SiRNA, siRNA conjugate, pharmaceutical composition and application thereof

Abstract

The invention relates to siRNA (small interfering Ribonucleic Acid) for inhibiting the expression of an angiotensinogen (AGT) gene, a siRNA conjugate, a pharmaceutical composition and application of the siRNA conjugate. The siRNA comprises a positive-sense strand and an antisense strand, and the antisense strand comprises at least 19 contiguous nucleotides which are different from any antisense strand shown in the table 1 by not more than 3 nucleotides. And a method for preventing and / or treating angiotensin disorder-related diseases by using at least one of the siRNA, the siRNA conjugate and the pharmaceutical composition.

Description

siRNA, siRNA conjugate, pharmaceutical composition and use thereof Technical Field

[0001] The present disclosure relates to the field of medical technology, and in particular to an siRNA, a conjugate thereof, and a pharmaceutical composition for inhibiting angiotensinogen (AGT) gene expression. The present disclosure also relates to a kit containing at least one of the siRNA, its conjugate, and the pharmaceutical composition, a method for preventing and / or treating diseases associated with angiotensinogen imbalance using at least one of the siRNA, its conjugate, and the pharmaceutical composition, and the use of at least one of the siRNA, its conjugate, and the pharmaceutical composition in the preparation of a medicament for preventing and / or treating diseases associated with angiotensinogen imbalance. Background Art

[0002] The renin-angiotensin-aldosterone system (RAAS) plays a key role in blood pressure regulation. The RAAS cascade begins with the secretion of renin into the circulation by juxtaglomerular cells in the kidney. Angiotensin-glucose (AGT) is the most upstream precursor in the RAAS, and its cascade has been demonstrated to play a role in blood pressure regulation. For example, inhibiting AGT expression can have a significant antihypertensive effect.

[0003] Hypertension, a condition characterized by persistently high blood pressure, is a major risk factor for related diseases such as stroke, heart disease, hemangioma, and kidney failure, and has become one of the leading causes of death worldwide. Therefore, the use of antihypertensive drugs to treat hypertension, improve blood pressure control rates, and lower patients' blood pressure levels has become an urgent need for hypertensive patients. However, despite the large number of antihypertensive drugs on the market, most patients do not effectively lower their blood pressure levels by taking a single antihypertensive drug and require taking multiple antihypertensive drugs simultaneously to achieve therapeutic effects. Therefore, the development of more effective antihypertensive drugs is urgent.

[0004] Small interfering RNA (siRNA) is an emerging and highly promising research candidate. Based on the RNA interference mechanism, it can inhibit or block the expression of target genes of interest in a sequence-specific manner, thereby achieving the goal of treating diseases. Because siRNA recognizes target RNA through complementary base pairing and sequence specificity, it can cleave the target RNA, thereby downregulating target RNA levels and inhibiting target gene expression. Therefore, siRNA has extremely broad application prospects.

[0005] However, compared to traditional drugs, siRNAs have poor stability and are susceptible to nuclease degradation when administered systemically. Furthermore, it is necessary to further enhance their activity while avoiding side effects such as off-target effects, immune stimulation, and cytotoxicity. Therefore, the development of more candidate siRNAs that inhibit AGT gene expression with good biological activity and / or stability in blood with low cytotoxicity has become an urgent challenge. Furthermore, the development of drugs that can effectively prevent and / or treat diseases associated with angiotensinogen dysregulation using these candidate siRNAs for AGT gene expression remains a clinical research necessity and a commercial reality.

[0006] Summary of the Invention

[0007] Based on the above situation, the purpose of the present disclosure is to provide an siRNA that can effectively inhibit the expression of the AGT gene, or an siRNA conjugate obtained by conjugating the siRNA with a conjugated molecule, or a pharmaceutical composition containing the siRNA as an active ingredient, or a kit comprising at least one of the siRNA, the siRNA conjugate, or the pharmaceutical composition, the use of at least one of the siRNA, the siRNA conjugate, or the pharmaceutical composition in the preparation of a medicament for preventing and / or treating diseases associated with angiotensinogen disorder, and a method for preventing and / or treating diseases associated with angiotensinogen disorder using at least one of the siRNA, the siRNA conjugate, or the pharmaceutical composition. The AGT gene can be in a cell, for example, a cell in a subject (e.g., a human).

[0008] In a first aspect, the present disclosure provides an siRNA for inhibiting AGT gene expression, the siRNA comprising a sense strand and an antisense strand, wherein the antisense strand comprises at least 19 consecutive nucleotides that differ by no more than 3 nucleotides from any of the antisense strand sequences shown in Table 1. Herein, unless otherwise specified, at least partial sequences of the sense strand and the antisense strand are capable of complementary binding.

[0009] In a second aspect, the present disclosure provides an siRNA conjugate, wherein the siRNA conjugate is obtained by conjugating the siRNA according to the first aspect with a conjugation molecule.

[0010] In a third aspect, the present disclosure provides a pharmaceutical composition comprising the siRNA according to the first aspect as an active ingredient and a pharmaceutically acceptable carrier.

[0011] In a fourth aspect, the present disclosure provides a kit comprising at least one of the siRNA according to the first aspect, the siRNA conjugate according to the second aspect, and the pharmaceutical composition according to the third aspect.

[0012] In a fifth aspect, the present disclosure provides use of at least one of the siRNA according to the first aspect, the siRNA conjugate according to the second aspect, and the pharmaceutical composition according to the third aspect in the preparation of a medicament for preventing and / or treating a disease associated with angiotensinogen disorder. Alternatively, the present disclosure provides use of at least one of the siRNA according to the first aspect, the siRNA conjugate according to the second aspect, and the pharmaceutical composition according to the third aspect for preventing and / or treating a disease associated with angiotensinogen disorder.

[0013] In a sixth aspect, the present disclosure provides a method for preventing and / or treating angiotensinogen disorder-related diseases, the method comprising administering at least one of the siRNA according to the first aspect, the siRNA conjugate according to the second aspect, and the pharmaceutical composition according to the third aspect to a subject in need.

[0014] In a seventh aspect, the present disclosure provides the siRNA according to the first aspect and / or the siRNA conjugate according to the second aspect and / or the pharmaceutical composition according to the third aspect for preventing and / or treating diseases related to angiotensinogen disorder.

[0015] The present disclosure provides an siRNA, a conjugate thereof, a pharmaceutical composition and uses thereof, which have the following beneficial effects: the siRNA, siRNA conjugate and pharmaceutical composition provided by the present disclosure have acceptable AGT gene inhibition activity and are expected to have good drugability.

[0016] Other features and advantages of the present disclosure will be described in detail in the following detailed description. DETAILED DESCRIPTION

[0017] The following describes the specific embodiments of the present disclosure in detail. It should be understood that the specific embodiments described herein are only used to illustrate and explain the present disclosure and are not intended to limit the present disclosure. Instead, various modifications, changes, or alterations may be made based on the spirit and concept of the present disclosure, and the contents after such modifications, changes, or alterations still fall within the scope of the present disclosure.

[0018] In the present disclosure, unless otherwise specified, the term "AGT" includes human AGT, whose amino acid and complete coding sequence can be found, for example, in GenBank Accession No. GI:188595658 (NM_001382817.3; SEQ ID NO: 1); cynomolgus monkey (Macaca fascicularis) AGT, whose amino acid and complete coding sequence can be found, for example, in GenBank Accession No. GI:90075391 (AB170313.1; SEQ ID NO: 2); mouse (Mus musculus) AGT, whose amino acid and complete coding sequence can be found, for example, in GenBank Accession No. GI:113461997 (NM_007428.3; SEQ ID NO: 3); and rat (Rattus norvegicus) AGT, whose amino acid and complete coding sequence can be found, for example, in GenBank Accession No. GI:51036672 (NM_134432; SEQ ID NO: 4). Additional examples of AGT mRNA sequences can also be readily obtained using publicly available databases (eg, GenBank, UniProt, OMIM, and the Macaca Genome Project website).

[0019] In the present disclosure, unless otherwise specified, capital letters C, G, U, and A represent the base composition of ribonucleotides; dC, dG, dT, and dA represent the base composition of deoxyribonucleotides; the lowercase letter m indicates that the nucleotide adjacent to the right of the letter m is a 2'-methoxy-modified nucleotide; the symbol i2F indicates that the nucleotide adjacent to the right of the symbol i2F is a 2'-fluorine-modified nucleotide; the symbol * indicates that the two nucleotides adjacent to the left and right of the symbol * are linked by a phosphorothioate group; the symbol # indicates that the two nucleotides adjacent to the left and right of the symbol # are linked by a methylsulfonylphosphamidate bond (MsPA); the symbol (E)-VP indicates that the nucleotide adjacent to the right of the symbol (E)-VP is a (E)-vinyl phosphate-modified nucleotide; the underline "_" indicates that the underlined nucleotide is a glycerol nucleotide (GNA); "T" represents the S-isomer of thymidine-diol nucleic acid (GNA), and their structures can be shown as follows (wherein Base represents a base):

[0020] In the present disclosure, unless otherwise specified, in the context of siRNA, "complementary" means that in the siRNA duplex molecule, the bases of one strand are paired with the bases on the other strand in a complementary manner, or the bases of the antisense strand of the siRNA are paired with the bases on the target gene or target sequence in a complementary manner. That is, when A / dA pairs with U / dT, and C / dC pairs with G / dG, the two strands are considered to be complementary. "Complementary" as described in the present disclosure can include base pairing formed by non-Watson-Crick base pairing and / or non-natural or modified nucleotides, as long as they hybridize and can form a double-stranded structure. Correspondingly, in the present disclosure, unless otherwise specified, in the context of siRNA, "mismatch" means that in the siRNA duplex molecule, the bases at corresponding positions are not paired in a complementary manner, or the bases of the antisense strand of the siRNA are not paired in a complementary manner with the bases at corresponding positions on the target gene or target sequence.

[0021] In the present disclosure, unless otherwise specified, "substantially complementary pairing" means that the number of mismatched nucleotides is no more than 3, for example, the number of mismatched nucleotides is 2 or 1.

[0022] In the present disclosure, unless otherwise specified, "conjugation" refers to the connection between two or more chemical moieties by covalent bonding; "conjugate" refers to a compound formed by covalent bonding between two or more chemical moieties; "siRNA conjugate" refers to a compound formed by covalently bonding one or more chemical moieties to siRNA. It should be noted that each chemical moiety can be directly connected to the siRNA or connected to the siRNA through a linker. For example, the conjugate molecule may include a linker moiety that is optionally used to connect to the siRNA and a functional moiety (e.g., a targeting moiety for targeting specific tissues or cells, such as GalNAc, etc.).

[0023] In the present disclosure, unless otherwise specified, the “-” in “linker-targeting ligand” means that the linker and the targeting ligand are covalently linked.

[0024] In the present disclosure, unless otherwise specified, the term "pharmaceutically acceptable" means that the carrier, vehicle, diluent, excipient and / or the salt / ester / hydrate formed therefrom are generally chemically or physically compatible with the other ingredients constituting a pharmaceutical dosage form and physiologically compatible with the receptor.

[0025] In the present disclosure, unless otherwise specified, the term "a 2'-fluoro nucleotide" refers to a nucleotide comprising a 2'-fluoro modification, which may also include modifications at positions other than the 2' position in the nucleotide structure. In the present disclosure, unless otherwise specified, the term "a 2'-methoxy nucleotide" refers to a nucleotide comprising a 2'-methoxy modification, which may also include modifications at positions other than the 2' position in the nucleotide structure.

[0026] In the present disclosure, unless otherwise specified, "target sequence" refers to a continuous portion of the nucleotide sequence of an mRNA molecule formed during transcription of the AGT gene, including mRNA that is an RNA processing product of a primary transcription product.

[0027] In this disclosure, unless otherwise specified, the term "inhibit" refers to a situation where the expression of a target gene is down-regulated due to siRNA-mediated degradation of the target gene's mRNA. The "down-regulation" refers to a situation where the expression level of the target gene decreases by 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 99% or more, or even 100%, relative to the level without siRNA treatment. A 100% decrease in the expression level of the target gene means that there is no detectable level of target gene expression.

[0028] In the present disclosure, unless otherwise specified, the terms "include, include and contain" or equivalents are open-ended expressions, which mean that in addition to the listed elements, components or steps, other unspecified elements, components or steps may also be included.

[0029] In this disclosure, unless otherwise specified, the term "identity" refers to the similarity between two nucleotide sequences or between two amino acid sequences. The percent identity between sequences can be determined by algorithms known to those skilled in the art (e.g., Needleman-Wunsch algorithm, Smith-Waterman algorithm, BLAST algorithm).

[0030] In the present disclosure, unless otherwise specified, the term "substantially complementary" means that two nucleic acid sequences are completely complementary or at least 90% (e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) of the nucleotides are complementary.

[0031] Unless otherwise indicated, herein, the parameter values ​​representing the amount of ingredients or physicochemical properties or reaction conditions, etc. should be understood as being modified by the term "about" in all cases. When the term "about" is used to describe the present application, the term "about" indicates that there is an error value, for example, it indicates a change within the range of ±5%, such as ±1% or ±0.1% of a particular value.

[0032] The terms "subject," "patient," and "individual" are used interchangeably herein and include mammals, including but not limited to domesticated animals (e.g., cows, sheep, cats, dogs, pigs, and horses), primates (e.g., humans, non-human primates such as monkeys), rabbits, and rodents (e.g., mice, rats, guinea pigs, hamsters), preferably humans, or non-mammalian vertebrates (e.g., chickens, emus, fish).

[0033] The terms "treating," "treatment," or "treat" as used herein refer to alleviating or relieving a disease or symptom, reducing the rate of onset or development of a disease or symptom, reducing the risk of developing a disease or symptom, or delaying the development of symptoms associated with a disease or symptom, reducing or terminating symptoms associated with a disease or symptom, producing complete or partial reversal of a disease or symptom, curing a disease or symptom, or a combination thereof.

[0034] Various aspects of the present disclosure will be described in detail below.

[0035] 1. siRNA of the present disclosure

[0036] In the present disclosure, the term "siRNA" refers to an RNA molecule that can sequence-specifically induce RNAi (RNA interference) phenomenon, comprises a sense strand and an antisense strand, and has a partially or completely complementary double-stranded structure.

[0037] The present disclosure provides an siRNA for inhibiting AGT gene expression, the siRNA comprising a sense strand and an antisense strand, wherein the antisense strand comprises at least 19 consecutive nucleotides that differ by no more than 3 nucleotides from any of the antisense strand sequences shown in Table 1. In some embodiments of the present disclosure, the region where the sense strand and the antisense strand complementarily bind comprises at least 15 consecutive nucleotides, for example, 20-21 consecutive nucleotides.

[0038] In some embodiments of the present disclosure, the antisense strand comprises at least 19 consecutive nucleotides that differ by no more than 2 nucleotides from any antisense strand sequence shown in Table 1. In some embodiments of the present disclosure, the antisense strand comprises at least 19 consecutive nucleotides that differ by no more than 1 nucleotide from any antisense strand sequence shown in Table 1.

[0039] In some embodiments of the present disclosure, the antisense strand comprises no more than 27, such as no more than 25, consecutive nucleotides.

[0040] In the present disclosure, "differences" in nucleotide sequences may include changes in the nucleotide sequence caused by addition, deletion or substitution of nucleotides.

[0041] The present disclosure provides an siRNA for inhibiting AGT gene expression, the siRNA comprising a sense strand and an antisense strand, wherein the antisense strand comprises a polypeptide selected from the group consisting of SEQ ID NO: 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, 90, The antisense strand sequence of any of 92, 94, 96, 98, 100, 102, 104, 106, 109, 111, 113, 115, 117, 119, 121, 123, 125, 127, 129, 131, 133, 135, 137, 139, 141, 143 differs by no more than 3 nucleotides for at least 19 consecutive nucleotides.

[0042] In some embodiments of the present disclosure, the antisense strand comprises the same sequence as SEQ ID NO: 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, 90, The antisense strand sequence of any of 92, 94, 96, 98, 100, 102, 104, 106, 109, 111, 113, 115, 117, 119, 121, 123, 125, 127, 129, 131, 133, 135, 137, 139, 141, 143 differs by no more than 2 nucleotides for at least 19 consecutive nucleotides.

[0043] In some embodiments of the present disclosure, the antisense strand comprises the same sequence as SEQ ID NO: 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, 90, at least 19 consecutive nucleotides in which the antisense strand sequence of any one of 92, 94, 96, 98, 100, 102, 104, 106, 109, 111, 113, 115, 117, 119, 121, 123, 125, 127, 129, 131, 133, 135, 137, 139, 141, 143 differs by no more than 1 nucleotide.

[0044] The present disclosure provides an siRNA for inhibiting AGT gene expression, the siRNA comprising a sense strand and an antisense strand, wherein the antisense strand comprises at least 19 consecutive nucleotides that differ by no more than 3 nucleotides from the antisense strand sequence of any one selected from SEQ ID NO: 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 30, 32, 34, 36, 38, 40, 44, 60, 66, 68, 92, 94, 104, 113, 131, 137, 139, 141, and 143.

[0045] In some embodiments of the present disclosure, the antisense strand comprises at least 19 consecutive nucleotides that differ from the antisense strand sequence of any one of SEQ ID NO: 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 30, 32, 34, 36, 38, 40, 44, 60, 66, 68, 92, 94, 104, 113, 131, 137, 139, 141, 143 by no more than 2 nucleotides. In some embodiments of the present disclosure, the antisense strand comprises at least 19 consecutive nucleotides that differ by no more than 1 nucleotide from the antisense strand sequence of any one of SEQ ID NOs: 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 30, 32, 34, 36, 38, 40, 44, 60, 66, 68, 92, 94, 104, 113, 131, 137, 139, 141, and 143. In some embodiments of the present disclosure, the antisense strand comprises at least 19 consecutive nucleotides that differ by no more than 3, no more than 2, or no more than 1 nucleotide from the antisense strand sequence of any one of SEQ ID NOs: 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 30, 92, 113, and 131.

[0046] In some embodiments of the present disclosure, the antisense strand in the siRNA comprises a terminal overhang of 1-5 nucleotides in length at the 3' end. In some embodiments of the present disclosure, the antisense strand in the siRNA comprises a terminal overhang of 1-4 nucleotides in length at the 3' end. In some embodiments of the present disclosure, the antisense strand in the siRNA comprises a terminal overhang of 1-3 nucleotides in length at the 3' end. In some embodiments of the present disclosure, the antisense strand in the siRNA comprises a terminal overhang of 2 nucleotides in length at the 3' end.

[0047] In some embodiments of the present disclosure, the 5' end of the antisense strand in the siRNA is blunt-ended.

