Sirna for inhibiting angiotensinogen expression and use thereof

Abstract

The present invention relates to a series of siRNA duplex molecules targeting angiotensinogen (AGT) mRNA, an siRNA-GalNAc delivery vector conjugate, and an application thereof. After an siRNA duplex molecule is delivered to a cell where an AGT mRNA target gene is being expressed, said molecule can perform effective silencing on the cell, thereby treating a disease caused by AGT.

Description

siRNA for inhibiting angiotensinogen expression and its use

[0001] The present invention claims priority to the Chinese patent application filed with the Patent Office of China on November 15, 2023, with application number 202311521272.1 and invention name “siRNA for inhibiting angiotensinogen expression and its use”, the entire contents of which are incorporated by reference into the application. Technical Field

[0002] The present invention belongs to the field of biomedicine technology, and specifically, the present invention relates to an siRNA for inhibiting angiotensinogen expression and its use. More specifically, the present invention relates to an siRNA duplex, an siRNA-delivery vector conjugate (GalNAc-siRNA), a pharmaceutical composition and its use. Background Art

[0003] Hypertension (hypertension) is a common cardiovascular disease that can cause damage to the heart, kidneys, brain, and other organs, leading to disability and even death. The World Health Organization (WHO) estimates that one billion people worldwide suffer from hypertension. The main treatments for hypertension include medication, lifestyle changes, and surgery. However, many patients do not receive effective treatment, and some suffer from side effects from medications. Therefore, new and more effective approaches to treat hypertension are needed.

[0004] Currently, the main way to control hypertension is through antihypertensive drugs. Currently, the drugs used to treat hypertension mainly include the following categories: (1) Diuretics: Diuretics reduce blood volume and blood pressure by affecting the renal reabsorption of sodium and water. Commonly used diuretics include loop diuretics (such as furosemide) and thiazide diuretics (such as hydrochlorothiazide). (2) ACEI (Angiotensin-Converting Enzyme Inhibitors): The function of ACEI is to inhibit the activation of the RAAS system, reduce the production of angiotensin II, and thus lower blood pressure. Common ACEIs include captopril and eplerenone. (3) ARB (Angiotensin Receptor Blockers): ARB is an angiotensin II receptor antagonist that blocks the binding of angiotensin II to its receptor, reduces vasoconstriction, and achieves the effect of lowering blood pressure. Commonly used ARBs include valsartan and irbesartan. (4) CCB (Calcium Channel Blockers): CCB blocks calcium channels on the cell membrane to reduce the concentration of calcium ions in vascular smooth muscle cells, relax blood vessels, and lower blood pressure. Common CCBs include nifedipine, amlodipine, etc. (5) β-blockers: β-blockers block cardiac β-receptors, reduce cardiac output and heart rate, and thus achieve the effect of lowering blood pressure. Common β-blockers include metoprolol, bisoprolol, etc. In addition to the above drugs, there are some other drugs that can also be used to treat hypertension, such as calcium ion antagonists, α-receptor blockers, etc. Although there are many antihypertensive drugs available, a large number of hypertensive patients still cannot achieve the ideal blood pressure control level. Therefore, there is a need to further develop new, efficient and safe antihypertensive drugs.

[0005] Angiotensinogen (AGT) is a precursor protein synthesized in the liver and serves as the starting material for the renin-angiotensin-aldosterone system (RAAS), which plays a role in the pathogenesis of hypertension. When renal blood flow is reduced, juxtaglomerular cells release renin, which converts angiotensinogen to angiotensin I (Ang I). Angiotensin-converting enzyme (ACE) on vascular endothelial cells converts Ang I to angiotensin II (Ang II). Ang II is a potent vasoconstrictor peptide that promotes contraction of vascular smooth muscle cells, narrowing blood vessels and increasing blood pressure. Ang II also stimulates the adrenal cortex to secrete aldosterone, which increases sodium reabsorption in the renal tubules, leading to water reabsorption and thus increasing blood volume and blood pressure. Angiotensin II also has multiple physiological effects, such as stimulating the sympathetic nervous system, increasing heart rate, cardiac contractility, and cardiac output, and promoting sodium and water reabsorption in the kidneys, which can exacerbate conditions such as cardiac hypertrophy and heart failure. Therefore, when the RAAS system is abnormally activated, angiotensin II levels increase, leading to elevated blood pressure. Furthermore, the RAAS is also involved in regulating kidney function. Chronic activation can cause glomerulosclerosis and kidney damage, exacerbating the development and progression of hypertension. Therefore, inhibiting the formation of AGT and angiotensin II is an important strategy for treating hypertension.

[0006] siRNA is a short RNA molecule that can specifically inhibit the expression of mRNA genes. Through the RNA interference mechanism, siRNA binds to the target gene's mRNA and guides RNA nucleases to cleave the corresponding mRNA molecules, thereby preventing mRNA translation and protein synthesis. Compared with other gene silencing technologies, siRNA technology offers advantages such as high efficiency, selectivity, and reproducibility.

[0007] In recent years, siRNA drugs targeting AGT have attracted considerable attention as a novel strategy for treating hypertension. The AGT gene sequence in humans is well-studied, and the structure and function of its mRNA are well understood. Therefore, by studying the AGT mRNA sequence, it is possible to design siRNA duplexes targeting AGT. In in vivo experiments, researchers successfully injected siRNA targeting AGT into mice. The results showed that this siRNA drug significantly reduced AGT mRNA and protein levels in the mice, as well as their blood pressure.

[0008] Furthermore, due to its targeted and reversible properties, siRNA can reduce side effects during treatment and restore normal gene expression levels in patients after treatment. siRNA technology also offers greater flexibility in drug design and is expected to become an important technology for the treatment of hypertension in the future.

[0009] In conclusion, AGT is an important factor leading to hypertension, and siRNA drugs targeting AGT have great potential as a new strategy for treating hypertension. Summary of the Invention

[0010] The present invention aims to, at least to some extent, address at least one of the technical problems existing in the prior art. To this end, the present invention provides an siRNA duplex for inhibiting angiotensinogen expression, a covalent conjugate thereof with a delivery vector, and uses thereof. The siRNA of the present invention can inhibit angiotensinogen expression and effectively treat diseases associated with angiotensinogen excess.

[0011] The present invention provides an siRNA duplex. According to an embodiment of the present invention, the siRNA comprises a sense strand and an antisense strand. The antisense strand comprises a complementary region that pairs with the sense strand. The sense strand is selected from a nucleotide sequence that differs by no more than 2 nucleotides from the nucleotide sequence of each strand in SEQ ID NO:1 to SEQ ID NO:11, and the antisense strand is selected from a nucleotide sequence that differs by no more than 2 nucleotides from the nucleotide sequence of each strand in SEQ ID NO:12 to SEQ ID NO:22. Through experimental design, the inventors have determined that the above-mentioned suitable small interfering RNA (siRNA) can specifically reduce the synthesis of AGT in hepatocytes while avoiding off-target effects. The siRNA forms an RNA-induced silencing complex (RISC) and pairs with the sequence of the target gene (AGT) mRNA, thereby degrading AGT mRNA, inhibiting AGT expression, and lowering blood pressure in the body, thereby effectively preventing or treating diseases related to excessive angiotensinogen, such as hypertension.

[0012] In the present invention, the "difference is no more than 2 nucleotides" means that compared with the target nucleotide sequence, there may be 1 or 2 nucleotide differences, and the difference includes but is not limited to nucleotide deletion, nucleotide insertion (which can be inserted into the 3'-end, 5'-end, or between any two nucleotides in the nucleotide sequence), nucleotide substitution, etc.

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

[0014] According to an embodiment of the present invention, the sense strand includes at least one of SEQ ID NO: 1 to SEQ ID NO: 11 shown in Table 1, and further includes a continuous nucleotide sequence that differs from the sense strand shown in Table 1 by 1 or 2 nucleotides.

[0015] According to an embodiment of the present invention, the antisense strand includes at least one of SEQ ID NO: 12 to SEQ ID NO: 22 shown in Table 1, and further includes a continuous nucleotide sequence that differs from the antisense strand shown in Table 1 (excluding the 3'-overhanging base) by 1 or 2 nucleotides.

[0016] For example, 5'-UUCAUUAGAAGAAAAGGUGGUU-3' (SEQ ID NO: 4) and 5'-UUCAUUAGAAGAAAAGGUGGGA-3', 5'-UUCAUUAGAAGAAAAGGUGGTT-3', etc. should be regarded as the same nucleotide sequence.

[0017] Table 1: Nucleotide sequences of siRNA

[0018] According to an embodiment of the present invention, the positive strand includes one of the following nucleotide sequences, or a nucleotide sequence that differs therefrom by no more than 2 nucleotides: SEQ ID NO:4 and / or SEQ ID NO:7; the antisense strand includes one of the following nucleotide sequences, or a nucleotide sequence that differs therefrom by no more than 2 nucleotides: SEQ ID NO:15 and SEQ ID NO:18.

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

[0020] NPS-112: (SEQ ID NO:1 and SEQ ID NO:12)

[0021] NPS-115: (SEQ ID NO:4 and SEQ ID NO:15)

[0022] NPS-118: (SEQ ID NO:7 and SEQ ID NO:18).

[0023] According to an embodiment of the present invention, the sense strand comprises at least 17 consecutive nucleotides of any sense strand nucleotide sequence selected from the following duplexes:

[0024] NPS-112: (SEQ ID NO:1 and SEQ ID NO:12)

[0025] NPS-115: (SEQ ID NO:4 and SEQ ID NO:15)

[0026] NPS-118: (SEQ ID NO:7 and SEQ ID NO:18).

[0027] According to an embodiment of the present invention, the sense and antisense strands comprise duplex nucleotide sequences selected from the group consisting of:

[0028] NPS-112: (SEQ ID NO:1 and SEQ ID NO:12)

[0029] NPS-115: (SEQ ID NO:4 and SEQ ID NO:15)

[0030] NPS-118: (SEQ ID NO:7 and SEQ ID NO:18).

[0031] According to an embodiment of the present invention, the antisense strand comprises at least 19 consecutive nucleotides of the nucleotide sequence of the antisense strand of NDS-115 (5'-UUCAUUAGAAGAAAAGGUGGUU-3', SEQ ID NO: 15). In certain embodiments, the sense strand comprises at least 19 consecutive nucleotides of the nucleotide sequence of the sense strand of NDS-115 (5'-CCACCUUUUCUUCUAAUGAA-3', SEQ ID NO: 4). In certain embodiments, the sense and antisense strands comprise the sense and antisense strand nucleotide sequences of NDS-115 (5'-CCACCUUUUCUUCUAAUGAA-3', SEQ ID NO: 4) and (5'-UUCAUUAGAAGAAAAGGUGGUU-3', SEQ ID NO: 15).

[0032] According to an embodiment of the present invention, the length of the complementary region is at least 19 bases.

[0033] According to an embodiment of the present invention, the length of the complementary region is 19 to 23 bases.

[0034] According to an embodiment of the present invention, one or more ribonucleotides are added to the 3' end of the sense strand and / or antisense strand of the siRNA as an overhang.

[0035] According to an embodiment of the present invention, the siRNA includes at least one modified nucleotide.

[0036] According to an embodiment of the present invention, the modified nucleotide is selected from at least one of phosphodiester chain modification, ribose modification and base modification, or any combination of these three types of modifications.

[0037] According to an embodiment of the present invention, the modified nucleotide is selected from at least one of the following:

[0038] 2'-O-methyl modified nucleotides: aM, gM, cM, and uM are 2'-O-Me A, 2'-O-Me G, 2'-O-Me C, and 2'-O-Me U, respectively;

[0039] 2'-Fluoro-modified nucleotides: aF, gF, cF, and uF are 2'-fluoro A, 2'-fluoro C, 2'-fluoro G, and 2'-fluoro U, respectively;

[0040] 2'-deoxy modified nucleotides: 2'-deoxycytidine-3'-phosphate, 2'-deoxyguanosine-3'-phosphate, 2'-deoxyadenosine-3'-phosphate, 2'-deoxyuridine-3'-phosphate;

[0041] 5'-(1,2,4)-triazole-modified nucleotides: cTA4, gTA4, aTA4, and uTA4 are 2'-O-methyl-5'-deoxy-(1-(1,2,4-triazole))-cytidine-3'-phosphate, 2'-O-methyl-5'-deoxy-(1-(1,2,4-triazole))-guanosine-3'-phosphate, 2'-O-methyl-5'-deoxy-(1-(1,2,4-triazole))-adenosine-3'-phosphate, and 2'-O-methyl-5'-deoxy-(1-(1,2,4-triazole))-uridine-3'-phosphate, respectively;

[0042] 5'-Thiomorpholinoline-modified nucleotides: cSMP, gSMP, aSMP, and uSMP are 2'-O-methyl-5'-N-(thiomorpholino)-cytidine-3'-phosphate, 2'-O-methyl-5'-N-(thiomorpholino)-guanosine-3'-phosphate, 2'-O-methyl-5'-N-(thiomorpholino)-adenosine-3'-phosphate, and 2'-O-methyl-5'-N-(thiomorpholino)-uridine-3'-phosphate, respectively;

[0043] 3'-Fluoro-modified nucleotides: cRF, gRF, aRF, and uRF are 3'-fluoro-3'-deoxycytidine-2'-phosphate, 3'-fluoro-3'-deoxyguanosine-2'-phosphate, 3'-fluoro-3'-deoxyadenosine-2'-phosphate, and 3'-fluoro-3'-deoxyuridine-2'-phosphate, respectively; cXF, gXF, aXF, and uXF are 3'-fluoro-3'-deoxycytidine xylosyl-2'-phosphate, 3'-fluoro-3'-deoxyguanine xylosyl-2'-phosphate, 3'-fluoro-3'-deoxyadenine xylosyl-2'-phosphate, and 3'-fluoro-3'-deoxyuridine xylosyl-2'-phosphate, respectively;

[0044] 3'-deoxy modified nucleotides: 3'-deoxycytidine-2'-phosphate, 3'-deoxyguanosine-2'-phosphate, 3'-deoxyadenosine-2'-phosphate, 3'-deoxyuridine-2'-phosphate;

[0045] 5'-phosphorothioate diester linkages and / or methylphosphonate nucleotides;

[0046] Nucleotides with unconventional bases;

[0047] 5'-trans-vinylphosphonate (E-VP) modified nucleotides.

[0048] It should be noted that when a modified nucleotide is selected from a 2'-modified nucleotide and a 5'-phosphorothioate diester modified nucleotide, the modified nucleotide has both a 2'-modification and a 5'-phosphorothioate diester chain modification.

[0049] As is known to those skilled in the art, a ribonucleotide molecule is composed of phosphate, ribose, and a base. As used herein, a "modified nucleotide" refers to a conventional nucleotide other than A, U, C, or G, or an unconventional nucleotide such as inosine (I) or pseudouridine (ψ), in which the group attached to the ribose sugar is altered, the phosphodiester linker group is altered, or a base is deleted or replaced.

[0050] According to an embodiment of the present invention, all nucleotides in the sense strand and / or the antisense strand are modified nucleotides, and the modified nucleotides are independently selected from at least one of 2'-O-methyl modified nucleotides, 2'-fluoro modified nucleotides, 2'-deoxy modified nucleotides, 3'-O-methyl modified nucleotides, 3'-fluoro modified nucleotides, 3'-deoxy modified nucleotides, 5'-(1,2,4)-triazole modified nucleotides, 5'-thiomorpholine modified nucleotides, 5'-thiophosphorodiester modified nucleotides and 5'-VP phosphonate modified nucleotides.

[0051] According to an embodiment of the present invention, in the sense chain and / or the antisense chain, the 2'-fluoro-modified nucleotides are present in the following positions: the nucleotides at the 5'-terminus of the sense chain are 2'-fluoro-modified nucleotides at positions 9, 10 and 11 of the starting point, and the remaining positions are 2'-O-methyl-modified nucleotides; and / or the nucleotides at the 5'-terminus of the antisense chain are 2'-fluoro-modified nucleotides at positions 2, 6, 14 and 16 of the starting point, and the remaining positions are 2'-O-methyl-modified nucleotides.

[0052] For example, the nucleotide at the 5'-terminus of the sense strand is the first nucleotide from the starting point and is a 2'-O-methyl modified nucleotide.

[0053] Illustratively, the 5'-terminal nucleotide of the antisense strand is the first nucleotide at the starting point, and the 3'-terminal nucleotide of the antisense strand is the first and second nucleotides at the starting point, which are both 2'-O-methyl modified nucleotides and 5'-phosphorothioate diester modified nucleotides.

[0054] According to an embodiment of the present invention, the 5'-modified nucleotide at position 1 of the nucleotide starting point at the 5'-end of the siRNA sense strand may be optionally a 5'-(1,2,4)-triazole-modified nucleotide: cTA4, gTA4, aTA4, and uTA4 are 2'-O-methyl-5'-deoxy-(1-(1,2,4-triazole))-cytidine-3'-phosphate, 2'-O-methyl-5'-deoxy-(1-(1,2,4-triazole))-guanosine-3'-phosphate, 2'-O-methyl-5'-deoxy-(1-(1,2,4-triazole))-adenosine-3'-phosphate, and 2'-O-methyl-5'-deoxy-(1-(1,2,4-triazole))-uridine-3'-phosphate, respectively; or

[0055] 5'-Thiomorpholinoline-modified nucleotides: cSMP, gSMP, aSMP, and uSMP are 2'-O-methyl-5'-N-(thiomorpholino)-cytidine-3'-phosphate, 2'-O-methyl-5'-N-(thiomorpholino)-guanosine-3'-phosphate, 2'-O-methyl-5'-N-(thiomorpholino)-adenosine-3'-phosphate, and 2'-O-methyl-5'-N-(thiomorpholino)-uridine-3'-phosphate, respectively.

[0056] For example, the nucleotide at the 5'-terminus of the sense strand may be the starting point, and the nucleotide at position 1 may be 2'-O-methyl-5'-deoxy-(1-(1,2,4-triazole))-cytidine-3'-phosphate.

[0057] According to an embodiment of the present invention, the nucleotide starting point at position 1 of the 5'-terminus of the antisense strand of the siRNA is a 5'-unmodified or 5'-trans vinylphosphonate (E-VP) modified nucleotide.

[0058] For example, the nucleotide at the 5'-terminus of the antisense strand is the first nucleotide at the starting point and may be 2'-O-methyl-5'-deoxy-(E)-vinyl phosphate-inosine-3'-phosphate.

[0059] According to an embodiment of the present invention, the nucleotides from position 5 to position 8 at the starting point of the 5'-end of the antisense strand of the siRNA can be optionally 3'-O-methyl or 3'-fluoro modified nucleotides.

[0060] For example, the nucleotide at position 7 of the starting point of the 5'-terminus of the antisense strand may be 3'-fluoro-3'-deoxyadenosine-2'-phosphate or 3'-fluoro-3'-deoxyadenosine-xylosyl-2'-phosphate.

[0061] According to embodiments of the present invention, siRNA double-stranded molecules, wherein the siRNA double-stranded molecules may further comprise at least one phosphorothioate or methylphosphonate internucleotide connection. In certain embodiments, the phosphorothioate or methylphosphonate internucleotide is connected at the 3'-end of a chain, wherein the chain is an antisense strand and / or a sense strand. In certain embodiments, the phosphorothioate or methylphosphonate internucleotide is connected at the 5'-end of a chain, wherein the chain is an antisense strand and / or a sense strand. In certain embodiments, the phosphorothioate or methylphosphonate internucleotide is connected at the 5'-end and 3'-end of a chain, wherein the chain is an antisense strand.

[0062] According to an embodiment of the present invention, in a double-stranded siRNA molecule, the base pair at position 1 of the 5′-end of the antisense strand of the duplex is an A:U base pair or an A:I base pair, wherein I is inosine.

