siRNA was transduced into the cells using 0.2 μL of LipoFectamine 2000 (Thermo, 11668-019) per well, and 5% CO₂ , cultured in a 37°C incubator for 24 hours. The expression levels of LPA were confirmed by measuring the expression of Firefly luciferase and Renilla luciferase using the Dual-Glo Luciferase Assay System (Promega E29440).

[0205] LPA inhibition rate (%) = {1 - [(Mean value of sample Renilla lum. - Background Renilla lum.) / (Mean value of sample Firefly lum. - Background Firefly lum.)] / [(Mean value of internal reference Renilla lum. - Background Renilla lum.) / (Mean value of internal reference Firefly lum. - Background Firefly lum.)]} × 100%. IC using the dose-response (variable slope) 4-parameter analysis method of GraphPad Prism software 50 The values ​​were calculated. The results are shown in Table 6 below.

[0206] Compd ID IC 50 (nM) Top inhibition (%) 190024-M1 0.77 54.88 190024-M8 0.41 78.01 190024-M2 0.23 83.84 190024-M5 0.10 85.84 190024-M3 0.25 71.19 190024-M4 0.14 79.35 190024-M7 0.40 78.04 190024-M9 0.50 78.61 190024-M12 0.31 84.45 190024-M10 0.86 65.72 190024-M11 0.47 75.66 NAG25-AMG890 0.41 79.97 Reference sequence 1 0.45 69.75 Reference sequence 2 >2.5 33.08

[0207] Example 4: In vivo testing of the efficacy of LPA RNAi preparations using transgenic mice

[0208] To evaluate the in vivo activity of the target siRNA, LPA humanized transgenic mice were used in this experiment to assess the in vivo activity of the target molecules. Transgenic mice were subcutaneously injected with 3 mg / kg of JAB-190024-1, JAB-190024-3, JAB-190024-5 and 1 mg / kg of JAB-190024-1, JAB-190024-3, JAB-190024-5, and SLN360 on day 0, while control mice were administered isovolume phosphate buffer (PBS). Mouse serum was collected before administration and on days 7, 14, 28, 42, and 56 after administration. Lp(a) levels in mouse serum were measured using a Human Lipoprotein(a) ELISA (Abcam ab212165) kit. The relative level of Lp(a) in the administration group was calculated by normalizing based on the Lp(a) level measured in the serum samples of the PBS-treated group. The results are shown in Table 7 and Figure 2.

[0209] Day 0 Day 7 Day 14 28th day Day 42 Day 56 Mean ± Standard Difference (%) Mean ± Standard Difference (%) Mean ± Standard Difference (%) Mean ± Standard Difference (%) Mean ± Standard Difference (%) Mean ± Standard Difference (%) PBS 100±50.4 100±35.3 100±46.5 100±54.8 100±41 100±41 GalNAC-SLN3601mg / kg 103.7±35.8 5.6±1.0 5.8±1.4 11.5±3.3 10.2±0.8 17.1±0.7 JAB-190024-13mg / kg 93.3±25.5 2.9±0.4 3.3±0.6 4.7±0.6 3.5±0.9 4.6±0.9 JAB-190024-11mg / kg 90.4±26.9 5.0±1.2 7.0±1.5 10.3±3.0 7.9±1.4 9.6±1.2 JAB-190024-33mg / kg 96.0±26.5 8.8±1.9 6.7±1.4 10.4±2.7 9.6±2.9 13.8±2.7 JAB-190024-31mg / kg 91.7±29.4 19.9±3.2 17.5±3.1 20.0±6.8 14.1±2.6 15.1±3.1 JAB-190024-53mg / kg 93.1±27.0 8.4±2.2 8.0±0.9 14.1±4.3 13.3±3.6 10.1±3.7 JAB-190024-51mg / kg 90.3±24.3 15.6±2.7 15.7±2.7 23.0±2.7 14.4±2.1 19.7±7.1

[0210] Example 5: In vivo testing of the efficacy of LPA RNAi preparations using transgenic mice

[0211] To evaluate the in vivo activity of the target siRNA, the in vivo activity of the target molecule was evaluated using LPA humanized transgenic mice in this experiment. On day 0, transgenic mice were subcutaneously injected with 1 mg / kg of AMG890, SLN360, JAB-190024-1, JAB-190024-2, JAB-190024-6, JAB-190024-4 and 0.3 mg / kg of JAB-190024-1, JAB-190024-2, JAB-190024-6, JAB-190024-4, while control mice were administered an equal volume of phosphate buffer (PBS). Mouse serum was collected on the day before administration (Day -1) and on days 7, 14, 28, 42, 56, and 84 after administration, and human Lp(a) levels in mouse serum were measured using Human Lipoprotein(a) ELISA (Abcam, ab212165). The relative Lp(a) levels of the administration group were calculated by normalizing based on the Lp(a) levels measured in the serum samples of the PBS-treated group. The results are shown in Table 8 and Figure 3.