[0048] In some embodiments of the present disclosure, the number of nucleotides in the sense strand of the siRNA is 16-25. In some embodiments of the present disclosure, the number of nucleotides in the sense strand of the siRNA is 16. In some embodiments of the present disclosure, the number of nucleotides in the sense strand of the siRNA is 17. In some embodiments of the present disclosure, the number of nucleotides in the sense strand of the siRNA is 18. In some embodiments of the present disclosure, the number of nucleotides in the sense strand of the siRNA is 19. In some embodiments of the present disclosure, the number of nucleotides in the sense strand of the siRNA is 20. In some embodiments of the present disclosure, the number of nucleotides in the sense strand of the siRNA is 21. In some embodiments of the present disclosure, the number of nucleotides in the sense strand of the siRNA is 22. In some embodiments of the present disclosure, the number of nucleotides in the sense strand of the siRNA is 23. In some embodiments of the present disclosure, the number of nucleotides in the sense strand of the siRNA is 24. In some embodiments of the present disclosure, the number of nucleotides in the sense strand of the siRNA is 25. In some embodiments of the present disclosure, the number of nucleotides in the antisense strand of the siRNA is 19-27. In some embodiments of the present disclosure, the number of nucleotides in the antisense strand of the siRNA is 19. In some embodiments of the present disclosure, the number of nucleotides in the antisense strand of the siRNA is 21. In some embodiments of the present disclosure, the number of nucleotides in the antisense strand of the siRNA is 22. In some embodiments of the present disclosure, the number of nucleotides in the antisense strand of the siRNA is 23. In some embodiments of the present disclosure, the number of nucleotides in the antisense strand of the siRNA is 24. In some embodiments of the present disclosure, the number of nucleotides in the antisense strand of the siRNA is 25. In some embodiments of the present disclosure, the number of nucleotides in the antisense strand of the siRNA is 26. In some embodiments of the present disclosure, the number of nucleotides in the antisense strand of the siRNA is 27.

[0049] In some embodiments of the present disclosure, the antisense strand in the siRNA differs from any of the antisense strands listed in Table 1 by no more than 3 nucleotides. In some embodiments of the present disclosure, the antisense strand in the siRNA differs from any of the antisense strands listed in Table 1 by no more than 2 nucleotides. In some embodiments of the present disclosure, the antisense strand in the siRNA differs from any of the antisense strands listed in Table 1 by no more than 1 nucleotide.

[0050] In some embodiments of the present disclosure, the antisense strand in the siRNA is identical to the antisense strand in SEQ ID 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, 90, 92, 94, 96, 98, 100, 102, 104, 106, 109, 111, 113, 115, 117, 119, 121, 123, 125, 127, 129, 131, 133, 135, 137, 139, 141, 143 differs in no more than 3 nucleotides.

[0051] In some embodiments of the present disclosure, the antisense strand in the siRNA is identical to the antisense strand in SEQ ID any of NO: 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, 90, 92, 94, 96, 98, 100, 102, 104, 106, 109, 111, 113, 115, 117, 119, 121, 123, 125, 127, 129, 131, 133, 135, 137, 139, 141, 143 differs by no more than 2 nucleotides.

[0052] In some embodiments of the present disclosure, in the siRNA, the antisense strand is identical to SEQ ID 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, 90, 92, 94, 96, 98, 100, 102, 104, 106, 109, 111, 113, 115, 117, 119, 121, 123, 125, 127, 129, 131, 133, 135, 137, 139, 141, 143 differs in no more than 1 nucleotide.

[0053] In some embodiments of the present disclosure, the antisense strand in the siRNA differs from any of SEQ ID NOs: 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 30, 32, 34, 36, 38, 40, 44, 60, 66, 68, 92, 94, 104, 113, 131, 137, 139, 141, 143 by no more than 3 nucleotides.

[0054] In some embodiments of the present disclosure, the antisense strand in the siRNA differs from any of SEQ ID NOs: 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 30, 32, 34, 36, 38, 40, 44, 60, 66, 68, 92, 94, 104, 113, 131, 137, 139, 141, 143 by no more than 2 nucleotides.

[0055] In some embodiments of the present disclosure, in the siRNA, the antisense strand differs from any of SEQ ID NOs: 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 30, 32, 34, 36, 38, 40, 44, 60, 66, 68, 92, 94, 104, 113, 131, 137, 139, 141, 143 by no more than 1 nucleotide.

[0056] In some embodiments of the present disclosure, the antisense strand in the siRNA is any one of the antisense strands shown in Table 1.

[0057] 6, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, 90, 92, 94, 96, 98, 100, 102, 104, 106, 32, 34, 36, 38, 40, 44, 60, 66, 68, 92, 94, 104, 113, 131, 137, 139, 141, 143.

[0058] In some embodiments of the present disclosure, the antisense strand in the siRNA is any one of SEQ ID NOs: 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 30, 32, 34, 36, 38, 40, 44, 60, 66, 68, 92, 94, 104, 113, 131, 137, 139, 141, and 143. Preferably, the antisense strand in the siRNA is any one of SEQ ID NOs: 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 30, 92, 113, and 131.

[0059] Table 1 Unmodified siRNA sequences that inhibit AGT gene expression

[0060] In some embodiments of the present disclosure, the sense strand and the antisense strand in the siRNA have at least one mismatch. In some embodiments of the present disclosure, the sense strand and the antisense strand in the siRNA have at most three mismatches. In some embodiments of the present disclosure, the sense strand and the antisense strand in the siRNA have at most two mismatches. In some embodiments of the present disclosure, the sense strand and the antisense strand in the siRNA have at most one mismatch. In some embodiments of the present disclosure, the sense strand and the antisense strand in the siRNA have no mismatches. In some embodiments of the present disclosure, the antisense strand in the siRNA has at most four mismatches with the target sequence. In some embodiments of the present disclosure, the antisense strand in the siRNA has at most three mismatches with the target sequence. In some embodiments of the present disclosure, the antisense strand in the siRNA has at most two mismatches with the target sequence. In some embodiments of the present disclosure, the antisense strand in the siRNA has at most one mismatch with the target sequence.

[0061] In some embodiments of the present disclosure, the first nucleotide from the 5' end to the 3' end of the siRNA antisense strand is mismatched with the target sequence. In some embodiments of the present disclosure, the first nucleotide from the 5' end to the 3' end of the siRNA antisense strand is mismatched with the target sequence, and at the site where the antisense strand and the target sequence are mismatched, the nucleotides of the antisense strand and the target sequence are different. In some embodiments of the present disclosure, the first nucleotide from the 5' end to the 3' end of the siRNA antisense strand is mismatched with the target sequence, and at the site where the antisense strand and the target sequence are mismatched, the nucleotides of the antisense strand and the target sequence are complementary. In some embodiments of the present disclosure, the first nucleotide from the 5' end to the 3' end of the siRNA antisense strand is mismatched with the target sequence, and at the site where the antisense strand and the target sequence are mismatched, the nucleotides of the antisense strand and the target sequence are different, and the nucleotides of the antisense strand and the sense strand are complementary. In some embodiments of the present disclosure, the first nucleotide from the 5' end to the 3' end of the siRNA antisense strand is U or A. In some embodiments of the present disclosure, the first nucleotide from the 5' end to the 3' end of the antisense strand of the siRNA is U or A, and the corresponding nucleotide in the sense strand complementary to the nucleotide is A or U.

[0062] In some embodiments of the present disclosure, the nucleotides from positions 16 to 23 in the 5' to 3' direction of the siRNA antisense strand have at most one mismatch with the target sequence. In some embodiments of the present disclosure, the nucleotide at position 16 in the 5' to 3' direction of the siRNA antisense strand has a mismatch with the target sequence. In some embodiments of the present disclosure, the nucleotide at position 17 in the 5' to 3' direction of the siRNA antisense strand has a mismatch with the target sequence. In some embodiments of the present disclosure, the nucleotide at position 18 in the 5' to 3' direction of the siRNA antisense strand has a mismatch with the target sequence. In some embodiments of the present disclosure, the nucleotide at position 19 in the 5' to 3' direction of the siRNA antisense strand has a mismatch with the target sequence. In some embodiments of the present disclosure, the nucleotide at position 20 in the 5' to 3' direction of the siRNA antisense strand has a mismatch with the target sequence. In some embodiments of the present disclosure, the nucleotide at position 21 in the 5' to 3' direction of the siRNA antisense strand has a mismatch with the target sequence. In some embodiments of the present disclosure, the nucleotide at position 22 from the 5' end to the 3' end of the antisense strand of the siRNA is mismatched with the target sequence. In some embodiments of the present disclosure, the nucleotide at position 23 from the 5' end to the 3' end of the antisense strand of the siRNA is mismatched with the target sequence. In some embodiments of the present disclosure, the antisense strand in the siRNA has at least one mismatch with the target sequence. In some embodiments of the present disclosure, the nucleotides from positions 16 to 21 from the 5' end to the 3' end of the antisense strand of the siRNA have at most one mismatch with the target sequence. In some embodiments of the present disclosure, the nucleotides from positions 16 to 22 from the 5' end to the 3' end of the antisense strand of the siRNA have at most three mismatches with the target sequence. In some embodiments of the present disclosure, among the nucleotides from positions 16 to 21 from the 5' end to the 3' end of the antisense strand of the siRNA, optionally one mismatch with the target sequence. In some embodiments of the present disclosure, among the nucleotides from positions 16 to 21 from the 5' end to the 3' end of the antisense strand of the siRNA, optionally two mismatches with the target sequence. In some embodiments of the present disclosure, among the nucleotides at positions 16 to 21 in the direction from the 5' end to the 3' end of the siRNA antisense strand, optionally 3 have mismatches with the target sequence. In some embodiments of the present disclosure, among the nucleotides at positions 19, 20 and 21 in the direction from the 5' end to the 3' end of the siRNA antisense strand, optionally 1 has mismatches with the target sequence. In some embodiments of the present disclosure, among the nucleotides at positions 19, 20 and 21 in the direction from the 5' end to the 3' end of the siRNA antisense strand, optionally 2 have mismatches with the target sequence. In some embodiments of the present disclosure, among the nucleotides at positions 19 and 21 in the direction from the 5' end to the 3' end of the siRNA antisense strand, optionally 2 have mismatches with the target sequence. In some embodiments of the present disclosure, among the nucleotides at positions 19 and 21 in the direction from the 5' end to the 3' end of the siRNA antisense strand, optionally 2 have mismatches with the target sequence.In some embodiments of the present disclosure, the nucleotides at positions 20 and 21 in the direction from the 5' end to the 3' end of the siRNA antisense strand are mismatched with the target sequence. In some embodiments of the present disclosure, the nucleotides at positions 19, 20 and 21 in the direction from the 5' end to the 3' end of the siRNA antisense strand are all mismatched with the target sequence. In some embodiments of the present disclosure, at the site where there is a mismatch between the siRNA antisense strand and the target sequence, the nucleotides of the antisense strand and the target sequence are the same. In some embodiments of the present disclosure, at the site where there is a mismatch between the siRNA antisense strand and the target sequence, the nucleotides of the target sequence and the siRNA sense strand are complementary. In some embodiments of the present disclosure, at the site where there is a mismatch between the siRNA antisense strand and the target sequence, the nucleotides of the antisense strand and the sense strand are swapped. In some embodiments of the present disclosure, at the site where there is a mismatch between the siRNA antisense strand and the target sequence, the nucleotides of the antisense strand and the sense strand are complementary. In some embodiments of the present disclosure, at the site where there is a mismatch between the antisense strand of the siRNA and the target sequence, the nucleotides of the antisense strand and the sense strand are swapped, and the nucleotides of the antisense strand and the sense strand are complementary.

[0063] In some embodiments of the present disclosure, the 16th nucleotide in the direction from the 5' end to the 3' end of the antisense strand is mismatched with the target sequence, and at the site where the antisense strand mismatches with the target sequence, the nucleotides of the antisense strand and the target sequence are the same, and the nucleotides of the antisense strand and the sense strand are complementary. In some embodiments of the present disclosure, the 17th nucleotide in the direction from the 5' end to the 3' end of the antisense strand is mismatched with the target sequence, and at the site where the antisense strand mismatches with the target sequence, the nucleotides of the antisense strand and the target sequence are the same, and the nucleotides of the antisense strand and the sense strand are complementary. In some embodiments of the present disclosure, the 18th nucleotide in the direction from the 5' end to the 3' end of the antisense strand is mismatched with the target sequence, and at the site where the antisense strand mismatches with the target sequence, the nucleotides of the antisense strand and the target sequence are the same, and the nucleotides of the antisense strand and the sense strand are complementary. In some embodiments of the present disclosure, the 19th nucleotide in the direction from the 5' end to the 3' end of the antisense strand is mismatched with the target sequence, and at the site where the antisense strand mismatches with the target sequence, the nucleotides of the antisense strand and the target sequence are the same, and the nucleotides of the antisense strand and the sense strand are complementary. In some embodiments of the present disclosure, the 20th nucleotide in the direction from the 5' end to the 3' end of the antisense strand is mismatched with the target sequence, and at the site where the antisense strand mismatches with the target sequence, the nucleotides of the antisense strand and the target sequence are the same, and the nucleotides of the antisense strand and the sense strand are complementary. In some embodiments of the present disclosure, the 21st nucleotide in the direction from the 5' end to the 3' end of the antisense strand is mismatched with the target sequence, and at the site where the antisense strand mismatches with the target sequence, the nucleotides of the antisense strand and the target sequence are the same, and the nucleotides of the antisense strand and the sense strand are complementary. In some embodiments of the present disclosure, the 22nd nucleotide in the direction from the 5' end to the 3' end of the antisense strand is mismatched with the target sequence, and at the site where the antisense strand mismatches with the target sequence, the nucleotides of the antisense strand and the target sequence are the same, and the nucleotides of the antisense strand and the sense strand are complementary. In some embodiments of the present disclosure, the 23rd nucleotide in the direction from the 5' end to the 3' end of the antisense strand is mismatched with the target sequence, and at the site where the antisense strand mismatches with the target sequence, the nucleotides of the antisense strand and the target sequence are the same, and the nucleotides of the antisense strand and the sense strand are complementary. In some embodiments of the present disclosure, the antisense strand has at most two mismatches with the target sequence, wherein the 1st and 20th nucleotides in the direction from the 5' end to the 3' end of the antisense strand are mismatched with the target sequence.

[0064] In some embodiments of the present disclosure, the 19th nucleotide in the direction from the 5' end to the 3' end of the antisense strand is mismatched with the target sequence, and at the site where the antisense strand mismatches with the target sequence, the nucleotides of the antisense strand and the target sequence are different, and the nucleotides of the antisense strand and the sense strand are complementary. In some embodiments of the present disclosure, the 20th nucleotide in the direction from the 5' end to the 3' end of the antisense strand is mismatched with the target sequence, and at the site where the antisense strand mismatches with the target sequence, the nucleotides of the antisense strand and the target sequence are different, and the nucleotides of the antisense strand and the sense strand are complementary. In some embodiments of the present disclosure, the 21st nucleotide in the direction from the 5' end to the 3' end of the antisense strand is mismatched with the target sequence, and at the site where the antisense strand mismatches with the target sequence, the nucleotides of the antisense strand and the target sequence are different, and the nucleotides of the antisense strand and the sense strand are complementary.

[0065] In some embodiments of the present disclosure, the antisense strand in the siRNA has no mismatches with the target sequence.

[0066] It is known to those skilled in the art that mismatches are permissive for siRNA activity.The methods described herein and / or methods known in the art can be used to determine whether an AGT siRNA comprising a mismatch effectively inhibits expression of the AGT gene.

[0067] In some embodiments of the present disclosure, the unmodified duplex of siRNA is selected from the duplex consisting of the sense strand sequence and the antisense strand sequence in the same row in Table 1.