[0063] According to an embodiment of the present invention, the siRNA antisense strand comprises any one of the chemically modified antisense strand nucleotide sequences selected from the following duplexes:

[0064] NPD011s-261 (SEQ ID NO. 1 and SEQ ID NO. 167)

[0065] NPD011s-265 (SEQ ID NO. 5 and SEQ ID NO. 171)

[0066] NPD011s-269 (SEQ ID NO. 9 and SEQ ID NO. 175)

[0067] NPD011s-278 (SEQ ID NO. 17 and SEQ ID NO. 183)

[0068] NPD011s-288 (SEQ ID NO. 24 and SEQ ID NO. 190)

[0069] NPD011s-289 (SEQ ID NO. 25 and SEQ ID NO. 191)

[0070] NPD011s-290 (SEQ ID NO. 26 and SEQ ID NO. 192)

[0071] NPD011s-291 (SEQ ID NO. 27 and SEQ ID NO. 193)

[0072] NPD011s-292 (SEQ ID NO. 28 and SEQ ID NO. 194)

[0073] NPD011s-293 ​​(SEQ ID NO. 29 and SEQ ID NO. 195)

[0074] NPD011s-294 (SEQ ID NO. 30 and SEQ ID NO. 196)

[0075] NPD011s-295 (SEQ ID NO. 31 and SEQ ID NO. 197)

[0076] NPD011s-296 (SEQ ID NO. 32 and SEQ ID NO. 198)

[0077] NPD011s-297 (SEQ ID NO. 33 and SEQ ID NO. 199)

[0078] NPD011s-298 (SEQ ID NO. 34 and SEQ ID NO. 200)

[0079] NPD011s-299 (SEQ ID NO. 35 and SEQ ID NO. 201)

[0080] NPD011s-300 (SEQ ID NO. 36 and SEQ ID NO. 202)

[0081] NPD011s-301 (SEQ ID NO. 37 and SEQ ID NO. 203)

[0082] NPD011s-302 (SEQ ID NO. 38 and SEQ ID NO. 204)

[0083] NPD011s-303 (SEQ ID NO. 39 and SEQ ID NO. 205)

[0084] NPD011s-304 (SEQ ID NO. 40 and SEQ ID NO. 206)

[0085] NPD011s-305 (SEQ ID NO. 41 and SEQ ID NO. 207)

[0086] NPD011s-306 (SEQ ID NO. 42 and SEQ ID NO. 208)

[0087] NPD011s-307 (SEQ ID NO. 43 and SEQ ID NO. 209)

[0088] NPD011s-308 (SEQ ID NO. 44 and SEQ ID NO. 210)

[0089] NPD011s-309 (SEQ ID NO. 45 and SEQ ID NO. 211)

[0090] NPD011s-310 (SEQ ID NO. 46 and SEQ ID NO. 212)

[0091] NPD011s-311 (SEQ ID NO. 47 and SEQ ID NO. 213)

[0092] NPD011s-312 (SEQ ID NO. 48 and SEQ ID NO. 214)

[0093] NPD011s-313 (SEQ ID NO. 49 and SEQ ID NO. 215)

[0094] NPD011s-314 (SEQ ID NO. 50 and SEQ ID NO. 216)

[0095] NPD011s-315 (SEQ ID NO. 51 and SEQ ID NO. 217)

[0096] NPD011s-316 (SEQ ID NO. 52 and SEQ ID NO. 218)

[0097] NPD011s-317 (SEQ ID NO. 53 and SEQ ID NO. 219)

[0098] NPD011s-318 (SEQ ID NO. 54 and SEQ ID NO. 220)

[0099] NPD011s-319 (SEQ ID NO. 55 and SEQ ID NO. 221)

[0100] NPD011s-320 (SEQ ID NO. 56 and SEQ ID NO. 222)

[0101] NPD011s-321 (SEQ ID NO. 57 and SEQ ID NO. 223)

[0102] NPD011s-322 (SEQ ID NO. 58 and SEQ ID NO. 224)

[0103] NPD011s-323 (SEQ ID NO. 59 and SEQ ID NO. 225)

[0104] NPD011s-324 (SEQ ID NO. 60 and SEQ ID NO. 226)

[0105] NPD011s-325 (SEQ ID NO. 61 and SEQ ID NO. 227)

[0106] NPD011s-326 (SEQ ID NO. 62 and SEQ ID NO. 228)

[0107] NPD011s-327 (SEQ ID NO. 63 and SEQ ID NO. 229)

[0108] NPD011s-328 (SEQ ID NO. 64 and SEQ ID NO. 230)

[0109] NPD011s-329 (SEQ ID NO. 65 and SEQ ID NO. 231)

[0110] NPD011s-330 (SEQ ID NO. 66 and SEQ ID NO. 232)

[0111] NPD011s-331 (SEQ ID NO. 67 and SEQ ID NO. 233)

[0112] NPD011s-332 (SEQ ID NO. 68 and SEQ ID NO. 234)

[0113] NPD011s-333 (SEQ ID NO. 69 and SEQ ID NO. 235)

[0114] NPD011s-334 (SEQ ID NO. 70 and SEQ ID NO. 236)

[0115] NPD011s-335 (SEQ ID NO. 71 and SEQ ID NO. 237)

[0116] NPD011s-336 (SEQ ID NO. 72 and SEQ ID NO. 238)

[0117] NPD011s-337 (SEQ ID NO. 73 and SEQ ID NO. 239)

[0118] NPD011s-338 (SEQ ID NO. 74 and SEQ ID NO. 240)

[0119] NPD011s-339 (SEQ ID NO. 75 and SEQ ID NO. 241)

[0120] NPD011s-340 (SEQ ID NO. 76 and SEQ ID NO. 242)

[0121] NPD011s-341 (SEQ ID NO. 77 and SEQ ID NO. 243)

[0122] NPD011s-342 (SEQ ID NO. 78 and SEQ ID NO. 244)

[0123] NPD011s-343 (SEQ ID NO. 79 and SEQ ID NO. 245)

[0124] NPD011s-344 (SEQ ID NO. 80 and SEQ ID NO. 246)

[0125] NPD011s-345 (SEQ ID NO. 81 and SEQ ID NO. 247)

[0126] NPD011s-346 (SEQ ID NO. 82 and SEQ ID NO. 248)

[0127] NPD011s-347 (SEQ ID NO. 83 and SEQ ID NO. 249)

[0128] NPD011s-348 (SEQ ID NO. 84 and SEQ ID NO. 250)

[0129] NPD011s-349 (SEQ ID NO. 85 and SEQ ID NO. 251)

[0130] NPD011s-350 (SEQ ID NO. 86 and SEQ ID NO. 252)

[0131] NPD011s-351 (SEQ ID NO. 87 and SEQ ID NO. 253)

[0132] NPD011s-352 (SEQ ID NO. 88 and SEQ ID NO. 254)

[0133] NPD011s-353 (SEQ ID NO. 89 and SEQ ID NO. 255)

[0134] NPD011s-354 (SEQ ID NO. 90 and SEQ ID NO. 256)

[0135] NPD011s-355 (SEQ ID NO.91 and SEQ ID NO.257)

[0136] NPD011s-356 (SEQ ID NO. 92 and SEQ ID NO. 258)

[0137] NPD011s-357 (SEQ ID NO. 93 and SEQ ID NO. 259)

[0138] NPD011s-358 (SEQ ID NO. 94 and SEQ ID NO. 260)

[0139] NPD011s-359 (SEQ ID NO. 95 and SEQ ID NO. 261)

[0140] NPD011s-360 (SEQ ID NO. 96 and SEQ ID NO. 262)

[0141] NPD011s-361 (SEQ ID NO. 97 and SEQ ID NO. 263)

[0142] NPD011s-362 (SEQ ID NO. 98 and SEQ ID NO. 264)

[0143] NPD011s-363 (SEQ ID NO. 99 and SEQ ID NO. 265)

[0144] NPD011s-364 (SEQ ID NO. 100 and SEQ ID NO. 266)

[0145] NPD011s-365 (SEQ ID NO. 101 and SEQ ID NO. 267)

[0146] NPD011s-366 (SEQ ID NO. 102 and SEQ ID NO. 268)

[0147] NPD011s-367 (SEQ ID NO. 103 and SEQ ID NO. 269)

[0148] NPD011s-368 (SEQ ID NO. 104 and SEQ ID NO. 270)

[0149] NPD011s-369 (SEQ ID NO. 105 and SEQ ID NO. 271)

[0150] NPD011s-370 (SEQ ID NO. 106 and SEQ ID NO. 272)

[0151] NPD011s-371 (SEQ ID NO. 107 and SEQ ID NO. 273)

[0152] NPD011s-372 (SEQ ID NO. 108 and SEQ ID NO. 274)

[0153] NPD011s-373 (SEQ ID NO. 109 and SEQ ID NO. 275)

[0154] NPD011s-374 (SEQ ID NO. 110 and SEQ ID NO. 276)

[0155] NPD011s-375 (SEQ ID NO. 111 and SEQ ID NO. 277)

[0156] NPD011s-376 (SEQ ID NO. 112 and SEQ ID NO. 278)

[0157] NPD011s-377 (SEQ ID NO. 113 and SEQ ID NO. 279)

[0158] NPD011s-378 (SEQ ID NO. 114 and SEQ ID NO. 280)

[0159] NPD011s-379 (SEQ ID NO. 115 and SEQ ID NO. 281)

[0160] NPD011s-380 (SEQ ID NO. 116 and SEQ ID NO. 282)

[0161] NPD011s-381 (SEQ ID NO. 117 and SEQ ID NO. 283)

[0162] NPD011s-382 (SEQ ID NO. 118 and SEQ ID NO. 284)

[0163] NPD011s-383 (SEQ ID NO. 119 and SEQ ID NO. 285)

[0164] NPD011s-384 (SEQ ID NO. 120 and SEQ ID NO. 286)

[0165] NPD011s-385 (SEQ ID NO. 121 and SEQ ID NO. 287)

[0166] NPD011s-386 (SEQ ID NO. 122 and SEQ ID NO. 288)

[0167] NPD011s-387 (SEQ ID NO. 123 and SEQ ID NO. 289)

[0168] NPD011s-388 (SEQ ID NO. 124 and SEQ ID NO. 290)

[0169] NPD011s-389 (SEQ ID NO. 125 and SEQ ID NO. 291)

[0170] NPD011s-390 (SEQ ID NO. 126 and SEQ ID NO. 292)

[0171] NPD011s-391 (SEQ ID NO. 127 and SEQ ID NO. 293)

[0172] NPD011s-392 (SEQ ID NO. 128 and SEQ ID NO. 294)

[0173] NPD011s-393 (SEQ ID NO. 129 and SEQ ID NO. 295)

[0174] NPD011s-394 (SEQ ID NO. 130 and SEQ ID NO. 296)

[0175] NPD011s-395 (SEQ ID NO. 131 and SEQ ID NO. 297)

[0176] NPD011s-396 (SEQ ID NO. 132 and SEQ ID NO. 298)

[0177] NPD011s-397 (SEQ ID NO. 133 and SEQ ID NO. 299)

[0178] NPD011s-398 (SEQ ID NO. 134 and SEQ ID NO. 300)

[0179] NPD011s-399 (SEQ ID NO. 135 and SEQ ID NO. 301)

[0180] NPD011s-400 (SEQ ID NO. 136 and SEQ ID NO. 302)

[0181] NPD011s-401 (SEQ ID NO. 137 and SEQ ID NO. 303)

[0182] NPD011s-402 (SEQ ID NO. 138 and SEQ ID NO. 304)

[0183] NPD011s-403 (SEQ ID NO. 139 and SEQ ID NO. 305)

[0184] NPD011s-404 (SEQ ID NO. 140 and SEQ ID NO. 306)

[0185] NPD011s-405 (SEQ ID NO. 141 and SEQ ID NO. 307)

[0186] NPD011s-406 (SEQ ID NO. 142 and SEQ ID NO. 308)

[0187] NPD011s-407 (SEQ ID NO. 143 and SEQ ID NO. 309)

[0188] NPD011s-408 (SEQ ID NO. 144 and SEQ ID NO. 310)

[0189] NPD011s-409 (SEQ ID NO. 145 and SEQ ID NO. 311)

[0190] NPD011s-410 (SEQ ID NO. 146 and SEQ ID NO. 312)

[0191] NPD011s-411 (SEQ ID NO. 147 and SEQ ID NO. 313)

[0192] NPD011s-412 (SEQ ID NO. 148 and SEQ ID NO. 314)

[0193] NPD011s-413 (SEQ ID NO. 149 and SEQ ID NO. 315)

[0194] NPD011s-414 (SEQ ID NO. 150 and SEQ ID NO. 316)

[0195] NPD011s-415 (SEQ ID NO. 151 and SEQ ID NO. 317)

[0196] NPD011s-416 (SEQ ID NO. 152 and SEQ ID NO. 318)

[0197] NPD011s-417 (SEQ ID NO. 153 and SEQ ID NO. 319)

[0198] NPD011s-418 (SEQ ID NO. 154 and SEQ ID NO. 320)

[0199] NPD011s-419 (SEQ ID NO. 155 and SEQ ID NO. 321)

[0200] NPD011s-420 (SEQ ID NO. 156 and SEQ ID NO. 322)

[0201] NPD011s-421 (SEQ ID NO. 157 and SEQ ID NO. 323)

[0202] NPD011s-422 (SEQ ID NO. 158 and SEQ ID NO. 324)

[0203] NPD011s-423 (SEQ ID NO. 159 and SEQ ID NO. 325)

[0204] NPD011s-424 (SEQ ID NO. 160 and SEQ ID NO. 326)

[0205] NPD011s-425 (SEQ ID NO. 161 and SEQ ID NO. 327)

[0206] NPD011s-426 (SEQ ID NO. 162 and SEQ ID NO. 328)

[0207] NPD011s-427 (SEQ ID NO. 163 and SEQ ID NO. 329)

[0208] NPD011s-428 (SEQ ID NO. 164 and SEQ ID NO. 330)

[0209] NPD011s-429 (SEQ ID NO. 165 and SEQ ID NO. 331)

[0210] NPD011s-430 (SEQ ID NO. 166 and SEQ ID NO. 332).

[0211] According to an embodiment of the present invention, the siRNA sense strand comprises any one of the chemically modified sense strand nucleotide sequences selected from the following duplexes:

[0212] NPD011s-261 (SEQ ID NO. 1 and SEQ ID NO. 167)

[0213] NPD011s-265 (SEQ ID NO. 5 and SEQ ID NO. 171)

[0214] NPD011s-269 (SEQ ID NO. 9 and SEQ ID NO. 175)

[0215] NPD011s-278 (SEQ ID NO. 17 and SEQ ID NO. 183)

[0216] NPD011s-288 (SEQ ID NO. 24 and SEQ ID NO. 190)

[0217] NPD011s-289 (SEQ ID NO. 25 and SEQ ID NO. 191)

[0218] NPD011s-290 (SEQ ID NO. 26 and SEQ ID NO. 192)

[0219] NPD011s-291 (SEQ ID NO. 27 and SEQ ID NO. 193)

[0220] NPD011s-292 (SEQ ID NO. 28 and SEQ ID NO. 194)

[0221] NPD011s-293 ​​(SEQ ID NO. 29 and SEQ ID NO. 195)

[0222] NPD011s-294 (SEQ ID NO. 30 and SEQ ID NO. 196)

[0223] NPD011s-295 (SEQ ID NO. 31 and SEQ ID NO. 197)

[0224] NPD011s-296 (SEQ ID NO. 32 and SEQ ID NO. 198)

[0225] NPD011s-297 (SEQ ID NO. 33 and SEQ ID NO. 199)

[0226] NPD011s-298 (SEQ ID NO. 34 and SEQ ID NO. 200)

[0227] NPD011s-299 (SEQ ID NO. 35 and SEQ ID NO. 201)

[0228] NPD011s-300 (SEQ ID NO. 36 and SEQ ID NO. 202)

[0229] NPD011s-301 (SEQ ID NO. 37 and SEQ ID NO. 203)

[0230] NPD011s-302 (SEQ ID NO. 38 and SEQ ID NO. 204)

[0231] NPD011s-303 (SEQ ID NO. 39 and SEQ ID NO. 205)

[0232] NPD011s-304 (SEQ ID NO. 40 and SEQ ID NO. 206)

[0233] NPD011s-305 (SEQ ID NO. 41 and SEQ ID NO. 207)

[0234] NPD011s-306 (SEQ ID NO. 42 and SEQ ID NO. 208)

[0235] NPD011s-307 (SEQ ID NO. 43 and SEQ ID NO. 209)

[0236] NPD011s-308 (SEQ ID NO. 44 and SEQ ID NO. 210)

[0237] NPD011s-309 (SEQ ID NO. 45 and SEQ ID NO. 211)

[0238] NPD011s-310 (SEQ ID NO. 46 and SEQ ID NO. 212)

[0239] NPD011s-311 (SEQ ID NO. 47 and SEQ ID NO. 213)

[0240] NPD011s-312 (SEQ ID NO. 48 and SEQ ID NO. 214)

[0241] NPD011s-313 (SEQ ID NO. 49 and SEQ ID NO. 215)

[0242] NPD011s-314 (SEQ ID NO. 50 and SEQ ID NO. 216)

[0243] NPD011s-315 (SEQ ID NO. 51 and SEQ ID NO. 217)

[0244] NPD011s-316 (SEQ ID NO. 52 and SEQ ID NO. 218)

[0245] NPD011s-317 (SEQ ID NO. 53 and SEQ ID NO. 219)

[0246] NPD011s-318 (SEQ ID NO. 54 and SEQ ID NO. 220)

[0247] NPD011s-319 (SEQ ID NO. 55 and SEQ ID NO. 221)

[0248] NPD011s-320 (SEQ ID NO. 56 and SEQ ID NO. 222)

[0249] NPD011s-321 (SEQ ID NO. 57 and SEQ ID NO. 223)

[0250] NPD011s-322 (SEQ ID NO. 58 and SEQ ID NO. 224)

[0251] NPD011s-323 (SEQ ID NO. 59 and SEQ ID NO. 225)

[0252] NPD011s-324 (SEQ ID NO. 60 and SEQ ID NO. 226)

[0253] NPD011s-325 (SEQ ID NO. 61 and SEQ ID NO. 227)

[0254] NPD011s-326 (SEQ ID NO. 62 and SEQ ID NO. 228)

[0255] NPD011s-327 (SEQ ID NO. 63 and SEQ ID NO. 229)

[0256] NPD011s-328 (SEQ ID NO. 64 and SEQ ID NO. 230)

[0257] NPD011s-329 (SEQ ID NO. 65 and SEQ ID NO. 231)

[0258] NPD011s-330 (SEQ ID NO. 66 and SEQ ID NO. 232)

[0259] NPD011s-331 (SEQ ID NO. 67 and SEQ ID NO. 233)

[0260] NPD011s-332 (SEQ ID NO. 68 and SEQ ID NO. 234)

[0261] NPD011s-333 (SEQ ID NO. 69 and SEQ ID NO. 235)

[0262] NPD011s-334 (SEQ ID NO. 70 and SEQ ID NO. 236)

[0263] NPD011s-335 (SEQ ID NO. 71 and SEQ ID NO. 237)

[0264] NPD011s-336 (SEQ ID NO. 72 and SEQ ID NO. 238)

[0265] NPD011s-337 (SEQ ID NO. 73 and SEQ ID NO. 239)

[0266] NPD011s-338 (SEQ ID NO. 74 and SEQ ID NO. 240)

[0267] NPD011s-339 (SEQ ID NO. 75 and SEQ ID NO. 241)

[0268] NPD011s-340 (SEQ ID NO. 76 and SEQ ID NO. 242)

[0269] NPD011s-341 (SEQ ID NO. 77 and SEQ ID NO. 243)

[0270] NPD011s-342 (SEQ ID NO. 78 and SEQ ID NO. 244)

[0271] NPD011s-343 (SEQ ID NO. 79 and SEQ ID NO. 245)

[0272] NPD011s-344 (SEQ ID NO. 80 and SEQ ID NO. 246)

[0273] NPD011s-345 (SEQ ID NO. 81 and SEQ ID NO. 247)

[0274] NPD011s-346 (SEQ ID NO. 82 and SEQ ID NO. 248)

[0275] NPD011s-347 (SEQ ID NO. 83 and SEQ ID NO. 249)

[0276] NPD011s-348 (SEQ ID NO. 84 and SEQ ID NO. 250)

[0277] NPD011s-349 (SEQ ID NO. 85 and SEQ ID NO. 251)

[0278] NPD011s-350 (SEQ ID NO. 86 and SEQ ID NO. 252)

[0279] NPD011s-351 (SEQ ID NO. 87 and SEQ ID NO. 253)

[0280] NPD011s-352 (SEQ ID NO. 88 and SEQ ID NO. 254)

[0281] NPD011s-353 (SEQ ID NO. 89 and SEQ ID NO. 255)

[0282] NPD011s-354 (SEQ ID NO. 90 and SEQ ID NO. 256)

[0283] NPD011s-355 (SEQ ID NO.91 and SEQ ID NO.257)

[0284] NPD011s-356 (SEQ ID NO. 92 and SEQ ID NO. 258)

[0285] NPD011s-357 (SEQ ID NO. 93 and SEQ ID NO. 259)

[0286] NPD011s-358 (SEQ ID NO. 94 and SEQ ID NO. 260)

[0287] NPD011s-359 (SEQ ID NO. 95 and SEQ ID NO. 261)

[0288] NPD011s-360 (SEQ ID NO. 96 and SEQ ID NO. 262)

[0289] NPD011s-361 (SEQ ID NO. 97 and SEQ ID NO. 263)

[0290] NPD011s-362 (SEQ ID NO. 98 and SEQ ID NO. 264)

[0291] NPD011s-363 (SEQ ID NO. 99 and SEQ ID NO. 265)

[0292] NPD011s-364 (SEQ ID NO. 100 and SEQ ID NO. 266)

[0293] NPD011s-365 (SEQ ID NO. 101 and SEQ ID NO. 267)

[0294] NPD011s-366 (SEQ ID NO. 102 and SEQ ID NO. 268)

[0295] NPD011s-367 (SEQ ID NO. 103 and SEQ ID NO. 269)

[0296] NPD011s-368 (SEQ ID NO. 104 and SEQ ID NO. 270)

[0297] NPD011s-369 (SEQ ID NO. 105 and SEQ ID NO. 271)

[0298] NPD011s-370 (SEQ ID NO. 106 and SEQ ID NO. 272)

[0299] NPD011s-371 (SEQ ID NO. 107 and SEQ ID NO. 273)

[0300] NPD011s-372 (SEQ ID NO. 108 and SEQ ID NO. 274)

[0301] NPD011s-373 (SEQ ID NO. 109 and SEQ ID NO. 275)

[0302] NPD011s-374 (SEQ ID NO. 110 and SEQ ID NO. 276)

[0303] NPD011s-375 (SEQ ID NO. 111 and SEQ ID NO. 277)

[0304] NPD011s-376 (SEQ ID NO. 112 and SEQ ID NO. 278)

[0305] NPD011s-377 (SEQ ID NO. 113 and SEQ ID NO. 279)

[0306] NPD011s-378 (SEQ ID NO. 114 and SEQ ID NO. 280)

[0307] NPD011s-379 (SEQ ID NO. 115 and SEQ ID NO. 281)

[0308] NPD011s-380 (SEQ ID NO. 116 and SEQ ID NO. 282)

[0309] NPD011s-381 (SEQ ID NO. 117 and SEQ ID NO. 283)

[0310] NPD011s-382 (SEQ ID NO. 118 and SEQ ID NO. 284)

[0311] NPD011s-383 (SEQ ID NO. 119 and SEQ ID NO. 285)

[0312] NPD011s-384 (SEQ ID NO. 120 and SEQ ID NO. 286)

[0313] NPD011s-385 (SEQ ID NO. 121 and SEQ ID NO. 287)

[0314] NPD011s-386 (SEQ ID NO. 122 and SEQ ID NO. 288)

[0315] NPD011s-387 (SEQ ID NO. 123 and SEQ ID NO. 289)

[0316] NPD011s-388 (SEQ ID NO. 124 and SEQ ID NO. 290)

[0317] NPD011s-389 (SEQ ID NO. 125 and SEQ ID NO. 291)

[0318] NPD011s-390 (SEQ ID NO. 126 and SEQ ID NO. 292)

[0319] NPD011s-391 (SEQ ID NO. 127 and SEQ ID NO. 293)

[0320] NPD011s-392 (SEQ ID NO. 128 and SEQ ID NO. 294)

[0321] NPD011s-393 (SEQ ID NO. 129 and SEQ ID NO. 295)