[0212] Day 0 Day 7 Day 14 28th day Day 42 Day 56 Day 84 Mean ± Standard Difference (%) Mean ± Standard Difference (%) Mean ± Standard Difference (%) Mean ± Standard Difference (%) Mean ± Standard Difference (%) Mean ± Standard Difference (%) Mean ± Standard Difference (%) PBS 100±24.8 100±11.0 100±16.3 100±9.5 100±16.6 100±8.8 100±5.4 NAG25-AMG 8901 mg / kg 98.9±23.1 5.3±1.4 3.9±1.6 5.4±1.5 5.9±1.6 9.5±3.8 14.3±3.7 GalNAC-SLN3601mg / kg 100.8±25.3 3.7±0.5 3.0±0.4 5.4±0.4 7.3±0.7 10.6±1.6 17.6±2.1 JAB-190024-10.3mg / kg 98.5±16.5 8.4±3.0 6.9±1.9 9.0±2.2 10.2±3.0 11.0±4.0 14.5±4.9 JAB-190024-11mg / kg 98.1±21.2 2.6±0.3 2.8±0.6 4.6±1.3 6.2±3.4 7.3±2.4 8.7±2.9 JAB-190024-20.3mg / kg 97.8±18.5 7.1±2.3 5.9±1.4 6.4±0.8 7.1±2.0 11.3±7.6 12.0±2.7 JAB-190024-21mg / kg 97.3±23.9 2.8±0.5 2.7±0.5 3.8±0.9 5.1±1.4 5.5±1.0 7.5±1.9 JAB-190024-61mg / kg 94.2±12.7 6.4±1.7 5.2±2.1 7.2±2.6 6.7±2.1 8.3±2.3 12.6±1.8 JAB-190024-41mg / kg 94.9±15.5 10.4±4.6 8.9±4.6 11.6±4.3 9.4±2.7 11.7±3.6 14.8±3.7

[0213] Example 6: In vivo testing of the efficacy of LPA RNAi preparations using cynomolgus monkeys

[0214] To evaluate the in vivo activity of the target siRNA in large animals, this experiment used male cynomolgus monkeys (4–7 years of age, body weight 3–6 kg) to assess the in vivo activity of the target molecules. The cynomolgus monkeys were housed in an animal enclosure, and environmental conditions were maintained at a temperature of 18–26°C and a relative humidity of 40–70%. JAB-190024-1, JAB-190024-2, and JAB-190024-6 were subcutaneously injected into the cynomolgus monkeys at a dose of 1 mg / kg. Serum was collected before administration and on days 7, 14, and 21 after administration. 0.5 mL of the collected serum was dispensed into two EP tubes and stored in a -80°C freezer for subsequent Lp(a) level testing. Serum Lp(a) levels were measured using the Mercodia Lp(a) ELISA (Mercodia, 10-1106-01) kit. The relative Lp(a) levels of each group were calculated at each time point after administration by normalizing based on the serum Lp(a) levels of cynomolgus monkeys before administration. The results are shown in Table 9 and Figure 4.

[0215] Day 7, percentage of Lp(a) expression before administration Day 14, percentage of Lp(a) expression before administration Day 21, percentage of Lp(a) expression before administration medium medium medium JAB-190024-11mg / kg 28.3 25.1 15.4 JAB-190024-21mg / kg 26.8 19.6 12.2 JAB-190024-61mg / kg 45.3 37.3 22.8

[0216] Example 7

[0217] Experiments on the interaction between nucleic acids and proteins were performed using the GE Biacore T200 instrument and the Cytiva S series SA chip based on the surface plasmon resonance principle.

[0218] According to the supplier manual, biotinylated modified AS strand RNA ligands were coupled to the channel surface of the Sensor Chip SA chip (Cytiva, catalog number BR-1005-31) using a standard ligand nucleic acid coupling program, and the target coupling amount was set to 500 RU.

[0219] For kinetic measurements, recombinant human Argonaute-2 / AGO2 protein (His tag) (SinoBiological, catalog number 11079-H07B) was injected under 1X HBS-EP+ buffer conditions at 25°C with a contact time of 180 seconds and gradually increasing concentration at a flow rate of 30 μL / min, and the signal over time was monitored. Specifically, the sample solution was injected onto the chip surface at a flow rate of 30 μL / min for 180 seconds, allowed to naturally dissociate for 1200 seconds after each binding reaction, and then 0.5% SDS was injected as a regeneration reagent at a flow rate of 30 μL / min for 30 seconds to allow the signal to return to the baseline. Data were fitted using a 1:1 binding model, and the tested sequences and obtained results are shown in Table 10 and Table 11, respectively.