[0068] In some embodiments of the present disclosure, the unmodified duplex of siRNA is selected from the group consisting of a duplex consisting of SEQ ID NO: 5 and SEQ ID NO: 6, a duplex consisting of SEQ ID NO: 7 and SEQ ID NO: 8, a duplex consisting of SEQ ID NO: 9 and SEQ ID NO: 10, a duplex consisting of SEQ ID NO: 11 and SEQ ID NO: 12, a duplex consisting of SEQ ID NO: 13 and SEQ ID NO: 14, a duplex consisting of SEQ ID NO: 15 and SEQ ID NO: 16, a duplex consisting of SEQ ID NO: 17 and SEQ ID NO: 18, a duplex consisting of SEQ ID NO: 19 and SEQ ID NO: 20, a duplex consisting of SEQ ID NO: 21 and SEQ ID NO: 22, a duplex consisting of SEQ ID NO: 23 and SEQ ID NO: 24, a duplex consisting of SEQ ID NO: 25 and SEQ ID NO: 26, a duplex consisting of SEQ ID NO: 27 and SEQ ID NO: 28, a duplex consisting of SEQ ID NO: 29 and SEQ ID NO: 30, a duplex consisting of SEQ ID NO: 31 and SEQ ID NO: 32. A duplex consisting of SEQ ID NO:31 and SEQ ID NO:32, a duplex consisting of SEQ ID NO:33 and SEQ ID NO:34, a duplex consisting of SEQ ID NO:35 and SEQ ID NO:36, a duplex consisting of SEQ ID NO:37 and SEQ ID NO:38, a duplex consisting of SEQ ID NO:39 and SEQ ID NO:40, a duplex consisting of SEQ ID NO:41 and SEQ ID NO:42, a duplex consisting of SEQ ID NO:43 and SEQ ID NO:44, a duplex consisting of SEQ ID NO:45 and SEQ ID NO:46, a duplex consisting of SEQ ID NO:47 and SEQ ID NO:48, a duplex consisting of SEQ ID NO:49 and SEQ ID NO:50, a duplex consisting of SEQ ID NO:51 and SEQ ID NO:52, a duplex consisting of SEQ ID NO:53 and SEQ ID NO:54, a duplex consisting of SEQ ID NO:55 and SEQ ID NO:56, a duplex consisting of SEQ ID NO:57 and SEQ ID NO:58 A duplex consisting of SEQ ID NO: 58, a duplex consisting of SEQ ID NO: 59 and SEQ ID NO: 60, a duplex consisting of SEQ ID NO: 61 and SEQ ID NO: 62, a duplex consisting of SEQ ID NO: 63 and SEQ ID NO: 64, a duplex consisting of SEQ ID NO: 65 and SEQ ID NO:A duplex consisting of SEQ ID NO: 66, a duplex consisting of SEQ ID NO: 67 and SEQ ID NO: 68, a duplex consisting of SEQ ID NO: 69 and SEQ ID NO: 70, a duplex consisting of SEQ ID NO: 71 and SEQ ID NO: 72, a duplex consisting of SEQ ID NO: 73 and SEQ ID NO: 74, a duplex consisting of SEQ ID NO: 75 and SEQ ID NO: 76, a duplex consisting of SEQ ID NO: 77 and SEQ ID NO: 78, a duplex consisting of SEQ ID NO: 79 and SEQ ID NO: 80, a duplex consisting of SEQ ID NO: 81 and SEQ ID NO: 82, a duplex consisting of SEQ ID NO: 83 and SEQ ID NO: 84, a duplex consisting of SEQ ID NO: 85 and SEQ ID NO: 86, a duplex consisting of SEQ ID NO: 87 and SEQ ID NO: 88, a duplex consisting of SEQ ID NO: 89 and SEQ ID NO: 90, a duplex consisting of SEQ ID NO: 91 and SEQ ID NO: 92, a duplex consisting of SEQ ID NO: A duplex consisting of SEQ ID NO: 93 and SEQ ID NO: 94, a duplex consisting of SEQ ID NO: 95 and SEQ ID NO: 96, a duplex consisting of SEQ ID NO: 97 and SEQ ID NO: 98, a duplex consisting of SEQ ID NO: 99 and SEQ ID NO: 100, a duplex consisting of SEQ ID NO: 101 and SEQ ID NO: 102, a duplex consisting of SEQ ID NO: 103 and SEQ ID NO: 104, a duplex consisting of SEQ ID NO: 105 and SEQ ID NO: 106, a duplex consisting of SEQ ID NO: 107 and SEQ ID NO: 106, a duplex consisting of SEQ ID NO: 108 and SEQ ID NO: 109, a duplex consisting of SEQ ID NO: 110 and SEQ ID NO: 111, a duplex consisting of SEQ ID NO: 112 and SEQ ID NO: 113. NO:111 duplex, a duplex consisting of SEQ ID NO:108 and SEQ ID NO:111, a duplex consisting of SEQ ID NO:112 and SEQ ID NO:113, a duplex consisting of SEQ ID NO:114 and SEQ ID NO:115, a duplex consisting of SEQ ID NO:116 and SEQ ID NO:: 117, a duplex consisting of SEQ ID NO: 118 and SEQ ID NO: 119, a duplex consisting of SEQ ID NO: 120 and SEQ ID NO: 121, a duplex consisting of SEQ ID NO: 122 and SEQ ID NO: 123, a duplex consisting of SEQ ID NO: 124 and SEQ ID NO: 125, a duplex consisting of SEQ ID NO: 126 and SEQ ID NO: 127, a duplex consisting of SEQ ID NO: 128 and SEQ ID NO: 129, a duplex consisting of SEQ ID NO: 130 and SEQ ID NO: 131, a duplex consisting of SEQ ID NO: 132 and SEQ ID NO: 133, a duplex consisting of SEQ ID NO: 134 and SEQ ID NO: 135, a duplex consisting of SEQ ID NO: 136 and SEQ ID NO: 137, a duplex consisting of SEQ ID NO: 138 and SEQ ID NO: 139, a duplex consisting of SEQ ID NO: 140 and SEQ ID NO: A duplex consisting of SEQ ID NO: 141, and a duplex consisting of SEQ ID NO: 142 and SEQ ID NO: 143. Preferably, in some embodiments of the present disclosure, the unmodified duplex of siRNA is selected from the group consisting of a duplex consisting of SEQ ID NO: 5 and SEQ ID NO: 6, a duplex consisting of SEQ ID NO: 7 and SEQ ID NO: 8, a duplex consisting of SEQ ID NO: 9 and SEQ ID NO: 10, a duplex consisting of SEQ ID NO: 11 and SEQ ID NO: 12, a duplex consisting of SEQ ID NO: 13 and SEQ ID NO: 14, a duplex consisting of SEQ ID NO: 15 and SEQ ID NO: 16, a duplex consisting of SEQ ID NO: 17 and SEQ ID NO: 18, a duplex consisting of SEQ ID NO: 19 and SEQ ID NO: 20, a duplex consisting of SEQ ID NO: 21 and SEQ ID NO: 22, a duplex consisting of SEQ ID NO: 23 and SEQ ID NO: 24, a duplex consisting of SEQ ID NO: 25 and SEQ ID NO: 26, a duplex consisting of SEQ ID NO: 27 and SEQ ID NO: 28, a duplex consisting of SEQ ID NO: 29 and SEQ ID NO: 30. A duplex consisting of SEQ ID NO: 30, a duplex consisting of SEQ ID NO: 31 and SEQ ID NO: 32, a duplex consisting of SEQ ID NO: 33 and SEQ ID NO: 34, a duplex consisting of SEQ ID NO: 35 and SEQ ID NO: 36, a duplex consisting of SEQ ID NO: 37 and SEQ ID NO: 38, a duplex consisting of SEQ ID NO: 39 and SEQ ID NO: 40, a duplex consisting of SEQ ID NO: 30 and SEQ ID NO: 31, a duplex consisting of SEQ ID NO: 32 and SEQ ID NO: 33, a duplex consisting of SEQ ID NO: 34 and SEQ ID NO: 35, a duplex consisting of SEQ ID NO: 36A duplex consisting of SEQ ID NO:37 and SEQ ID NO:38, a duplex consisting of SEQ ID NO:39 and SEQ ID NO:40, a duplex consisting of SEQ ID NO:41 and SEQ ID NO:42, a duplex consisting of SEQ ID NO:43 and SEQ ID NO:44, a duplex consisting of SEQ ID NO:59 and SEQ ID NO:60, a duplex consisting of SEQ ID NO:65 and SEQ ID NO:66, a duplex consisting of SEQ ID NO:67 and SEQ ID NO:68, a duplex consisting of SEQ ID NO:91 and SEQ ID NO:92, a duplex consisting of SEQ ID NO:93 and SEQ ID NO:94, a duplex consisting of SEQ ID NO:103 and SEQ ID NO:104, and a duplex consisting of SEQ ID NO:112 and SEQ ID NO:113. More preferably, in some embodiments of the present disclosure, the unmodified duplex of siRNA is selected from the group consisting of a duplex of SEQ ID NO: 5 and SEQ ID NO: 6, a duplex of SEQ ID NO: 7 and SEQ ID NO: 8, a duplex of SEQ ID NO: 9 and SEQ ID NO: 10, a duplex of SEQ ID NO: 11 and SEQ ID NO: 12, a duplex of SEQ ID NO: 13 and SEQ ID NO: 14, a duplex of SEQ ID NO: 15 and SEQ ID NO: 16, a duplex of SEQ ID NO: 17 and SEQ ID NO: 18, a duplex of SEQ ID NO: 19 and SEQ ID NO: 20, a duplex of SEQ ID NO: 21 and SEQ ID NO: 22, a duplex of SEQ ID NO: 23 and SEQ ID NO: 24, a duplex of SEQ ID NO: 29 and SEQ ID NO: 30, a duplex of SEQ ID NO: 91 and SEQ ID NO: 92, a duplex of SEQ ID NO: 112 and SEQ ID NO: 113. A duplex consisting of NO:113.

[0069] In some embodiments of the present disclosure, the unmodified duplex of the siRNA is selected from at least one of duplex 1 to duplex 27;

[0070] Duplex 1

[0071] Sense strand: 5'-ACCGACCAGCUUGUUUGUGAA-3' (SEQ ID NO: 5)

[0072] Antisense strand: 5′-UUCACAAACAAGCUGGUCGGUUG-3′ (SEQ ID NO: 6);

[0073] Duplex 2

[0074] Sense strand: 5'-CCAGCUUGUUUGUGAAACAAA-3' (SEQ ID NO: 7)

[0075] Antisense strand: 5′-UUUGUUUCACAAACAAGCUGGUC-3′ (SEQ ID NO: 8);

[0076] Duplex 3

[0077] Sense strand: 5'-GACCAGCUUGUUUGUGAAACA-3' (SEQ ID NO: 9)

[0078] Antisense strand: 5′-UGUUUCACAAACAAGCUGGUCGG-3′ (SEQ ID NO: 10);

[0079] Duplex 4

[0080] Sense strand: 5'-AGUGUUCCCUUUUCAAGUUGA-3' (SEQ ID NO: 11)

[0081] Antisense strand: 5′-UCAACUUGAAAAGGGAACACUUU-3′ (SEQ ID NO: 12);

[0082] Duplex 5

[0083] Sense strand: 5'-GAGGUGCUGAACAGCAUUUUU-3' (SEQ ID NO: 13)

[0084] Antisense strand: 5′-AAAAAUGCUGUUCAGCACCUCCC-3′ (SEQ ID NO: 14);

[0085] Duplex 6

[0086] Sense strand: 5'-AACAAAAAAGUGUUCCCUUUU-3' (SEQ ID NO: 15)

[0087] Antisense strand: 5′-AAAAGGGAACACUUUUUUGUUUC-3′ (SEQ ID NO: 16);

[0088] Duplex 7

[0089] Sense strand: 5'-AACCGACCAGCUUGUUUGUGA-3' (SEQ ID NO: 17)

[0090] Antisense strand: 5′-UCACAAACAAGCUGGUCGGUUGG-3′ (SEQ ID NO: 18);

[0091] Duplex 8

[0092] Sense strand: 5'-CCUGUUUGCUGUGUAUGAUCA-3' (SEQ ID NO: 19)

[0093] Antisense strand: 5′-UGAUCAUACACAGCAAACAGGAA-3′ (SEQ ID NO: 20);

[0094] Duplex 9

[0095] Sense strand: 5'-AGCUUGUUUGUGAAACAAAAA-3' (SEQ ID NO: 21)

[0096] Antisense strand: 5′-UUUUUGUUUCACAAACAAGCUGG-3′ (SEQ ID NO: 22);

[0097] Duplex 10

[0098] Sense strand: 5'-UCCCACCUUUUCUUCUAAUGA-3' (SEQ ID NO: 23)

[0099] Antisense strand: 5′-UCAUUAGAAGAAAAGGUGGGAGA-3′ (SEQ ID NO: 24);

[0100] Duplex 11

[0101] Sense strand: 5'-GUUCCCUUUUCAAGUUGAGAA-3' (SEQ ID NO: 25)

[0102] Antisense strand: 5′-UUCUCAACUUGAAAAGGGAACAC-3′ (SEQ ID NO: 26);

[0103] Duplex 12

[0104] Sense strand: 5'-AAAAAAGUGUUCCCUUUUCAA-3' (SEQ ID NO: 27)

[0105] Antisense strand: 5′-UUGAAAAGGGAACACUUUUUUUGU-3′ (SEQ ID NO: 28);

[0106] Duplex 13

[0107] Sense strand: 5'-ACCAGCUUGUUUGUGAAACAA-3' (SEQ ID NO: 29)

[0108] Antisense strand: 5′-UUGUUUCACAAACAAGCUGGUCG-3′ (SEQ ID NO: 30);

[0109] Duplex 14

[0110] Sense strand: 5'-CUGUUCCAAAAAGAAUUCCAA-3' (SEQ ID NO: 31)

[0111] Antisense strand: 5′-UUGGAAUUCUUUUUGGAACAGUA-3′ (SEQ ID NO: 32);

[0112] Duplex 15

[0113] Sense strand: 5'-UUUGUGAAACAAAAAAGUGUU-3' (SEQ ID NO: 33)

[0114] Antisense strand: 5′-AACACUUUUUUGUUUCACAAACA-3′ (SEQ ID NO: 34);

[0115] Duplex 16

[0116] Sense strand: 5'-GUCUCCCACCUUUUCUUCUAA-3' (SEQ ID NO: 35)

[0117] Antisense strand: 5′-UUAGAAGAAAAGGUGGGAGACUG-3′ (SEQ ID NO: 36);

[0118] Duplex 17

[0119] Sense strand: 5'-GAGGGUCUCACUUUCCAGCAA-3' (SEQ ID NO: 37)

[0120] Antisense strand: 5′-UUGCUGGAAAGUGAGACCCUCCA-3′ (SEQ ID NO: 38);

[0121] Duplex 18

[0122] Sense strand: 5'-CCCAUUCCUGUUUGCUGUGUA-3' (SEQ ID NO: 39)

[0123] Antisense strand: 5′-UACACAGCAAACAGGAAUGGGCG-3′ (SEQ ID NO: 40);

[0124] Duplex 19

[0125] Sense strand: 5'-GCUGGGUUUAUUUUAGAGAAU-3' (SEQ ID NO: 41)

[0126] Antisense strand: 5′-AUUCUCUAAAAUAAACCCAGCAA-3′ (SEQ ID NO: 42);

[0127] Duplex 20

[0128] Sense strand: 5'-CCCAGUUUGCUGGGUUUAUUU-3' (SEQ ID NO: 43)

[0129] Antisense strand: 5′-AAAUAAACCCAGCAAACUGGGAG-3′ (SEQ ID NO: 44);

[0130] Duplex 21

[0131] Sense strand: 5'-CACCUUUUCUUCUAAUGAGUU-3' (SEQ ID NO: 59)

[0132] Antisense strand: 5′-AACUCAUUAGAAGAAAAGGUGGG-3′ (SEQ ID NO: 60);

[0133] Duplex 22

[0134] Sense strand: 5'-CUCCUUUUCUUCUAAUGAGUU-3' (SEQ ID NO: 65)

[0135] Antisense strand: 5′-AACUCAUUAGAAGAAAAGGAGGG-3′ (SEQ ID NO: 66);

[0136] Duplex 23

[0137] Sense strand: 5'-CAGCUUUUCUUCUAAUGAGUU-3' (SEQ ID NO: 67)

[0138] Antisense strand: 5′-AACUCAUUAGAAGAAAAGCUGGG-3′ (SEQ ID NO: 68);

[0139] Duplex 24

[0140] Sense strand: 5'-CACCUUUUCUUCUAAUGAGUA-3' (SEQ ID NO: 91)

[0141] Antisense strand: 5′-UACUCAUUAGAAGAAAAGGUGGG-3′ (SEQ ID NO: 92);

[0142] Duplex 25

[0143] Sense strand: 5'-CGCCUUUUCUUCUAAUGAGUA-3' (SEQ ID NO: 93)

[0144] Antisense strand: 5′-UACUCAUUAGAAGAAAAGGCGGG-3′ (SEQ ID NO: 94);

[0145] Duplex 26

[0146] Sense strand: 5'-CUCCUUUUCUUCUAAUGAGUA-3' (SEQ ID NO: 112)

[0147] Antisense strand: 5′-UACUCAUUAGAAGAAAAGGAGGG-3′ (SEQ ID NO: 113);

[0148] Duplex 27

[0149] Sense strand: 5'-ACCUUUUCUUCUAAUGAGUA-3' (SEQ ID NO: 103)

[0150] Antisense strand: 5'-UACUCAUUAGAAGAAAAGGUGG-3' (SEQ ID NO: 104).

[0151] In some embodiments of the present disclosure, the unmodified duplex of the siRNA is a duplex that differs from any of the duplexes of duplexes 1 to 27 by no more than 2 nucleotides.

[0152] In some embodiments of the present disclosure, the unmodified duplex of the siRNA differs from duplex 21 by no more than 2 nucleotides. In some embodiments of the present disclosure, the unmodified duplex of the siRNA differs from duplex 24 by no more than 2 nucleotides. In some embodiments of the present disclosure, the unmodified duplex of the siRNA differs from duplex 24 by 2 nucleotides. In some embodiments of the present disclosure, the sense strand of the unmodified duplex of the siRNA differs from the sense strand of duplex 24 by no more than 1 nucleotide, and the antisense strand of the unmodified duplex of the siRNA differs from the antisense strand of duplex 24 by no more than 1 nucleotide.

[0153] In some embodiments of the present disclosure, the sense strand of the unmodified siRNA duplex differs from the sense strand of duplex 24 by 1 nucleotide, and the difference is located between positions 1 to 3 in the 5'-to-3' direction of the sense strand, and the antisense strand of the unmodified siRNA duplex differs from the antisense strand of duplex 24 by 1 nucleotide, and the difference is located between positions 19 to 21 in the 5'-to-3' direction of the antisense strand. In some embodiments of the present disclosure, the difference between the sense strand of the unmodified siRNA duplex and the sense strand of duplex 24 is located at the 1st nucleotide in the 5'-to-3' direction of the sense strand, and the difference between the antisense strand of the unmodified siRNA duplex and the antisense strand of duplex 24 is located at the 21st nucleotide in the 5'-to-3' direction of the antisense strand. In some embodiments of the present disclosure, the difference between the sense strand of the unmodified siRNA duplex and the sense strand of duplex 24 is located at the 2nd nucleotide in the direction from the 5' end to the 3' end of the sense strand, and the difference between the antisense strand of the unmodified siRNA duplex and the antisense strand of duplex 24 is located at the 20th nucleotide in the direction from the 5' end to the 3' end of the antisense strand. In some embodiments of the present disclosure, the difference between the sense strand of the unmodified siRNA duplex and the sense strand of duplex 24 is located at the 3rd nucleotide in the direction from the 5' end to the 3' end of the sense strand, and the difference between the antisense strand of the unmodified siRNA duplex and the antisense strand of duplex 24 is located at the 19th nucleotide in the direction from the 5' end to the 3' end of the antisense strand.

[0154] In some embodiments of the present disclosure, the difference between the sense chain of the unmodified duplex of siRNA and the sense chain of duplex 24 is located at the 2nd nucleotide from the 5' end to the 3' end of the sense chain, and the difference between the antisense chain of the unmodified duplex of siRNA and the antisense chain of duplex 24 is located at the 20th nucleotide from the 5' end to the 3' end of the antisense chain, and the 2nd nucleotide from the 5' end to the 3' end of the sense chain of the unmodified duplex of siRNA and the 20th nucleotide from the 5' end to the 3' end of the antisense chain are complementary.

[0155] In some embodiments of the present disclosure, the siRNA may further contain modified nucleotides or nucleotide analogs as needed, provided that the modified nucleotides or nucleotide analogs do not significantly weaken or abolish the siRNA's ability to inhibit AGT gene expression. Currently, there are a variety of methods available in the art for modifying siRNA, including, for example, backbone modifications (e.g., phosphate group modifications), ribose group modifications, and base modifications (Watts, JK, GF Deleavey, and MJ Damha, Chemically modified siRNA: tools and applications. Drug Discov Today, 2008. 13(19-20): p. 842-55).

[0156] In some embodiments of the present disclosure, at least one nucleotide in the sense strand or antisense strand of the siRNA is a modified nucleotide. For example, the modified nucleotide includes a ribose group and an optional phosphate group-modified nucleotide group, but is not limited thereto. In some preferred embodiments of the present disclosure, the modified nucleotide is a nucleotide modified at the 2' position of its ribose, for example, a nucleotide with the following 2' modification: 2'-deoxy, 2'-fluoro, 2'-amino, 2'-methyl, 2'-ethyl, 2'-methyl-O-methyl, 2'-ethyl-O-methyl, 2'-O-methyl (2'-OMe), 2'-O-ethyl, 2'-O-methoxyethyl (2'-O-MOE), 2'-methoxyethyl (2'-MOE), 2'-O-ethyl-O-methyl or 2'-O-allyl.

[0157] In some embodiments of the present disclosure, at least one nucleotide in the sense strand of the siRNA is a modified nucleotide. In some embodiments of the present disclosure, all nucleotides in the sense strand of the siRNA are modified nucleotides. In some embodiments of the present disclosure, at least one nucleotide in the antisense strand of the siRNA is a modified nucleotide. In some embodiments of the present disclosure, all nucleotides in the antisense strand of the siRNA are modified nucleotides.