[0322] NPD011s-394 (SEQ ID NO. 130 and SEQ ID NO. 296)

[0323] NPD011s-395 (SEQ ID NO. 131 and SEQ ID NO. 297)

[0324] NPD011s-396 (SEQ ID NO. 132 and SEQ ID NO. 298)

[0325] NPD011s-397 (SEQ ID NO. 133 and SEQ ID NO. 299)

[0326] NPD011s-398 (SEQ ID NO. 134 and SEQ ID NO. 300)

[0327] NPD011s-399 (SEQ ID NO. 135 and SEQ ID NO. 301)

[0328] NPD011s-400 (SEQ ID NO. 136 and SEQ ID NO. 302)

[0329] NPD011s-401 (SEQ ID NO. 137 and SEQ ID NO. 303)

[0330] NPD011s-402 (SEQ ID NO. 138 and SEQ ID NO. 304)

[0331] NPD011s-403 (SEQ ID NO. 139 and SEQ ID NO. 305)

[0332] NPD011s-404 (SEQ ID NO. 140 and SEQ ID NO. 306)

[0333] NPD011s-405 (SEQ ID NO. 141 and SEQ ID NO. 307)

[0334] NPD011s-406 (SEQ ID NO. 142 and SEQ ID NO. 308)

[0335] NPD011s-407 (SEQ ID NO. 143 and SEQ ID NO. 309)

[0336] NPD011s-408 (SEQ ID NO. 144 and SEQ ID NO. 310)

[0337] NPD011s-409 (SEQ ID NO. 145 and SEQ ID NO. 311)

[0338] NPD011s-410 (SEQ ID NO. 146 and SEQ ID NO. 312)

[0339] NPD011s-411 (SEQ ID NO. 147 and SEQ ID NO. 313)

[0340] NPD011s-412 (SEQ ID NO. 148 and SEQ ID NO. 314)

[0341] NPD011s-413 (SEQ ID NO. 149 and SEQ ID NO. 315)

[0342] NPD011s-414 (SEQ ID NO. 150 and SEQ ID NO. 316)

[0343] NPD011s-415 (SEQ ID NO. 151 and SEQ ID NO. 317)

[0344] NPD011s-416 (SEQ ID NO. 152 and SEQ ID NO. 318)

[0345] NPD011s-417 (SEQ ID NO. 153 and SEQ ID NO. 319)

[0346] NPD011s-418 (SEQ ID NO. 154 and SEQ ID NO. 320)

[0347] NPD011s-419 (SEQ ID NO. 155 and SEQ ID NO. 321)

[0348] NPD011s-420 (SEQ ID NO. 156 and SEQ ID NO. 322)

[0349] NPD011s-421 (SEQ ID NO. 157 and SEQ ID NO. 323)

[0350] NPD011s-422 (SEQ ID NO. 158 and SEQ ID NO. 324)

[0351] NPD011s-423 (SEQ ID NO. 159 and SEQ ID NO. 325)

[0352] NPD011s-424 (SEQ ID NO. 160 and SEQ ID NO. 326)

[0353] NPD011s-425 (SEQ ID NO. 161 and SEQ ID NO. 327)

[0354] NPD011s-426 (SEQ ID NO. 162 and SEQ ID NO. 328)

[0355] NPD011s-427 (SEQ ID NO. 163 and SEQ ID NO. 329)

[0356] NPD011s-428 (SEQ ID NO. 164 and SEQ ID NO. 330)

[0357] NPD011s-429 (SEQ ID NO. 165 and SEQ ID NO. 331)

[0358] NPD011s-430 (SEQ ID NO. 166 and SEQ ID NO. 332).

[0359] According to an embodiment of the present invention, the siRNA antisense strand and the sense strand comprise a chemically modified nucleotide sequence of a duplex selected from the group consisting of:

[0360] NPD011s-261 (SEQ ID NO. 1 and SEQ ID NO. 167)

[0361] NPD011s-265 (SEQ ID NO. 5 and SEQ ID NO. 171)

[0362] NPD011s-269 (SEQ ID NO. 9 and SEQ ID NO. 175)

[0363] NPD011s-278 (SEQ ID NO. 17 and SEQ ID NO. 183)

[0364] NPD011s-288 (SEQ ID NO. 24 and SEQ ID NO. 190)

[0365] NPD011s-289 (SEQ ID NO. 25 and SEQ ID NO. 191)

[0366] NPD011s-290 (SEQ ID NO. 26 and SEQ ID NO. 192)

[0367] NPD011s-291 (SEQ ID NO. 27 and SEQ ID NO. 193)

[0368] NPD011s-292 (SEQ ID NO. 28 and SEQ ID NO. 194)

[0369] NPD011s-293 ​​(SEQ ID NO. 29 and SEQ ID NO. 195)

[0370] NPD011s-294 (SEQ ID NO. 30 and SEQ ID NO. 196)

[0371] NPD011s-295 (SEQ ID NO. 31 and SEQ ID NO. 197)

[0372] NPD011s-296 (SEQ ID NO. 32 and SEQ ID NO. 198)

[0373] NPD011s-297 (SEQ ID NO. 33 and SEQ ID NO. 199)

[0374] NPD011s-298 (SEQ ID NO. 34 and SEQ ID NO. 200)

[0375] NPD011s-299 (SEQ ID NO. 35 and SEQ ID NO. 201)

[0376] NPD011s-300 (SEQ ID NO. 36 and SEQ ID NO. 202)

[0377] NPD011s-301 (SEQ ID NO. 37 and SEQ ID NO. 203)

[0378] NPD011s-302 (SEQ ID NO. 38 and SEQ ID NO. 204)

[0379] NPD011s-303 (SEQ ID NO. 39 and SEQ ID NO. 205)

[0380] NPD011s-304 (SEQ ID NO. 40 and SEQ ID NO. 206)

[0381] NPD011s-305 (SEQ ID NO. 41 and SEQ ID NO. 207)

[0382] NPD011s-306 (SEQ ID NO. 42 and SEQ ID NO. 208)

[0383] NPD011s-307 (SEQ ID NO. 43 and SEQ ID NO. 209)

[0384] NPD011s-308 (SEQ ID NO. 44 and SEQ ID NO. 210)

[0385] NPD011s-309 (SEQ ID NO. 45 and SEQ ID NO. 211)

[0386] NPD011s-310 (SEQ ID NO. 46 and SEQ ID NO. 212)

[0387] NPD011s-311 (SEQ ID NO. 47 and SEQ ID NO. 213)

[0388] NPD011s-312 (SEQ ID NO. 48 and SEQ ID NO. 214)

[0389] NPD011s-313 (SEQ ID NO. 49 and SEQ ID NO. 215)

[0390] NPD011s-314 (SEQ ID NO. 50 and SEQ ID NO. 216)

[0391] NPD011s-315 (SEQ ID NO. 51 and SEQ ID NO. 217)

[0392] NPD011s-316 (SEQ ID NO. 52 and SEQ ID NO. 218)

[0393] NPD011s-317 (SEQ ID NO. 53 and SEQ ID NO. 219)

[0394] NPD011s-318 (SEQ ID NO. 54 and SEQ ID NO. 220)

[0395] NPD011s-319 (SEQ ID NO. 55 and SEQ ID NO. 221)

[0396] NPD011s-320 (SEQ ID NO. 56 and SEQ ID NO. 222)

[0397] NPD011s-321 (SEQ ID NO. 57 and SEQ ID NO. 223)

[0398] NPD011s-322 (SEQ ID NO. 58 and SEQ ID NO. 224)

[0399] NPD011s-323 (SEQ ID NO. 59 and SEQ ID NO. 225)

[0400] NPD011s-324 (SEQ ID NO. 60 and SEQ ID NO. 226)

[0401] NPD011s-325 (SEQ ID NO. 61 and SEQ ID NO. 227)

[0402] NPD011s-326 (SEQ ID NO. 62 and SEQ ID NO. 228)

[0403] NPD011s-327 (SEQ ID NO. 63 and SEQ ID NO. 229)

[0404] NPD011s-328 (SEQ ID NO. 64 and SEQ ID NO. 230)

[0405] NPD011s-329 (SEQ ID NO. 65 and SEQ ID NO. 231)

[0406] NPD011s-330 (SEQ ID NO. 66 and SEQ ID NO. 232)

[0407] NPD011s-331 (SEQ ID NO. 67 and SEQ ID NO. 233)

[0408] NPD011s-332 (SEQ ID NO. 68 and SEQ ID NO. 234)

[0409] NPD011s-333 (SEQ ID NO. 69 and SEQ ID NO. 235)

[0410] NPD011s-334 (SEQ ID NO. 70 and SEQ ID NO. 236)

[0411] NPD011s-335 (SEQ ID NO. 71 and SEQ ID NO. 237)

[0412] NPD011s-336 (SEQ ID NO. 72 and SEQ ID NO. 238)

[0413] NPD011s-337 (SEQ ID NO. 73 and SEQ ID NO. 239)

[0414] NPD011s-338 (SEQ ID NO. 74 and SEQ ID NO. 240)

[0415] NPD011s-339 (SEQ ID NO. 75 and SEQ ID NO. 241)

[0416] NPD011s-340 (SEQ ID NO. 76 and SEQ ID NO. 242)

[0417] NPD011s-341 (SEQ ID NO. 77 and SEQ ID NO. 243)

[0418] NPD011s-342 (SEQ ID NO. 78 and SEQ ID NO. 244)

[0419] NPD011s-343 (SEQ ID NO. 79 and SEQ ID NO. 245)

[0420] NPD011s-344 (SEQ ID NO. 80 and SEQ ID NO. 246)

[0421] NPD011s-345 (SEQ ID NO. 81 and SEQ ID NO. 247)

[0422] NPD011s-346 (SEQ ID NO. 82 and SEQ ID NO. 248)

[0423] NPD011s-347 (SEQ ID NO. 83 and SEQ ID NO. 249)

[0424] NPD011s-348 (SEQ ID NO. 84 and SEQ ID NO. 250)

[0425] NPD011s-349 (SEQ ID NO. 85 and SEQ ID NO. 251)

[0426] NPD011s-350 (SEQ ID NO. 86 and SEQ ID NO. 252)

[0427] NPD011s-351 (SEQ ID NO. 87 and SEQ ID NO. 253)

[0428] NPD011s-352 (SEQ ID NO. 88 and SEQ ID NO. 254)

[0429] NPD011s-353 (SEQ ID NO. 89 and SEQ ID NO. 255)

[0430] NPD011s-354 (SEQ ID NO. 90 and SEQ ID NO. 256)

[0431] NPD011s-355 (SEQ ID NO.91 and SEQ ID NO.257)

[0432] NPD011s-356 (SEQ ID NO. 92 and SEQ ID NO. 258)

[0433] NPD011s-357 (SEQ ID NO. 93 and SEQ ID NO. 259)

[0434] NPD011s-358 (SEQ ID NO. 94 and SEQ ID NO. 260)

[0435] NPD011s-359 (SEQ ID NO. 95 and SEQ ID NO. 261)

[0436] NPD011s-360 (SEQ ID NO. 96 and SEQ ID NO. 262)

[0437] NPD011s-361 (SEQ ID NO. 97 and SEQ ID NO. 263)

[0438] NPD011s-362 (SEQ ID NO. 98 and SEQ ID NO. 264)

[0439] NPD011s-363 (SEQ ID NO. 99 and SEQ ID NO. 265)

[0440] NPD011s-364 (SEQ ID NO. 100 and SEQ ID NO. 266)

[0441] NPD011s-365 (SEQ ID NO. 101 and SEQ ID NO. 267)

[0442] NPD011s-366 (SEQ ID NO. 102 and SEQ ID NO. 268)

[0443] NPD011s-367 (SEQ ID NO. 103 and SEQ ID NO. 269)

[0444] NPD011s-368 (SEQ ID NO. 104 and SEQ ID NO. 270)

[0445] NPD011s-369 (SEQ ID NO. 105 and SEQ ID NO. 271)

[0446] NPD011s-370 (SEQ ID NO. 106 and SEQ ID NO. 272)

[0447] NPD011s-371 (SEQ ID NO. 107 and SEQ ID NO. 273)

[0448] NPD011s-372 (SEQ ID NO. 108 and SEQ ID NO. 274)

[0449] NPD011s-373 (SEQ ID NO. 109 and SEQ ID NO. 275)

[0450] NPD011s-374 (SEQ ID NO. 110 and SEQ ID NO. 276)

[0451] NPD011s-375 (SEQ ID NO. 111 and SEQ ID NO. 277)

[0452] NPD011s-376 (SEQ ID NO. 112 and SEQ ID NO. 278)

[0453] NPD011s-377 (SEQ ID NO. 113 and SEQ ID NO. 279)

[0454] NPD011s-378 (SEQ ID NO. 114 and SEQ ID NO. 280)

[0455] NPD011s-379 (SEQ ID NO. 115 and SEQ ID NO. 281)

[0456] NPD011s-380 (SEQ ID NO. 116 and SEQ ID NO. 282)

[0457] NPD011s-381 (SEQ ID NO. 117 and SEQ ID NO. 283)

[0458] NPD011s-382 (SEQ ID NO. 118 and SEQ ID NO. 284)

[0459] NPD011s-383 (SEQ ID NO. 119 and SEQ ID NO. 285)

[0460] NPD011s-384 (SEQ ID NO. 120 and SEQ ID NO. 286)

[0461] NPD011s-385 (SEQ ID NO. 121 and SEQ ID NO. 287)

[0462] NPD011s-386 (SEQ ID NO. 122 and SEQ ID NO. 288)

[0463] NPD011s-387 (SEQ ID NO. 123 and SEQ ID NO. 289)

[0464] NPD011s-388 (SEQ ID NO. 124 and SEQ ID NO. 290)

[0465] NPD011s-389 (SEQ ID NO. 125 and SEQ ID NO. 291)

[0466] NPD011s-390 (SEQ ID NO. 126 and SEQ ID NO. 292)

[0467] NPD011s-391 (SEQ ID NO. 127 and SEQ ID NO. 293)

[0468] NPD011s-392 (SEQ ID NO. 128 and SEQ ID NO. 294)

[0469] NPD011s-393 (SEQ ID NO. 129 and SEQ ID NO. 295)

[0470] NPD011s-394 (SEQ ID NO. 130 and SEQ ID NO. 296)

[0471] NPD011s-395 (SEQ ID NO. 131 and SEQ ID NO. 297)

[0472] NPD011s-396 (SEQ ID NO. 132 and SEQ ID NO. 298)

[0473] NPD011s-397 (SEQ ID NO. 133 and SEQ ID NO. 299)

[0474] NPD011s-398 (SEQ ID NO. 134 and SEQ ID NO. 300)

[0475] NPD011s-399 (SEQ ID NO. 135 and SEQ ID NO. 301)

[0476] NPD011s-400 (SEQ ID NO. 136 and SEQ ID NO. 302)

[0477] NPD011s-401 (SEQ ID NO. 137 and SEQ ID NO. 303)

[0478] NPD011s-402 (SEQ ID NO. 138 and SEQ ID NO. 304)

[0479] NPD011s-403 (SEQ ID NO. 139 and SEQ ID NO. 305)

[0480] NPD011s-404 (SEQ ID NO. 140 and SEQ ID NO. 306)

[0481] NPD011s-405 (SEQ ID NO. 141 and SEQ ID NO. 307)

[0482] NPD011s-406 (SEQ ID NO. 142 and SEQ ID NO. 308)

[0483] NPD011s-407 (SEQ ID NO. 143 and SEQ ID NO. 309)

[0484] NPD011s-408 (SEQ ID NO. 144 and SEQ ID NO. 310)

[0485] NPD011s-409 (SEQ ID NO. 145 and SEQ ID NO. 311)

[0486] NPD011s-410 (SEQ ID NO. 146 and SEQ ID NO. 312)

[0487] NPD011s-411 (SEQ ID NO. 147 and SEQ ID NO. 313)

[0488] NPD011s-412 (SEQ ID NO. 148 and SEQ ID NO. 314)

[0489] NPD011s-413 (SEQ ID NO. 149 and SEQ ID NO. 315)

[0490] NPD011s-414 (SEQ ID NO. 150 and SEQ ID NO. 316)

[0491] NPD011s-415 (SEQ ID NO. 151 and SEQ ID NO. 317)

[0492] NPD011s-416 (SEQ ID NO. 152 and SEQ ID NO. 318)

[0493] NPD011s-417 (SEQ ID NO. 153 and SEQ ID NO. 319)

[0494] NPD011s-418 (SEQ ID NO. 154 and SEQ ID NO. 320)

[0495] NPD011s-419 (SEQ ID NO. 155 and SEQ ID NO. 321)

[0496] NPD011s-420 (SEQ ID NO. 156 and SEQ ID NO. 322)

[0497] NPD011s-421 (SEQ ID NO. 157 and SEQ ID NO. 323)

[0498] NPD011s-422 (SEQ ID NO. 158 and SEQ ID NO. 324)

[0499] NPD011s-423 (SEQ ID NO. 159 and SEQ ID NO. 325)

[0500] NPD011s-424 (SEQ ID NO. 160 and SEQ ID NO. 326)

[0501] NPD011s-425 (SEQ ID NO. 161 and SEQ ID NO. 327)

[0502] NPD011s-426 (SEQ ID NO. 162 and SEQ ID NO. 328)

[0503] NPD011s-427 (SEQ ID NO. 163 and SEQ ID NO. 329)

[0504] NPD011s-428 (SEQ ID NO. 164 and SEQ ID NO. 330)

[0505] NPD011s-429 (SEQ ID NO. 165 and SEQ ID NO. 331)

[0506] NPD011s-430 (SEQ ID NO. 166 and SEQ ID NO. 332).

[0507] In another aspect, the present invention provides an siRNA conjugate. According to an embodiment of the present invention, the siRNA conjugate comprises: the aforementioned siRNA and a delivery vector, wherein the siRNA is covalently linked to the delivery vector. The inventors have experimentally discovered that the addition of a delivery vector to the siRNA conjugate can further enhance the degradation of AGT mRNA, specifically reducing AGT synthesis in hepatocytes, thereby lowering blood pressure in vivo and effectively preventing or treating diseases caused by excessive angiotensinogen, such as hypertension.

[0508] A delivery vector refers to a class of substances that can alter the tissue distribution of siRNA and target specific tissues, for example, compared to species without the delivery vector, the delivery vector provides enhanced affinity for the selected target (e.g., a molecule, cell or cell type, compartment (e.g., a cell or organ compartment, body tissue, organ or region)). The delivery vector can be a natural protein (e.g., human serum albumin (HSA)), a carbohydrate (e.g., dextran and chitosan), or a lipid; it can also be a recombinant or synthetic molecule, such as a synthetic polymer. Preferably, the delivery vector does not participate in the pairing of the sense and antisense strands in the siRNA.

[0509] According to an embodiment of the present invention, the delivery vector is connected to the sense strand of the siRNA.

[0510] According to an embodiment of the present invention, the ligand is linked to the 5'-end or 3'-end of the sense strand in the siRNA via a phosphate bond or a phosphorothioate bond.

[0511] According to an embodiment of the present invention, the delivery vector is a GalNAc-derived compound;

[0512] According to an embodiment of the present invention, the GalNAc derivative compound includes at least one selected from 1043, 1046, 1048, 1059 and 1060:

[0513] According to an embodiment of the present invention, the antisense strand of the siRNA conjugate comprises a chemically modified nucleotide sequence selected from the following duplexes:

[0514] NPD011s-261 (SEQ ID NO. 1 and SEQ ID NO. 167)

[0515] NPD011s-265 (SEQ ID NO. 5 and SEQ ID NO. 171)

[0516] NPD011s-269 (SEQ ID NO. 9 and SEQ ID NO. 175)

[0517] NPD011s-278 (SEQ ID NO. 17 and SEQ ID NO. 183)

[0518] NPD011s-288 (SEQ ID NO. 24 and SEQ ID NO. 190)

[0519] NPD011s-289 (SEQ ID NO. 25 and SEQ ID NO. 191)

[0520] NPD011s-290 (SEQ ID NO. 26 and SEQ ID NO. 192)

[0521] NPD011s-291 (SEQ ID NO. 27 and SEQ ID NO. 193)

[0522] NPD011s-292 (SEQ ID NO. 28 and SEQ ID NO. 194)

[0523] NPD011s-293 ​​(SEQ ID NO. 29 and SEQ ID NO. 195)

[0524] NPD011s-348 (SEQ ID NO. 84 and SEQ ID NO. 250)

[0525] NPD011s-349 (SEQ ID NO. 85 and SEQ ID NO. 251)

[0526] NPD011s-350 (SEQ ID NO. 86 and SEQ ID NO. 252)

[0527] NPD011s-351 (SEQ ID NO. 87 and SEQ ID NO. 253)

[0528] NPD011s-352 (SEQ ID NO. 88 and SEQ ID NO. 254)

[0529] NPD011s-353 (SEQ ID NO. 89 and SEQ ID NO. 255)

[0530] NPD011s-354 (SEQ ID NO. 90 and SEQ ID NO. 256)

[0531] NPD011s-355 (SEQ ID NO.91 and SEQ ID NO.257)

[0532] NPD011s-356 (SEQ ID NO. 92 and SEQ ID NO. 258)

[0533] NPD011s-357 (SEQ ID NO. 93 and SEQ ID NO. 259)

[0534] NPD011s-358 (SEQ ID NO. 94 and SEQ ID NO. 260)

[0535] NPD011s-359 (SEQ ID NO. 95 and SEQ ID NO. 261)

[0536] NPD011s-360 (SEQ ID NO. 96 and SEQ ID NO. 262)

[0537] NPD011s-361 (SEQ ID NO. 97 and SEQ ID NO. 263)

[0538] NPD011s-362 (SEQ ID NO. 98 and SEQ ID NO. 264)

[0539] NPD011s-363 (SEQ ID NO. 99 and SEQ ID NO. 265)

[0540] NPD011s-364 (SEQ ID NO. 100 and SEQ ID NO. 266)

[0541] NPD011s-365 (SEQ ID NO. 101 and SEQ ID NO. 267)

[0542] NPD011s-366 (SEQ ID NO. 102 and SEQ ID NO. 268)

[0543] NPD011s-367 (SEQ ID NO. 103 and SEQ ID NO. 269)

[0544] NPD011s-368 (SEQ ID NO. 104 and SEQ ID NO. 270)

[0545] NPD011s-369 (SEQ ID NO. 105 and SEQ ID NO. 271)

[0546] NPD011s-370 (SEQ ID NO. 106 and SEQ ID NO. 272)

[0547] NPD011s-371 (SEQ ID NO. 107 and SEQ ID NO. 273)

[0548] NPD011s-372 (SEQ ID NO. 108 and SEQ ID NO. 274)

[0549] NPD011s-402 (SEQ ID NO. 138 and SEQ ID NO. 304)

[0550] NPD011s-403 (SEQ ID NO. 139 and SEQ ID NO. 305)

[0551] NPD011s-404 (SEQ ID NO. 140 and SEQ ID NO. 306)

[0552] NPD011s-405 (SEQ ID NO. 141 and SEQ ID NO. 307)

[0553] NPD011s-406 (SEQ ID NO. 142 and SEQ ID NO. 308)

[0554] NPD011s-407 (SEQ ID NO. 143 and SEQ ID NO. 309)

[0555] NPD011s-408 (SEQ ID NO. 144 and SEQ ID NO. 310)

[0556] NPD011s-409 (SEQ ID NO. 145 and SEQ ID NO. 311)

[0557] NPD011s-410 (SEQ ID NO. 146 and SEQ ID NO. 312)

[0558] NPD011s-411 (SEQ ID NO. 147 and SEQ ID NO. 313)

[0559] NPD011s-412 (SEQ ID NO. 148 and SEQ ID NO. 314)

[0560] NPD011s-413 (SEQ ID NO. 149 and SEQ ID NO. 315)

[0561] NPD011s-414 (SEQ ID NO. 150 and SEQ ID NO. 316)

[0562] NPD011s-415 (SEQ ID NO. 151 and SEQ ID NO. 317)

[0563] NPD011s-416 (SEQ ID NO. 152 and SEQ ID NO. 318)

[0564] NPD011s-417 (SEQ ID NO. 153 and SEQ ID NO. 319)

[0565] NPD011s-418 (SEQ ID NO. 154 and SEQ ID NO. 320)

[0566] NPD011s-419 (SEQ ID NO. 155 and SEQ ID NO. 321)

[0567] NPD011s-420 (SEQ ID NO. 156 and SEQ ID NO. 322)

[0568] NPD011s-421 (SEQ ID NO. 157 and SEQ ID NO. 323)

[0569] NPD011s-422 (SEQ ID NO. 158 and SEQ ID NO. 324)

[0570] NPD011s-423 (SEQ ID NO. 159 and SEQ ID NO. 325)

[0571] NPD011s-424 (SEQ ID NO. 160 and SEQ ID NO. 326)

[0572] NPD011s-425 (SEQ ID NO. 161 and SEQ ID NO. 327)

[0573] NPD011s-426 (SEQ ID NO. 162 and SEQ ID NO. 328)

[0574] NPD011s-427 (SEQ ID NO. 163 and SEQ ID NO. 329)

[0575] NPD011s-428 (SEQ ID NO. 164 and SEQ ID NO. 330)

[0576] NPD011s-429 (SEQ ID NO. 165 and SEQ ID NO. 331)

[0577] NPD011s-430 (SEQ ID NO. 166 and SEQ ID NO. 332).