[0220] RNA 5'-3' JAB-1900242AS-biotin(SEQ ID NO.557) VpmU*fA*mUmAmAfCmAfAmUmAmAmGmGfAmGfCmUmGmC*dT*dT(biotin) Reference sequence 1-AS-biotin (SEQ ID NO.558) PmU*fA*mUfAmAfCmAfAmUfAmAfGmGfAmGfCmUfGmC*dT*dT(biotin) Reference sequence 2-AS-biotin (SEQ ID NO.559) mU*fA*mUmAmAfCmAmAmUmAmAmGmGfAmGfCmUmGmCmCmA*mC*mA(biotin) JAB-1900241AS-biotin(SEQ ID NO.560) mU*fA*mUmAmAfCmAfAmUmAmAmGmGfAmGfCmUmGmC*dT*dT(biotin)

[0221] RNA KD (M) JAB-1900242AS-biotin 8.556E-11　 Reference sequence 1-AS-biotin 6.370E-10 Reference sequence 2-AS-biotin 5.527E-10 JAB-1900241AS-biotin 3.644E-10

[0222] Although embodiments of the present invention have been presented and described above, it should be understood that such embodiments are illustrative and should not be construed as limiting the invention. Those skilled in the art may make changes, modifications, substitutions, and variations to the above embodiments within the scope of the invention.

Claims

Claim 1 siRNA or a pharmaceutically acceptable salt thereof, wherein the siRNA comprises a sense strand and an antisense strand, the antisense strand comprises a sequence complementary to an LPA mRNA sequence, and the sequence of the antisense strand comprises the sequence of any one of the antisense strands in Table 1. Claim 2 In claim 1, the length of the antisense strand is 19-26 nucleotides long, siRNA or a pharmaceutically acceptable salt thereof. Claim 3 In paragraph 2, the length of the antisense strand is 19-21 nucleotides long, siRNA or a pharmaceutically acceptable salt thereof. Claim 4 siRNA or a pharmaceutically acceptable salt thereof, wherein, in any one of claims 1 to 3, the sense strand comprises a sequence substantially complementary to the antisense strand and forms a duplex complementary region of 15 to 26 consecutive base pairs. Claim 5 In paragraph 4, the length of the duplex complementary region is 18 to 23 consecutive base pairs long, siRNA or a pharmaceutically acceptable salt thereof. Claim 6 In claim 5, the length of the duplex complementary region is 19 to 21 consecutive base pairs long, siRNA or a pharmaceutically acceptable salt thereof. Claim 7 siRNA or a pharmaceutically acceptable salt thereof, wherein, in any one of claims 1 to 6, the length of the sense strand is 19 to 26 nucleobases long. Claim 8 siRNA or a pharmaceutically acceptable salt thereof, wherein the length of the sense strand is 19-21 nucleobases long, in any one of claims 1 to 7. Claim 9 siRNA or a pharmaceutically acceptable salt thereof, wherein in any one of claims 1 to 8, the sequence of the sense strand comprises the sequence of any one of the sense strands in Table 1. Claim 10 In any one of claims 1 to 9, the antisense strand comprises any one of the sequences SEQ ID NO. 128-150, 253-254, siRNA or a pharmaceutically acceptable salt thereof. Claim 11 In any one of claims 1 to 10, the sense strand comprises a sequence of any one of SEQ ID NO. 1-23, 126-127, siRNA or a pharmaceutically acceptable salt thereof. Claim 12 In any one of claims 1 to 11, the siRNA comprises any one of the siRNAs in Table 1, or a pharmaceutically acceptable salt thereof. Claim 13 In any one of claims 1 to 12, among the siRNA: the antisense strand comprises SEQ ID NO. 128, and the sense strand comprises SEQ ID NO. 1; the antisense strand comprises SEQ ID NO. 129, and the sense strand comprises SEQ ID NO. 2; the antisense strand comprises SEQ ID NO. 130, and the sense strand comprises SEQ ID NO. 3; the antisense strand comprises SEQ ID NO. 131, and the sense strand comprises SEQ ID NO. 4; the antisense strand comprises SEQ ID NO. 132, and the sense strand comprises SEQ ID NO. 5; the antisense strand comprises SEQ ID NO. 133, and the sense strand comprises SEQ ID NO. 6; the antisense strand comprises SEQ ID NO. 134, and the sense strand comprises SEQ ID NO. Including 7; the antisense strand includes SEQ ID NO. 135, and the sense strand includes SEQ ID NO. 8; the antisense strand includes SEQ ID NO. 136, and the sense strand includes SEQ ID NO. 9; the antisense strand includes SEQ ID NO. 137, and the sense strand includes SEQ ID NO. 10; the antisense strand includes SEQ ID NO. 138, and the sense strand includes SEQ ID NO. 11; the antisense strand includes SEQ ID NO. 139, and the sense strand includes SEQ ID NO. 12; the antisense strand includes SEQ ID NO. 140, and the sense strand includes SEQ ID NO. 13; the antisense strand includes SEQ ID NO. 141, and the sense strand includes SEQ ID NO. Includes 14; said antisense strand includes SEQ ID NO. 142, and said sense strand includes SEQ ID NO.Including 15; said antisense strand including SEQ ID NO. 143, and said sense strand including SEQ ID NO. 16; said antisense strand including SEQ ID NO. 144, and said sense strand including SEQ ID NO. 17; said antisense strand including SEQ ID NO. 145, and said sense strand including SEQ ID NO. 18; said antisense strand including SEQ ID NO. 146, and said sense strand including SEQ ID NO. 19; said antisense strand including SEQ ID NO. 147, and said sense strand including SEQ ID NO. 20; said antisense strand including SEQ ID NO. 148, and said sense strand including SEQ ID NO. 21; said antisense strand including SEQ ID NO. 149, and said sense strand including SEQ ID NO. 22; siRNA or a pharmaceutically acceptable salt thereof, wherein the antisense strand comprises SEQ ID NO. 150 and the sense strand comprises SEQ ID NO. 23; the antisense strand comprises SEQ ID NO. 253 and the sense strand comprises SEQ ID NO. 126, or the antisense strand comprises SEQ ID NO. 254 and the sense strand comprises SEQ ID NO.