[0158] In some embodiments of the present disclosure, the modified nucleotide is selected from at least one of: 2'-methoxy nucleotides, 2'-fluoro nucleotides, 2'-deoxy nucleotides, 2'-methoxyethyl nucleotides, 2'-amino nucleotides, 2'-alkyl nucleotides, and 3'-methoxy nucleotides, but the present disclosure is not limited thereto. In some embodiments of the present disclosure, the modified nucleotide is selected from 2'-methoxy nucleotides and 2'-fluoro nucleotides.

[0159] In some embodiments of the present disclosure, the modified nucleotides are phosphate analogue-modified nucleotides. In some embodiments of the present disclosure, the phosphate analogue-modified nucleotides may include (E)-vinyl phosphate ((E)-VP) modified nucleotides, (Z)-vinyl phosphate ((Z)-VP) modified nucleotides, thiophosphate-modified (Ps) nucleotides, Sp-configured thiophosphate-modified nucleotides, Rp-configured thiophosphate-modified nucleotides (Anastasia Khvorova, Jonathan K. Watts, The chemical evolution of oligonucleotide therapies of clinical utility. Nature Biotichnology, 2017, 35(3): p. 238-248) or methylsulfonylphosphoramidite-modified (MsPA) nucleotides, etc.

[0160] In some embodiments of the present disclosure, the nucleotide analog refers to a group that can replace a nucleotide in a nucleic acid, but has a base structure different from adenine ribonucleotide, guanine ribonucleotide, cytosine ribonucleotide, uracil ribonucleotide or thymine deoxyribonucleotide. In some embodiments of the present disclosure, these nucleotide analogs may include locked nucleic acid (LNA), unlocked nucleic acid (UNA) or glycerol nucleic acid (GNA). In some embodiments of the present disclosure, the nucleotide analog includes locked nucleic acid (LNA) or glycerol nucleic acid (GNA).

[0161] In the present disclosure, unless otherwise specified, each nucleotide may have more than one modification at the same time. For example, a nucleotide may be a 2'-fluoro nucleotide and a (E)-vinyl phosphate ((E)-VP) modified nucleotide at the same time.

[0162] The inventors of the present disclosure have found that the preferred siRNA of the present disclosure has achieved surprising stability and gene silencing efficiency, as well as satisfactory cytotoxicity and immunostimulatory properties in animal experiments.

[0163] In some embodiments of the present disclosure, all nucleotides in the sense strand and / or antisense strand of the siRNA are modified nucleotides or nucleotide analogs.

[0164] In some embodiments of the present disclosure, each nucleotide in the sense strand and the antisense strand of the siRNA can independently be a 2'-methoxy nucleotide, a 2'-fluoro nucleotide, a 2'-deoxy nucleotide, or a phosphorothioate nucleotide (a nucleotide containing a phosphorothioate group, such as a phosphorothioate group in the Rp configuration or a phosphorothioate group in the Sp configuration).

[0165] In some embodiments of the present disclosure, three, four, five or six nucleotides of the sense strand are 2'-fluoro nucleotides, and the 2'-fluoro nucleotides are selected from the nucleotides at positions 1, 3, 5, 6, 7, 9, 11, 12, 13, 15, 17, 19, and optionally 21 in the direction from the 3' end to the 5' end of the sense strand, and the nucleotides at positions 11 and 13 are both 2'-fluoro nucleotides.

[0166] In some embodiments of the present disclosure, the sense strand has four, five, or six nucleotides that are 2'-fluoro nucleotides, the 2'-fluoro nucleotides being selected from the group consisting of the 1st, 3rd, 5th, 6th, 7th, 9th, 11th, 12th, 13th, 15th, 17th, 19th, and optionally the 21st nucleotide in the direction from the 3' end to the 5' end of the sense strand, and the nucleotides at positions 11, 12, and 13 are all 2'-fluoro nucleotides. In some embodiments of the present disclosure, the sense strand has four, five, or six nucleotides that are 2'-fluoro nucleotides, the 2'-fluoro nucleotides being selected from the group consisting of the 1st, 3rd, 5th, 7th, 9th, 11th, 12th, 13th, 15th, 17th, 19th, and optionally the 21st nucleotide in the direction from the 3' end to the 5' end of the sense strand, and the nucleotides at positions 11, 12, and 13 are all 2'-fluoro nucleotides. In some embodiments of the present disclosure, the sense strand has four, five, or six nucleotides that are 2'-fluoro nucleotides, and the 2'-fluoro nucleotides are selected from the nucleotides at positions 1, 3, 5, 6, 7, 9, 11, 12, 13, 15, 17, 19, and optionally 21 in the direction from the 3' end to the 5' end of the sense strand, and the nucleotides at positions 9, 11, 12, and 13 are all 2'-fluoro nucleotides. In some embodiments of the present disclosure, the sense strand has four, five, or six nucleotides that are 2'-fluoro nucleotides, and the 2'-fluoro nucleotides are selected from the nucleotides at positions 1, 3, 5, 7, 9, 11, 12, 13, 15, 17, 19, and optionally 21 in the direction from the 3' end to the 5' end of the sense strand, and the nucleotides at positions 9, 11, 12, and 13 are all 2'-fluoro nucleotides. In some embodiments of the present disclosure, the sense strand has four, five, or six nucleotides that are 2'-fluoro nucleotides, and the 2'-fluoro nucleotides are selected from the nucleotides at positions 1, 3, 5, 6, 7, 9, 11, 12, 13, 15, 17, 19, and optionally 21 in the direction from the 3' end to the 5' end of the sense strand, and the nucleotides at positions 7, 11, 12, and 13 are all 2'-fluoro nucleotides. In some embodiments of the present disclosure, the sense strand has four, five, or six nucleotides that are 2'-fluoro nucleotides, and the 2'-fluoro nucleotides are selected from the nucleotides at positions 1, 3, 5, 6, 7, 9, 11, 12, 13, 15, 17, 19, and optionally 21 in the direction from the 3' end to the 5' end of the sense strand, and the nucleotides at positions 5, 11, 12, and 13 are all 2'-fluoro nucleotides. In some embodiments of the present disclosure, four, five, or six nucleotides of the sense strand are 2'-fluoro nucleotides, and the 2'-fluoro nucleotides are selected from the nucleotides at positions 1, 3, 5, 7, 9, 11, 12, 13, 15, 17, 19, and optionally 21 in the direction from the 3' end to the 5' end of the sense strand, and the nucleotides at positions 5, 11, 12, and 13 are all 2'-fluoro nucleotides.

[0167] In some embodiments of the present disclosure, the sense strand has four, five, or six nucleotides that are 2'-fluoro nucleotides, and the 2'-fluoro nucleotides are selected from the nucleotides at positions 1, 3, 5, 6, 7, 9, 11, 12, 13, 15, 17, 19, and optionally 21 in the direction from the 3' end to the 5' end of the sense strand, and the nucleotides at positions 3, 11, 12, and 13 are all 2'-fluoro nucleotides. In some embodiments of the present disclosure, the sense strand has four, five, or six nucleotides that are 2'-fluoro nucleotides, and the 2'-fluoro nucleotides are selected from the nucleotides at positions 1, 3, 5, 6, 7, 9, 11, 12, 13, 15, 17, 19, and optionally 21 in the direction from the 3' end to the 5' end of the sense strand, and the nucleotides at positions 1, 11, 12, and 13 are all 2'-fluoro nucleotides. In some embodiments of the present disclosure, the sense strand has four, five, or six nucleotides that are 2'-fluoro nucleotides, the 2'-fluoro nucleotides being selected from the group consisting of nucleotides at positions 1, 3, 5, 7, 9, 11, 12, 13, 15, 17, 19, and optionally 21, from the 3' to the 5' direction of the sense strand, and the nucleotides at positions 1, 11, 12, and 13 are all 2'-fluoro nucleotides. In some embodiments of the present disclosure, the sense strand has four, five, or six nucleotides that are 2'-fluoro nucleotides, the 2'-fluoro nucleotides being selected from the group consisting of nucleotides at positions 1, 3, 5, 6, 7, 9, 11, 12, 13, 15, 17, 19, and optionally 21, from the 3' to the 5' direction of the sense strand, and the nucleotides at positions 1, 3, 11, 12, and 13 are all 2'-fluoro nucleotides. In some embodiments of the present disclosure, the sense strand has four, five, or six nucleotides that are 2'-fluoro nucleotides, the 2'-fluoro nucleotides being selected from the group consisting of nucleotides at positions 1, 3, 5, 6, 7, 9, 11, 12, 13, 15, 17, 19, and optionally 21, from the 3' end to the 5' end of the sense strand, and the nucleotides at positions 1, 5, 11, 12, and 13 are all 2'-fluoro nucleotides. In some embodiments of the present disclosure, the sense strand has four, five, or six nucleotides that are 2'-fluoro nucleotides, the 2'-fluoro nucleotides being selected from the group consisting of nucleotides at positions 1, 3, 5, 7, 9, 11, 12, 13, 15, 17, 19, and optionally 21, from the 3' end to the 5' end of the sense strand, and the nucleotides at positions 1, 5, 11, 12, and 13 are all 2'-fluoro nucleotides. In some embodiments of the present disclosure, four, five or six nucleotides of the sense strand are 2'-fluoro nucleotides, and the 2'-fluoro nucleotides are selected from positions 1, 3, 5, 6, 7, 9, 11, 12, 13, 15, 17, 19, and optionally 21 in the direction from the 3' end to the 5' end of the sense strand, and the nucleotides at positions 1, 7, 11, 12 and 13 are all 2'-fluoro nucleotides.In some embodiments of the present disclosure, the sense strand has four, five, or six nucleotides that are 2'-fluoro nucleotides, the 2'-fluoro nucleotides being selected from the group consisting of positions 1, 3, 5, 6, 7, 9, 11, 12, 13, 15, 17, 19, and optionally 21, from the 3' to the 5' direction of the sense strand, and the nucleotides at positions 1, 9, 11, 12, and 13 are all 2'-fluoro nucleotides. In some embodiments of the present disclosure, the sense strand has four, five, or six nucleotides that are 2'-fluoro nucleotides, the 2'-fluoro nucleotides being selected from the group consisting of positions 1, 3, 5, 7, 9, 11, 12, 13, 15, 17, 19, and optionally 21, from the 3' to the 5' direction of the sense strand, and the nucleotides at positions 1, 9, 11, 12, and 13 are all 2'-fluoro nucleotides. In some embodiments of the present disclosure, four, five or six nucleotides of the sense strand are 2'-fluoro nucleotides, and the 2'-fluoro nucleotides are selected from the nucleotides at positions 1, 3, 5, 7, 9, 11, 12, 13, 15, 17, 19, and optionally 21 in the direction from the 3' end to the 5' end of the sense strand, and the nucleotides at positions 5, 9, 11, 12 and 13 are all 2'-fluoro nucleotides.

[0168] In some embodiments of the present disclosure, four nucleotides of the sense strand are 2'-fluoro nucleotides, and the four 2'-fluoro nucleotides are located at positions 11, 12, 13, and 15 in the direction from the 3' end to the 5' end of the sense strand.

[0169] In some embodiments of the present disclosure, five nucleotides of the sense strand are 2'-fluoro nucleotides, and the five 2'-fluoro nucleotides are located at positions 9, 11, 12, 13, and 15 in the 3' to 5' direction of the sense strand.

[0170] In some embodiments of the present disclosure, the sense strand has six nucleotides that are 2'-fluoro nucleotides, and the six 2'-fluoro nucleotides are located at positions 1, 5, 9, 11, 12, and 13 in the 3' to 5' direction of the sense strand. In some embodiments of the present disclosure, the sense strand has six nucleotides that are 2'-fluoro nucleotides, and the six 2'-fluoro nucleotides are located at positions 5, 9, 11, 12, 13, and 15 in the 3' to 5' direction of the sense strand.

[0171] In some embodiments of the present disclosure, the antisense strand has four, five, six, or seven nucleotides that are 2'-fluoro nucleotides, the 2'-fluoro nucleotides being selected from positions 2, 3, 4, 5, 6, 7, 8, 9, 10, 14, 16, 18, 20, 21, and optionally 22, from the 5' end to the 3' end of the antisense strand, and the nucleotides at positions 2, 6, 14, and 16 are all 2'-fluoro nucleotides. In some embodiments of the present disclosure, the antisense strand has four, five, six, or seven nucleotides that are 2'-fluoro nucleotides, the 2'-fluoro nucleotides being selected from positions 2, 3, 4, 5, 6, 7, 8, 9, 10, 14, 16, 18, 20, 21, and optionally 22, from the 5' end to the 3' end of the antisense strand, and the nucleotides at positions 2, 6, 14, 16, and optionally 22 are all 2'-fluoro nucleotides. In some embodiments of the present disclosure, the antisense strand has four, five, six, or seven nucleotides that are 2'-fluoro nucleotides, the 2'-fluoro nucleotides being selected from positions 2, 3, 4, 5, 6, 7, 8, 9, 10, 14, 16, 18, 20, 21, and optionally 23, from the 5' end to the 3' end of the antisense strand, and the nucleotides at positions 2, 6, 14, 16, and optionally 22 are all 2'-fluoro nucleotides. In some embodiments of the present disclosure, the antisense strand has four, five, six, or seven nucleotides that are 2'-fluoro nucleotides, the 2'-fluoro nucleotides being selected from positions 2, 3, 4, 5, 6, 7, 8, 9, 10, 14, 16, 18, 20, 21, and optionally 24, from the 5' end to the 3' end of the antisense strand, and the nucleotides at positions 2, 6, 14, 16, and optionally 22 are all 2'-fluoro nucleotides. In some embodiments of the present disclosure, the antisense strand has four, five, six, or seven nucleotides that are 2'-fluoro nucleotides, the 2'-fluoro nucleotides being selected from positions 2, 4, 6, 7, 8, 9, 10, 14, 16, 18, 20, 21, and optionally 25, from the 5' end to the 3' end of the antisense strand, and the nucleotides at positions 2, 6, 14, 16, and optionally 22 are all 2'-fluoro nucleotides. In some embodiments of the present disclosure, the antisense strand has four, five, six, or seven nucleotides that are 2'-fluoro nucleotides, the 2'-fluoro nucleotides being selected from positions 2, 3, 4, 5, 6, 7, 8, 9, 10, 14, 16, 18, 20, 21, and optionally 26, from the 5' end to the 3' end of the antisense strand, and the nucleotides at positions 2, 6, 14, and 16 are all 2'-fluoro nucleotides.

[0172] In some embodiments of the present disclosure, the antisense strand has five nucleotides that are 2'-fluoro nucleotides, and the 2'-fluoro nucleotides are selected from positions 2, 3, 4, 5, 6, 7, 8, 9, 10, 14, 16, 18, 20, 21, and optionally 22 from the 5' end to the 3' end of the antisense strand, and the nucleotides at positions 2, 6, 14, and 16 are all 2'-fluoro nucleotides.

[0173] In some embodiments of the present disclosure, the antisense strand has five nucleotides that are 2'-fluoro nucleotides, and the five 2'-fluoro nucleotides are located at nucleotide positions 2, 6, 14, 16, and optionally 22 in the 5' to 3' direction of the antisense strand. In some embodiments of the present disclosure, the antisense strand has five nucleotides that are 2'-fluoro nucleotides, and the five 2'-fluoro nucleotides are located at nucleotide positions 2, 6, 14, 16, and optionally 23 in the 5' to 3' direction of the antisense strand. In some embodiments of the present disclosure, the antisense strand has five nucleotides that are 2'-fluoro nucleotides, and the five 2'-fluoro nucleotides are located at nucleotide positions 2, 6, 14, 16, and optionally 24 in the 5' to 3' direction of the antisense strand. In some embodiments of the present disclosure, the antisense strand has five nucleotides that are 2'-fluoro nucleotides, and the five 2'-fluoro nucleotides are located at nucleotide positions 2, 6, 14, 16, and optionally 25 in the 5' to 3' direction of the antisense strand. In some embodiments of the present disclosure, the antisense strand has five nucleotides that are 2'-fluoro nucleotides, and the five 2'-fluoro nucleotides are located at nucleotides 2, 6, 14, 16, and optionally 26 in the 5' to 3' direction of the antisense strand. In some embodiments of the present disclosure, the antisense strand has five nucleotides that are 2'-fluoro nucleotides, and the five 2'-fluoro nucleotides are located at nucleotides 2, 6, 14, 16, and 22 in the 5' to 3' direction of the antisense strand.

[0174] In some embodiments of the present disclosure, the antisense strand has six nucleotides that are 2'-fluoro nucleotides, and the six 2'-fluoro nucleotides are selected from the nucleotides at positions 2, 3, 4, 5, 6, 7, 8, 9, 10, 14, 16, 18, 20, 21, and optionally 22 in the direction from the 5' end to the 3' end of the antisense strand, and the nucleotides at positions 2, 6, 14, 16, and optionally 22 are all 2'-fluoro nucleotides.

[0175] In some embodiments of the present disclosure, the antisense strand has six nucleotides that are 2'-fluoro nucleotides, and the six 2'-fluoro nucleotides are selected from the nucleotides at positions 2, 4, 6, 7, 8, 10, 14, 16, 18, 20, and optionally 22 in the 5' to 3' direction of the antisense strand, and the nucleotides at positions 2, 6, 14, 16, and optionally 22 are all 2'-fluoro nucleotides. In some embodiments of the present disclosure, the antisense strand has six nucleotides that are 2'-fluoro nucleotides, and the nucleotides at positions 2, 6, 7, 14, 16, and 22 in the 5' to 3' direction of the antisense strand are all 2'-fluoro nucleotides.

[0176] In some embodiments of the present disclosure, the antisense strand has seven nucleotides that are 2'-fluoro nucleotides, and the seven 2'-fluoro nucleotides are selected from the nucleotides at positions 2, 3, 4, 5, 6, 7, 8, 9, 10, 14, 16, 18, 20, 21, and optionally 22 in the direction from the 5' end to the 3' end of the antisense strand, and the nucleotides at positions 2, 6, 14, 16, and optionally 22 are all 2'-fluoro nucleotides.

[0177] In some embodiments of the present disclosure, the antisense strand has four, five, or six nucleotides that are 2'-fluoro nucleotides, the 2'-fluoro nucleotides being selected from the group consisting of nucleotides at positions 2, 4, 6, 7, 8, 10, 14, 16, 18, 20, and optionally 22, from the 5' end to the 3' end of the antisense strand, and the nucleotides at positions 2, 6, 14, and 16 are all 2'-fluoro nucleotides. In some embodiments of the present disclosure, the antisense strand has four, five, or six nucleotides that are 2'-fluoro nucleotides, the 2'-fluoro nucleotides being selected from the group consisting of nucleotides at positions 2, 4, 6, 7, 8, 10, 14, 16, 18, 20, and optionally 22, from the 5' end to the 3' end of the antisense strand, and the nucleotides at positions 2, 6, 14, 16, and optionally 22 are all 2'-fluoro nucleotides. In some embodiments of the present disclosure, the antisense strand has four or five nucleotides that are 2'-fluoro nucleotides, and the 2'-fluoro nucleotides are selected from the nucleotides at positions 2, 4, 6, 7, 8, 10, 14, 16, 18, 20, and optionally 22 in the direction from the 5' end to the 3' end of the antisense strand, and the nucleotides at positions 2, 6, 14, and 16 are all 2'-fluoro nucleotides.