[0578] According to an embodiment of the present invention, the sense strand of the siRNA conjugate comprises a chemically modified nucleotide sequence selected from the following duplexes:

[0579] NPD011s-261 (SEQ ID NO. 1 and SEQ ID NO. 167)

[0580] NPD011s-265 (SEQ ID NO. 5 and SEQ ID NO. 171)

[0581] NPD011s-269 (SEQ ID NO. 9 and SEQ ID NO. 175)

[0582] NPD011s-278 (SEQ ID NO. 17 and SEQ ID NO. 183)

[0583] NPD011s-288 (SEQ ID NO. 24 and SEQ ID NO. 190)

[0584] NPD011s-289 (SEQ ID NO. 25 and SEQ ID NO. 191)

[0585] NPD011s-290 (SEQ ID NO. 26 and SEQ ID NO. 192)

[0586] NPD011s-291 (SEQ ID NO. 27 and SEQ ID NO. 193)

[0587] NPD011s-292 (SEQ ID NO. 28 and SEQ ID NO. 194)

[0588] NPD011s-293 ​​(SEQ ID NO. 29 and SEQ ID NO. 195)

[0589] NPD011s-348 (SEQ ID NO. 84 and SEQ ID NO. 250)

[0590] NPD011s-349 (SEQ ID NO. 85 and SEQ ID NO. 251)

[0591] NPD011s-350 (SEQ ID NO. 86 and SEQ ID NO. 252)

[0592] NPD011s-351 (SEQ ID NO. 87 and SEQ ID NO. 253)

[0593] NPD011s-352 (SEQ ID NO. 88 and SEQ ID NO. 254)

[0594] NPD011s-353 (SEQ ID NO. 89 and SEQ ID NO. 255)

[0595] NPD011s-354 (SEQ ID NO. 90 and SEQ ID NO. 256)

[0596] NPD011s-355 (SEQ ID NO.91 and SEQ ID NO.257)

[0597] NPD011s-356 (SEQ ID NO. 92 and SEQ ID NO. 258)

[0598] NPD011s-357 (SEQ ID NO. 93 and SEQ ID NO. 259)

[0599] NPD011s-358 (SEQ ID NO. 94 and SEQ ID NO. 260)

[0600] NPD011s-359 (SEQ ID NO. 95 and SEQ ID NO. 261)

[0601] NPD011s-360 (SEQ ID NO. 96 and SEQ ID NO. 262)

[0602] NPD011s-361 (SEQ ID NO. 97 and SEQ ID NO. 263)

[0603] NPD011s-362 (SEQ ID NO. 98 and SEQ ID NO. 264)

[0604] NPD011s-363 (SEQ ID NO. 99 and SEQ ID NO. 265)

[0605] NPD011s-364 (SEQ ID NO. 100 and SEQ ID NO. 266)

[0606] NPD011s-365 (SEQ ID NO. 101 and SEQ ID NO. 267)

[0607] NPD011s-366 (SEQ ID NO. 102 and SEQ ID NO. 268)

[0608] NPD011s-367 (SEQ ID NO. 103 and SEQ ID NO. 269)

[0609] NPD011s-368 (SEQ ID NO. 104 and SEQ ID NO. 270)

[0610] NPD011s-369 (SEQ ID NO. 105 and SEQ ID NO. 271)

[0611] NPD011s-370 (SEQ ID NO. 106 and SEQ ID NO. 272)

[0612] NPD011s-371 (SEQ ID NO. 107 and SEQ ID NO. 273)

[0613] NPD011s-372 (SEQ ID NO. 108 and SEQ ID NO. 274)

[0614] NPD011s-402 (SEQ ID NO. 138 and SEQ ID NO. 304)

[0615] NPD011s-403 (SEQ ID NO. 139 and SEQ ID NO. 305)

[0616] NPD011s-404 (SEQ ID NO. 140 and SEQ ID NO. 306)

[0617] NPD011s-405 (SEQ ID NO. 141 and SEQ ID NO. 307)

[0618] NPD011s-406 (SEQ ID NO. 142 and SEQ ID NO. 308)

[0619] NPD011s-407 (SEQ ID NO. 143 and SEQ ID NO. 309)

[0620] NPD011s-408 (SEQ ID NO. 144 and SEQ ID NO. 310)

[0621] NPD011s-409 (SEQ ID NO. 145 and SEQ ID NO. 311)

[0622] NPD011s-410 (SEQ ID NO. 146 and SEQ ID NO. 312)

[0623] NPD011s-411 (SEQ ID NO. 147 and SEQ ID NO. 313)

[0624] NPD011s-412 (SEQ ID NO. 148 and SEQ ID NO. 314)

[0625] NPD011s-413 (SEQ ID NO. 149 and SEQ ID NO. 315)

[0626] NPD011s-414 (SEQ ID NO. 150 and SEQ ID NO. 316)

[0627] NPD011s-415 (SEQ ID NO. 151 and SEQ ID NO. 317)

[0628] NPD011s-416 (SEQ ID NO. 152 and SEQ ID NO. 318)

[0629] NPD011s-417 (SEQ ID NO. 153 and SEQ ID NO. 319)

[0630] NPD011s-418 (SEQ ID NO. 154 and SEQ ID NO. 320)

[0631] NPD011s-419 (SEQ ID NO. 155 and SEQ ID NO. 321)

[0632] NPD011s-420 (SEQ ID NO. 156 and SEQ ID NO. 322)

[0633] NPD011s-421 (SEQ ID NO. 157 and SEQ ID NO. 323)

[0634] NPD011s-422 (SEQ ID NO. 158 and SEQ ID NO. 324)

[0635] NPD011s-423 (SEQ ID NO. 159 and SEQ ID NO. 325)

[0636] NPD011s-424 (SEQ ID NO. 160 and SEQ ID NO. 326)

[0637] NPD011s-425 (SEQ ID NO. 161 and SEQ ID NO. 327)

[0638] NPD011s-426 (SEQ ID NO. 162 and SEQ ID NO. 328)

[0639] NPD011s-427 (SEQ ID NO. 163 and SEQ ID NO. 329)

[0640] NPD011s-428 (SEQ ID NO. 164 and SEQ ID NO. 330)

[0641] NPD011s-429 (SEQ ID NO. 165 and SEQ ID NO. 331)

[0642] NPD011s-430 (SEQ ID NO. 166 and SEQ ID NO. 332).

[0643] According to an embodiment of the present invention, the sense strand and the antisense strand of the siRNA conjugate comprise a chemically modified nucleotide sequence of a duplex selected from the group consisting of:

[0644] NPD011s-261 (SEQ ID NO. 1 and SEQ ID NO. 167)

[0645] NPD011s-265 (SEQ ID NO. 5 and SEQ ID NO. 171)

[0646] NPD011s-269 (SEQ ID NO. 9 and SEQ ID NO. 175)

[0647] NPD011s-278 (SEQ ID NO. 17 and SEQ ID NO. 183)

[0648] NPD011s-288 (SEQ ID NO. 24 and SEQ ID NO. 190)

[0649] NPD011s-289 (SEQ ID NO. 25 and SEQ ID NO. 191)

[0650] NPD011s-290 (SEQ ID NO. 26 and SEQ ID NO. 192)

[0651] NPD011s-291 (SEQ ID NO. 27 and SEQ ID NO. 193)

[0652] NPD011s-292 (SEQ ID NO. 28 and SEQ ID NO. 194)

[0653] NPD011s-293 ​​(SEQ ID NO. 29 and SEQ ID NO. 195)

[0654] NPD011s-348 (SEQ ID NO. 84 and SEQ ID NO. 250)

[0655] NPD011s-349 (SEQ ID NO. 85 and SEQ ID NO. 251)

[0656] NPD011s-350 (SEQ ID NO. 86 and SEQ ID NO. 252)

[0657] NPD011s-351 (SEQ ID NO. 87 and SEQ ID NO. 253)

[0658] NPD011s-352 (SEQ ID NO. 88 and SEQ ID NO. 254)

[0659] NPD011s-353 (SEQ ID NO. 89 and SEQ ID NO. 255)

[0660] NPD011s-354 (SEQ ID NO. 90 and SEQ ID NO. 256)

[0661] NPD011s-355 (SEQ ID NO.91 and SEQ ID NO.257)

[0662] NPD011s-356 (SEQ ID NO. 92 and SEQ ID NO. 258)

[0663] NPD011s-357 (SEQ ID NO. 93 and SEQ ID NO. 259)

[0664] NPD011s-358 (SEQ ID NO. 94 and SEQ ID NO. 260)

[0665] NPD011s-359 (SEQ ID NO. 95 and SEQ ID NO. 261)

[0666] NPD011s-360 (SEQ ID NO. 96 and SEQ ID NO. 262)

[0667] NPD011s-361 (SEQ ID NO. 97 and SEQ ID NO. 263)

[0668] NPD011s-362 (SEQ ID NO. 98 and SEQ ID NO. 264)

[0669] NPD011s-363 (SEQ ID NO. 99 and SEQ ID NO. 265)

[0670] NPD011s-364 (SEQ ID NO. 100 and SEQ ID NO. 266)

[0671] NPD011s-365 (SEQ ID NO. 101 and SEQ ID NO. 267)

[0672] NPD011s-366 (SEQ ID NO. 102 and SEQ ID NO. 268)

[0673] NPD011s-367 (SEQ ID NO. 103 and SEQ ID NO. 269)

[0674] NPD011s-368 (SEQ ID NO. 104 and SEQ ID NO. 270)

[0675] NPD011s-369 (SEQ ID NO. 105 and SEQ ID NO. 271)

[0676] NPD011s-370 (SEQ ID NO. 106 and SEQ ID NO. 272)

[0677] NPD011s-371 (SEQ ID NO. 107 and SEQ ID NO. 273)

[0678] NPD011s-372 (SEQ ID NO. 108 and SEQ ID NO. 274)

[0679] NPD011s-402 (SEQ ID NO. 138 and SEQ ID NO. 304)

[0680] NPD011s-403 (SEQ ID NO. 139 and SEQ ID NO. 305)

[0681] NPD011s-404 (SEQ ID NO. 140 and SEQ ID NO. 306)

[0682] NPD011s-405 (SEQ ID NO. 141 and SEQ ID NO. 307)

[0683] NPD011s-406 (SEQ ID NO. 142 and SEQ ID NO. 308)

[0684] NPD011s-407 (SEQ ID NO. 143 and SEQ ID NO. 309)

[0685] NPD011s-408 (SEQ ID NO. 144 and SEQ ID NO. 310)

[0686] NPD011s-409 (SEQ ID NO. 145 and SEQ ID NO. 311)

[0687] NPD011s-410 (SEQ ID NO. 146 and SEQ ID NO. 312)

[0688] NPD011s-411 (SEQ ID NO. 147 and SEQ ID NO. 313)

[0689] NPD011s-412 (SEQ ID NO. 148 and SEQ ID NO. 314)

[0690] NPD011s-413 (SEQ ID NO. 149 and SEQ ID NO. 315)

[0691] NPD011s-414 (SEQ ID NO. 150 and SEQ ID NO. 316)

[0692] NPD011s-415 (SEQ ID NO. 151 and SEQ ID NO. 317)

[0693] NPD011s-416 (SEQ ID NO. 152 and SEQ ID NO. 318)

[0694] NPD011s-417 (SEQ ID NO. 153 and SEQ ID NO. 319)

[0695] NPD011s-418 (SEQ ID NO. 154 and SEQ ID NO. 320)

[0696] NPD011s-419 (SEQ ID NO. 155 and SEQ ID NO. 321)

[0697] NPD011s-420 (SEQ ID NO. 156 and SEQ ID NO. 322)

[0698] NPD011s-421 (SEQ ID NO. 157 and SEQ ID NO. 323)

[0699] NPD011s-422 (SEQ ID NO. 158 and SEQ ID NO. 324)

[0700] NPD011s-423 (SEQ ID NO. 159 and SEQ ID NO. 325)

[0701] NPD011s-424 (SEQ ID NO. 160 and SEQ ID NO. 326)

[0702] NPD011s-425 (SEQ ID NO. 161 and SEQ ID NO. 327)

[0703] NPD011s-426 (SEQ ID NO. 162 and SEQ ID NO. 328)

[0704] NPD011s-427 (SEQ ID NO. 163 and SEQ ID NO. 329)

[0705] NPD011s-428 (SEQ ID NO. 164 and SEQ ID NO. 330)

[0706] NPD011s-429 (SEQ ID NO. 165 and SEQ ID NO. 331)

[0707] NPD011s-430 (SEQ ID NO. 166 and SEQ ID NO. 332).

[0708] In yet another aspect, the present invention provides a pharmaceutical composition. According to an embodiment of the present invention, the pharmaceutical composition comprises: the aforementioned siRNA; or the aforementioned siRNA conjugate. The pharmaceutical composition according to an embodiment of the present invention can specifically reduce AGT synthesis in hepatocytes, thereby lowering blood pressure in vivo, and effectively preventing or treating diseases related to excessive angiotensinogen, such as hypertension.

[0709] It should be noted that the pharmaceutical composition herein may include one or more of the aforementioned siRNAs or siRNA conjugates.

[0710] According to an embodiment of the present invention, the pharmaceutical composition further comprises: a pharmaceutically acceptable excipient.

[0711] In another aspect of the present invention, the present invention provides a use of the aforementioned siRNA, the aforementioned siRNA conjugate or the aforementioned pharmaceutical composition in preparing a drug, wherein the drug is used to inhibit the expression of angiotensinogen.

[0712] In another aspect of the present invention, the present invention provides a use of the aforementioned siRNA, the aforementioned siRNA conjugate or the aforementioned pharmaceutical composition in preparing a drug for preventing and / or treating diseases related to excessive angiotensinogen.

[0713] According to an embodiment of the present invention, the disease related to excessive angiotensinogen is selected from hypertension.

[0714] According to an embodiment of the present invention, the hypertension includes critical hypertension, essential hypertension, secondary hypertension, hypertensive crisis, hypertensive emergency state, isolated systolic and diastolic hypertension, pregnancy-related hypertension, diabetic hypertension, resistant hypertension, resistant hypertension, paroxysmal hypertension, renovascular hypertension, Goldblatt's hypertension, pulmonary hypertension, portal hypertension, systemic venous hypertension, systolic hypertension and unstable hypertension.

[0715] In yet another aspect, the present invention provides a method for preventing and / or treating diseases associated with excessive angiotensinogen. According to an embodiment of the present invention, the method comprises administering a pharmaceutically acceptable amount of the aforementioned siRNA, siRNA conjugate, or pharmaceutical composition to a subject. According to an embodiment of the present invention, the method can effectively prevent and / or treat diseases associated with excessive angiotensinogen.

[0716] The effective amount of the siRNA, siRNA conjugate or pharmaceutical composition of the present invention may vary depending on the mode of administration and the severity of the disease to be treated. The selection of the preferred effective amount can be determined by a person of ordinary skill in the art based on various factors (e.g., through clinical trials). Such factors include, but are not limited to: pharmacokinetic parameters of the active ingredient, such as bioavailability, metabolism, half-life, etc.; the severity of the disease to be treated, the patient's weight, the patient's immune status, the route of administration, etc. For example, depending on the urgency of the treatment condition, several divided doses may be administered daily, for example, once every several days, several weeks, or several months.

[0717] The drug can be administered to a subject by any suitable route known in the art, including but not limited to subcutaneous administration, intravenous administration, intramuscular administration, transdermal administration, airway administration (aerosol), pulmonary administration, nasal administration, rectal administration, and topical administration (including buccal administration and sublingual administration), preferably subcutaneous administration.

[0718] According to an embodiment of the present invention, the administration route of the method is subcutaneous injection.

[0719] According to an embodiment of the present invention, the disease related to excessive angiotensinogen is selected from hypertension.

[0720] According to an embodiment of the present invention, the hypertension includes critical hypertension, essential hypertension, secondary hypertension, hypertensive crisis, hypertensive emergency state, isolated systolic and diastolic hypertension, pregnancy-related hypertension, diabetic hypertension, resistant hypertension, resistant hypertension, paroxysmal hypertension, renovascular hypertension, Goldblatt's hypertension, pulmonary hypertension, portal hypertension, systemic venous hypertension, systolic hypertension and unstable hypertension.

[0721] Additional aspects and advantages of the present invention will be set forth in part in the description which follows and, in part, will be obvious from the description which follows, or may be learned by practice of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0722] Figure 1 Changes in plasma AGT levels in transgenic mice (0.5 mg / kg)

[0723] Figure 2 Changes in plasma AGT levels in transgenic mice (0.5 mg / kg)

[0724] Figure 3 Changes in plasma AGT levels in transgenic mice DETAILED DESCRIPTION

[0725] The embodiments of the present invention are described in detail below. The embodiments described below are exemplary and are only used to explain the present invention, and should not be understood as limiting the present invention.

[0726] It should be noted that the terms "first" and "second" are used for descriptive purposes only and should not be understood to indicate or imply relative importance or implicitly specify the number of the technical features indicated. Therefore, features defined as "first" or "second" may explicitly or implicitly include one or more of such features. Furthermore, in the description of the present invention, unless otherwise specified, "plurality" means two or more.

[0727] In this document, the terms “include” or “comprising” are open expressions, that is, including the contents specified in the present invention, but not excluding other contents.

[0728] As used herein, the terms "optionally," "optional," or "optionally" generally mean that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.

[0729] As used herein, the term "small interfering RNA (siRNA)" refers to a double-stranded RNA of 17 to 25 nucleotides in length, comprising a sense strand and an antisense strand. siRNA mediates the targeted cleavage of target mRNAs via the RNA-induced silencing complex (RISC) pathway by forming a silencing complex. Specifically, siRNA guides the specific degradation of mRNA sequences through the known RNA interference (RNAi) process, inhibiting the translation of mRNA into protein. For example, siRNA can regulate (e.g., inhibit) the expression of AGT in cells.

[0730] As used herein, the term "antisense strand (or guide strand)" includes a region that is substantially complementary to a target sequence, such as AGT mRNA. The "follower strand" refers to an RNAi strand that contains a region that is substantially complementary to the antisense strand. The term "substantially complementary" refers to complete complementarity or at least partial complementarity, for example, the antisense strand is completely complementary to the target sequence or at least partially complementary. In the case of partial complementarity, mismatches can exist within the interior or terminal regions of the molecule, wherein the most tolerated mismatches exist within the terminal regions, for example, within 5, 4, 3 or 2 nucleotides of the 5' end and / or 3' end of the RNAi.

[0731] It should be noted that "at least a portion of the antisense strand is substantially complementary to an mRNA" means that the antisense strand comprises a polynucleotide that is substantially complementary to a continuous portion of an mRNA of interest (e.g., an mRNA encoding AGT). Alternatively, if a polynucleotide is substantially non-interruptedly complementary to a portion of an mRNA encoding AGT, then the antisense strand is complementary to at least a portion of an AGT mRNA.

[0732] As used herein, the term "target sequence" refers to a contiguous portion of the nucleotide sequence of an mRNA molecule formed during transcription of the AGT gene, including mRNA that is a product of RNA processing of the primary transcript.