127. Claim 14 In any one of claims 1 to 13, the antisense strand or sense strand is siRNA or a pharmaceutically acceptable salt thereof containing 1, 2, 3, 4, 5, or 6 extensions. Claim 15 siRNA or a pharmaceutically acceptable salt thereof, wherein, in any one of claims 1 to 14, the extension of the antisense strand or sense strand is dT. Claim 16 In any one of claims 1 to 15, the antisense strand or sense strand is siRNA or a pharmaceutically acceptable salt thereof containing two dT extensions. Claim 17 In any one of claims 1 to 15, the 3' end of the antisense strand contains two dT extensions, and the sense strand is a siRNA or a pharmaceutically acceptable salt thereof that does not contain dT. Claim 18 In any one of claims 1 to 17, the antisense strand comprises the sequence of any one of the antisense strands in Table 2, siRNA or a pharmaceutically acceptable salt thereof. Claim 19 In any one of claims 1 to 18, the antisense strand comprises a sequence of any one of SEQ ID NO. 380-402, 544-546, siRNA or a pharmaceutically acceptable salt thereof. Claim 20 In any one of claims 1 to 17, the sense strand comprises a sequence of any one of the sense strands in Table 2, siRNA or a pharmaceutically acceptable salt thereof. Claim 21 In any one of claims 1 to 20, the sense strand comprises a sequence of any one of SEQ ID NO. 255-277, 541-543, siRNA or a pharmaceutically acceptable salt thereof. Claim 22 In any one of claims 1 to 21, the siRNA comprises any one of the siRNAs in Table 2, or a pharmaceutically acceptable salt thereof. Claim 23 In any one of claims 1 to 22, among the siRNA: the antisense strand comprises SEQ ID NO. 380, and the sense strand comprises SEQ ID NO. 255; the antisense strand comprises SEQ ID NO. 381, and the sense strand comprises SEQ ID NO. 256; the antisense strand comprises SEQ ID NO. 382, ​​and the sense strand comprises SEQ ID NO. 257; the antisense strand comprises SEQ ID NO. 383, and the sense strand comprises SEQ ID NO. 258; the antisense strand comprises SEQ ID NO. 384, and the sense strand comprises SEQ ID NO. 259; the antisense strand comprises SEQ ID NO. 385, and the sense strand comprises SEQ ID NO. Includes 260; said antisense strand includes SEQ ID NO. 386, and said sense strand includes SEQ ID NO. 261; said antisense strand includes SEQ ID NO. 387, and said sense strand includes SEQ ID NO. 262; said antisense strand includes SEQ ID NO. 388, and said sense strand includes SEQ ID NO. 263; said antisense strand includes SEQ ID NO. 389, and said sense strand includes SEQ ID NO. Includes 264; said antisense strand includes SEQ ID NO. 390, and said sense strand includes SEQ ID NO. 265; said antisense strand includes SEQ ID NO. 391, and said sense strand includes SEQ ID NO. 266; said antisense strand includes SEQ ID NO. 392, and said sense strand includes SEQ ID NO. 267; said antisense strand includes SEQ ID NO. 393, and said sense strand includes SEQ ID NO. 268; said antisense strand includes SEQ ID NO.Includes 394, and the sense strand includes SEQ ID NO. 269; the antisense strand includes SEQ ID NO. 395, and the sense strand includes SEQ ID NO. 270; the antisense strand includes SEQ ID NO. 396, and the sense strand includes SEQ ID NO. 271; the antisense strand includes SEQ ID NO. 397, and the sense strand includes SEQ ID NO. 272; the antisense strand includes SEQ ID NO. 398, and the sense strand includes SEQ ID NO. 273; the antisense strand includes SEQ ID NO. 399, and the sense strand includes SEQ ID NO. 274; the antisense strand includes SEQ ID NO. 400, and the sense strand includes SEQ ID NO. siRNA or a pharmaceutically acceptable salt thereof, comprising 275; said antisense strand comprising SEQ ID NO. 401, and said sense strand comprising SEQ ID NO. 276; said antisense strand comprising SEQ ID NO. 402, and said sense strand comprising SEQ ID NO. 277; said antisense strand comprising SEQ ID NO. 541, and said sense strand comprising SEQ ID NO. 544; said antisense strand comprising SEQ ID NO. 542, and said sense strand comprising SEQ ID NO. 545; or said antisense strand comprising SEQ ID NO. 543, and said sense strand comprising SEQ ID NO.