[0178] In some embodiments of the present disclosure, the antisense strand has four nucleotides that are 2'-fluoro nucleotides, and the four 2'-fluoro nucleotides are at positions 2, 6, 14, and 16 in the 5' to 3' direction of the antisense strand. In some embodiments of the present disclosure, the antisense strand has five or six nucleotides that are 2'-fluoro nucleotides, and the 2'-fluoro nucleotides are selected from the nucleotides at positions 2, 4, 6, 7, 8, 10, 14, 16, 18, 20, and optionally 22 in the 5' to 3' direction of the antisense strand, and the nucleotides at positions 20 and optionally 22 are both 2'-fluoro nucleotides. In some embodiments of the present disclosure, the antisense strand has five or six nucleotides that are 2'-fluoro nucleotides, and the 2'-fluoro nucleotides are selected from the nucleotides at positions 2, 4, 6, 8, 10, 14, 16, 18, 20, and optionally 22 in the 5' to 3' direction of the antisense strand, and the nucleotides at positions 4, 8, 20, and optionally 22 are both 2'-fluoro nucleotides.

[0179] In some embodiments of the present disclosure, in the siRNA, the sense strand contains at least four 2'-fluoro nucleotides at positions 11, 12, 13 and 15 from its 3' end to its 5' end, and the antisense strand contains at least four 2'-fluoro nucleotides at positions 2, 6, 14 and 16 from its 5' end to its 3' end.

[0180] In some embodiments of the present disclosure, the sense strand has four nucleotides that are 2'-fluoro nucleotides, and the four 2'-fluoro nucleotides are located at positions 11, 12, 13, and 15 in the direction from the 3' end to the 5' end of the sense strand, and the antisense strand has four nucleotides that are 2'-fluoro nucleotides, and the four 2'-fluoro nucleotides are located at positions 2, 6, 14, and 16 in the direction from the 5' end to the 3' end of the antisense strand.

[0181] In some embodiments of the present disclosure, in the siRNA, the sense strand contains at least four 2'-fluoro nucleotides, and the 2'-fluoro nucleotides are located at positions 11, 12, 13 and 15 from the 3' end to the 5' end of the sense strand, and optionally at one or more of positions 1, 3, 5, 7, 9 and 19; the antisense strand contains at least five 2'-fluoro nucleotides, and the 2'-fluoro nucleotides are located at positions 2, 6, 14 and 16 from the 5' end to the 3' end of the antisense strand, and at least one of positions 3, 4, 5, 7, 8, 9, 10, 18, 20, 21, 22, 23, 24, 25, 26.

[0182] In some embodiments of the present disclosure, in the siRNA, the sense strand comprises at least five 2'-fluoro nucleotides, and the 2'-fluoro nucleotides are located at positions 11, 12, 13, and 15, and at least one of positions 1, 3, 5, 6, 7, 9, and 19 (e.g., at least one of positions 5 and 9) from the 3' end to the 5' end of the sense strand; the antisense strand comprises at least four 2'-fluoro nucleotides, and the 2'-fluoro nucleotides are located at position 14, and at least three of positions 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 16, 18, 20, 21, 22, 23, 24, 25, and 26 of the antisense strand from the 5' end to the 3' end.

[0183] In some embodiments of the present disclosure, in the siRNA, the sense strand comprises at least five 2'-fluoro nucleotides, and the 2'-fluoro nucleotides are located at positions 11, 12, 13, and 15, and at least one of positions 1, 3, 5, 6, 7, 9, and 19 (for example, at least one of positions 5 and 9) from the 3' end to the 5' end of the sense strand; the antisense strand comprises at least five 2'-fluoro nucleotides, and the 2'-fluoro nucleotides are located at positions 2, 6, 14, and 16, and at least one of positions 3, 4, 5, 7, 8, 9, 10, 12, 18, 20, 21, 22, 23, 24, 25, and 26 from the 5' end to the 3' end of the antisense strand. In some embodiments of the present disclosure, in the siRNA, the sense strand comprises at least five 2'-fluoro nucleotides, and the 2'-fluoro nucleotides are located at positions 9, 11, 12, 13 and 15, and optionally at one or more of positions 1, 3, 5, 7 and 19, from the 3' end to the 5' end of the sense strand; the antisense strand comprises at least five 2'-fluoro nucleotides, and the 2'-fluoro nucleotides are located at positions 2, 6, 14, 16 and 22, and optionally at one or more of positions 3, 4, 5, 7, 8, 9, 10, 18, 20, 21, 23, 24, 25 and 26, from the 5' end to the 3' end of the antisense strand.

[0184] In some embodiments of the present disclosure, in the siRNA, the sense strand comprises at least six 2'-fluoro nucleotides, wherein the 2'-fluoro nucleotides are located at positions 11, 12, 13, and 15, and at least two of positions 1, 3, 5, 6, 7, 9, and 19 (e.g., at least two of positions 1, 5, and 9) in the 3' to 5' direction of the sense strand;

[0185] In some embodiments of the present disclosure, the sense strand has five nucleotides that are 2'-fluoro nucleotides, and the five 2'-fluoro nucleotides are selected from the 1st, 3rd, 5th, 6th, 7th, 9th, 11th, 12th, 13th, 15th, 17th, 19th, and optionally the 21st position from the 3' end to the 5' end of the sense strand, and the nucleotides at positions 11, 12, and 13 are all 2'-fluoro nucleotides; the antisense strand has five nucleotides that are 2'-fluoro nucleotides, and the five 2'-fluoro nucleotides are selected from the 2nd, 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 14th, 16th, 18th, 20th, 21st, and optionally the 22nd position from the 5' end to the 3' end of the antisense strand, and the nucleotides at positions 2, 6, 14, and 16 are all 2'-fluoro nucleotides.

[0186] In some embodiments of the present disclosure, the sense strand has five nucleotides that are 2'-fluoro nucleotides, and the five 2'-fluoro nucleotides are selected from the nucleotides at positions 1, 3, 5, 7, 9, 11, 12, 13, 15, 17, 19, and optionally 21 in the direction from the 3' end to the 5' end of the sense strand, and the nucleotides at positions 11, 12, and 13 are all 2'-fluoro nucleotides; the antisense strand has five nucleotides that are 2'-fluoro nucleotides, and the five 2'-fluoro nucleotides are selected from the nucleotides at positions 2, 4, 6, 8, 10, 14, 16, 18, 20, and optionally 22 in the direction from the 5' end to the 3' end of the antisense strand, and the nucleotides at positions 2, 6, 14, and 16 are all 2'-fluoro nucleotides.

[0187] In some embodiments of the present disclosure, the sense strand has five nucleotides that are 2'-fluoro nucleotides, and the five 2'-fluoro nucleotides are selected from positions 1, 3, 5, 6, 7, 9, 11, 12, 13, 15, 17, 19, and optionally 21 in the direction from the 3' end to the 5' end of the sense strand, and the nucleotides at positions 11, 12, and 13 are all 2'-fluoro nucleotides; the antisense strand has five nucleotides that are 2'-fluoro nucleotides, and the five 2'-fluoro nucleotides are at positions 2, 6, 14, 16, and optionally 22 in the direction from the 5' end to the 3' end of the antisense strand.

[0188] In some embodiments of the present disclosure, the sense strand has five nucleotides that are 2'-fluoro nucleotides, and the five 2'-fluoro nucleotides are selected from the nucleotides at positions 1, 3, 5, 7, 9, 11, 12, 13, 15, 17, 19, and optionally 21 in the direction from the 3' end to the 5' end of the sense strand, and the nucleotides at positions 11, 12, and 13 are all 2'-fluoro nucleotides; the antisense strand has five nucleotides that are 2'-fluoro nucleotides, and the five 2'-fluoro nucleotides are at positions 2, 6, 14, 16, and optionally 22 in the direction from the 5' end to the 3' end of the antisense strand.

[0189] In some embodiments of the present disclosure, the sense strand has five nucleotides that are 2'-fluoro nucleotides, and the five 2'-fluoro nucleotides are nucleotides at positions 9, 11, 12, 13, and 15 in the direction from the 3' end to the 5' end of the sense strand, and the antisense strand has five nucleotides that are 2'-fluoro nucleotides, and the five 2'-fluoro nucleotides are nucleotides at positions 2, 6, 14, 16, and 22 in the direction from the 5' end to the 3' end of the antisense strand.

[0190] In some embodiments of the present disclosure, the sense strand has five nucleotides that are 2'-fluoro nucleotides, and the five 2'-fluoro nucleotides are selected from the nucleotides at positions 1, 3, 5, 6, 7, 9, 11, 12, 13, 15, 17, 19, and optionally 21 in the direction from the 3' end to the 5' end of the sense strand, and the nucleotides at positions 11, 12, and 13 are all 2'-fluoro nucleotides; the antisense strand has five nucleotides that are 2'-fluoro nucleotides, and the five 2'-fluoro nucleotides are selected from the nucleotides at positions 2, 3, 4, 5, 6, 7, 8, 9, 10, 14, 16, 18, 20, 21, and optionally 23 in the direction from the 5' end to the 3' end of the antisense strand, and the nucleotides at positions 2, 6, 14, and 16 are all 2'-fluoro nucleotides.

[0191] In some embodiments of the present disclosure, the sense strand has five nucleotides that are 2'-fluoro nucleotides, and the five 2'-fluoro nucleotides are selected from the nucleotides at positions 1, 3, 5, 6, 7, 9, 11, 12, 13, 15, 17, 19, and optionally 21 in the direction from the 3' end to the 5' end of the sense strand, and the nucleotides at positions 11, 12, and 13 are all 2'-fluoro nucleotides; the antisense strand has five nucleotides that are 2'-fluoro nucleotides, and the five 2'-fluoro nucleotides are at nucleotides 2, 6, 14, 16, and optionally 23 in the direction from the 5' end to the 3' end of the antisense strand.

[0192] In some embodiments of the present disclosure, the sense strand has five nucleotides that are 2'-fluoro nucleotides, and the five 2'-fluoro nucleotides are selected from the nucleotides at positions 1, 3, 5, 6, 7, 9, 11, 12, 13, 15, 17, 19, and optionally 21 in the direction from the 3' end to the 5' end of the sense strand, and the nucleotides at positions 11, 12, and 13 are all 2'-fluoro nucleotides; the antisense strand has five nucleotides that are 2'-fluoro nucleotides, and the five 2'-fluoro nucleotides are selected from the nucleotides at positions 2, 3, 4, 5, 6, 7, 8, 9, 10, 14, 16, 18, 20, 21, and optionally 24 in the direction from the 5' end to the 3' end of the antisense strand, and the nucleotides at positions 2, 6, 14, and 16 are all 2'-fluoro nucleotides.

[0193] In some embodiments of the present disclosure, the sense strand has five nucleotides that are 2'-fluoro nucleotides, and the five 2'-fluoro nucleotides are selected from the nucleotides at positions 1, 3, 5, 6, 7, 9, 11, 12, 13, 15, 17, 19, and optionally 21 in the direction from the 3' end to the 5' end of the sense strand, and the nucleotides at positions 11, 12, and 13 are all 2'-fluoro nucleotides; the antisense strand has five nucleotides that are 2'-fluoro nucleotides, and the five 2'-fluoro nucleotides are at nucleotides 2, 6, 14, 16, and optionally 24 in the direction from the 5' end to the 3' end of the antisense strand.

[0194] In some embodiments of the present disclosure, the sense strand has five nucleotides that are 2'-fluoro nucleotides, and the five 2'-fluoro nucleotides are selected from the nucleotides at positions 1, 3, 5, 6, 7, 9, 11, 12, 13, 15, 17, 19, and optionally 21 in the direction from the 3' end to the 5' end of the sense strand, and the nucleotides at positions 11, 12, and 13 are all 2'-fluoro nucleotides; the antisense strand has five nucleotides that are 2'-fluoro nucleotides, and the five 2'-fluoro nucleotides are selected from the nucleotides at positions 2, 3, 4, 5, 6, 7, 8, 9, 10, 14, 16, 18, 20, 21, and optionally 25 in the direction from the 5' end to the 3' end of the antisense strand, and the nucleotides at positions 2, 6, 14, and 16 are all 2'-fluoro nucleotides.

[0195] In some embodiments of the present disclosure, the sense strand has five nucleotides that are 2'-fluoro nucleotides, and the five 2'-fluoro nucleotides are selected from the nucleotides at positions 1, 3, 5, 6, 7, 9, 11, 12, 13, 15, 17, 19, and optionally 21 in the direction from the 3' end to the 5' end of the sense strand, and the nucleotides at positions 11, 12, and 13 are all 2'-fluoro nucleotides; the antisense strand has five nucleotides that are 2'-fluoro nucleotides, and the five 2'-fluoro nucleotides are at nucleotides 2, 6, 14, 16, and optionally 25 in the direction from the 5' end to the 3' end of the antisense strand.

[0196] In some embodiments of the present disclosure, the sense strand has five nucleotides that are 2'-fluoro nucleotides, and the five 2'-fluoro nucleotides are selected from the nucleotides at positions 1, 3, 5, 6, 7, 9, 11, 12, 13, 15, 17, 19, and optionally 21 in the direction from the 3' end to the 5' end of the sense strand, and the nucleotides at positions 11, 12, and 13 are all 2'-fluoro nucleotides; the antisense strand has five nucleotides that are 2'-fluoro nucleotides, and the five 2'-fluoro nucleotides are selected from the nucleotides at positions 2, 3, 4, 5, 6, 7, 8, 9, 10, 14, 16, 18, 20, 21, and optionally 26 in the direction from the 5' end to the 3' end of the antisense strand, and the nucleotides at positions 2, 6, 14, and 16 are all 2'-fluoro nucleotides.

[0197] In some embodiments of the present disclosure, the sense strand has five nucleotides that are 2'-fluoro nucleotides, and the five 2'-fluoro nucleotides are selected from the nucleotides at positions 1, 3, 5, 6, 7, 9, 11, 12, 13, 15, 17, 19, and optionally 21 in the direction from the 3' end to the 5' end of the sense strand, and the nucleotides at positions 11, 12, and 13 are all 2'-fluoro nucleotides; the antisense strand has five nucleotides that are 2'-fluoro nucleotides, and the five 2'-fluoro nucleotides are at nucleotides 2, 6, 14, 16, and optionally 26 in the direction from the 5' end to the 3' end of the antisense strand.

[0198] In some embodiments of the present disclosure, the sense strand has five nucleotides that are 2'-fluoro nucleotides, and the five 2'-fluoro nucleotides are selected from the nucleotides at positions 1, 3, 5, 7, 9, 11, 12, 13, 15, 17, 19, and optionally 21 in the direction from the 3' end to the 5' end of the sense strand, and the nucleotides at positions 11, 12, and 13 are all 2'-fluoro nucleotides; the antisense strand has six nucleotides that are 2'-fluoro nucleotides, and the six 2'-fluoro nucleotides are selected from the nucleotides at positions 2, 4, 6, 8, 10, 14, 16, 18, 20, and optionally 22 in the direction from the 5' end to the 3' end of the antisense strand, and the nucleotides at positions 2, 6, 14, and 16 are all 2'-fluoro nucleotides.

[0199] In some embodiments of the present disclosure, the sense strand has five nucleotides that are 2'-fluoro nucleotides, and the five 2'-fluoro nucleotides are selected from the nucleotides at positions 1, 3, 5, 7, 9, 11, 12, 13, 15, 17, 19, and optionally 21 in the direction from the 3' end to the 5' end of the sense strand, and the nucleotides at positions 11, 12, and 13 are all 2'-fluoro nucleotides; the antisense strand has six nucleotides that are 2'-fluoro nucleotides, and the six 2'-fluoro nucleotides are selected from the nucleotides at positions 2, 4, 6, 8, 10, 14, 16, 18, 20, and optionally 22 in the direction from the 5' end to the 3' end of the antisense strand, and the nucleotides at positions 2, 6, 14, 16, and 22 are all 2'-fluoro nucleotides. In some embodiments of the present disclosure, the sense strand has five nucleotides that are 2'-fluoro nucleotides, and the five 2'-fluoro nucleotides are selected from the nucleotides at positions 1, 3, 5, 6, 7, 9, 11, 12, 13, 15, 17, 19, and optionally 21 in the direction from the 3' end to the 5' end of the sense strand, and the nucleotides at positions 11, 12, and 13 are all 2'-fluoro nucleotides; the antisense strand has six nucleotides that are 2'-fluoro nucleotides, and the six 2'-fluoro nucleotides are selected from positions 2, 3, 4, 5, 6, 7, 8, 9, 10, 14, 16, 18, 20, 21, and optionally 22 in the direction from the 5' end to the 3' end of the antisense strand, and the nucleotides at positions 2, 6, 14, and 16 are all 2'-fluoro nucleotides.

[0200] In some embodiments of the present disclosure, the sense strand has six nucleotides that are 2'-fluoro nucleotides, and the six 2'-fluoro nucleotides are selected from the nucleotides at positions 1, 3, 5, 6, 7, 9, 11, 12, 13, 15, 17, 19, and optionally 21 in the direction from the 3' end to the 5' end of the sense strand, and the nucleotides at positions 11, 12, and 13 are all 2'-fluoro nucleotides; the antisense strand has five nucleotides that are 2'-fluoro nucleotides, and the five 2'-fluoro nucleotides are selected from positions 2, 3, 4, 5, 6, 7, 8, 9, 10, 14, 16, 18, 20, 21, and optionally 22 in the direction from the 5' end to the 3' end of the antisense strand, and the nucleotides at positions 2, 6, 14, and 16 are all 2'-fluoro nucleotides.

[0201] In some embodiments of the present disclosure, the sense strand has six nucleotides that are 2'-fluoro nucleotides, and the six 2'-fluoro nucleotides are selected from the nucleotides at positions 1, 3, 5, 7, 9, 11, 12, 13, 15, 17, 19, and optionally 21 in the direction from the 3' end to the 5' end of the sense strand, and the nucleotides at positions 11, 12, and 13 are all 2'-fluoro nucleotides; the antisense strand has five nucleotides that are 2'-fluoro nucleotides, and the five 2'-fluoro nucleotides are selected from the nucleotides at positions 2, 4, 6, 8, 10, 14, 16, 18, 20, and optionally 22 in the direction from the 5' end to the 3' end of the antisense strand, and the nucleotides at positions 2, 6, 14, and 16 are all 2'-fluoro nucleotides.

[0202] In some embodiments of the present disclosure, the sense strand has six nucleotides that are 2'-fluoro nucleotides, and the six 2'-fluoro nucleotides are nucleotides at positions 5, 9, 11, 12, 13, and 15 in the direction from the 3' end to the 5' end of the sense strand, and the antisense strand has five nucleotides that are 2'-fluoro nucleotides, and the five 2'-fluoro nucleotides are nucleotides at positions 2, 6, 14, 16, and 22 in the direction from the 5' end to the 3' end of the antisense strand.