[0733] As used herein, the term "inhibiting the expression of an AGT gene" includes any level of inhibition of an AGT gene, for example, at least partial inhibition of AGT gene expression, such as inhibition of at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99%. AGT gene expression can be assessed based on the level of any variable associated with AGT gene expression, for example, AGT mRNA levels or AGT protein levels. Inhibition can be assessed by a decrease in the absolute or relative level of one or more of these variables compared to a control level. The control level can be any type of control level utilized in the art, e.g., a baseline level prior to administration, or a level determined from a similar subject, cell, or sample that has not been treated or has been treated with a control (e.g., a buffer-only control or a no active agent control).

[0734] As used herein, the term "AGT" includes mRNA or its complete coding sequence for AGT, such as human AGT, which can be found, for example, in GenBank Accession No. GI: ​​188595658 (NM_000029.3). Other examples of AGT mRNA sequences can be obtained using publicly available databases, such as GenBank and genome project websites such as UniProt. The term "AGT" can also refer to naturally occurring DNA sequence variations of the AGT gene, such as single nucleotide polymorphisms (SNPs) in the AGT gene.

[0735] As used herein, the terms "expression vector" and "construct" are used interchangeably and are capable of delivering one or more genes or sequences of interest into a host cell and preferably expressing the genes or sequences in the host cell. Examples of vectors include, but are not limited to, viral vectors, plasmids, cosmids, or phage vectors.

[0736] As used herein, "pharmaceutical composition" may refer to a composition for use in treating a disease or in vitro cell culture experiments. When used in treating a disease, the term "pharmaceutical composition" generally refers to a unit dosage form and can be prepared by any of the methods well known in the pharmaceutical art. All methods include the step of combining the active ingredient with an excipient that constitutes one or more adjunct ingredients. Typically, the composition is prepared by uniformly and thoroughly combining the active siRNA or siRNA conjugate with a liquid excipient, a finely divided solid excipient, or both.

[0737] As used herein, the term "pharmaceutically acceptable" means that the substance or composition must be chemically and / or toxicologically compatible with the other ingredients of the formulation and / or the mammal to be treated therewith. Preferably, the term "pharmaceutically acceptable" as used herein means approved by federal regulatory agencies or national governments or listed in the U.S. Pharmacopoeia or other generally recognized pharmacopeia for use in animals, particularly humans.

[0738] As used herein, the term "pharmaceutically acceptable excipient" is recognized in the art and includes pharmaceutically acceptable materials, compositions, or carriers suitable for administering the siRNA or siRNA conjugates of the present disclosure to mammals. Such excipients include liquid or solid fillers, diluents, excipients, solvents, or encapsulating materials that participate in carrying the subject substance or transferring it from one organ or part of the body to another. Each excipient must be "acceptable" in the sense of being compatible with the other ingredients in the formulation and not harmful to the patient. Some examples of materials that can be used as pharmaceutically acceptable excipients include: sugars, such as lactose, glucose, and sucrose; cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate, powdered gum tragacanth, malt, gelatin, talc, excipients such as cocoa butter and suppository waxes; oleyl glycols, such as propylene glycol; polyols, such as glycerol, sorbitol, mannitol, and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; buffers, such as magnesium hydroxide and aluminum hydroxide; ethanol; phosphate buffers; and other nontoxic, compatible substances used in pharmaceutical formulations.

[0739] In addition to any conventional excipients, to the extent that they are incompatible with the siRNA or siRNA conjugates of the present invention, such as any adverse biological effects produced or interactions with any other components of the pharmaceutically acceptable composition in a deleterious manner, their use is also contemplated by the present invention.

[0740] The pharmaceutical compositions of the present disclosure include formulations suitable for oral, nasal, topical, buccal, sublingual, rectal and / or parenteral administration. The formulations can be conveniently present in unit dosage form and can be prepared by any method known in the pharmaceutical field. The amount of active ingredient that can be combined with excipients to prepare a single dose form is generally the amount of siRNA or siRNA conjugate that produces a therapeutic effect. Generally speaking, in percent units, this amount is from about 1% to about 99% active ingredient, preferably from about 5% to about 70%, and most preferably from about 10% to about 30%.

[0741] As used herein, the term "treatment" refers to any process used to refer to obtaining a desired pharmacological and / or physiological effect. The effect may be preventive in terms of completely or partially preventing a disease or its symptoms, and / or therapeutic in terms of partially or completely curing a disease and / or the adverse effects caused by the disease. "Treatment" as used herein covers diseases in mammals, particularly humans, and includes: (a) preventing the occurrence of a disease or condition in an individual who is susceptible to the disease but has not yet been diagnosed with the disease; (b) inhibiting the disease, such as arresting the progression of the disease; or (c) alleviating the disease, such as alleviating the symptoms associated with the disease. "Treatment" as used herein covers any medication that administers siRNA, siRNA conjugates or drugs to an individual to treat, cure, alleviate, improve, reduce or inhibit the individual's disease, including but not limited to administering a drug containing the siRNA or siRNA conjugates described herein to an individual in need.

[0742] The scheme of the present invention will be explained below in conjunction with embodiment. Those skilled in the art will understand that the following examples are only used to illustrate the present invention and should not be regarded as limiting the scope of the present invention. Where specific techniques or conditions are not specified in the examples, they are carried out according to the techniques or conditions described in the literature in this area or according to the product specifications. Where the manufacturer of the reagents or instruments is not specified, they are all conventional products that can be purchased commercially.

[0743] Example 1: Design of siRNA

[0744] siRNA technology is an innovative gene knockout method with the advantages of high efficiency, specificity and reliability. It has received widespread attention in the fields of disease treatment and genetic research. The 111 siRNAs designed by the custom Python script proposed in this example for the human AGT gene (NCBI refseqID NM_000029.3; NCBI GeneID: 183) are an important advancement in this technology. The REFSEQ mRNA version of this gene is version 3, with a length of 2587 bases. Unlike traditional siRNA design methods, the siRNA design method of this example relies on an independently developed Python script, which can quickly and accurately determine the appropriate siRNA sequence. In this experiment, 12 unmodified siRNA duplexes were prepared, named NDS112 to NDS122. The nucleotide sequences of the sense and antisense chains of these siRNAs are given in Table 1.

[0745] Example 2: Synthesis of siRNA and conjugates

[0746] Table 2: Nucleotide monomer abbreviations used in nucleic acid sequences

[0747] Deprotection, condensation, capping, oxidation or thiolation were performed according to standard oligonucleotide solid-phase synthesis protocols using commercially available 5'-DMT-2'-OMe-U phosphoramidite monomers, 5'-DMT-2'-OMe-A(Bz) phosphoramidite monomers, 5'-DMT-2'-OMe-C(Ac) phosphoramidite monomers, 5'-DMT-2'-OMe-G(ibu) phosphoramidite monomers, 5'-DMT-2'-F-dU phosphoramidite monomers, 5'-DMT-2'-F-Ac-dC phosphoramidite monomers, 5'-DMT-2'-F-ibu-dG phosphoramidite monomers, 5'-DMT-2'-F-Bz-dA phosphoramidite monomers, and synthetic GalNAc phosphoramidite monomers. RNA was synthesized at a 500 nmol or 4 μmol scale. A 50 mM RNA phosphoramidite solution and a 200 mM GalNAc monomer solution were prepared in acetonitrile. 0.3 M benzylthiotetrazolium (BTT) in acetonitrile was used as an activator to synthesize the sense and antisense strands in the 3'-to-5' direction. During synthesis, trivalent phosphorus was converted to pentavalent phosphorus using a 0.1 M oxidizing agent (I2:pyridine:THF:water) or a 0.2 M hydroxanthin / pyridine solution to stabilize the phosphate backbone. Following synthesis, aminolysis was performed using either an AMA solution (40% methylamine:ammonia solution = 1:1) at 55°C for 50 min or 28% ammonia solution at 65°C for 5 h. The AMA or ammonia solution was removed by vacuum centrifugation. Purification was performed using a PS-15Q ion purification column with a phosphate and sodium chloride solution as the mobile phase, or a C18 reverse-phase column with an aqueous triethylamine acetate solution and acetonitrile as the mobile phase. LCMS and HPLC were used for in-process control. The sense and antisense strands were mixed at a molar ratio of 1:1 and annealed at 90°C to form double-stranded siRNA and siRNA conjugates. The inventors verified the prepared conjugates (compound 1048 linked to the 5' end of the sense strand; compounds 1059 and 1060 linked to the 3' end of the sense strand). The mass spectrometry data of the modified siRNA sequence are shown in Table 3.

[0748] Table 3: Modified sense and antisense strand sequences of double-stranded RNAi agents

[0749] Table 4: Modified sense and antisense strand sequences of double-stranded RNAi agents (reference sequences)

[0750] aM represents 2'-O-methyladenosine, uM represents 2'-O-methyluridine, gM represents 2'-O-methylguanosine, cM represents 2'-O-methylcytosine, aF represents 2'-fluoroadenosine, uF represents 2'-fluorouridine, gF represents 2'-fluoroguanosine, cF represents 2'-fluorocytosine, dA represents deoxyadenosine-3'-phosphate, dC represents deoxycytidine-3'-phosphate, dG represents deoxyguanosine-3'-phosphate, dT represents deoxythymidine-3'-phosphate, iVPM represents =2'-O-methyl-5'-deoxy-(E)-vinylphosphonate-inosine-3'-phosphate, uVPM represents 2'-O-methyl-5'-deoxy-(E)-vinylphosphonate-uridine-3'-phosphate, aTA4 represents 2'-O-methyl-5'-deoxy-(1-(1,2,4-triazole))-adenosine-3'-phosphate, cTA4 represents 2'-O-methyl-5'-deoxy-(1-(1,2,4-triazole))-cytidine-3'-phosphate, and gTA4 represents 2'-O-methyl-5'-deoxy-(1-(1,2,4 -triazole)-guanosine-3'-phosphate, uTA4 represents 2'-O-methyl-5'-deoxy-(1-(1,2,4-triazole))-uridine-3'-phosphate, aSMP represents 2'-O-methyl-5'-N-(thiomorpholino)-adenosine-3'-phosphate, cSMP represents 2'-O-methyl-5'-N-(thiomorpholino)-cytidine-3'-phosphate, gSMP represents 2'-O-methyl-5'-N-(thiomorpholino)-guanosine-3'-phosphate, and uSMP represents 2'-O-methyl-5'-N-(thiomorpholino)-uridine -3'-phosphate, aRF represents 3'-fluoro-3'-deoxyadenosine-2'-phosphate, cRF represents 3'-fluoro-3'-deoxycytidine-2'-phosphate, gRF represents 3'-fluoro-3'-deoxyguanosine-2'-phosphate, uRF represents 3'-fluoro-3'-deoxyuridine-2'-phosphate, cXF represents 3'-fluoro-3'-deoxycytidine xylosyl-2'-phosphate, * indicates that two nucleotides (or compounds 1048, 1059, 1060 and nucleotides) are linked by a phosphorothioate diester bond, and there is no symbol between directly adjacent nucleotides.

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

[0752] iVP was prepared according to the method described in patent CN202110008013.3; aTA4, cTA4, gTA4, uTA4, aSMP, cSMP, gSMP and uSMP were prepared according to the method described in patent CN202110008013.3; aRF, cRF, gRF, uRF, aXF, cXF, gXF and uXF were prepared according to the method described in patent CN202110008013.3; compounds 1059 and 1060 were prepared according to the method described in patent CN202110008013.3; compound 1048 was prepared according to the method described in patent CN202110008013.3.

[0753] Example 3: In vitro cell model (Hep 3B cells) testing the activity of small interfering nucleic acids (siRNA)

[0754] Human hepatocellular carcinoma Hep 3B cells (Shanghai Cell Bank, Chinese Academy of Sciences) were cultured in DMEM (Gibco, US) supplemented with 10% fetal bovine serum (Gibco, US) at 37°C and 5% CO2 (il60, Thermos Fisher). On the day of transfection, cells were digested with 0.25% Trypsin (Gibco, US), counted, and seeded at a density of 70,000 cells / well in a 24-well plate. RNAiMAX (Thermos Fisher) was used as the vector for transfection according to standard protocols, with 1 μL of RNAiMAX per well. Final siRNA concentrations were 10 nM and 0.1 nM or 1 nM and 0.01 nM, with two replicate wells set up for each test substance at each dose. A control group containing only the transfection reagent without siRNA was used as the transfection system.

[0755] 24 hours after transfection, RNA was extracted from cells using Trizol (Solarbio R1100). Subsequently, the qPCR reaction system was configured according to the standard protocol using the HiScript II One Step qRT-PCR SYBR Green Kit (VAZYME Q221-01). The expression level of the target gene was quantified using a high-throughput qPCR instrument (Analytikjena qTOWER 384G). The relative expression changes of the target gene in the test and control samples were analyzed using the ΔΔCT method.

[0756] The activities of the siRNA sequences are shown in Table 5. The reference sequence information is shown in Table 4.

[0757] Table 5: In vitro silencing efficiency of siRNA duplexes (0.01 nM and 1 nM)

[0758] Example 4: In vitro cytotoxicity test of GalNAc-siRNA

[0759] siRNA targeting PLK1 mRNA served as a positive control, and modified AGT-siRNA sequences, which showed high activity in in vitro activity screening, served as test compounds. Human liver tumor Hep3B cells were used as an in vitro screening model. Test siRNA samples were transfected with the commercially available transfection reagent RNAiMAX, and CCK8 assays were performed at selected time points to assess cytotoxicity. Human Hep3B hepatocellular carcinoma cells (Shanghai Cell Bank, Chinese Academy of Sciences) were cultured in DMEM (Gibco, US) supplemented with 10% fetal bovine serum (FBS) (Gibco, US) at 37°C and 5% CO2 (il60, Thermos Fisher). The day before transfection, cells were digested with 0.25% Trypsin (Gibco, US), counted, and seeded in 96-well plates at a density of 5,000 cells / well in a volume of 100 μL / well. On the day of transfection, RNAiMAX (Thermos Fisher) was used as the vector for transfection according to standard protocols, with 0.25 μL of RNAiMAX per well. Final siRNA concentrations were 0.3 nM, 1 nM, 3 nM, 10 nM, 30 nM, 100 nM, and 300 nM. 72 hours after transfection, the culture medium was replaced and 10 μL of CCK8 (Solebol) was added to each well. After incubation for 1-2 hours, absorbance was measured at 450 nm using a SYNERGY H1 microplate reader (BioTek). Data are presented as mean cell viability (%).

[0760] The results showed that the test substances NPD011s-265, 269, 270, 273, 274, 277, 279, 280, and 281 exhibited high in vitro safety. The data are summarized in Table 6. The reference sequence information is shown in Table 4.

[0761] Example 5: Free uptake test of GalNAc-siRNA activity in cynomolgus monkey and human primary liver cells

[0762] The purpose of this study was to evaluate the in vitro inhibition of AGT mRNA by siRNA using primary human hepatocytes (PHH) and primary cynomolgus macaque hepatocytes (PCH). PHH (Lot No. JMJ) were provided by WuXi AppTec and purchased from Read Liver Disease Research (Shanghai) Co., Ltd. PHH were cultured in InvitroGRO CP Medium (BIOIVT, Catalog No. S03316) supplemented with 10% fetal bovine serum (ExCell Bio, Catalog No. FSP500) and 1% penicillin-streptomycin (HyClone, Catalog No. SV30010). PCH (Lot No. GSYG) were provided by WuXi AppTec and purchased from Read Liver Disease Research (Shanghai) Co., Ltd. PCH were revived in InvitroGRO HT Medium (BIOIVT, catalog number S03317) containing 10% fetal bovine serum and 1% penicillin-streptomycin, and then cultured in InvitroGRO CP Medium containing 10% fetal bovine serum and 1% penicillin-streptomycin.

[0763] The test compound was diluted to 10 times the final concentration with nuclease-free water (e.g., if the final concentration is 10 nM, dilute to 100 nM). The final concentrations of the tested compounds are shown in Table 3. The diluted siRNA was then added to a 96-well plate pre-coated with collagen at a volume of 10 μL / well. A total of four concentration points were added: 100 nM, 10 nM, 1 nM, and 0.1 nM. Each concentration was replicated in triplicate. Nuclease-free water was also added as a control. Frozen PHH and PCH cells were then thawed in a 37°C water bath. The completely thawed PHH and PCH cells were transferred to 10% FBS InvitroGRO CP Medium and 10% FBS InvitroGRO HT medium, respectively, and mixed thoroughly. PCH cells were centrifuged at 50g for 5 minutes, and the supernatant was discarded. The cells were resuspended in 10% FBS InvitroGRO CP medium and counted using an automated cell fluorescence analyzer. The cell density was adjusted to 6 x 10^5 cells / mL based on the count results. The adjusted PHH and PCH cells were then added to the corresponding 96-well cell plates at a volume of 90 μL / well, for a final volume of 100 μL per well. The cell plates were incubated in a 5% CO2, 37°C incubator for 48 hours.

[0764] Intracellular RNA was extracted according to the Qiagen-74182 RNA extraction kit instructions, and then reverse transcribed into cDNA according to the Vazyme-R323-01 RNA reverse transcription kit instructions. Target gene cDNA was detected by qPCR, with GAPDH / β-actin serving as an internal reference gene. qPCR was performed in 384-well plates. The Taqman probe-based qPCR reaction program was: 95°C for 10 minutes, followed by 40 cycles of 95°C for 15 seconds and 60°C for 1 minute. The SYBR dye-based qPCR reaction program was: 50°C for 2 minutes, 95°C for 2 minutes, followed by 40 cycles of 95°C for 5 seconds and 60°C for 30 seconds, with a final melting step of 95°C for 15 seconds, 60°C for 1 minute, and 95°C for 15 seconds.

[0765] The free uptake dosing method was used to evaluate the effect of siRNA on the target gene AGT mRNA in PHH and PCH cells. The results showed that compound NPD011s-53 had inhibitory activity on the AGT gene in PHH cells at different concentrations, and was dose-dependent. The highest concentration of 100nM had an inhibition rate of 92.94%, and the lowest concentration of 0.1nM had an inhibition rate of 47.25%; NPD011s-280 had an activity close to that of NPD011s-53 at all concentrations, with the lowest inhibition rate being 40.93%; the other three test compounds NPD011s-269, NPD011s-274 and NPD011s-278 all showed higher inhibitory activity against the target gene than NPD011s-53 at all tested concentrations, and the inhibitory activities at 0.1nM were 58.91%, 66.41% and 74.94%, respectively. In PCH cells, NPD011s-53 exhibited target gene inhibition rates of 94.80%, 94.04%, 84.93%, and 51.84% at the four tested concentrations, respectively. Compound NPD011s-278 exhibited higher inhibitory activity against the target gene than NPD011s-53 at all tested concentrations, with an inhibitory activity of 57.61% at 0.1 nM. NPD011s-269 and NPD011s-280 exhibited lower inhibitory activity against the target gene than NPD011s-53 at all tested concentrations; however, NPD011s-274 exhibited comparable activity to NPD011s-53. Compound activities are summarized in Table 7.

[0766] Table 7. Average inhibition rate and SD of AGT mRNA by test compounds

[0767] Example 6: Activity test of GalNAc-siRNA in transgenic mice

[0768] The in vivo efficacy of the molecule was tested by subcutaneous administration on AGT humanized transgenic mice. The experimental animals, humanized AGT mice, were purchased from Saiye (Suzhou) Biotechnology Co., Ltd. and are SPF-grade animals. Before administration, the mice were weighed and their conditions were observed, and animals with uniform weight and normal conditions were selected for subsequent experiments. The experimental animals were randomly divided into groups of 5 per group and administered subcutaneously at a dose of 0.5 mg / kg. The day of administration was recorded as day 0. At selected time points after administration, blood was collected from the suborbital vein and plasma was separated. The Angiotensinogen Total (Human) ELISA (IBL-America) kit was used to detect the expression level of AGT in animal plasma. The experimental steps are as follows: set up standard wells and test sample wells, add 100μL of standard or test sample (100,000-fold dilution of plasma sample) to each well, cover with a plate sticker, and incubate at 37°C for 60 minutes; discard the liquid in the well, add 250μL of wash buffer to each well, soak for 1-2 minutes, discard the liquid in the well, repeat washing 4 times, add 100μL of labeled antibody to each well; cover with a plate sticker, incubate at 37°C for 30 minutes; discard the liquid in the well, add 250μL of wash buffer to each well, soak for 1-2 minutes, discard the liquid in the well, and spin dry; repeat washing 3 times; add 100μL of TMB solution to each well; cover with a plate sticker, incubate at room temperature for 30 minutes, add 100μL of stop solution to each well, and immediately measure the absorbance at 450nm.

[0769] The experimental results showed that the activity of NPD011s-261 was comparable to that of NPD011s-247, the activities of NPD011s-265 and NPD011s-266 were slightly lower than those of NPD011s-247; the activities of NPD011s-269 and NPD011s-270 were comparable to those of NPD011s-261.

[0770] Example 7: Dose-dependent activity test of GalNAc-siRNA in transgenic mice

[0771] The in vivo efficacy of the molecule was tested by subcutaneous administration on AGT humanized transgenic mice. The experimental animals, humanized AGT mice, were purchased from Saiye (Suzhou) Biotechnology Co., Ltd. and are SPF-grade animals. Before administration, the mice were weighed and their conditions were observed, and animals with uniform weight and normal conditions were selected for subsequent experiments. The experimental animals were randomly divided into groups of 5 per group and administered subcutaneously at doses of 1 mg / kg, 6 mg / kg and 12 mg / kg. The day of administration was recorded as day 0. At selected time points after administration, blood was collected from the suborbital vein and plasma was separated. The Angiotensinogen Total (Human) ELISA (IBL-America) kit was used to detect the expression level of AGT in animal plasma. The experimental steps are as follows: set up standard wells and test sample wells, add 100μL of standard or test sample (100,000-fold dilution of plasma sample) to each well, cover with a plate sticker, and incubate at 37°C for 60 minutes; discard the liquid in the well, add 250μL of wash buffer to each well, soak for 1-2 minutes, discard the liquid in the well, repeat washing 4 times, add 100μL of labeled antibody to each well; cover with a plate sticker, incubate at 37°C for 30 minutes; discard the liquid in the well, add 250μL of wash buffer to each well, soak for 1-2 minutes, discard the liquid in the well, and spin dry; repeat washing 3 times; add 100μL of TMB solution to each well; cover with a plate sticker, incubate at room temperature for 30 minutes, add 100μL of stop solution to each well, and immediately measure the absorbance at 450nm.