546. Claim 24 In any one of claims 1 to 23, the sense strand and / or antisense strand independently comprise one or more modified nucleotides, siRNA or a pharmaceutically acceptable salt thereof. Claim 25 In any one of claims 1 to 24, the modified nucleotide is a 2'-modified nucleotide, siRNA or a pharmaceutically acceptable salt thereof. Claim 26 In any one of claims 1 to 25, the modified nucleotide comprises 2'-O-methyl modified nucleotide, 2'-O-methoxyethyl modified nucleotide, 2'-fluoro modified nucleotide, 2'-deoxy modified nucleotide, 2'-O-alkenyl modified nucleotide, lock nucleotide, GNA, LNA, baseless nucleotide, deoxythymidine, reverse deoxythymidine, deoxyadenosine, reverse deoxyadenosine, 2'-amino-modified nucleotide, 2'-alkyl-modified nucleotide, morpholino nucleotide, nucleotide containing a non-natural base, 5'-(E)-vinylphosphonate modified nucleotide, or a combination thereof, siRNA or a pharmaceutically acceptable salt thereof. Claim 27 siRNA or a pharmaceutically acceptable salt thereof, wherein, in any one of claims 1 to 26, the nucleotides are all modified nucleotides. Claim 28 siRNA or a pharmaceutically acceptable salt thereof, wherein the modified nucleotide comprises a 2'-O-methyl modified nucleotide, a -2'-fluoro modified nucleotide, a deoxythymidine and a 5'-(E)-vinylphosphonate modified nucleotide, or a combination thereof. Claim 29 siRNA or a pharmaceutically acceptable salt thereof, wherein the sense strand, antisense strand, or sense strand and antisense strand comprises one or more phosphorothioate or phosphorodithioate internucleoside bonds. Claim 30 In claim 29, the antisense strand comprises two consecutive phosphorothioate internucleoside bonds between 3'- and 5'-terminal nucleotides, siRNA or a pharmaceutically acceptable salt thereof. Claim 31 In claim 29 or 30, the sense strand comprises two consecutive phosphorothioate internucleoside bonds between 3'- and 5'-terminal nucleotides, siRNA or a pharmaceutically acceptable salt thereof. Claim 32 siRNA or a pharmaceutically acceptable salt thereof, wherein, in claim 29 or 30, it comprises two consecutive phosphorothioate internucleoside bonds between the 5'-terminal nucleotides of the sense strand and one phosphorothioate internucleoside bond between the 3'-terminal nucleotides of the sense strand. Claim 33 siRNA or a pharmaceutically acceptable salt thereof, wherein the siRNA comprises two consecutive phosphorothioate internucleoside bonds between the 5'-terminal nucleotides of the sense strand and one phosphorothioate internucleoside bond between the 3'-terminal nucleotides of the sense strand; and the antisense strand comprises two consecutive phosphorothioate internucleoside bonds between the 3'-terminal and 5'-terminal nucleotides. Claim 34 In any one of claims 1 to 33, 1) the sense strand comprises 21 nucleotides and the antisense strand comprises 23 nucleotides, the length of the duplex complementary region is 21 base pairs, the nucleotides at positions 9, 10, and 11 from the 5' end of the sense strand are all 2'-fluoro-modified nucleotides, and the remaining nucleotides of the sense strand are all 2'-O-methyl-modified nucleotides; and the nucleotides at positions 8, 10, 18, and 22 from the 3' end of the antisense strand are all 2'-fluoro-modified nucleotides, and the remaining nucleotides of the antisense strand are all 2'-O-methyl-modified nucleotides; The nucleotides between the 5' end of the sense strand and positions 1 through 3, the nucleotides between the 3' end of the sense strand and positions 1 through 3, the nucleotides between the 5' end of the antisense strand and positions 1 through 3, and the nucleotides between the 3' end of the antisense strand and positions 1 through 3 are all connected via phosphothioate bonds, and the remaining nucleotides of the sense strand and the antisense strand are all connected via phosphodiester bonds; 2) the sense strand comprises 19 nucleotides, the antisense strand comprises 21 nucleotides, the length of the duplex complementary region is 19 base pairs, the nucleotides at positions 7, 8, and 9 from the 5' end of the sense strand are all 2'-fluoro-modified nucleotides, and the remaining nucleotides of the sense strand are all It is a 2'-O-methyl modified nucleotide; the first and second positions from the 3' end of the antisense strand are two dTs, the nucleotides at positions 6, 8, 14, 16, and 20 from the 3' end of the antisense strand are all 2'-fluoro modified nucleotides, and the remaining nucleotides of the antisense strand are all 2'-O-methyl modified nucleotides;The nucleotides between the 5' end of the sense strand and positions 1 through 3, the nucleotides between the 3' end of the sense strand and positions 1 through 3, the nucleotides between the 5' end of the antisense strand and positions 1 through 