[0203] In some embodiments of the present disclosure, the sense strand has six nucleotides that are 2'-fluoro nucleotides, and the six 2'-fluoro nucleotides are selected from the nucleotides at positions 1, 3, 5, 6, 7, 9, 11, 12, 13, 15, 17, 19, and optionally 21 in the direction from the 3' end to the 5' end of the sense strand, and the nucleotides at positions 11, 12, and 13 are all 2'-fluoro nucleotides; the antisense strand has six nucleotides that are 2'-fluoro nucleotides, and the six 2'-fluoro nucleotides are selected from the nucleotides at positions 2, 3, 4, 5, 6, 7, 8, 9, 10, 14, 16, 18, 20, 21, and optionally 22 in the direction from the 5' end to the 3' end of the antisense strand, and the nucleotides at positions 2, 6, 14, and 16 are all 2'-fluoro nucleotides. In some embodiments of the present disclosure, the sense strand has six nucleotides that are 2'-fluoro nucleotides, and the six 2'-fluoro nucleotides are selected from the nucleotides at positions 1, 3, 5, 7, 9, 11, 12, 13, 15, 17, 19, and optionally 21 in the direction from the 3' end to the 5' end of the sense strand, and the nucleotides at positions 11, 12, and 13 are all 2'-fluoro nucleotides; the antisense strand has six nucleotides that are 2'-fluoro nucleotides, and the six 2'-fluoro nucleotides are selected from the nucleotides at positions 2, 4, 6, 8, 10, 14, 16, 18, and optionally 22 in the direction from the 5' end to the 3' end of the antisense strand, and the nucleotides at positions 2, 6, 14, and 16 are all 2'-fluoro nucleotides.

[0204] In some embodiments of the present disclosure, the sense strand has six nucleotides that are 2'-fluoro nucleotides, and the six 2'-fluoro nucleotides are located at positions 5, 9, 11, 12, 13, and 15 in the direction from the 3' end to the 5' end of the sense strand, and the antisense strand has six nucleotides that are 2'-fluoro nucleotides, and the six 2'-fluoro nucleotides are selected from the nucleotides at positions 2, 3, 4, 5, 6, 7, 8, 9, 10, 14, 16, 18, 20, 21, and optionally 22 in the direction from the 5' end to the 3' end of the antisense strand, and the nucleotides at positions 2, 6, 14, and 16 are all 2'-fluoro nucleotides.

[0205] In some embodiments of the present disclosure, the sense strand has six nucleotides that are 2'-fluoro nucleotides, and the six 2'-fluoro nucleotides are located at positions 5, 9, 11, 12, 13, and 15 in the direction from the 3' end to the 5' end of the sense strand, and the antisense strand has six nucleotides that are 2'-fluoro nucleotides, and the six 2'-fluoro nucleotides are selected from the nucleotides at positions 2, 4, 6, 8, 10, 14, 16, 18, 20, and optionally 22 in the direction from the 5' end to the 3' end of the antisense strand, and the nucleotides at positions 2, 6, 14, and 16 are all 2'-fluoro nucleotides.

[0206] In some embodiments of the present disclosure, the sense strand has six nucleotides that are 2'-fluoro nucleotides, and the six 2'-fluoro nucleotides are located at positions 5, 9, 11, 12, 13, and 15 in the direction from the 3' end to the 5' end of the sense strand, and the antisense strand has six nucleotides that are 2'-fluoro nucleotides, and the six 2'-fluoro nucleotides are selected from the nucleotides at positions 2, 3, 4, 5, 6, 7, 8, 9, 10, 14, 16, 18, 20, 21, and optionally 22 in the direction from the 5' end to the 3' end of the antisense strand, and the nucleotides at positions 2, 6, 14, 16, and 22 are all 2'-fluoro nucleotides.

[0207] In some embodiments of the present disclosure, all nucleotides in the sense strand and the antisense strand of the siRNA are independently 2'-methoxy nucleotides or 2'-fluoro nucleotides.

[0208] In some embodiments of the present disclosure, at least the 11th, 12th and 13th nucleotides in the direction from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other sites of the sense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the 11th, 12th and 13th nucleotides in the direction from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other sites of the sense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the 11th, 12th, 13th and 15th nucleotides in the direction from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other sites of the sense strand may be 2'-methoxy nucleotides.

[0209] In some embodiments of the present disclosure, the nucleotides at positions 1, 3, 5, 6, 7, 9, 11, 12, 13, 15, 17, 19, and optionally 21 from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 1, 3, 5, 7, 9, 11, 12, 13, 15, 17, 19, and optionally 21 from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides.

[0210] In some embodiments of the present disclosure, the nucleotides at positions 1, 3, 5, 6, 7, 9, 11, 12, 13, 15, 17, 19, and 21 from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 1, 3, 5, 7, 9, 11, 12, 13, 15, 17, 19, and 21 from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides.

[0211] In some embodiments of the present disclosure, the nucleotides at positions 11, 12, 13, and 15 in the direction from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at at least one of positions 1, 3, 5, 6, 7, 9, 17, 19, and 21 may be 2'-fluoro nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 11, 12, 13, and 15 in the direction from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at at least one of positions 1, 3, 5, 7, and 9 may be 2'-fluoro nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 11, 12, 13, and 15 in the direction from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at at least one of positions 1, 3, 5, 6, 7, 9, 17, 19, and 21 may be 2'-fluoro nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 11, 12, 13, and 15 in the direction from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at one of positions 1, 3, 5, 7, and 9 may be 2'-fluoro nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 11, 12, 13, and 15 in the direction from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at at least two of positions 1, 3, 5, 6, 7, 9, 17, 19, and 21 may be 2'-fluoro nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 11, 12, 13, and 15 in the direction from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at at least two of positions 1, 3, 5, 7, and 9 may be 2'-fluoro nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 11, 12, 13, and 15 from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and two of the nucleotides at positions 1, 3, 5, 7, and 9 may be 2'-fluoro nucleotides.

[0212] In some embodiments of the present disclosure, the nucleotides at positions 9, 11, 12, 13, and 15 in the direction from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other sites of the sense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 7, 11, 12, 13, and 15 in the direction from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other sites of the sense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 6, 11, 12, 13, and 15 in the direction from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other sites of the sense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 5, 11, 12, 13, and 15 in the direction from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other sites of the sense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 3, 11, 12, 13, and 15 in the direction from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other sites of the sense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 1, 11, 12, 13, and 15 in the direction from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other sites of the sense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 11, 12, 13, 15, and optionally 21 in the direction from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other sites of the sense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 11, 12, 13, 15, and 21 in the direction from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other sites of the sense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 11, 12, 13, 15, and 19 in the 3' to 5' direction of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 11, 12, 13, 15, and 17 in the 3' to 5' direction of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides.

[0213] In some embodiments of the present disclosure, at least the nucleotides at positions 2, 6, 14, and 16 from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, at least the nucleotides at positions 2, 6, 14, and 16 from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, at least the nucleotides at positions 2, 6, 14, and 16 from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides.

[0214] In some embodiments of the present disclosure, the nucleotides at positions 2, 3, 4, 5, 6, 7, 8, 9, 10, 14, 16, 18, 20, 21, 22, 23, 24, 25, and 26 of the antisense strand from the 5' end to the 3' end are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 2, 4, 6, 8, 10, 14, 16, 18, and optionally 22 of the antisense strand from the 5' end to the 3' end are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 2, 3, 4, 5, 6, 7, 8, 9, 10, 14, 16, 18, 20, 21, and 22 of the antisense strand from the 5' end to the 3' end are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 2, 4, 6, 8, 10, 14, 16, 18, and 22 of the antisense strand from the 5' end to the 3' end are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 2, 3, 4, 5, 6, 7, 8, 9, 10, 14, 16, 18, 20, 21, and 23 of the antisense strand from the 5' end to the 3' end are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 2, 3, 4, 5, 6, 7, 8, 9, 10, 14, 16, 18, 20, 21, and 24 of the antisense strand from the 5' end to the 3' end are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 2, 3, 4, 5, 6, 7, 8, 9, 10, 14, 16, 18, 20, 21, and 25 of the antisense strand from the 5' end to the 3' end are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 2, 3, 4, 5, 6, 7, 8, 9, 10, 14, 16, 18, 20, 21, and 26 of the antisense strand from the 5' end to the 3' end are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 2, 6, 14, and 16 of the antisense strand from the 5' end to the 3' end are 2'-fluoro nucleotides, and the nucleotides at at least one of positions 3, 4, 5, 7, 8, 9, 10, 18, 20, 21, and 22 are 2'-fluoro nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 2, 6, 14, and 16 from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and at least one of the nucleotides at positions 4, 8, 10, 18, 20, and 22 is a 2'-fluoro nucleotide.In some embodiments of the present disclosure, the nucleotides at positions 2, 6, 14, and 16 in the direction from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and at least two of the nucleotides at positions 3, 4, 5, 7, 8, 9, 10, 18, 20, 21, and 22 are 2'-fluoro nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 2, 6, 14, and 16 in the direction from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and at least two of the nucleotides at positions 3, 4, 5, 7, 8, 9, 10, 18, 20, 21, and 22 are 2'-fluoro nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 2, 6, 14, and 16 from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and at least two of the nucleotides at positions 4, 8, 10, 18, 20, and 22 are 2'-fluoro nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 2, 6, 14, and 16 from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and at least two of the nucleotides at positions 3, 4, 5, 7, 8, 9, 10, 18, 20, 21, and 22 are 2'-fluoro nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 2, 6, 14, and 16 from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and at least two of the nucleotides at positions 4, 8, 10, 18, 20, and 22 are 2'-fluoro nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 2, 6, 14, and 16 from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at at least three positions among positions 3, 4, 5, 7, 8, 9, 10, 18, 20, 21, and 22 are 2'-fluoro nucleotides.

[0215] In some embodiments of the present disclosure, the nucleotides at positions 2, 6, 10, 14, and 16 in the direction from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 2, 6, 14, 16, and 18 in the direction from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 2, 6, 14, 16, and 20 in the direction from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 2, 6, 14, 16, and 21 in the direction from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 2, 6, 14, 16, and 22 in the direction from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 2, 6, 14, 16, and 23 in the direction from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 2, 6, 14, 16, and 24 in the direction from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 2, 6, 14, 16, and 25 in the direction from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 2, 6, 14, 16, and 26 from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 2, 4, 6, 14, and 16 from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 2, 6, 8, 14, and 16 from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 2, 6, 14, 16, 20, and 22 from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides.In some embodiments of the present disclosure, the nucleotides at positions 2, 6, 8, 14, 16, and 22 from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 2, 4, 6, 14, 16, and 22 from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 2, 6, 10, 14, 16, and 22 from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 4, 6, 14, 16, and 22 from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 6, 8, 14, 16, and 22 from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other sites of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 6, 14, 16, 18, and 22 from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other sites of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 2, 4, 6, 14, and 22 from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other sites of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 2, 6, 8, 14, and 22 from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other sites of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 2, 6, 14, 18, and 22 from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 2, 4, 14, 16, and 22 from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 2, 8, 14, 16, and 22 from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 6, 9, 14, 16, and 22 from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides.In some embodiments of the present disclosure, the nucleotides at positions 2, 9, 14, 16, and 22 from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 2, 6, 9, 14, and 22 from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 4, 6, 14, 16, and 22 from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 2, 6, 12, 14, 16, and 22 from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 2, 6, 8, 9, 14, 16, and 22 from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 2, 3, 6, 10, 14, 16, and 22 from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 2, 5, 6, 14, 16, and 22 from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 2, 6, 7, 14, 16, and 22 from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 2, 6, 9, 10, 14, 16, and 22 of the antisense strand in the direction from the 5' end to the 3' end are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 2, 6, 7, 10, 14, 16, and 22 of the antisense strand in the direction from the 5' end to the 3' end are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 2, 6, 7, 14, 16, and 20 of the antisense strand in the direction from the 5' end to the 3' end are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 2, 6, 7, 10, 14, 16, and 20 of the antisense strand in the direction from the 5' end to the 3' end are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides.In some embodiments of the present disclosure, the nucleotides at positions 2, 6, 7, 14, 16, and 21 from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 2, 6, 7, 14, 16, and 23 from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides.

[0216] In some embodiments of the present disclosure, the nucleotides at positions 11, 12, and 13 from the 3' end to the 5' end of the sense chain are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense chain may be 2'-methoxy nucleotides. The nucleotides at positions 2, 6, 14, and 16 from the 5' end to the 3' end of the antisense chain are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense chain may be 2'-methoxy nucleotides.

[0217] In some embodiments of the present disclosure, the nucleotides at positions 11, 12, 13, and 15 in the direction from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides. The nucleotides at positions 2, 6, 14, and 16 in the direction from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 11, 12, 13, and 15 in the direction from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides. The nucleotides at positions 2, 6, 8, 9, 14, and 16 in the direction from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 11, 12, 13, and 15 in the direction from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides. The nucleotides at positions 2, 6, 10, 14, and 16 in the direction from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 11, 12, 13, and 15 in the direction from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides. The nucleotides at positions 2, 6, 14, 16, and 18 in the direction from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 11, 12, 13, and 15 from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides. The nucleotides at positions 2, 6, 14, 16, and 20 from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 11, 12, 13, and 15 from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides. The nucleotides at positions 2, 6, 14, 16, and 21 from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 11, 12, 13, and 15 from the 3' end to the 5' end of the sense chain are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense chain may be 2'-methoxy nucleotides. The nucleotides at positions 2, 6, 14, 16, and 22 from the 5' end to the 3' end of the antisense chain are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense chain may be 2'-methoxy nucleotides.In some embodiments of the present disclosure, the nucleotides at positions 11, 12, 13, and 15 in the direction from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides. The nucleotides at positions 2, 4, 6, 14, and 16 in the direction from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 11, 12, 13, and 15 in the direction from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides. The nucleotides at positions 2, 6, 8, 14, and 16 in the direction from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides.

[0218] In some embodiments of the present disclosure, the nucleotides at positions 7, 11, 12, 13, and 15 in the direction from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides. The nucleotides at positions 2, 4, 6, 14, and 16 in the direction from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 7, 11, 12, 13, and 15 in the direction from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides. The nucleotides at positions 2, 6, 8, 14, and 16 in the direction from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 7, 11, 12, 13, and 15 in the direction from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides. The nucleotides at positions 2, 6, 10, 14, and 16 in the direction from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 7, 11, 12, 13, and 15 in the direction from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides. The nucleotides at positions 2, 6, 14, 16, and 18 in the direction from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 7, 11, 12, 13, and 15 from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides. The nucleotides at positions 2, 6, 14, 16, and 20 from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 7, 11, 12, 13, and 15 from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides. The nucleotides at positions 2, 6, 14, 16, and 21 from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides.In some embodiments of the present disclosure, the nucleotides at positions 7, 11, 12, 13, and 15 in the direction from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides. The nucleotides at positions 2, 6, 14, 16, and 22 in the direction from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 7, 11, 12, 13, and 15 in the direction from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides. The nucleotides at positions 2, 4, 6, 14, and 16 in the direction from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 7, 11, 12, 13, and 15 from the 3' end to the 5' end of the sense chain are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense chain may be 2'-methoxy nucleotides. The nucleotides at positions 2, 6, 8, 14, and 16 from the 5' end to the 3' end of the antisense chain are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense chain may be 2'-methoxy nucleotides.

[0219] In some embodiments of the present disclosure, the nucleotides at positions 6, 11, 12, 13, and 15 from the 3' end to the 5' end of the sense chain are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense chain may be 2'-methoxy nucleotides. The nucleotides at positions 2, 4, 6, 14, and 16 from the 5' end to the 3' end of the antisense chain are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense chain may be 2'-methoxy nucleotides.

[0220] In some embodiments of the present disclosure, the nucleotides at positions 5, 11, 12, 13, and 15 from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides. The nucleotides at positions 2, 4, 6, 14, and 16 from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 5, 11, 12, 13, and 15 from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides. The nucleotides at positions 2, 6, 8, 14, and 16 from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 5, 11, 12, 13, and 15 from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides. The nucleotides at positions 2, 6, 10, 14, and 16 from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 5, 11, 12, 13, and 15 from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides. The nucleotides at positions 2, 6, 14, 16, and 18 from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 5, 11, 12, 13, and 15 from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides. The nucleotides at positions 2, 6, 14, 16, and 20 from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 5, 11, 12, 13, and 15 from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides. The nucleotides at positions 2, 6, 14, 16, and 21 from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides.In some embodiments of the present disclosure, the nucleotides at positions 5, 11, 12, 13, and 15 from the 3' end to the 5' end of the sense chain are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense chain may be 2'-methoxy nucleotides. The nucleotides at positions 2, 6, 14, 16, and 22 from the 5' end to the 3' end of the antisense chain are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense chain may be 2'-methoxy nucleotides.

[0221] In some embodiments of the present disclosure, the nucleotides at positions 3, 11, 12, 13, and 15 in the direction from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides. The nucleotides at positions 2, 4, 6, 14, and 16 in the direction from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 3, 11, 12, 13, and 15 in the direction from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides. The nucleotides at positions 2, 6, 8, 14, and 16 in the direction from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 3, 11, 12, 13, and 15 in the direction from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides. The nucleotides at positions 2, 6, 10, 14, and 16 in the direction from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 3, 11, 12, 13, and 15 in the direction from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides. The nucleotides at positions 2, 6, 14, 16, and 18 in the direction from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 3, 11, 12, 13, and 15 in the direction from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides. The nucleotides at positions 2, 6, 14, 16, and 20 in the direction from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 3, 11, 12, 13, and 15 in the direction from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides. The nucleotides at positions 2, 6, 14, 16, and 21 in the direction from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides.In some embodiments of the present disclosure, the nucleotides at positions 3, 11, 12, 13, and 15 from the 3' end to the 5' end of the sense chain are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense chain may be 2'-methoxy nucleotides. The nucleotides at positions 2, 6, 14, 16, and 22 from the 5' end to the 3' end of the antisense chain are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense chain may be 2'-methoxy nucleotides.

[0222] In some embodiments of the present disclosure, the nucleotides at positions 1, 11, 12, 13, and 15 in the direction from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides. The nucleotides at positions 2, 4, 6, 14, and 16 in the direction from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 1, 11, 12, 13, and 15 in the direction from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides. The nucleotides at positions 2, 6, 8, 14, and 16 in the direction from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 1, 11, 12, 13, and 15 in the direction from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides. The nucleotides at positions 2, 6, 10, 14, and 16 in the direction from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 1, 11, 12, 13, and 15 in the direction from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides. The nucleotides at positions 2, 6, 14, 16, and 18 in the direction from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 1, 11, 12, 13, and 15 in the direction from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides. The nucleotides at positions 2, 6, 14, 16, and 20 in the direction from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 1, 11, 12, 13, and 15 in the direction from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides. The nucleotides at positions 2, 6, 14, 16, and 21 in the direction from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides.In some embodiments of the present disclosure, the nucleotides at positions 1, 11, 12, 13, and 15 from the 3' end to the 5' end of the sense chain are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense chain may be 2'-methoxy nucleotides. The nucleotides at positions 2, 6, 14, 16, and 22 from the 5' end to the 3' end of the antisense chain are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense chain may be 2'-methoxy nucleotides.