[0772] The experimental results showed that both the test substances NPD011s-265 and NPD011s-269 exhibited dose-dependence, among which NPD011s-269 was more active than NPD011s-265.

[0773] Example 8: GalNAc-siRNA activity test in normal cynomolgus monkeys

[0774] Twelve male cynomolgus monkeys (5-7 years old, 5-7 kg) were selected for the experiment based on body weight, blood biochemical indicators (ALT, AST, ALP, TBIL) and blood cell counts. The animals were randomly divided into 4 groups, 3 animals per group, based on the baseline (Day-14 and Day-7) plasma AGT levels. On Day 0, the cynomolgus monkeys were weighed and the test substance was administered by a single subcutaneous injection. After administration, animal plasma was collected on Day 7, Day 14, Day 21, Day 28, Day 35, Day 42, Day 49, Day 56, Day 63, Day 70, Day 77, and Day 84. Blood samples were centrifuged as soon as possible at 4°C and 3500 rpm for 10 minutes. The collected plasma was stored at -80°C. Plasma AGT levels were detected using ELISA.

[0775] In the description of this specification, the reference terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" mean that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described can be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art can combine and combine different embodiments or examples described in this specification and features of different embodiments or examples without contradiction.

[0776] Although the embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are illustrative and are not to be construed as limitations on the present invention. A person skilled in the art may change, modify, replace and modify the above embodiments within the scope of the present invention.

Claims

1. A siRNA duplex molecule for targeting angiotensinogen (AGT) mRNA, characterized in that: The siRNA duplex is composed of a sense strand and an antisense strand through relevant base pairing, wherein the sense strand is selected from a nucleotide sequence that differs from the nucleotide sequence of each strand in SEQ ID NO:1 to SEQ ID NO:11 by no more than 2 nucleotides, and the antisense strand is selected from a nucleotide sequence that differs from the nucleotide sequence of each strand in SEQ ID NO:12 to SEQ ID NO:22 by no more than 2 nucleotides.

2. The siRNA duplex according to claim 1, wherein The sense strand is selected from at least 17 consecutive identical nucleotides in any nucleotide sequence of SEQ ID NO: 1 to SEQ ID NO:

11.

3. The siRNA duplex according to any one of claims 1 to 2, characterized in that The antisense strand is selected from at least 19 consecutive nucleotides that are consistent with any one of the nucleotide sequences in SEQ ID NO: 12 to SEQ ID NO:

22.

4. The siRNA duplex according to any one of claims 1 to 3, characterized in that The sense strand comprises at least 17 consecutive identical nucleotides selected from any sense strand nucleotide sequence of the following duplexes: NPS-112: (SEQ ID NO:1 and SEQ ID NO:12) NPS-115: (SEQ ID NO:4 and SEQ ID NO:15) NPS-118: (SEQ ID NO:7 and SEQ ID NO:18).

5. The siRNA duplex according to any one of claims 1 to 4, characterized in that The antisense strand comprises at least 19 consecutive identical nucleotides in any antisense strand nucleotide sequence selected from the following duplexes: NPS-112: (SEQ ID NO:1 and SEQ ID NO:12) NPS-115: (SEQ ID NO:4 and SEQ ID NO:15) NPS-118: (SEQ ID NO:7 and SEQ ID NO:18).

6. The siRNA duplex according to any one of claims 1 to 5, characterized in that The sense strand and antisense strand are selected from any of the following duplex nucleotide sequences: NPS-112: (SEQ ID NO:1 and SEQ ID NO:12) NPS-115: (SEQ ID NO:4 and SEQ ID NO:15) NPS-118: (SEQ ID NO:7 and SEQ ID NO:18).

7. The siRNA duplex according to any one of claims 1 to 6, wherein The siRNA duplex comprises at least one modified nucleotide.

8. The siRNA duplex according to any one of claims 1 to 7, wherein Substantially all nucleotides of the sense strand and substantially all nucleotides of the antisense strand comprise modifications.

9. The siRNA duplex according to any one of claims 1 to 7, wherein All nucleotides of the sense strand and all nucleotides of the antisense strand contain modifications.

10. The siRNA duplex according to any one of claims 7 to 9, characterized in that the modified nucleotides are selected from at least one of phosphodiester linker modification, ribosyl modification and base modification, or any combination of these three types of modifications.

11. The siRNA duplex according to claim 10, characterized in that The modification of the phosphodiester linker in the modified nucleotide is selected from one of the following general formula I: Wherein, X=O or S, preferably O R 1 Optional: OH, SH, BH 3+ ,NHCH2CH2NMe2,NHS(O)2R 2 , (R 2 is a C1-C4 alkyl), OCH2CH2SC(O)t-But, etc., wherein t-But is a tert-butyl group, preferably OH or SH.

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

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

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

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

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

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

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

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

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

21. The siRNA duplex according to any one of claims 10 to 20, characterized in that The siRNA duplex sense strand and antisense strand include the following optional combinations of one or more groups of different types of modifications: 2'-O-methyl modified nucleotides: aM, gM, cM and uM are 2'-O-Me A, 2'-O-Me G, 2'-O-Me C and 2'-O-Me U, respectively; 2'-Fluoro-modified nucleotides: aF, gF, cF and uF are 2'-Fluoro A, 2'-Fluoro C, 2'-Fluoro G and 2'-Fluoro U, respectively; 2'-deoxy modified nucleotides: 2'-deoxycytidine-3'-phosphate, 2'-deoxyguanosine-3'-phosphate, 2'-deoxyadenosine-3'-phosphate, 2'-deoxyuridine-3'-phosphate; 5'-(1,2,4)-triazole-modified nucleotides: cTA4, gTA4, aTA4, and uTA4 are 2'-O-methyl-5'-deoxy-(1-(1,2,4-triazole))-cytidine-3'-phosphate, 2'-O-methyl-5'-deoxy-(1-(1,2,4-triazole))-guanosine-3'-phosphate, 2'-O-methyl-5'-deoxy-(1-(1,2,4-triazole))-adenosine-3'-phosphate, and 2'-O-methyl-5'-deoxy-(1-(1,2,4-triazole))-uridine-3'-phosphate, respectively; 5'-thiomorpholine-modified nucleotides: cSMP, gSMP, aSMP, and uSMP are 2'-O-methyl-5'-N-(thiomorpholine)-cytidine-3'-phosphate, 2'-O-methyl-5'-N-(thiomorpholine)-guanosine-3'-phosphate, 2'-O-methyl-5'-N-(thiomorpholine)-adenosine-3'-phosphate, and 2'-O-methyl-5'-N-(thiomorpholine)-uridine-3'-phosphate, respectively; 3'-Fluoro-modified nucleotides: cRF, gRF, aRF, and uRF are 3'-fluoro-3'-deoxycytidine-2'-phosphate, 3'-fluoro-3'-deoxyguanosine-2'-phosphate, 3'-fluoro-3'-deoxyadenosine-2'-phosphate, and 3'-fluoro-3'-deoxyuridine-2'-phosphate, respectively; cXF, gXF, aXF, and uXF are 3'-fluoro-3'-deoxycytidine xylosyl-2'-phosphate, 3'-fluoro-3'-deoxyguanine xylosyl-2'-phosphate, 3'-fluoro-3'-deoxyadenine xylosyl-2'-phosphate, and 3'-fluoro-3'-deoxyuridine xylosyl-2'-phosphate, respectively; 3'-deoxy modified nucleotides: 3'-deoxycytidine-2'-phosphate, 3'-deoxyguanosine-2'-phosphate, 3'-deoxyadenosine-2'-phosphate, 3'-deoxyuridine-2'-phosphate; 5'-phosphothioate diester-linked or methylphosphonate nucleotides; Nucleotides with unconventional bases; 5'-trans-vinylphosphonate (E-VP) modified nucleotides.

22. The siRNA duplex according to any one of claims 1 to 21, wherein The length of each strand of the siRNA molecule is independently no more than 30 nucleotides.

23. The siRNA duplex of claim 22, wherein: The length of the siRNA double strand is 19-23 nucleotides.

24. The siRNA duplex of claim 23, wherein: The length of the siRNA double-stranded region can be 21 nucleotides.

25. The siRNA duplex of claim 23, wherein: At least one strand of the siRNA comprises a 3'-overhang of at least 1 nucleotide.

26. The siRNA duplex of claim 23, wherein: At least one strand of the siRNA comprises a 3'-overhang of at least 2 nucleotides.

27. The siRNA duplex according to any one of claims 1 to 26, wherein The siRNA duplex further comprises at least one 5'-phosphothioate diester or methylphosphonate nucleotide linkage.

28. The siRNA duplex of claim 27, wherein The 5'-phosphorothioate diester or methylphosphonate nucleotide is linked to the 3'-end of one chain.

29. The siRNA duplex of claim 28, wherein The strand is the antisense strand.

30. The siRNA duplex of claim 28, wherein The strand described is the sense strand.

31. The siRNA duplex of claim 27, wherein the 5'-phosphorothioate diester or methylphosphonate nucleotide is linked to the 5'-end of one strand.

32. The siRNA duplex of claim 31, wherein The strand is the antisense strand.

33. The siRNA duplex of claim 31, wherein The strand described is the sense strand.

34. The siRNA duplex of claim 27, wherein the 5'-phosphorothioate diester or methylphosphonate nucleotides are linked at the 5'-end and the 3'-end of one strand.

35. The siRNA duplex of claim 34, wherein: The strand is the antisense strand.

36. The siRNA duplex according to any one of claims 1 to 35, wherein The first base pair at the 5′-end of the antisense strand of the siRNA duplex is an A:U base pair or an A:I base pair, wherein I is inosine.

37. The siRNA duplex according to any one of claims 7 to 36, wherein The siRNA antisense strand comprises any antisense strand nucleotide sequence of a chemically modified duplex selected from the following: NPD011s-261 (SEQ ID NO. 1 and SEQ ID NO. 167) NPD011s-265 (SEQ ID NO. 5 and SEQ ID NO. 171) NPD011s-269 (SEQ ID NO.9 and SEQ ID NO.175) NPD011s-278 (SEQ ID NO. 17 and SEQ ID NO. 183) NPD011s-288 (SEQ ID NO.24 and SEQ ID NO.190) NPD011s-289 (SEQ ID NO.25 and SEQ ID NO.191) NPD011s-290 (SEQ ID NO.26 and SEQ ID NO.192) NPD011s-291 (SEQ ID NO.27 and SEQ ID NO.193) NPD011s-292 (SEQ ID NO.28 and SEQ ID NO.194) NPD011s-293 ​​(SEQ ID NO.29 and SEQ ID NO.195) NPD011s-294 (SEQ ID NO.30 and SEQ ID NO.196) NPD011s-295 (SEQ ID NO.31 and SEQ ID NO.197) NPD011s-296 (SEQ ID NO.32 and SEQ ID NO.198) NPD011s-297 (SEQ ID NO.33 and SEQ ID NO.199) NPD011s-298 (SEQ ID NO.34 and SEQ ID NO.200) NPD011s-299 (SEQ ID NO.35 and SEQ ID NO.201) NPD011s-300 (SEQ ID NO.36 and SEQ ID NO.202) NPD011s-301 (SEQ ID NO.37 and SEQ ID NO.203) NPD011s-302 (SEQ ID NO.38 and SEQ ID NO.204) NPD011s-303 (SEQ ID NO.39 and SEQ ID NO.205) NPD011s-304 (SEQ ID NO.40 and SEQ ID NO.206) NPD011s-305 (SEQ ID NO.41 and SEQ ID NO.207) NPD011s-306 (SEQ ID NO.42 and SEQ ID NO.208) NPD011s-307 (SEQ ID NO.43 and SEQ ID NO.209) NPD011s-308 (SEQ ID NO.44 and SEQ ID NO.210) NPD011s-309 (SEQ ID NO.45 and SEQ ID NO.211) NPD011s-310 (SEQ ID NO.46 and SEQ ID NO.212) NPD011s-311 (SEQ ID NO.47 and SEQ ID NO.213) NPD011s-312 (SEQ ID NO.48 and SEQ ID NO.214) NPD011s-313 (SEQ ID NO.49 and SEQ ID NO.215) NPD011s-314 (SEQ ID NO.50 and SEQ ID NO.216) NPD011s-315 (SEQ ID NO.51 and SEQ ID NO.217) NPD011s-316 (SEQ ID NO.52 and SEQ ID NO.218) NPD011s-317 (SEQ ID NO.53 and SEQ ID NO.219) NPD011s-318 (SEQ ID NO.54 and SEQ ID NO.220) NPD011s-319 (SEQ ID NO.55 and SEQ ID NO.221) NPD011s-320 (SEQ ID NO.56 and SEQ ID NO.222) NPD011s-321 (SEQ ID NO.57 and SEQ ID NO.223) NPD011s-322 (SEQ ID NO.58 and SEQ ID NO.224) NPD011s-323 (SEQ ID NO.59 and SEQ ID NO.225) NPD011s-324 (SEQ ID NO.60 and SEQ ID NO.226) NPD011s-325 (SEQ ID NO.61 and SEQ ID NO.227) NPD011s-326 (SEQ ID NO.62 and SEQ ID NO.228) NPD011s-327 (SEQ ID NO.63 and SEQ ID NO.229) NPD011s-328 (SEQ ID NO.64 and SEQ ID NO.230) NPD011s-329 (SEQ ID NO.65 and SEQ ID NO.231) NPD011s-330 (SEQ ID NO.66 and SEQ ID NO.232) NPD011s-331 (SEQ ID NO.67 and SEQ ID NO.233) NPD011s-332 (SEQ ID NO.68 and SEQ ID NO.234) NPD011s-333 (SEQ ID NO.69 and SEQ ID NO.235) NPD011s-334 (SEQ ID NO.70 and SEQ ID NO.236) NPD011s-335 (SEQ ID NO.71 and SEQ ID NO.237) NPD011s-336 (SEQ ID NO.72 and SEQ ID NO.238) NPD011s-337 (SEQ ID NO.73 and SEQ ID NO.239) NPD011s-338 (SEQ ID NO.74 and SEQ ID NO.240) NPD011s-339 (SEQ ID NO.75 and SEQ ID NO.241) NPD011s-340 (SEQ ID NO.76 and SEQ ID NO.242) NPD011s-341 (SEQ ID NO.77 and SEQ ID NO.243) NPD011s-342 (SEQ ID NO.78 and SEQ ID NO.244) NPD011s-343 (SEQ ID NO.79 and SEQ ID NO.245) NPD011s-344 (SEQ ID NO.80 and SEQ ID NO.246) NPD011s-345 (SEQ ID NO.81 and SEQ ID NO.247) NPD011s-346 (SEQ ID NO.82 and SEQ ID NO.248) NPD011s-347 (SEQ ID NO.83 and SEQ ID NO.249) NPD011s-348 (SEQ ID NO.84 and SEQ ID NO.250) NPD011s-349 (SEQ ID NO.85 and SEQ ID NO.251) NPD011s-350 (SEQ ID NO.86 and SEQ ID NO.252) NPD011s-351 (SEQ ID NO.87 and SEQ ID NO.253) NPD011s-352 (SEQ ID NO.88 and SEQ ID NO.254) NPD011s-353 (SEQ ID NO.89 and SEQ ID NO.255) NPD011s-354 (SEQ ID NO.90 and SEQ ID NO.256) NPD011s-355 (SEQ ID NO.91 and SEQ ID NO.257) NPD011s-356 (SEQ ID NO.92 and SEQ ID NO.258) NPD011s-357 (SEQ ID NO.93 and SEQ ID NO.259) NPD011s-358 (SEQ ID NO.94 and SEQ ID NO.260) NPD011s-359 (SEQ ID NO.95 and SEQ ID NO.261) NPD011s-360 (SEQ ID NO.96 and SEQ ID NO.262) NPD011s-361 (SEQ ID NO.97 and SEQ ID NO.263) NPD011s-362 (SEQ ID NO.98 and SEQ ID NO.264) NPD011s-363 (SEQ ID NO.99 and SEQ ID NO.265) NPD011s-364 (SEQ ID NO.100 and SEQ ID NO.266) NPD011s-365 (SEQ ID NO.101 and SEQ ID NO.267) NPD011s-366 (SEQ ID NO.102 and SEQ ID NO.268) NPD011s-367 (SEQ ID NO.103 and SEQ ID NO.269) NPD011s-368 (SEQ ID NO.104 and SEQ ID NO.270) NPD011s-369 (SEQ ID NO.105 and SEQ ID NO.271) NPD011s-370 (SEQ ID NO.106 and SEQ ID NO.272) NPD011s-371 (SEQ ID NO.107 and SEQ ID NO.273) NPD011s-372 (SEQ ID NO.108 and SEQ ID NO.274) NPD011s-373 (SEQ ID NO.109 and SEQ ID NO.275) NPD011s-374 (SEQ ID NO.110 and SEQ ID NO.276) NPD011s-375 (SEQ ID NO.111 and SEQ ID NO.277) NPD011s-376 (SEQ ID NO.112 and SEQ ID NO.278) NPD011s-377 (SEQ ID NO.113 and SEQ ID NO.279) NPD011s-378 (SEQ ID NO.114 and SEQ ID NO.280) NPD011s-379 (SEQ ID NO.115 and SEQ ID NO.281) NPD011s-380 (SEQ ID NO.116 and SEQ ID NO.282) NPD011s-381 (SEQ ID NO.117 and SEQ ID NO.283) NPD011s-382 (SEQ ID NO.118 and SEQ ID NO.284) NPD011s-383 (SEQ ID NO.119 and SEQ ID NO.285) NPD011s-384 (SEQ ID NO.120 and SEQ ID NO.286) NPD011s-385 (SEQ ID NO.121 and SEQ ID NO.287) NPD011s-386 (SEQ ID NO.122 and SEQ ID NO.288) NPD011s-387 (SEQ ID NO.123 and SEQ ID NO.289) NPD011s-388 (SEQ ID NO.124 and SEQ ID NO.290) NPD011s-389 (SEQ ID NO.125 and SEQ ID NO.291) NPD011s-390 (SEQ ID NO.126 and SEQ ID NO.292) NPD011s-391 (SEQ ID NO.127 and SEQ ID NO.293) NPD011s-392 (SEQ ID NO.128 and SEQ ID NO.294) NPD011s-393 (SEQ ID NO.129 and SEQ ID NO.295) NPD011s-394 (SEQ ID NO.130 and SEQ ID NO.296) NPD011s-395 (SEQ ID NO.131 and SEQ ID NO.297) NPD011s-396 (SEQ ID NO.132 and SEQ ID NO.298) NPD011s-397 (SEQ ID NO.133 and SEQ ID NO.299) NPD011s-398 (SEQ ID NO.134 and SEQ ID NO.300) NPD011s-399 (SEQ ID NO.135 and SEQ ID NO.301) NPD011s-400 (SEQ ID NO.136 and SEQ ID NO.302) NPD011s-401 (SEQ ID NO.137 and SEQ ID NO.303) NPD011s-402 (SEQ ID NO.138 and SEQ ID NO.304) NPD011s-403 (SEQ ID NO.139 and SEQ ID NO.305) NPD011s-404 (SEQ ID NO.140 and SEQ ID NO.306) NPD011s-405 (SEQ ID NO.141 and SEQ ID NO.307) NPD011s-406 (SEQ ID NO.142 and SEQ ID NO.308) NPD011s-407 (SEQ ID NO.143 and SEQ ID NO.309) NPD011s-408 (SEQ ID NO.144 and SEQ ID NO.310) NPD011s-409 (SEQ ID NO.145 and SEQ ID NO.311) NPD011s-410 (SEQ ID NO.146 and SEQ ID NO.312) NPD011s-411 (SEQ ID NO.147 and SEQ ID NO.313) NPD011s-412 (SEQ ID NO.148 and SEQ ID NO.314) NPD011s-413 (SEQ ID NO.149 and SEQ ID NO.315) NPD011s-414 (SEQ ID NO.150 and SEQ ID NO.316) NPD011s-415 (SEQ ID NO.151 and SEQ ID NO.317) NPD011s-416 (SEQ ID NO.152 and SEQ ID NO.318) NPD011s-417 (SEQ ID NO.153 and SEQ ID NO.319) NPD011s-418 (SEQ ID NO.154 and SEQ ID NO.320) NPD011s-419 (SEQ ID NO.155 and SEQ ID NO.321) NPD011s-420 (SEQ ID NO.156 and SEQ ID NO.322) NPD011s-421 (SEQ ID NO.157 and SEQ ID NO.323) NPD011s-422 (SEQ ID NO.158 and SEQ ID NO.324) NPD011s-423 (SEQ ID NO.159 and SEQ ID NO.325) NPD011s-424 (SEQ ID NO.160 and SEQ ID NO.326) NPD011s-425 (SEQ ID NO.161 and SEQ ID NO.327) NPD011s-426 (SEQ ID NO.162 and SEQ ID NO.328) NPD011s-427 (SEQ ID NO.163 and SEQ ID NO.329) NPD011s-428 (SEQ ID NO.164 and SEQ ID NO.330) NPD011s-429 (SEQ ID NO.165 and SEQ ID NO.331) NPD011s-430 (SEQ ID NO. 166 and SEQ ID NO. 332).