3, and the nucleotides between the 3' end of the antisense strand and positions 1 through 3 are all connected via phosphothioate bonds, and the remaining nucleotides of the sense strand and the antisense strand are all connected via phosphodiester bonds; 3) The sense strand comprises 19 nucleotides, the antisense strand comprises 21 nucleotides, the length of the duplex complementary region is 19 base pairs, the nucleotides at positions 7, 8, and 9 from the 5' end of the sense strand are all 2'-fluoro-modified nucleotides, and the remaining nucleotides of the sense strand are all 2'-O-methyl-modified nucleotides; the first and second positions from the 3' end of the antisense strand are two dTs, the nucleotides at positions 4, 6, 8, 16, and 20 from the 3' end of the antisense strand are all 2'-fluoro-modified nucleotides, and the remaining nucleotides of the antisense strand are all 2'-O-methyl-modified nucleotides; The nucleotides between the 5' end of the sense strand and positions 1 through 3, the nucleotides between the 3' end of the sense strand and positions 1 through 3, the nucleotides between the 5' end of the antisense strand and positions 1 through 3, and the nucleotides between the 3' end of the antisense strand and positions 1 through 3 are all connected via phosphothioate bonds, and the remaining nucleotides of the sense strand and the antisense strand are all connected via phosphodiester bonds;4) The sense strand comprises 21 nucleotides, the antisense strand comprises 21 nucleotides, the length of the duplex complementary region is 21 base pairs, the nucleotides at positions 9, 10, and 11 from the 5' end of the sense strand are all 2'-fluoro-modified nucleotides, and the remaining nucleotides of the sense strand are all 2'-O-methyl-modified nucleotides; the nucleotides at positions 3 through 4, 6, 8, 10, 16, 18, and 20 from the 3' end of the antisense strand are all 2'-fluoro-modified nucleotides, and the remaining nucleotides of the antisense strand are all 2'-O-methyl-modified nucleotides; The nucleotides between the 5' end of the sense strand and positions 1 through 3, the nucleotides between the 3' end of the sense strand and positions 1 through 3, the nucleotides between the 5' end of the antisense strand and positions 1 through 3, and the nucleotides between the 3' end of the antisense strand and positions 1 through 3 are all connected via phosphothioate bonds, and the remaining nucleotides of the sense strand and the antisense strand are all connected via phosphodiester bonds; 5) The sense strand comprises 21 nucleotides, the antisense strand comprises 21 nucleotides, the length of the duplex complementary region is 21 base pairs, the nucleotides at positions 9, 10, and 11 from the 5' end of the sense strand are all 2'-fluoro modified nucleotides, and the remaining nucleotides of the sense strand are all 2'-O-methyl modified nucleotides;The nucleotides at positions 3 through 4, 6, 8, 10, 16, 18, and 20 from the 3' end of the antisense strand are all 2'-fluoro modified nucleotides, the remaining nucleotides of the antisense strand are all 2'-O-methyl modified nucleotides, and the nucleotide at position 1 of the 5' end of the antisense strand is VP modified; the nucleotides between positions 1 through 3 from the 5' end of the sense strand, the nucleotides between positions 1 through 3 from the 3' end of the sense strand, the nucleotides between positions 1 through 3 from the 5' end of the antisense strand, and the nucleotides between positions 1 through 3 from the 3' end of the antisense strand are all connected via phosphorothioate bonds, and the remaining nucleotides between the sense strand and the antisense strand are all connected via phosphodiester bonds; 6) The sense strand comprises 19 nucleotides, the antisense strand comprises 21 nucleotides, the length of the duplex complementary region is 19 base pairs, the nucleotides at positions 7, 8, and 9 from the 5' end of the sense strand are all 2'-fluoro-modified nucleotides, and the remaining nucleotides of the sense strand are all 2'-O-methyl-modified nucleotides; the 1st and 2nd positions from the 3' end of the antisense strand are two dTs, the nucleotides at positions 6, 8, 14, 16, and 20 from the 3' end of the antisense strand are all 2'-fluoro-modified nucleotides, the remaining nucleotides of the antisense strand are all 2'-O-methyl-modified nucleotides, and the nucleotide at position 1 of the 5' end of the antisense strand is VP-modified;The nucleotides between the 5' end of the sense strand and positions 1 through 3, the nucleotides between the 3' end of the sense strand and positions 1 through 3, the nucleotides between the 5' end of the antisense strand and positions 1 through 3, and the nucleotides between the 3' end of the antisense strand and positions 1 