[0223] In some embodiments of the present disclosure, the nucleotides at positions 11, 12, 13, 15, and 21 from the 3' end to the 5' end of the sense chain are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense chain may be 2'-methoxy nucleotides. The nucleotides at positions 2, 6, 10, 14, and 16 from the 5' end to the 3' end of the antisense chain are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense chain may be 2'-methoxy nucleotides.

[0224] In some embodiments of the present disclosure, the nucleotides at positions 1, 11, 12, 13, 15, and 21 in the direction from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides. The nucleotides at positions 2, 6, 14, 16, and 18 in the direction from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 1, 11, 12, 13, 15, and 21 in the direction from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides. The nucleotides at positions 2, 6, 14, 16, and 20 in the direction from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 1, 11, 12, 13, 15, and 21 from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides. The nucleotides at positions 2, 4, 6, 14, and 16 from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 1, 11, 12, 13, 15, and 21 from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides. The nucleotides at positions 2, 6, 8, 14, and 16 from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides.

[0225] In some embodiments of the present disclosure, the nucleotides at positions 11, 12, 13, 15, and 19 from the 3' end to the 5' end of the sense chain are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense chain may be 2'-methoxy nucleotides. The nucleotides at positions 2, 6, 10, 14, and 16 from the 5' end to the 3' end of the antisense chain are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense chain may be 2'-methoxy nucleotides.

[0226] In some embodiments of the present disclosure, the nucleotides at positions 1, 11, 12, 13, 15, and 19 in the direction from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides. The nucleotides at positions 2, 6, 14, 16, and 18 in the direction from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 1, 11, 12, 13, 15, and 19 in the direction from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides. The nucleotides at positions 2, 6, 14, 16, and 20 in the direction from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 1, 11, 12, 13, 15, and 19 in the direction from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides. The nucleotides at positions 2, 4, 6, 14, and 16 in the direction from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 1, 11, 12, 13, 15, and 19 in the direction from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides. The nucleotides at positions 2, 6, 8, 14, and 16 in the direction from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides.

[0227] In some embodiments of the present disclosure, the nucleotides at positions 11, 12, 13, 15, and 17 from the 3' end to the 5' end of the sense chain are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense chain may be 2'-methoxy nucleotides. The nucleotides at positions 2, 6, 10, 14, and 16 from the 5' end to the 3' end of the antisense chain are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense chain may be 2'-methoxy nucleotides.

[0228] In some embodiments of the present disclosure, the nucleotides at positions 1, 11, 12, 13, 15, and 17 in the direction from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides. The nucleotides at positions 2, 6, 14, 16, and 18 in the direction from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 1, 11, 12, 13, 15, and 17 in the direction from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides. The nucleotides at positions 2, 6, 14, 16, and 20 in the direction from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 1, 11, 12, 13, 15, and 17 in the direction from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides. The nucleotides at positions 2, 4, 6, 14, and 16 in the direction from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 1, 11, 12, 13, 15, and 17 in the direction from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides. The nucleotides at positions 2, 6, 8, 14, and 16 in the direction from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides.

[0229] In some embodiments of the present disclosure, the nucleotides at positions 5, 6, 11, 12, 13, and 15 from the 3' end to the 5' end of the sense chain are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense chain may be 2'-methoxy nucleotides. The nucleotides at positions 2, 6, 8, 9, 14, and 16 from the 5' end to the 3' end of the antisense chain are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense chain may be 2'-methoxy nucleotides.

[0230] In some embodiments of the present disclosure, the nucleotides at positions 9, 11, 12, 13, and 15 in the direction from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides. The nucleotides at positions 2, 4, 6, 14, and 16 in the direction from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 9, 11, 12, 13, and 15 in the direction from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides. The nucleotides at positions 2, 6, 8, 14, and 16 in the direction from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 9, 11, 12, 13, and 15 in the direction from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides. The nucleotides at positions 2, 6, 10, 14, and 16 in the direction from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 9, 11, 12, 13, and 15 in the direction from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides. The nucleotides at positions 2, 6, 14, 16, and 18 in the direction from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 9, 11, 12, 13, and 15 in the direction from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides. The nucleotides at positions 2, 6, 14, 16, and 20 in the direction from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 9, 11, 12, 13, and 15 in the direction from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides. The nucleotides at positions 2, 6, 14, 16, and 22 in the direction from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides.In some embodiments of the present disclosure, the nucleotides at positions 9, 11, 12, 13, and 15 in the direction from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides. The nucleotides at positions 2, 6, 14, 16, 20, and 22 in the direction from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 9, 11, 12, 13, and 15 in the direction from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides. The nucleotides at positions 2, 6, 8, 14, 16, and 22 in the direction from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 9, 11, 12, 13, and 15 in the direction from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides. The nucleotides at positions 2, 4, 6, 14, 16, and 22 in the direction from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 9, 11, 12, 13, and 15 in the direction from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides. The nucleotides at positions 4, 6, 14, 16, and 22 in the direction from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 9, 11, 12, 13, and 15 in the direction from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides. The nucleotides at positions 6, 8, 14, 16, and 22 in the direction from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 9, 11, 12, 13, and 15 in the direction from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides. The nucleotides at positions 6, 14, 16, 18, and 22 in the direction from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides.In some embodiments of the present disclosure, the nucleotides at positions 9, 11, 12, 13, and 15 in the direction from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides. The nucleotides at positions 2, 4, 6, 14, and 22 in the direction from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 9, 11, 12, 13, and 15 in the direction from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides. The nucleotides at positions 2, 6, 8, 14, and 22 in the direction from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 9, 11, 12, 13, and 15 in the direction from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides. The nucleotides at positions 2, 6, 14, 18, and 22 in the direction from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 9, 11, 12, 13, and 15 in the direction from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides. The nucleotides at positions 2, 4, 14, 16, and 22 in the direction from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 9, 11, 12, 13, and 15 in the direction from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides. The nucleotides at positions 2, 8, 14, 16, and 22 in the direction from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 9, 11, 12, 13, and 15 in the direction from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides. The nucleotides at positions 6, 9, 14, 16, and 22 in the direction from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides.In some embodiments of the present disclosure, the nucleotides at positions 9, 11, 12, 13, and 15 in the direction from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides. The nucleotides at positions 2, 9, 14, 16, and 22 in the direction from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 9, 11, 12, 13, and 15 in the direction from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides. The nucleotides at positions 2, 6, 9, 14, and 22 in the direction from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 9, 11, 12, 13, and 15 in the direction from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides. The nucleotides at positions 2, 6, 8, 9, 14, 16, and 22 in the direction from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 9, 11, 12, 13, and 15 in the direction from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides. The nucleotides at positions 2, 6, 10, 14, 16, and 22 in the direction from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 9, 11, 12, 13, and 15 in the direction from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides. The nucleotides at positions 2, 3, 6, 10, 14, 16, and 22 in the direction from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 9, 11, 12, 13, and 15 in the direction from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides. The nucleotides at positions 2, 5, 6, 14, 16, and 22 in the direction from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides.In some embodiments of the present disclosure, the nucleotides at positions 9, 11, 12, 13, and 15 in the direction from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides. The nucleotides at positions 2, 6, 7, 14, 16, and 22 in the direction from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 9, 11, 12, 13, and 15 in the direction from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides. The nucleotides at positions 2, 6, 9, 10, 14, 16, and 22 in the direction from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 9, 11, 12, 13, and 15 in the direction from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides. The nucleotides at positions 2, 6, 14, 16, and 26 in the direction from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 9, 11, 12, 13, and 15 in the direction from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides. The nucleotides at positions 2, 6, 14, 16, and 25 in the direction from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 9, 11, 12, 13, and 15 in the direction from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides. The nucleotides at positions 2, 6, 14, 16, and 24 in the direction from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 9, 11, 12, 13, and 15 in the direction from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides. The nucleotides at positions 2, 6, 14, 16, and 23 in the direction from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides.In some embodiments of the present disclosure, the nucleotides at positions 9, 11, 12, 13, and 15 in the direction from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides. The nucleotides at positions 2, 6, 14, 16, and 21 in the direction from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 9, 11, 12, 13, and 15 in the direction from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides. The nucleotides at positions 2, 6, 7, 10, 14, 16, and 18 in the direction from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 9, 11, 12, 13, and 15 in the direction from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides. The nucleotides at positions 2, 6, 10, 14, 16, and 20 in the direction from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 9, 11, 12, 13, and 15 in the direction from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides. The nucleotides at positions 2, 6, 7, 14, 16, and 20 in the direction from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 9, 11, 12, 13, and 15 in the direction from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides. The nucleotides at positions 2, 6, 7, 10, 14, 16, and 20 in the direction from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 9, 11, 12, 13, and 15 in the direction from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides. The nucleotides at positions 2, 6, 7, 14, 16, and 21 in the direction from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides.In some embodiments of the present disclosure, the nucleotides at positions 9, 11, 12, 13, and 15 from the 3' end to the 5' end of the sense chain are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense chain may be 2'-methoxy nucleotides. The nucleotides at positions 2, 6, 7, 14, 16, and 23 from the 5' end to the 3' end of the antisense chain are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense chain may be 2'-methoxy nucleotides.

[0231] In some embodiments of the present disclosure, the nucleotides at positions 5, 9, 11, 12, 13, and 15 from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides. The nucleotides at positions 2, 6, 14, 16, and 22 from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 5, 9, 11, 12, 13, and 15 from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides. The nucleotides at positions 4, 6, 14, 16, and 22 from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 5, 9, 11, 12, 13, and 15 from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides. The nucleotides at positions 2, 6, 14, 16, and 20 from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 5, 9, 11, 12, 13, and 15 from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides. The nucleotides at positions 6, 8, 14, 16, and 22 from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 5, 9, 11, 12, 13, and 15 from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides. The nucleotides at positions 6, 14, 16, 18, and 22 from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 5, 9, 11, 12, 13, and 15 from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides. The nucleotides at positions 2, 4, 6, 14, and 22 from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides.In some embodiments of the present disclosure, the nucleotides at positions 5, 9, 11, 12, 13, and 15 from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides. The nucleotides at positions 2, 6, 8, 14, and 22 from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 5, 9, 11, 12, 13, and 15 from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides. The nucleotides at positions 2, 6, 14, 18, and 22 from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 5, 9, 11, 12, 13, and 15 from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides. The nucleotides at positions 2, 4, 14, 16, and 22 from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 5, 9, 11, 12, 13, and 15 from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides. The nucleotides at positions 2, 8, 14, 16, and 22 from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 5, 9, 11, 12, 13, and 15 from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides. The nucleotides at positions 6, 9, 14, 16, and 22 from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 5, 9, 11, 12, 13, and 15 from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides. The nucleotides at positions 2, 9, 14, 16, and 22 from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides.In some embodiments of the present disclosure, the nucleotides at positions 5, 9, 11, 12, 13, and 15 from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides. The nucleotides at positions 2, 6, 9, 14, and 22 from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 5, 9, 11, 12, 13, and 15 from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides. The nucleotides at positions 2, 6, 8, 9, 14, 16, and 22 from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides. In some embodiments of the present disclosure, the nucleotides at positions 5, 11, 12, 13, and 15 from the 3' end to the 5' end of the sense chain are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense chain may be 2'-methoxy nucleotides. The nucleotides at positions 2, 6, 9, 10, 14, 16, and 22 from the 5' end to the 3' end of the antisense chain are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense chain may be 2'-methoxy nucleotides.

[0232] In some embodiments of the present disclosure, the nucleotides at positions 1, 9, 11, 12, 13, and 15 from the 3' end to the 5' end of the sense chain are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense chain may be 2'-methoxy nucleotides. The nucleotides at positions 2, 6, 14, 16, and 22 from the 5' end to the 3' end of the antisense chain are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense chain may be 2'-methoxy nucleotides.

[0233] In some embodiments of the present disclosure, the nucleotides at positions 11, 13, and 15 from the 3' end to the 5' end of the sense chain are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense chain may be 2'-methoxy nucleotides. The nucleotides at positions 2, 6, 12, 14, 16, and 22 from the 5' end to the 3' end of the antisense chain are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense chain may be 2'-methoxy nucleotides.

[0234] In some embodiments of the present disclosure, the nucleotides at positions 9, 11, and 13 from the 3' end to the 5' end of the sense chain are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense chain may be 2'-methoxy nucleotides. The nucleotides at positions 2, 6, 12, 14, 16, and 22 from the 5' end to the 3' end of the antisense chain are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense chain may be 2'-methoxy nucleotides.

[0235] In some embodiments of the present disclosure, the nucleotides at positions 5, 11, and 13 from the 3' end to the 5' end of the sense chain are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense chain may be 2'-methoxy nucleotides. The nucleotides at positions 2, 6, 12, 14, 16, and 22 from the 5' end to the 3' end of the antisense chain are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense chain may be 2'-methoxy nucleotides.

[0236] In some embodiments of the present disclosure, the nucleotides at positions 5, 11, and 13 from the 3' end to the 5' end of the sense chain are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense chain may be 2'-methoxy nucleotides. The nucleotides at positions 2, 6, 14, 16, and 22 from the 5' end to the 3' end of the antisense chain are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense chain may be 2'-methoxy nucleotides.

[0237] In some embodiments of the present disclosure, the nucleotides at positions 11, 12, and 13 from the 3' end to the 5' end of the sense chain are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense chain may be 2'-methoxy nucleotides. The nucleotides at positions 2, 6, 14, 16, and 22 from the 5' end to the 3' end of the antisense chain are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense chain may be 2'-methoxy nucleotides.

[0238] In some embodiments of the present disclosure, at least one of the nucleotides between the 1st and 2nd positions at the 5' end of the sense strand, the nucleotides between the 2nd and 3rd positions at the 5' end of the sense strand, the nucleotides between the 1st and 2nd positions at the 3' end of the antisense strand, the nucleotides between the 2nd and 3rd positions at the 3' end of the antisense strand, the nucleotides between the 1st and 2nd positions at the 5' end of the antisense strand, and the nucleotides between the 2nd and 3rd positions at the 5' end of the antisense strand is connected by a thiophosphate group, a thiophosphate group with an Rp configuration, or a thiophosphate group with an Sp configuration.

[0239] In some embodiments of the present disclosure, at least four or six of the nucleotides between the 1st and 2nd positions at the 5' end of the sense strand, between the 2nd and 3rd positions at the 5' end of the sense strand, between the 1st and 2nd positions at the 3' end of the antisense strand, between the 2nd and 3rd positions at the 3' end of the antisense strand, between the 1st and 2nd positions at the 5' end of the antisense strand, and between the 2nd and 3rd positions at the 5' end of the antisense strand are connected by thiophosphate groups, thiophosphate groups with Rp configuration, or thiophosphate groups with Sp configuration.

[0240] In some embodiments of the present disclosure, the nucleotides at positions 1 and 2 of the 5' end of the sense strand and the nucleotides at positions 2 and 3 are connected by a thiophosphate group, a thiophosphate group of Rp configuration, or a thiophosphate group of Sp configuration. In some embodiments of the present disclosure, the nucleotides at positions 1 and 2 of the 5' end of the sense strand and the nucleotides at positions 2 and 3 are connected by a thiophosphate group, a thiophosphate group of Rp configuration, or a thiophosphate group of Sp configuration, and the nucleotides at positions 1 and 2 of the 3' end of the sense strand and the nucleotides at positions 2 and 3 are connected by a thiophosphate group, a thiophosphate group of Rp configuration, or a thiophosphate group of Sp configuration. In some embodiments of the present disclosure, the nucleotides at positions 1 and 2 of the 5' end of the antisense strand and the nucleotides at positions 2 and 3 are connected by a thiophosphate group, a thiophosphate group of Rp configuration, or a thiophosphate group of Sp configuration. In some embodiments of the present disclosure, the nucleotides at positions 1 and 2 at the 3' end of the antisense strand and the nucleotides at positions 2 and 3 are linked by a phosphorothioate group, a phosphorothioate group with an Rp configuration, or a phosphorothioate group with an Sp configuration. In some embodiments of the present disclosure, the nucleotides at positions 1 and 2 at the 3' end of the antisense strand and the nucleotides at positions 2 and 3 are linked by a phosphorothioate group, a phosphorothioate group with an Rp configuration, or a phosphorothioate group with an Sp configuration, and the nucleotides at positions 1 and 2 at the 5' end of the antisense strand and the nucleotides at positions 2 and 3 are linked by a phosphorothioate group, a phosphorothioate group with an Rp configuration, or a phosphorothioate group with an Sp configuration.

[0241] In some embodiments of the present disclosure, the nucleotides at positions 1 and 2, the nucleotides at positions 2 and 3, the nucleotides at positions 3 and 4, and the nucleotides at positions 4 and 5 of the 3' end of the antisense strand are all connected by phosphorothioate groups, phosphorothioate groups with Rp configuration, or phosphorothioate groups with Sp configuration, and the nucleotides at positions 1 and 2, and the nucleotides at positions 2 and 3 of the 5' end of the antisense strand are connected by phosphorothioate groups, phosphorothioate groups with Rp configuration, or phosphorothioate groups with Sp configuration.

[0242] In some embodiments of the present disclosure, the second nucleotide at the 3' end of the sense strand may be a thermolabile nucleotide. In some embodiments of the present disclosure, the second nucleotide at the 3' end of the sense strand may be a thermolabile nucleotide.

[0243] In some embodiments of the present disclosure, at least one of the nucleotides at positions 6, 7, and 8 at the 5' end of the antisense strand is a thermolabile nucleotide. In some embodiments of the present disclosure, the nucleotide at position 6 at the 5' end of the antisense strand is a thermolabile nucleotide. In some embodiments of the present disclosure, the nucleotide at position 7 at the 5' end of the antisense strand is a thermolabile nucleotide. In some embodiments of the present disclosure, the nucleotide at position 8 at the 5' end of the antisense strand is a thermolabile nucleotide. In some embodiments of the present disclosure, the thermolabile nucleotide may be selected from LNA, UNA, or GNA. In some embodiments of the present disclosure, the thermolabile nucleotide may be GNA.

[0244] In some embodiments of the present disclosure, the first nucleotide at the 5' end of the antisense strand may be a (E)-VP modified nucleotide. In some embodiments of the present disclosure, the first nucleotide at the 5' end of the antisense strand may be a (E)-VP modified nucleotide.