38. The siRNA duplex according to any one of claims 7 to 36, wherein The siRNA sense strand comprises any sense strand nucleotide sequence of a chemically modified duplex selected from the following: NPD011s-261 (SEQ ID NO. 1 and SEQ ID NO. 167) NPD011s-265 (SEQ ID NO. 5 and SEQ ID NO. 171) NPD011s-269 (SEQ ID NO.9 and SEQ ID NO.175) NPD011s-278 (SEQ ID NO. 17 and SEQ ID NO. 183) NPD011s-288 (SEQ ID NO.24 and SEQ ID NO.190) NPD011s-289 (SEQ ID NO.25 and SEQ ID NO.191) NPD011s-290 (SEQ ID NO.26 and SEQ ID NO.192) NPD011s-291 (SEQ ID NO.27 and SEQ ID NO.193) NPD011s-292 (SEQ ID NO.28 and SEQ ID NO.194) NPD011s-293 ​​(SEQ ID NO.29 and SEQ ID NO.195) NPD011s-294 (SEQ ID NO.30 and SEQ ID NO.196) NPD011s-295 (SEQ ID NO.31 and SEQ ID NO.197) NPD011s-296 (SEQ ID NO.32 and SEQ ID NO.198) NPD011s-297 (SEQ ID NO.33 and SEQ ID NO.199) NPD011s-298 (SEQ ID NO.34 and SEQ ID NO.200) NPD011s-299 (SEQ ID NO.35 and SEQ ID NO.201) NPD011s-300 (SEQ ID NO.36 and SEQ ID NO.202) NPD011s-301 (SEQ ID NO.37 and SEQ ID NO.203) NPD011s-302 (SEQ ID NO.38 and SEQ ID NO.204) NPD011s-303 (SEQ ID NO.39 and SEQ ID NO.205) NPD011s-304 (SEQ ID NO.40 and SEQ ID NO.206) NPD011s-305 (SEQ ID NO.41 and SEQ ID NO.207) NPD011s-306 (SEQ ID NO.42 and SEQ ID NO.208) NPD011s-307 (SEQ ID NO.43 and SEQ ID NO.209) NPD011s-308 (SEQ ID NO.44 and SEQ ID NO.210) NPD011s-309 (SEQ ID NO.45 and SEQ ID NO.211) NPD011s-310 (SEQ ID NO.46 and SEQ ID NO.212) NPD011s-311 (SEQ ID NO.47 and SEQ ID NO.213) NPD011s-312 (SEQ ID NO.48 and SEQ ID NO.214) NPD011s-313 (SEQ ID NO.49 and SEQ ID NO.215) NPD011s-314 (SEQ ID NO.50 and SEQ ID NO.216) NPD011s-315 (SEQ ID NO.51 and SEQ ID NO.217) NPD011s-316 (SEQ ID NO.52 and SEQ ID NO.218) NPD011s-317 (SEQ ID NO.53 and SEQ ID NO.219) NPD011s-318 (SEQ ID NO.54 and SEQ ID NO.220) NPD011s-319 (SEQ ID NO.55 and SEQ ID NO.221) NPD011s-320 (SEQ ID NO.56 and SEQ ID NO.222) NPD011s-321 (SEQ ID NO.57 and SEQ ID NO.223) NPD011s-322 (SEQ ID NO.58 and SEQ ID NO.224) NPD011s-323 (SEQ ID NO.59 and SEQ ID NO.225) NPD011s-324 (SEQ ID NO.60 and SEQ ID NO.226) NPD011s-325 (SEQ ID NO.61 and SEQ ID NO.227) NPD011s-326 (SEQ ID NO.62 and SEQ ID NO.228) NPD011s-327 (SEQ ID NO.63 and SEQ ID NO.229) NPD011s-328 (SEQ ID NO.64 and SEQ ID NO.230) NPD011s-329 (SEQ ID NO.65 and SEQ ID NO.231) NPD011s-330 (SEQ ID NO.66 and SEQ ID NO.232) NPD011s-331 (SEQ ID NO.67 and SEQ ID NO.233) NPD011s-332 (SEQ ID NO.68 and SEQ ID NO.234) NPD011s-333 (SEQ ID NO.69 and SEQ ID NO.235) NPD011s-334 (SEQ ID NO.70 and SEQ ID NO.236) NPD011s-335 (SEQ ID NO.71 and SEQ ID NO.237) NPD011s-336 (SEQ ID NO.72 and SEQ ID NO.238) NPD011s-337 (SEQ ID NO.73 and SEQ ID NO.239) NPD011s-338 (SEQ ID NO.74 and SEQ ID NO.240) NPD011s-339 (SEQ ID NO.75 and SEQ ID NO.241) NPD011s-340 (SEQ ID NO.76 and SEQ ID NO.242) NPD011s-341 (SEQ ID NO.77 and SEQ ID NO.243) NPD011s-342 (SEQ ID NO.78 and SEQ ID NO.244) NPD011s-343 (SEQ ID NO.79 and SEQ ID NO.245) NPD011s-344 (SEQ ID NO.80 and SEQ ID NO.246) NPD011s-345 (SEQ ID NO.81 and SEQ ID NO.247) NPD011s-346 (SEQ ID NO.82 and SEQ ID NO.248) NPD011s-347 (SEQ ID NO.83 and SEQ ID NO.249) NPD011s-348 (SEQ ID NO.84 and SEQ ID NO.250) NPD011s-349 (SEQ ID NO.85 and SEQ ID NO.251) NPD011s-350 (SEQ ID NO.86 and SEQ ID NO.252) NPD011s-351 (SEQ ID NO.87 and SEQ ID NO.253) NPD011s-352 (SEQ ID NO.88 and SEQ ID NO.254) NPD011s-353 (SEQ ID NO.89 and SEQ ID NO.255) NPD011s-354 (SEQ ID NO.90 and SEQ ID NO.256) NPD011s-355 (SEQ ID NO.91 and SEQ ID NO.257) NPD011s-356 (SEQ ID NO.92 and SEQ ID NO.258) NPD011s-357 (SEQ ID NO.93 and SEQ ID NO.259) NPD011s-358 (SEQ ID NO.94 and SEQ ID NO.260) NPD011s-359 (SEQ ID NO.95 and SEQ ID NO.261) NPD011s-360 (SEQ ID NO.96 and SEQ ID NO.262) NPD011s-361 (SEQ ID NO.97 and SEQ ID NO.263) NPD011s-362 (SEQ ID NO.98 and SEQ ID NO.264) NPD011s-363 (SEQ ID NO.99 and SEQ ID NO.265) NPD011s-364 (SEQ ID NO.100 and SEQ ID NO.266) NPD011s-365 (SEQ ID NO.101 and SEQ ID NO.267) NPD011s-366 (SEQ ID NO.102 and SEQ ID NO.268) NPD011s-367 (SEQ ID NO.103 and SEQ ID NO.269) NPD011s-368 (SEQ ID NO.104 and SEQ ID NO.270) NPD011s-369 (SEQ ID NO.105 and SEQ ID NO.271) NPD011s-370 (SEQ ID NO.106 and SEQ ID NO.272) NPD011s-371 (SEQ ID NO.107 and SEQ ID NO.273) NPD011s-372 (SEQ ID NO.108 and SEQ ID NO.274) NPD011s-373 (SEQ ID NO.109 and SEQ ID NO.275) NPD011s-374 (SEQ ID NO.110 and SEQ ID NO.276) NPD011s-375 (SEQ ID NO.111 and SEQ ID NO.277) NPD011s-376 (SEQ ID NO.112 and SEQ ID NO.278) NPD011s-377 (SEQ ID NO.113 and SEQ ID NO.279) NPD011s-378 (SEQ ID NO.114 and SEQ ID NO.280) NPD011s-379 (SEQ ID NO.115 and SEQ ID NO.281) NPD011s-380 (SEQ ID NO.116 and SEQ ID NO.282) NPD011s-381 (SEQ ID NO.117 and SEQ ID NO.283) NPD011s-382 (SEQ ID NO.118 and SEQ ID NO.284) NPD011s-383 (SEQ ID NO.119 and SEQ ID NO.285) NPD011s-384 (SEQ ID NO.120 and SEQ ID NO.286) NPD011s-385 (SEQ ID NO.121 and SEQ ID NO.287) NPD011s-386 (SEQ ID NO.122 and SEQ ID NO.288) NPD011s-387 (SEQ ID NO.123 and SEQ ID NO.289) NPD011s-388 (SEQ ID NO.124 and SEQ ID NO.290) NPD011s-389 (SEQ ID NO.125 and SEQ ID NO.291) NPD011s-390 (SEQ ID NO.126 and SEQ ID NO.292) NPD011s-391 (SEQ ID NO.127 and SEQ ID NO.293) NPD011s-392 (SEQ ID NO.128 and SEQ ID NO.294) NPD011s-393 (SEQ ID NO.129 and SEQ ID NO.295) NPD011s-394 (SEQ ID NO.130 and SEQ ID NO.296) NPD011s-395 (SEQ ID NO.131 and SEQ ID NO.297) NPD011s-396 (SEQ ID NO.132 and SEQ ID NO.298) NPD011s-397 (SEQ ID NO.133 and SEQ ID NO.299) NPD011s-398 (SEQ ID NO.134 and SEQ ID NO.300) NPD011s-399 (SEQ ID NO.135 and SEQ ID NO.301) NPD011s-400 (SEQ ID NO.136 and SEQ ID NO.302) NPD011s-401 (SEQ ID NO.137 and SEQ ID NO.303) NPD011s-402 (SEQ ID NO.138 and SEQ ID NO.304) NPD011s-403 (SEQ ID NO.139 and SEQ ID NO.305) NPD011s-404 (SEQ ID NO.140 and SEQ ID NO.306) NPD011s-405 (SEQ ID NO.141 and SEQ ID NO.307) NPD011s-406 (SEQ ID NO.142 and SEQ ID NO.308) NPD011s-407 (SEQ ID NO.143 and SEQ ID NO.309) NPD011s-408 (SEQ ID NO.144 and SEQ ID NO.310) NPD011s-409 (SEQ ID NO.145 and SEQ ID NO.311) NPD011s-410 (SEQ ID NO.146 and SEQ ID NO.312) NPD011s-411 (SEQ ID NO.147 and SEQ ID NO.313) NPD011s-412 (SEQ ID NO.148 and SEQ ID NO.314) NPD011s-413 (SEQ ID NO.149 and SEQ ID NO.315) NPD011s-414 (SEQ ID NO.150 and SEQ ID NO.316) NPD011s-415 (SEQ ID NO.151 and SEQ ID NO.317) NPD011s-416 (SEQ ID NO.152 and SEQ ID NO.318) NPD011s-417 (SEQ ID NO.153 and SEQ ID NO.319) NPD011s-418 (SEQ ID NO.154 and SEQ ID NO.320) NPD011s-419 (SEQ ID NO.155 and SEQ ID NO.321) NPD011s-420 (SEQ ID NO.156 and SEQ ID NO.322) NPD011s-421 (SEQ ID NO.157 and SEQ ID NO.323) NPD011s-422 (SEQ ID NO.158 and SEQ ID NO.324) NPD011s-423 (SEQ ID NO.159 and SEQ ID NO.325) NPD011s-424 (SEQ ID NO.160 and SEQ ID NO.326) NPD011s-425 (SEQ ID NO.161 and SEQ ID NO.327) NPD011s-426 (SEQ ID NO.162 and SEQ ID NO.328) NPD011s-427 (SEQ ID NO.163 and SEQ ID NO.329) NPD011s-428 (SEQ ID NO.164 and SEQ ID NO.330) NPD011s-429 (SEQ ID NO.165 and SEQ ID NO.331) NPD011s-430 (SEQ ID NO. 166 and SEQ ID NO. 332).

39. The siRNA duplex according to any one of claims 7 to 36, wherein The siRNA antisense strand and the sense strand comprise a chemically modified nucleotide sequence of a duplex selected from the following: NPD011s-261 (SEQ ID NO. 1 and SEQ ID NO. 167) NPD011s-265 (SEQ ID NO. 5 and SEQ ID NO. 171) NPD011s-269 (SEQ ID NO.9 and SEQ ID NO.175) NPD011s-278 (SEQ ID NO. 17 and SEQ ID NO. 183) NPD011s-288 (SEQ ID NO.24 and SEQ ID NO.190) NPD011s-289 (SEQ ID NO.25 and SEQ ID NO.191) NPD011s-290 (SEQ ID NO.26 and SEQ ID NO.192) NPD011s-291 (SEQ ID NO.27 and SEQ ID NO.193) NPD011s-292 (SEQ ID NO.28 and SEQ ID NO.194) NPD011s-293 ​​(SEQ ID NO.29 and SEQ ID NO.195) NPD011s-294 (SEQ ID NO.30 and SEQ ID NO.196) NPD011s-295 (SEQ ID NO.31 and SEQ ID NO.197) NPD011s-296 (SEQ ID NO.32 and SEQ ID NO.198) NPD011s-297 (SEQ ID NO.33 and SEQ ID NO.199) NPD011s-298 (SEQ ID NO.34 and SEQ ID NO.200) NPD011s-299 (SEQ ID NO.35 and SEQ ID NO.201) NPD011s-300 (SEQ ID NO.36 and SEQ ID NO.202) NPD011s-301 (SEQ ID NO.37 and SEQ ID NO.203) NPD011s-302 (SEQ ID NO.38 and SEQ ID NO.204) NPD011s-303 (SEQ ID NO.39 and SEQ ID NO.205) NPD011s-304 (SEQ ID NO.40 and SEQ ID NO.206) NPD011s-305 (SEQ ID NO.41 and SEQ ID NO.207) NPD011s-306 (SEQ ID NO.42 and SEQ ID NO.208) NPD011s-307 (SEQ ID NO.43 and SEQ ID NO.209) NPD011s-308 (SEQ ID NO.44 and SEQ ID NO.210) NPD011s-309 (SEQ ID NO.45 and SEQ ID NO.211) NPD011s-310 (SEQ ID NO.46 and SEQ ID NO.212) NPD011s-311 (SEQ ID NO.47 and SEQ ID NO.213) NPD011s-312 (SEQ ID NO.48 and SEQ ID NO.214) NPD011s-313 (SEQ ID NO.49 and SEQ ID NO.215) NPD011s-314 (SEQ ID NO.50 and SEQ ID NO.216) NPD011s-315 (SEQ ID NO.51 and SEQ ID NO.217) NPD011s-316 (SEQ ID NO.52 and SEQ ID NO.218) NPD011s-317 (SEQ ID NO.53 and SEQ ID NO.219) NPD011s-318 (SEQ ID NO.54 and SEQ ID NO.220) NPD011s-319 (SEQ ID NO.55 and SEQ ID NO.221) NPD011s-320 (SEQ ID NO.56 and SEQ ID NO.222) NPD011s-321 (SEQ ID NO.57 and SEQ ID NO.223) NPD011s-322 (SEQ ID NO.58 and SEQ ID NO.224) NPD011s-323 (SEQ ID NO.59 and SEQ ID NO.225) NPD011s-324 (SEQ ID NO.60 and SEQ ID NO.226) NPD011s-325 (SEQ ID NO.61 and SEQ ID NO.227) NPD011s-326 (SEQ ID NO.62 and SEQ ID NO.228) NPD011s-327 (SEQ ID NO.63 and SEQ ID NO.229) NPD011s-328 (SEQ ID NO.64 and SEQ ID NO.230) NPD011s-329 (SEQ ID NO.65 and SEQ ID NO.231) NPD011s-330 (SEQ ID NO.66 and SEQ ID NO.232) NPD011s-331 (SEQ ID NO.67 and SEQ ID NO.233) NPD011s-332 (SEQ ID NO.68 and SEQ ID NO.234) NPD011s-333 (SEQ ID NO.69 and SEQ ID NO.235) NPD011s-334 (SEQ ID NO.70 and SEQ ID NO.236) NPD011s-335 (SEQ ID NO.71 and SEQ ID NO.237) NPD011s-336 (SEQ ID NO.72 and SEQ ID NO.238) NPD011s-337 (SEQ ID NO.73 and SEQ ID NO.239) NPD011s-338 (SEQ ID NO.74 and SEQ ID NO.240) NPD011s-339 (SEQ ID NO.75 and SEQ ID NO.241) NPD011s-340 (SEQ ID NO.76 and SEQ ID NO.242) NPD011s-341 (SEQ ID NO.77 and SEQ ID NO.243) NPD011s-342 (SEQ ID NO.78 and SEQ ID NO.244) NPD011s-343 (SEQ ID NO.79 and SEQ ID NO.245) NPD011s-344 (SEQ ID NO.80 and SEQ ID NO.246) NPD011s-345 (SEQ ID NO.81 and SEQ ID NO.247) NPD011s-346 (SEQ ID NO.82 and SEQ ID NO.248) NPD011s-347 (SEQ ID NO.83 and SEQ ID NO.249) NPD011s-348 (SEQ ID NO.84 and SEQ ID NO.250) NPD011s-349 (SEQ ID NO.85 and SEQ ID NO.251) NPD011s-350 (SEQ ID NO.86 and SEQ ID NO.252) NPD011s-351 (SEQ ID NO.87 and SEQ ID NO.253) NPD011s-352 (SEQ ID NO.88 and SEQ ID NO.254) NPD011s-353 (SEQ ID NO.89 and SEQ ID NO.255) NPD011s-354 (SEQ ID NO.90 and SEQ ID NO.256) NPD011s-355 (SEQ ID NO.91 and SEQ ID NO.257) NPD011s-356 (SEQ ID NO.92 and SEQ ID NO.258) NPD011s-357 (SEQ ID NO.93 and SEQ ID NO.259) NPD011s-358 (SEQ ID NO.94 and SEQ ID NO.260) NPD011s-359 (SEQ ID NO.95 and SEQ ID NO.261) NPD011s-360 (SEQ ID NO.96 and SEQ ID NO.262) NPD011s-361 (SEQ ID NO.97 and SEQ ID NO.263) NPD011s-362 (SEQ ID NO.98 and SEQ ID NO.264) NPD011s-363 (SEQ ID NO.99 and SEQ ID NO.265) NPD011s-364 (SEQ ID NO.100 and SEQ ID NO.266) NPD011s-365 (SEQ ID NO.101 and SEQ ID NO.267) NPD011s-366 (SEQ ID NO.102 and SEQ ID NO.268) NPD011s-367 (SEQ ID NO.103 and SEQ ID NO.269) NPD011s-368 (SEQ ID NO.104 and SEQ ID NO.270) NPD011s-369 (SEQ ID NO.105 and SEQ ID NO.271) NPD011s-370 (SEQ ID NO.106 and SEQ ID NO.272) NPD011s-371 (SEQ ID NO.107 and SEQ ID NO.273) NPD011s-372 (SEQ ID NO.108 and SEQ ID NO.274) NPD011s-373 (SEQ ID NO.109 and SEQ ID NO.275) NPD011s-374 (SEQ ID NO.110 and SEQ ID NO.276) NPD011s-375 (SEQ ID NO.111 and SEQ ID NO.277) NPD011s-376 (SEQ ID NO.112 and SEQ ID NO.278) NPD011s-377 (SEQ ID NO.113 and SEQ ID NO.279) NPD011s-378 (SEQ ID NO.114 and SEQ ID NO.280) NPD011s-379 (SEQ ID NO.115 and SEQ ID NO.281) NPD011s-380 (SEQ ID NO.116 and SEQ ID NO.282) NPD011s-381 (SEQ ID NO.117 and SEQ ID NO.283) NPD011s-382 (SEQ ID NO.118 and SEQ ID NO.284) NPD011s-383 (SEQ ID NO.119 and SEQ ID NO.285) NPD011s-384 (SEQ ID NO.120 and SEQ ID NO.286) NPD011s-385 (SEQ ID NO.121 and SEQ ID NO.287) NPD011s-386 (SEQ ID NO.122 and SEQ ID NO.288) NPD011s-387 (SEQ ID NO.123 and SEQ ID NO.289) NPD011s-388 (SEQ ID NO.124 and SEQ ID NO.290) NPD011s-389 (SEQ ID NO.125 and SEQ ID NO.291) NPD011s-390 (SEQ ID NO.126 and SEQ ID NO.292) NPD011s-391 (SEQ ID NO.127 and SEQ ID NO.293) NPD011s-392 (SEQ ID NO.128 and SEQ ID NO.294) NPD011s-393 (SEQ ID NO.129 and SEQ ID NO.295) NPD011s-394 (SEQ ID NO.130 and SEQ ID NO.296) NPD011s-395 (SEQ ID NO.131 and SEQ ID NO.297) NPD011s-396 (SEQ ID NO.132 and SEQ ID NO.298) NPD011s-397 (SEQ ID NO.133 and SEQ ID NO.299) NPD011s-398 (SEQ ID NO.134 and SEQ ID NO.300) NPD011s-399 (SEQ ID NO.135 and SEQ ID NO.301) NPD011s-400 (SEQ ID NO.136 and SEQ ID NO.302) NPD011s-401 (SEQ ID NO.137 and SEQ ID NO.303) NPD011s-402 (SEQ ID NO.138 and SEQ ID NO.304) NPD011s-403 (SEQ ID NO.139 and SEQ ID NO.305) NPD011s-404 (SEQ ID NO.140 and SEQ ID NO.306) NPD011s-405 (SEQ ID NO.141 and SEQ ID NO.307) NPD011s-406 (SEQ ID NO.142 and SEQ ID NO.308) NPD011s-407 (SEQ ID NO.143 and SEQ ID NO.309) NPD011s-408 (SEQ ID NO.144 and SEQ ID NO.310) NPD011s-409 (SEQ ID NO.145 and SEQ ID NO.311) NPD011s-410 (SEQ ID NO.146 and SEQ ID NO.312) NPD011s-411 (SEQ ID NO.147 and SEQ ID NO.313) NPD011s-412 (SEQ ID NO.148 and SEQ ID NO.314) NPD011s-413 (SEQ ID NO.149 and SEQ ID NO.315) NPD011s-414 (SEQ ID NO.150 and SEQ ID NO.316) NPD011s-415 (SEQ ID NO.151 and SEQ ID NO.317) NPD011s-416 (SEQ ID NO.152 and SEQ ID NO.318) NPD011s-417 (SEQ ID NO.153 and SEQ ID NO.319) NPD011s-418 (SEQ ID NO.154 and SEQ ID NO.320) NPD011s-419 (SEQ ID NO.155 and SEQ ID NO.321) NPD011s-420 (SEQ ID NO.156 and SEQ ID NO.322) NPD011s-421 (SEQ ID NO.157 and SEQ ID NO.323) NPD011s-422 (SEQ ID NO.158 and SEQ ID NO.324) NPD011s-423 (SEQ ID NO.159 and SEQ ID NO.325) NPD011s-424 (SEQ ID NO.160 and SEQ ID NO.326) NPD011s-425 (SEQ ID NO.161 and SEQ ID NO.327) NPD011s-426 (SEQ ID NO.162 and SEQ ID NO.328) NPD011s-427 (SEQ ID NO.163 and SEQ ID NO.329) NPD011s-428 (SEQ ID NO.164 and SEQ ID NO.330) NPD011s-429 (SEQ ID NO.165 and SEQ ID NO.331) NPD011s-430 (SEQ ID NO. 166 and SEQ ID NO. 332).