through 3 are all connected via phosphothioate bonds, and the remaining nucleotides of the sense strand and the antisense strand are all connected via phosphodiester bonds; 7) The sense strand comprises 19 nucleotides, the antisense strand comprises 21 nucleotides, the length of the duplex complementary region is 19 base pairs, the nucleotides at positions 7, 8, and 9 from the 5' end of the sense strand are all 2'-fluoro-modified nucleotides, and the remaining nucleotides of the sense strand are all 2'-O-methyl-modified nucleotides; the first and second positions from the 3' end of the antisense strand are two dTs, the nucleotides at positions 6, 8, 14, 16, and 20 from the 3' end of the antisense strand are all 2'-fluoro-modified nucleotides, and the remaining nucleotides of the antisense strand are all 2'-O-methyl-modified nucleotides; The nucleotides between the 5' end of the sense strand and positions 1 through 3, the nucleotides between the 3' end of the sense strand and positions 1 through 2, the nucleotides between the 5' end of the antisense strand and positions 1 through 3, and the nucleotides between the 3' end of the antisense strand and positions 1 through 3 are all connected via phosphothioate bonds, and the remaining nucleotides of the sense strand and the antisense strand are all connected via phosphodiester bonds;or 8) the sense strand comprises 19 nucleotides and the antisense strand comprises 21 nucleotides, the length of the duplex complementary region is 19 base pairs, the nucleotides at positions 7, 8, and 9 from the 5' end of the sense strand are all 2'-fluoro modified nucleotides, and the remaining nucleotides of the sense strand are all 2'-O-methyl modified nucleotides; the 1st and 2nd positions from the 3' end of the antisense strand are two dTs, the nucleotides at positions 6, 8, 14, 16, and 20 from the 3' end of the antisense strand are all 2'-fluoro modified nucleotides, the remaining nucleotides of the antisense strand are all 2'-O-methyl modified nucleotides, and the nucleotide at position 1 of the 5' end of the antisense strand is VP modified; siRNA or a pharmaceutically acceptable salt thereof, wherein the nucleotides between the 5' end of the sense strand and positions 1 through 3, the nucleotides between the 3' end of the sense strand and positions 1 through 2, the nucleotides between the 5' end of the antisense strand and positions 1 through 3, and the nucleotides between the 3' end of the antisense strand and positions 1 through 3 are all connected via phosphothioate bonds, and the remaining nucleotides of the sense strand and the antisense strand are all connected via phosphodiester bonds. Claim 35 In any one of claims 1 to 34, the antisense strand comprises an antisense strand of any one of Table 3, siRNA or a pharmaceutically acceptable salt thereof. Claim 36 siRNA or a pharmaceutically acceptable salt thereof, wherein in any one of claims 1 to 35, the antisense strand comprises any one of SEQ ID NO. 505, 507, 509, 511, 513, 515, 517, 519, 521, 523, 525 and 527 antisense strand. Claim 37 In any one of claims 1 to 36, the sense strand comprises any one of the sense strands in Table 3, siRNA or a pharmaceutically acceptable salt thereof. Claim 38 siRNA or a pharmaceutically acceptable salt thereof, wherein in any one of claims 1 to 37, the sense strand comprises any one of SEQ ID NO. 506, 508, 510, 512, 514, 516, 518, 520, 522, 524, 526 and 528 sense strand. Claim 39 In any one of claims 1 to 38, the siRNA comprises any one of the siRNAs in Table 3, or a pharmaceutically acceptable salt thereof. Claim 40 In any one of claims 1 to 39, among the siRNA: the antisense strand comprises SEQ ID NO. 505, and the sense strand comprises SEQ ID NO. 506; the antisense strand comprises SEQ ID NO. 507, and the sense strand comprises SEQ ID NO. 508; the antisense strand comprises SEQ ID NO. 509, and the sense strand comprises SEQ ID NO. 510; the antisense strand comprises SEQ ID NO. 511, and the sense strand comprises SEQ ID NO. 512; the antisense strand comprises SEQ ID NO. 513, and the sense strand comprises SEQ ID NO. 514; the antisense strand comprises SEQ ID NO. 515, and the sense strand comprises SEQ ID NO. 516; the antisense strand comprises SEQ ID NO. 517, and the sense A strand comprising SEQ ID NO. 518; said antisense strand comprising SEQ ID NO. 519, and said sense strand comprising SEQ ID NO. 520; said antisense strand comprising SEQ ID NO. 521, and said sense strand comprising SEQ ID NO. 522; said antisense strand comprising SEQ ID NO. 523, and said sense strand comprising SEQ ID NO. 524; said antisense strand comprising SEQ ID NO. 525, and said sense strand comprising SEQ ID NO. 526; or said antisense strand comprising SEQ ID NO. 527, and said sense strand comprising SEQ ID NO. 528, siRNA or a pharmaceutically acceptable salt thereof. Claim 41 In any one of claims 1 to 40, the siRNA is a siRNA or a pharmaceutically acceptable salt thereof that further comprises a targeting group. Claim 42 In claim 41, the targeting group comprises an asialoglycoprotein receptor ligand, siRNA, or a pharmaceutically acceptable salt thereof. Claim 43 In paragraph 42, the asialoglycoprotein receptor ligand is siRNA or a pharmaceutically acceptable salt thereof comprising a galactose cluster. Claim 44 In paragraph 43, the galactose cluster is a siRNA or a pharmaceutically acceptable salt thereof that is a monovalent, divalent, trivalent, or tetravalent galactose derivative. Claim 45 In paragraph 44, the galactose derivative is siRNA or a pharmaceutically acceptable salt thereof, which is N-acetylgalactosamine (GalNAc). Claim 46 In paragraph 45, the galactose cluster is siRNA or a pharmaceutically acceptable salt thereof which is trivalent N-acetylgalactosamine. Claim 47 siRNA or a pharmaceutically acceptable salt thereof, wherein in any one of claims 1 to 46, the galactose cluster is connected to a branch center through a linker, and the branch center is conjugated to a nucleotide of siRNA through a linker. Claim 48 In any one of claims 1 to 47, the targeting group is siRNA or a pharmaceutically acceptable salt thereof that is conjugated to the 5' phase of the sense strand. Claim 49 In any one of claims 1 to 47, the targeting group is siRNA or a pharmaceutically acceptable salt thereof that is conjugated to the 3' phase of the sense strand. Claim 50 In any one of claims 1 to 47, the following fragment comprising a targeting group is siRNA or a pharmaceutically acceptable salt thereof that is conjugated to the 5' end or 3' end of a sense strand: or Claim 51 In paragraph 50, the fragment containing the targeting group is siRNA or a pharmaceutically acceptable salt thereof conjugated to the 5' end of the sense strand. Claim 52 In paragraph 51, the fragment containing the targeting group is siRNA or a pharmaceutically acceptable salt thereof conjugated to the 3' end of the sense strand. Claim 53 In any one of claims 1 to 52, the siRNA comprises any one of the siRNAs in Table 4, or a pharmaceutically acceptable salt thereof. Claim 54 In paragraph 53, the sense strand is siRNA or a pharmaceutically acceptable salt thereof, which is any one of the sense strands in Table 4. Claim 55 In paragraph 53, the antisense strand is siRNA or a pharmaceutically acceptable salt thereof, which is an antisense strand of any one of Table 4. Claim 56 A drug composition comprising siRNA or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 55, and a pharmaceutically acceptable salt thereof. Claim 57 A method for lowering the LPA expression level in a subject, wherein the method comprises administering to the subject siRNA according to any one of claims 1 to 55, a pharmaceutically acceptable salt thereof, or a drug composition according to claim 56. Claim 58 The application of siRNA according to any one of claims 1 to 55 or a pharmaceutically acceptable salt thereof or a drug composition according to claim 56 in the manufacture of a drug for preventing or treating diseases associated with LPA expression. Claim 59 In paragraph 58, the disease associated with the above LPA expression is a cardiovascular disease, application. Claim 60 In paragraph 59, the above cardiovascular disease includes stroke, atherosclerosis, thrombosis, coronary artery sclerosis or aortic valve stenosis, and other diseases or pathologies associated with elevated levels of Lp(a) particles. Claim 61 A method for the prevention or treatment of a disease associated with LPA expression, wherein the method comprises administering to a subject siRNA according to any one of claims 1 to 55, a pharmaceutically acceptable salt thereof, or a drug composition according to claim 56. Claim 62 In paragraph 61, the disease associated with the above LPA expression is a cardiovascular disease. Claim 63 In paragraph 62, the above cardiovascular disease includes stroke, atherosclerosis, thrombosis, coronary artery sclerosis or aortic valve stenosis, and other diseases or pathologies associated with elevated levels of Lp(a) particles. Claim 64 siRNA according to any one of claims 1 to 55 or a pharmaceutically acceptable salt thereof or a drug composition according to claim 56 for preventing or treating diseases associated with LPA expression. Claim 65 In Clause 64, the disease associated with the above LPA expression is a cardiovascular disease, application. Claim 66 In paragraph 65, the above cardiovascular disease includes stroke, atherosclerosis, thrombosis, coronary artery stenosis or aortic valve stenosis, and other diseases or pathologies associated with elevated levels of Lp(a) particles.

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