40. The siRNA duplex according to any one of claims 7 to 39, wherein The siRNA molecules can be further conjugated to a delivery vector.

41. The siRNA duplex of claim 40, wherein The delivery vector is covalently conjugated to the 5'-end or 3'-end of the sense strand of the siRNA duplex to form a covalent conjugate of the siRNA and the delivery vector.

42. The covalent conjugate of siRNA and a delivery vector as claimed in claim 40, characterized in that The siRNA is covalently coupled to an N-acetylgalactosamine (GalNAc) derivative carrier, wherein the GalNAc derivative carrier is selected from one of the following:

43. The siRNA duplex-GalNAc delivery vector conjugate according to any one of claims 42, characterized in that, The siRNA antisense strand comprises a chemically modified nucleotide sequence selected from the following duplexes: NPD011s-261 (SEQ ID NO. 1 and SEQ ID NO. 167) NPD011s-265 (SEQ ID NO. 5 and SEQ ID NO. 171) NPD011s-269 (SEQ ID NO.9 and SEQ ID NO.175) NPD011s-278 (SEQ ID NO. 17 and SEQ ID NO. 183) NPD011s-288 (SEQ ID NO.24 and SEQ ID NO.190) NPD011s-289 (SEQ ID NO.25 and SEQ ID NO.191) NPD011s-290 (SEQ ID NO.26 and SEQ ID NO.192) NPD011s-291 (SEQ ID NO.27 and SEQ ID NO.193) NPD011s-292 (SEQ ID NO.28 and SEQ ID NO.194) NPD011s-293 ​​(SEQ ID NO.29 and SEQ ID NO.195) NPD011s-348 (SEQ ID NO.84 and SEQ ID NO.250) NPD011s-349 (SEQ ID NO.85 and SEQ ID NO.251) NPD011s-350 (SEQ ID NO.86 and SEQ ID NO.252) NPD011s-351 (SEQ ID NO.87 and SEQ ID NO.253) NPD011s-352 (SEQ ID NO.88 and SEQ ID NO.254) NPD011s-353 (SEQ ID NO.89 and SEQ ID NO.255) NPD011s-354 (SEQ ID NO.90 and SEQ ID NO.256) NPD011s-355 (SEQ ID NO.91 and SEQ ID NO.257) NPD011s-356 (SEQ ID NO.92 and SEQ ID NO.258) NPD011s-357 (SEQ ID NO.93 and SEQ ID NO.259) NPD011s-358 (SEQ ID NO.94 and SEQ ID NO.260) NPD011s-359 (SEQ ID NO.95 and SEQ ID NO.261) NPD011s-360 (SEQ ID NO.96 and SEQ ID NO.262) NPD011s-361 (SEQ ID NO.97 and SEQ ID NO.263) NPD011s-362 (SEQ ID NO.98 and SEQ ID NO.264) NPD011s-363 (SEQ ID NO.99 and SEQ ID NO.265) NPD011s-364 (SEQ ID NO.100 and SEQ ID NO.266) NPD011s-365 (SEQ ID NO.101 and SEQ ID NO.267) NPD011s-366 (SEQ ID NO.102 and SEQ ID NO.268) NPD011s-367 (SEQ ID NO.103 and SEQ ID NO.269) NPD011s-368 (SEQ ID NO.104 and SEQ ID NO.270) NPD011s-369 (SEQ ID NO.105 and SEQ ID NO.271) NPD011s-370 (SEQ ID NO.106 and SEQ ID NO.272) NPD011s-371 (SEQ ID NO.107 and SEQ ID NO.273) NPD011s-372 (SEQ ID NO.108 and SEQ ID NO.274) NPD011s-402 (SEQ ID NO.138 and SEQ ID NO.304) NPD011s-403 (SEQ ID NO.139 and SEQ ID NO.305) NPD011s-404 (SEQ ID NO.140 and SEQ ID NO.306) NPD011s-405 (SEQ ID NO.141 and SEQ ID NO.307) NPD011s-406 (SEQ ID NO.142 and SEQ ID NO.308) NPD011s-407 (SEQ ID NO.143 and SEQ ID NO.309) NPD011s-408 (SEQ ID NO.144 and SEQ ID NO.310) NPD011s-409 (SEQ ID NO.145 and SEQ ID NO.311) NPD011s-410 (SEQ ID NO.146 and SEQ ID NO.312) NPD011s-411 (SEQ ID NO.147 and SEQ ID NO.313) NPD011s-412 (SEQ ID NO.148 and SEQ ID NO.314) NPD011s-413 (SEQ ID NO.149 and SEQ ID NO.315) NPD011s-414 (SEQ ID NO.150 and SEQ ID NO.316) NPD011s-415 (SEQ ID NO.151 and SEQ ID NO.317) NPD011s-416 (SEQ ID NO.152 and SEQ ID NO.318) NPD011s-417 (SEQ ID NO.153 and SEQ ID NO.319) NPD011s-418 (SEQ ID NO.154 and SEQ ID NO.320) NPD011s-419 (SEQ ID NO.155 and SEQ ID NO.321) NPD011s-420 (SEQ ID NO.156 and SEQ ID NO.322) NPD011s-421 (SEQ ID NO.157 and SEQ ID NO.323) NPD011s-422 (SEQ ID NO.158 and SEQ ID NO.324) NPD011s-423 (SEQ ID NO.159 and SEQ ID NO.325) NPD011s-424 (SEQ ID NO.160 and SEQ ID NO.326) NPD011s-425 (SEQ ID NO.161 and SEQ ID NO.327) NPD011s-426 (SEQ ID NO.162 and SEQ ID NO.328) NPD011s-427 (SEQ ID NO.163 and SEQ ID NO.329) NPD011s-428 (SEQ ID NO.164 and SEQ ID NO.330) NPD011s-429 (SEQ ID NO.165 and SEQ ID NO.331) NPD011s-430 (SEQ ID NO. 166 and SEQ ID NO. 332).

44. The siRNA duplex-GalNAc delivery vector conjugate according to any one of claims 42, characterized in that The siRNA sense strand comprises a chemically modified nucleotide sequence selected from the following duplexes: NPD011s-261 (SEQ ID NO. 1 and SEQ ID NO. 167) NPD011s-265 (SEQ ID NO. 5 and SEQ ID NO. 171) NPD011s-269 (SEQ ID NO.9 and SEQ ID NO.175) NPD011s-278 (SEQ ID NO. 17 and SEQ ID NO. 183) NPD011s-288 (SEQ ID NO.24 and SEQ ID NO.190) NPD011s-289 (SEQ ID NO.25 and SEQ ID NO.191) NPD011s-290 (SEQ ID NO.26 and SEQ ID NO.192) NPD011s-291 (SEQ ID NO.27 and SEQ ID NO.193) NPD011s-292 (SEQ ID NO.28 and SEQ ID NO.194) NPD011s-293 ​​(SEQ ID NO.29 and SEQ ID NO.195) NPD011s-348 (SEQ ID NO.84 and SEQ ID NO.250) NPD011s-349 (SEQ ID NO.85 and SEQ ID NO.251) NPD011s-350 (SEQ ID NO.86 and SEQ ID NO.252) NPD011s-351 (SEQ ID NO.87 and SEQ ID NO.253) NPD011s-352 (SEQ ID NO.88 and SEQ ID NO.254) NPD011s-353 (SEQ ID NO.89 and SEQ ID NO.255) NPD011s-354 (SEQ ID NO.90 and SEQ ID NO.256) NPD011s-355 (SEQ ID NO.91 and SEQ ID NO.257) NPD011s-356 (SEQ ID NO.92 and SEQ ID NO.258) NPD011s-357 (SEQ ID NO.93 and SEQ ID NO.259) NPD011s-358 (SEQ ID NO.94 and SEQ ID NO.260) NPD011s-359 (SEQ ID NO.95 and SEQ ID NO.261) NPD011s-360 (SEQ ID NO.96 and SEQ ID NO.262) NPD011s-361 (SEQ ID NO.97 and SEQ ID NO.263) NPD011s-362 (SEQ ID NO.98 and SEQ ID NO.264) NPD011s-363 (SEQ ID NO.99 and SEQ ID NO.265) NPD011s-364 (SEQ ID NO.100 and SEQ ID NO.266) NPD011s-365 (SEQ ID NO.101 and SEQ ID NO.267) NPD011s-366 (SEQ ID NO.102 and SEQ ID NO.268) NPD011s-367 (SEQ ID NO.103 and SEQ ID NO.269) NPD011s-368 (SEQ ID NO.104 and SEQ ID NO.270) NPD011s-369 (SEQ ID NO.105 and SEQ ID NO.271) NPD011s-370 (SEQ ID NO.106 and SEQ ID NO.272) NPD011s-371 (SEQ ID NO.107 and SEQ ID NO.273) NPD011s-372 (SEQ ID NO.108 and SEQ ID NO.274) NPD011s-402 (SEQ ID NO.138 and SEQ ID NO.304) NPD011s-403 (SEQ ID NO.139 and SEQ ID NO.305) NPD011s-404 (SEQ ID NO.140 and SEQ ID NO.306) NPD011s-405 (SEQ ID NO.141 and SEQ ID NO.307) NPD011s-406 (SEQ ID NO.142 and SEQ ID NO.308) NPD011s-407 (SEQ ID NO.143 and SEQ ID NO.309) NPD011s-408 (SEQ ID NO.144 and SEQ ID NO.310) NPD011s-409 (SEQ ID NO.145 and SEQ ID NO.311) NPD011s-410 (SEQ ID NO.146 and SEQ ID NO.312) NPD011s-411 (SEQ ID NO.147 and SEQ ID NO.313) NPD011s-412 (SEQ ID NO.148 and SEQ ID NO.314) NPD011s-413 (SEQ ID NO.149 and SEQ ID NO.315) NPD011s-414 (SEQ ID NO.150 and SEQ ID NO.316) NPD011s-415 (SEQ ID NO.151 and SEQ ID NO.317) NPD011s-416 (SEQ ID NO.152 and SEQ ID NO.318) NPD011s-417 (SEQ ID NO.153 and SEQ ID NO.319) NPD011s-418 (SEQ ID NO.154 and SEQ ID NO.320) NPD011s-419 (SEQ ID NO.155 and SEQ ID NO.321) NPD011s-420 (SEQ ID NO.156 and SEQ ID NO.322) NPD011s-421 (SEQ ID NO.157 and SEQ ID NO.323) NPD011s-422 (SEQ ID NO.158 and SEQ ID NO.324) NPD011s-423 (SEQ ID NO.159 and SEQ ID NO.325) NPD011s-424 (SEQ ID NO.160 and SEQ ID NO.326) NPD011s-425 (SEQ ID NO.161 and SEQ ID NO.327) NPD011s-426 (SEQ ID NO.162 and SEQ ID NO.328) NPD011s-427 (SEQ ID NO.163 and SEQ ID NO.329) NPD011s-428 (SEQ ID NO.164 and SEQ ID NO.330) NPD011s-429 (SEQ ID NO.165 and SEQ ID NO.331) NPD011s-430 (SEQ ID NO. 166 and SEQ ID NO. 332).

45. The siRNA duplex-GalNAc delivery vector conjugate according to any one of claims 42, characterized in that, The siRNA sense strand and antisense strand contain a chemically modified nucleotide sequence selected from the following duplexes: NPD011s-261 (SEQ ID NO. 1 and SEQ ID NO. 167) NPD011s-265 (SEQ ID NO. 5 and SEQ ID NO. 171) NPD011s-269 (SEQ ID NO.9 and SEQ ID NO.175) NPD011s-278 (SEQ ID NO. 17 and SEQ ID NO. 183) NPD011s-288 (SEQ ID NO.24 and SEQ ID NO.190) NPD011s-289 (SEQ ID NO.25 and SEQ ID NO.191) NPD011s-290 (SEQ ID NO.26 and SEQ ID NO.192) NPD011s-291 (SEQ ID NO.27 and SEQ ID NO.193) NPD011s-292 (SEQ ID NO.28 and SEQ ID NO.194) NPD011s-293 ​​(SEQ ID NO.29 and SEQ ID NO.195) NPD011s-348 (SEQ ID NO.84 and SEQ ID NO.250) NPD011s-349 (SEQ ID NO.85 and SEQ ID NO.251) NPD011s-350 (SEQ ID NO.86 and SEQ ID NO.252) NPD011s-351 (SEQ ID NO.87 and SEQ ID NO.253) NPD011s-352 (SEQ ID NO.88 and SEQ ID NO.254) NPD011s-353 (SEQ ID NO.89 and SEQ ID NO.255) NPD011s-354 (SEQ ID NO.90 and SEQ ID NO.256) NPD011s-355 (SEQ ID NO.91 and SEQ ID NO.257) NPD011s-356 (SEQ ID NO.92 and SEQ ID NO.258) NPD011s-357 (SEQ ID NO.93 and SEQ ID NO.259) NPD011s-358 (SEQ ID NO.94 and SEQ ID NO.260) NPD011s-359 (SEQ ID NO.95 and SEQ ID NO.261) NPD011s-360 (SEQ ID NO.96 and SEQ ID NO.262) NPD011s-361 (SEQ ID NO.97 and SEQ ID NO.263) NPD011s-362 (SEQ ID NO.98 and SEQ ID NO.264) NPD011s-363 (SEQ ID NO.99 and SEQ ID NO.265) NPD011s-364 (SEQ ID NO.100 and SEQ ID NO.266) NPD011s-365 (SEQ ID NO.101 and SEQ ID NO.267) NPD011s-366 (SEQ ID NO.102 and SEQ ID NO.268) NPD011s-367 (SEQ ID NO.103 and SEQ ID NO.269) NPD011s-368 (SEQ ID NO.104 and SEQ ID NO.270) NPD011s-369 (SEQ ID NO.105 and SEQ ID NO.271) NPD011s-370 (SEQ ID NO.106 and SEQ ID NO.272) NPD011s-371 (SEQ ID NO.107 and SEQ ID NO.273) NPD011s-372 (SEQ ID NO.108 and SEQ ID NO.274) NPD011s-402 (SEQ ID NO.138 and SEQ ID NO.304) NPD011s-403 (SEQ ID NO.139 and SEQ ID NO.305) NPD011s-404 (SEQ ID NO.140 and SEQ ID NO.306) NPD011s-405 (SEQ ID NO.141 and SEQ ID NO.307) NPD011s-406 (SEQ ID NO.142 and SEQ ID NO.308) NPD011s-407 (SEQ ID NO.143 and SEQ ID NO.309) NPD011s-408 (SEQ ID NO.144 and SEQ ID NO.310) NPD011s-409 (SEQ ID NO.145 and SEQ ID NO.311) NPD011s-410 (SEQ ID NO.146 and SEQ ID NO.312) NPD011s-411 (SEQ ID NO.147 and SEQ ID NO.313) NPD011s-412 (SEQ ID NO.148 and SEQ ID NO.314) NPD011s-413 (SEQ ID NO.149 and SEQ ID NO.315) NPD011s-414 (SEQ ID NO.150 and SEQ ID NO.316) NPD011s-415 (SEQ ID NO.151 and SEQ ID NO.317) NPD011s-416 (SEQ ID NO.152 and SEQ ID NO.318) NPD011s-417 (SEQ ID NO.153 and SEQ ID NO.319) NPD011s-418 (SEQ ID NO.154 and SEQ ID NO.320) NPD011s-419 (SEQ ID NO.155 and SEQ ID NO.321) NPD011s-420 (SEQ ID NO.156 and SEQ ID NO.322) NPD011s-421 (SEQ ID NO.157 and SEQ ID NO.323) NPD011s-422 (SEQ ID NO.158 and SEQ ID NO.324) NPD011s-423 (SEQ ID NO.159 and SEQ ID NO.325) NPD011s-424 (SEQ ID NO.160 and SEQ ID NO.326) NPD011s-425 (SEQ ID NO.161 and SEQ ID NO.327) NPD011s-426 (SEQ ID NO.162 and SEQ ID NO.328) NPD011s-427 (SEQ ID NO.163 and SEQ ID NO.329) NPD011s-428 (SEQ ID NO.164 and SEQ ID NO.330) NPD011s-429 (SEQ ID NO.165 and SEQ ID NO.331) NPD011s-430 (SEQ ID NO. 166 and SEQ ID NO. 332).

46. ​​A cell comprising AGT mRNA targeted by the siRNA duplex of any one of claims 1 to 45.

47. A pharmaceutical composition for inhibiting the expression of a gene encoding AGT, comprising the siRNA duplex according to any one of claims 1 to 45.

48. A pharmaceutical composition comprising the siRNA duplex of any one of claims 1 to 45 and a lipid formulation.

49. A method for inhibiting the expression of AGT gene in a cell, the method comprising allowing the cell to act with the siRNA duplex according to any one of claims 1 to 45 or the pharmaceutical composition according to claim 47 or 48, thereby inhibiting the expression of AGT gene in the cell.

50. The method of claim 49, wherein: The cell is in a subject.

51. The method of claim 50, wherein: The subject is a human being.

52. The method of claim 51, wherein: The subject is diagnosed with clinical symptoms associated with AGT.

53. The method of claim 52, wherein: The AGT-related clinical symptoms are selected from the group consisting of hypertension, isolated systolic or diastolic hypertension, pregnancy-related hypertension, secondary hypertension, diabetic hypertension, refractory hypertension, hypertension associated with low plasma renin activity or plasma renin concentration, essential hypertension, systolic hypertension, paroxysmal hypertension, glaucoma, ocular hypertension, pulmonary hypertension, portal hypertension, systemic venous hypertension, critical hypertension, Goldblatt's hypertension, hypertensive heart disease, hypertensive nephropathy, atherosclerosis, arteriosclerosis, vascular lesions, diabetes Diabetic nephropathy, diabetic retinopathy, chronic heart failure, cardiomyopathy, diabetic cardiomyopathy, glomerulosclerosis, aortic coarctation, aortic aneurysm, ventricular fibrosis, heart failure, myocardial infarction, angina pectoris, stroke, kidney disease, renal failure, systemic sclerosis, intrauterine growth retardation (IUGR), fetal growth restriction, obesity, non-alcoholic steatohepatitis (NASH), hepatic steatosis / fatty liver, non-alcoholic fatty liver disease (NAFLD), glucose intolerance, type 2 diabetes mellitus (non-insulin-dependent diabetes mellitus), and metabolic syndrome.

54. The method of claim 51, wherein: The subject has a systolic blood pressure of at least 130 mmHg or a diastolic blood pressure of at least 90 mmHg.

55. The method of claim 51, wherein: The subject has a systolic blood pressure of at least 140 mmHg and a diastolic blood pressure of at least 90 mmHg.

56. The method of claim 51, wherein: The subject is a person who is sensitive or susceptible to salt, or a person who is overweight, obese, or pregnant.

57. The method according to any one of claims 46 to 49, characterized in that The siRNA duplex inhibits the expression of AGT mRNA by at least 50%, 60%, 70%, 80%, 90%, or 95% on the cells.

58. The method according to any one of claims 50 to 56, characterized in that The inhibition of AGT expression reduces the AGT protein level in the serum of the subject by at least 50%, 60%, 70%, 80%, 90% or 95%.

59. A method for treating AGT-related clinical symptoms in a subject, comprising administering to the subject an siRNA duplex as described in any one of claims 1 to 45 or a pharmaceutical composition as described in claim 47 or 48, thereby treating the AGT-related clinical symptoms in the subject.

60. The method of claim 59, wherein: The subject has a systolic blood pressure of at least 130 mmHg or a diastolic blood pressure of at least 90 mmHg.

61. The method of claim 59, wherein: The subject has a systolic blood pressure of at least 140 mmHg and a diastolic blood pressure of at least 90 mmHg.

62. The method of claim 59, wherein: The subject is a human being.

63. The method of claim 59, wherein: The subject is a person who is sensitive or susceptible to salt, or is overweight, obese, or pregnant.

64. The method according to any one of claims 52 to 63, characterized in that The siRNA duplex is administered to the subject at a dose of about 0.01 mg / kg to about 50 mg / kg.

65. The method according to any one of claims 52 to 63, characterized in that The siRNA-GalNAc conjugate is subcutaneously injected into the subject.

66. The method according to any one of claims 52 to 65, characterized in that Further comprising determining the level of AGT protein in a sample from the subject.

67. The method of claim 66, wherein: The AGT protein expression level in the subject sample is derived from the test of blood samples, serum samples or urine samples.

68. The method according to any one of claims 52 to 67, characterized in that Further comprising administering to the subject an additional therapeutic agent for treating hypertension.

69. The method of claim 68, wherein: The additional therapeutic agent is selected from: diuretics, angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, beta-blockers, vasodilators, calcium channel blockers, aldosterone antagonists, alpha2-agonists, renin inhibitors, alpha-blockers, peripherally acting adrenergic agents, selective D1 receptor partial agonists, non-selective alpha-adrenergic antagonists, synthetic steroidal anti-mineralocorticoids, angiotensin receptor-neprilysin inhibitors (ARNi), sacubitril / valsartan; or endothelin receptor antagonists (ERA), sitaxsentan, ambrisentan, atrasentan, BQ-123, zilpotentan, bosentan, macitentan and tezosentan; combinations of any of the above therapeutic agents; and hypertension therapeutic agents formulated as a combination of agents.

70. The method of claim 68, wherein: The additional therapeutic agent includes an angiotensin II receptor antagonist.

71. The method of claim 70, wherein: The angiotensin II receptor antagonist is selected from the group consisting of losartan, valsartan, olmesartan, eprosartan and azilsartan.

72. The method of claim 68, wherein: The additional therapeutic agent includes angiotensin converting enzyme (ACE) inhibitor.

73. The method of claim 72, wherein: The angiotensin converting enzyme (ACE) inhibitor is selected from the group consisting of: captopril, enalapril, quinapril, benazepril, cilazapril, perindopril and fosinopril.

74. Use of the siRNA duplex of any one of claims 1 to 45 or the pharmaceutical composition of claim 46 or 47 for treating clinical symptoms associated with AGT.

75. The use of claim 74, for use in a method as claimed in any one of claims 50 to 73.

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