[0245] In some embodiments of the present disclosure, the sense strand has the following modified nucleotides:

[0246] (1) The nucleotides at positions 9, 11, 12, 13, and 15 from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides; the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides;

[0247] (2) The nucleotides at positions 11, 12, 13, and 15 from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides; one of the nucleotides at positions 1, 3, 5, 6, 7, and 19 from the 3' end to the 5' end of the sense strand may further be a 2'-fluoro nucleotide; the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides;

[0248] (3) The nucleotides at positions 1, 9, 11, 12, 13, and 15 from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides; the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides;

[0249] (4) The nucleotides at positions 9, 11, 12, 13, and 15 from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, and the nucleotide at position 2 is GNA; the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides;

[0250] (5) The nucleotides at positions 5, 9, 11, 12, 13, and 15 from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides; the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides (preferably, the nucleotides at positions 9, 11, 12, 13, and 15 from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides; the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides; or, the nucleotides at positions 5, 11, 12, 13, and 15 from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides; the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides);

[0251] (6) The nucleotides at positions 11 and 13 from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides; one of the nucleotides at positions 5, 9, 12, 15, and 19 from the 3' end to the 5' end of the sense strand can further be a 2'-fluoro nucleotide; the nucleotides at other positions of the sense strand can be 2'-methoxy nucleotides.

[0252] In some embodiments of the present disclosure, the antisense strand has the following modified nucleotides:

[0253] (1) The nucleotides at positions 2, 6, 7, 14, 16, and 22 from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides; the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides; the nucleotide at position 1 from the 5' end to the 3' end of the antisense strand further has an (E)-VP modification;

[0254] (2) The nucleotides at positions 2, 6, 14, and 16 from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides; one or two of the nucleotides at positions 4, 8, 9, 10, 18, and 20 from the 5' end to the 3' end of the antisense strand may further be 2'-fluoro nucleotides; the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides;

[0255] (3) The nucleotides at positions 2, 6, 14, and 16 from the 5' end to the 3' end of the antisense strand and the nucleotides at position 2 from the 3' end to the 5' end are 2'-fluoro nucleotides; one or two of the nucleotides at positions 3, 4, 5, 7, 8, 9, 10, 12, and 20 from the 5' end to the 3' end of the antisense strand may further be 2'-fluoro nucleotides; the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides; the nucleotide at position 1 from the 5' end to the 3' end of the antisense strand may further have an (E)-VP modification;

[0256] (4) The nucleotides at positions 2, 6, 7, 14, and 16 from the 5' end to the 3' end of the antisense strand and the nucleotide at position 2 from the 3' end to the 5' end are 2'-fluoro nucleotides; the nucleotide at position 10 from the 5' end to the 3' end of the antisense strand may further be a 2'-fluoro nucleotide; the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides; the nucleotide at position 1 from the 5' end to the 3' end of the antisense strand further has an (E)-VP modification;

[0257] (5) The nucleotides at positions 2, 14, and 16 from the 5' end to the 3' end of the antisense strand and the nucleotides at position 2 from the 3' end to the 5' end are 2'-fluoro nucleotides; one of the nucleotides at positions 4, 8, and 9 from the 5' end to the 3' end of the antisense strand may further be a 2'-fluoro nucleotide; the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides;

[0258] (6) The nucleotides at positions 2, 6, and 14 from the 5' end to the 3' end of the antisense strand and the nucleotides at position 2 from the 3' end to the 5' end are 2'-fluoro nucleotides; one of the nucleotides at positions 4, 8, 9, and 18 from the 5' end to the 3' end of the antisense strand may further be a 2'-fluoro nucleotide; the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides; or

[0259] (7) The nucleotides at positions 6, 14, and 16 from the 5' end to the 3' end of the antisense chain and at position 2 from the 3' end to the 5' end are 2'-fluoro nucleotides; one of the nucleotides at positions 4, 8, 9, and 18 from the 5' end to the 3' end of the antisense chain can further be a 2'-fluoro nucleotide; the nucleotides at other positions of the antisense chain can be 2'-methoxy nucleotides.

[0260] In some embodiments of the present disclosure, the siRNA comprises the following sense and antisense strands:

[0261] The nucleotides at positions 9, 11, 12, 13, and 15 from the 3' end to the 5' end of the sense strand are 2'-fluoro nucleotides, the nucleotides at other positions of the sense strand are 2'-methoxy nucleotides, and the nucleotides at positions 19 and 20, and the nucleotides at positions 20 and 21 from the 3' end to the 5' end of the sense strand are linked by phosphorothioate groups, and

[0262] The nucleotides at positions 2, 6, 7, 14, 16, and 22 from the 5' end to the 3' end of the antisense chain are 2'-fluoro nucleotides, the nucleotides at other positions of the antisense chain are 2'-methoxy nucleotides, the nucleotide at position 1 from the 5' end to the 3' end of the antisense chain further has an (E)-VP modification, and the nucleotides at positions 1 and 2, nucleotides at positions 2 and 3, nucleotides at positions 21 and 22, and nucleotides at positions 22 and 23 from the 5' end to the 3' end of the antisense chain are connected by thiophosphate groups.

[0263] In some embodiments of the present disclosure, the siRNA comprises the following sense and antisense strands:

[0264] The nucleotides at positions 5, 9, 11, 12, 13, and 15 in the 3'-to-5' direction of the sense strand are 2'-fluoro nucleotides; the nucleotides at other positions of the sense strand may be 2'-methoxy nucleotides, and the nucleotides at positions 19 and 20, and nucleotides at positions 20 and 21 in the 3'-to-5' direction of the sense strand are linked by phosphorothioate groups;

[0265] The nucleotides at positions 2, 6, 14, and 16 from the 5' end to the 3' end of the antisense chain and the nucleotides at position 2 from the 3' end to the 5' end are 2'-fluoro nucleotides (or the nucleotides at positions 2, 6, 14, 16, and 22 from the 5' end to the 3' end of the antisense chain are 2'-fluoro nucleotides), and one or two of the nucleotides at positions 3, 4, 5, 7, 8, 9, and 10 from the 5' end to the 3' end of the antisense chain may further be 2'-fluoro nucleotides, the nucleotides at other positions of the antisense chain may be 2'-methoxy nucleotides, the nucleotide at position 1 from the 5' end to the 3' end of the antisense chain may further have an (E)-VP modification, and the nucleotides at positions 1 and 2, nucleotides at positions 2 and 3, nucleotides at positions 21 and 22, and nucleotides at positions 22 and 23 from the 5' end to the 3' end of the antisense chain are linked by thiophosphate groups.

[0266] In some embodiments of the present disclosure, the siRNA may be selected from at least one of modified duplex 46 to modified duplex 50, modified duplex 60 to modified duplex 125, modified duplex 129 to modified duplex 130, modified duplex 133 to modified duplex 149, and modified duplex 152 to modified duplex 201;

[0267] Modified duplex 46

[0268] Sense strand: 5'-mU*mC*mCmCmAmCi2FCmUi2FUi2FUi2FUmCmUmUmCmUmAmAmUmGmA-3' (SEQ ID NO: 144)

[0269] Antisense strand: 5'-mU*i2FC*mAmUmUi2FAmGmAmAmGmAmAmAi2FAmGi2FGmUmGmGmGmA*mG*mA-3' (SEQ ID NO: 145);

[0270] Modified duplex 47

[0271] Sense strand: 5'-mU*mC*mCmCmAmCi2FCmUi2FUi2FUi2FUmCi2FUmUmCmUmAmAmUmGmA-3' (SEQ ID NO: 146)

[0272] Antisense strand: 5'-mU*i2FC*mAi2FUmUi2FAmGmAmAmGmAmAmAi2FAmGi2FGmUmGmGmGmA*mG*mA-3' (SEQ ID NO: 147);

[0273] Modified duplex 48

[0274] Sense strand: 5'-mU*mC*mCmCmAmCi2FCmUi2FUi2FUi2FUmCmUmUi2FCmUmAmAmUmGmA-3' (SEQ ID NO: 148)

[0275] Antisense strand: 5'-mU*i2FC*mAi2FUmUi2FAmGmAmAmGmAmAmAi2FAmGi2FGmUmGmGmGmA*mG*mA-3' (SEQ ID NO: 147);

[0276] Modified duplex 49

[0277] Sense strand: 5'-mU*mC*mCmCmAmCi2FCmUi2FUi2FUi2FUmCmUmUmCmUi2FAmAmUmGmA-3' (SEQ ID NO: 149)

[0278] Antisense strand: 5'-mU*i2FC*mAmUmUi2FAmGmAmAmGmAmAmAi2FAmGi2FGmUmGmGi2FGmA*mG*mA-3' (SEQ ID NO: 150);

[0279] Modified duplex 50

[0280] Sense strand: 5'-mU*mC*i2FCmCmAmCi2FCmUi2FUi2FUi2FUmCmUmUmCmUmAmAmUmGmA-3' (SEQ ID NO: 151)

[0281] Antisense strand: 5'-mU*i2FC*mAmUmUi2FAmGmAmAi2FGmAmAmAi2FAmGi2FGmUmGmGmGmA*mG*mA-3' (SEQ ID NO: 152);

[0282] Modified duplex 60

[0283] Sense strand: 5'-mU*mC*mCmCmAmCi2FCmUi2FUi2FUi2FUmCmUmUmCi2FUmAmAmUmGmA-3' (SEQ ID NO: 153)

[0284] Antisense strand: 5'-mU*i2FC*mAi2FUmUi2FAmGmAmAmGmAmAmAi2FAmGi2FGmUmGmGmGmA*mG*mA-3' (SEQ ID NO: 147);

[0285] Modified duplex 61

[0286] Sense strand: 5'-mC*mC*mAmGmUmCi2FUmCi2FCi2FCi2FAmCmCmUmUmUmCmUmUmUmU-3' (SEQ ID NO: 154)

[0287] Antisense strand: 5'-mA*i2FA*mAmGmAi2FAmAmAmGmGmUmGmGi2FGmAi2FGmAmCmUmGmG*mG*mG-3' (SEQ ID NO: 155);

[0288] Modified duplex 62

[0289] Sense strand: 5'-mC*mA*mGmUmCmUi2FCmCi2FCi2FAi2FCmCmUmUmUmUmCmUmUmCmU-3' (SEQ ID NO: 156)

[0290] Antisense strand: 5′-mA*i2FG*mAmAmGi2FAmAmAmAmGmGmUmGi2FGmGi2FAmGmAmCmUmG*mG*mG-3′ (SEQ ID NO: 157);

[0291] Modified duplex 63

[0292] Sense strand: 5'-mA*mG*mUmCmUmCi2FCmCi2FAi2FCi2FCmUmUmUmUmCmUmUmCmUmA-3' (SEQ ID NO: 158)

[0293] Antisense strand: 5'-mU*i2FA*mGmAmAi2FGmAmAmAmAmGmGmUi2FGmGi2FGmAmGmAmCmU*mG*mG-3' (SEQ ID NO: 159);

[0294] Modified duplex 64

[0295] Sense strand: 5'-mG*mU*mCmUmCmCi2FCmAi2FCi2FCi2FUmUmUmUmCmUmUmCmUmAmA-3' (SEQ ID NO: 160)

[0296] Antisense strand: 5'-mU*i2FU*mAmGmAi2FAmGmAmAmAmAmGmGi2FUmGi2FGmGmAmGmAmC*mU*mG-3' (SEQ ID NO: 161);

[0297] Modified duplex 65

[0298] Sense strand: 5'-mU*mC*mUmCmCmCi2FAmCi2FCi2FUi2FUmUmUmCmUmUmCmUmAmAmU-3' (SEQ ID NO: 162)

[0299] Antisense strand: 5'-mA*i2FU*mUmAmGi2FAmAmGmAmAmAmAmGi2FGmUi2FGmGmGmAmGmA*mC*mU-3' (SEQ ID NO: 163);

[0300] Modified duplex 66

[0301] Sense strand: 5'-mC*mU*mCmCmCmAi2FCmCi2FUi2FUi2FUmUmCmUmUmCmUmAmAmUmU-3' (SEQ ID NO: 164)

[0302] Antisense strand: 5'-mA*i2FA*mUmUmAi2FGmAmAmGmAmAmAmAi2FGmGi2FUmGmGmGmAmG*mA*mC-3' (SEQ ID NO: 165);

[0303] Modified duplex 67

[0304] Sense strand: 5'-mC*mC*mCmAmCmCi2FUmUi2FUi2FUi2FCmUmUmCmUmAmAmUmGmAmU-3' (SEQ ID NO: 166)

[0305] Antisense strand: 5'-mA*i2FU*mCmAmUi2FUmAmGmAmAmGmAmAi2FAmAi2FGmGmUmGmGmG*mA*mG-3' (SEQ ID NO: 167);

[0306] Modified duplex 68

[0307] Sense strand: 5'-mC*mC*mAmCmCmUi2FUmUi2FUi2FCi2FUmUmCmUmAmAmUmGmAmGmU-3' (SEQ ID NO: 168)

[0308] Antisense strand: 5'-mA*i2FC*mUmCmAi2FUmUmAmGmAmAmGmAi2FAmAi2FAmGmGmUmGmG*mG*mA-3' (SEQ ID NO: 169);

[0309] Modified duplex 69

[0310] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCmUmAmAmUmGmAmGmUmU-3' (SEQ ID NO: 170)

[0311] Antisense strand: 5'-mA*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAmGmGmUmG*mG*mG-3' (SEQ ID NO: 171);

[0312] Modified duplex 70

[0313] Sense strand: 5'-mA*mC*mCmUmUmUi2FUmCi2FUi2FUi2FCmUmAmAmUmGmAmGmUmCmU-3' (SEQ ID NO: 172)

[0314] Antisense strand: 5′-mA*i2FG*mAmCmUi2FCmAmUmUmAmGmAmAi2FGmAi2FAmAmAmGmGmU*mG*mG-3′ (SEQ ID NO: 173);

[0315] Modified duplex 71

[0316] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmU-3' (SEQ ID NO: 174)

[0317] Antisense strand: 5'-mA*i2FA*mCi2FUmCi2FAmUmUmUmAmGmAmAmGi2FAmAi2FAmAmGmGmUmG*mG*mG-3' (SEQ ID NO: 175);

[0318] Modified duplex 72

[0319] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmU-3' (SEQ ID NO: 174)

[0320] Antisense strand: 5'-mA*i2FA*mCmUmCi2FAmUi2FUmAmGmAmAmGi2FAmAi2FAmAmGmGmUmG*mG*mG-3' (SEQ ID NO: 176);

[0321] Modified duplex 73

[0322] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmU-3' (SEQ ID NO: 174)

[0323] Antisense strand: 5′-mA*i2FA*mCmUmCi2FAmUmUmAi2FGmAmAmGi2FAmAi2FAmAmGmGmUmG*mG*mG-3′ (SEQ ID NO: 177);

[0324] Modified duplex 74

[0325] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmU-3' (SEQ ID NO: 174)

[0326] Antisense strand: 5′-mA*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAi2FGmGmUmG*mG*mG-3′ (SEQ ID NO: 178);

[0327] Modified duplex 75

[0328] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmU-3' (SEQ ID NO: 174)

[0329] Antisense strand: 5′-mA*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAmGmGi2FUmG*mG*mG-3′ (SEQ ID NO: 179);

[0330] Modified duplex 76

[0331] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmU-3' (SEQ ID NO: 174)

[0332] Antisense strand: 5'-mA*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAmGmGmUmG*i2FG*mG-3' (SEQ ID NO: 180);

[0333] Modified duplex 77

[0334] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCmUmAi2FAmUmGmAmGmUmU-3' (SEQ ID NO: 181)

[0335] Antisense strand: 5'-mA*i2FA*mCi2FUmCi2FAmUmUmUmAmGmAmAmGi2FAmAi2FAmAmGmGmUmG*mG*mG-3' (SEQ ID NO: 175);

[0336] Modified duplex 78

[0337] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCmUmAi2FAmUmGmAmGmUmU-3' (SEQ ID NO: 181)

[0338] Antisense strand: 5'-mA*i2FA*mCmUmCi2FAmUi2FUmAmGmAmAmGi2FAmAi2FAmAmGmGmUmG*mG*mG-3' (SEQ ID NO: 176);

[0339] Modified duplex 79

[0340] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCmUmAi2FAmUmGmAmGmUmU-3' (SEQ ID NO: 181)

[0341] Antisense strand: 5′-mA*i2FA*mCmUmCi2FAmUmUmAi2FGmAmAmGi2FAmAi2FAmAmGmGmUmG*mG*mG-3′ (SEQ ID NO: 177);

[0342] Modified duplex 80

[0343] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCmUmAi2FAmUmGmAmGmUmU-3' (SEQ ID NO: 181)

[0344] Antisense strand: 5′-mA*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAi2FGmGmUmG*mG*mG-3′ (SEQ ID NO: 178);

[0345] Modified duplex 81

[0346] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCmUmAi2FAmUmGmAmGmUmU-3' (SEQ ID NO: 181)

[0347] Antisense strand: 5'-mA*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAmGmGi2FUmG*mG*mG-3' (SEQ ID NO: 179);

[0348] Modified duplex 82

[0349] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCmUmAi2FAmUmGmAmGmUmU-3' (SEQ ID NO: 181)

[0350] Antisense strand: 5'-mA*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAmGmGmUmG*i2FG*mG-3' (SEQ ID NO: 180);

[0351] Modified duplex 83

[0352] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCmUmAmAmUi2FGmAmGmUmU-3' (SEQ ID NO: 182)

[0353] Antisense strand: 5'-mA*i2FA*mCi2FUmCi2FAmUmUmUmAmGmAmAmGi2FAmAi2FAmAmGmGmUmG*mG*mG-3' (SEQ ID NO: 175);

[0354] Modified duplex 84

[0355] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCmUmAmAmUi2FGmAmGmUmU-3' (SEQ ID NO: 182)

[0356] Antisense strand: 5'-mA*i2FA*mCmUmCi2FAmUi2FUmAmGmAmAmGi2FAmAi2FAmAmGmGmUmG*mG*mG-3' (SEQ ID NO: 176);

[0357] Modified duplex 85

[0358] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCmUmAmAmUi2FGmAmGmUmU-3' (SEQ ID NO: 182)

[0359] Antisense strand: 5′-mA*i2FA*mCmUmCi2FAmUmUmAi2FGmAmAmGi2FAmAi2FAmAmGmGmUmG*mG*mG-3′ (SEQ ID NO: 177);

[0360] Modified duplex 86

[0361] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCmUmAmAmUi2FGmAmGmUmU-3' (SEQ ID NO: 182)

[0362] Antisense strand: 5′-mA*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAi2FGmGmUmG*mG*mG-3′ (SEQ ID NO: 178);

[0363] Modified duplex 87

[0364] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCmUmAmAmUi2FGmAmGmUmU-3' (SEQ ID NO: 182)

[0365] Antisense strand: 5′-mA*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAmGmGi2FUmG*mG*mG-3′ (SEQ ID NO: 179);

[0366] Modified duplex 88

[0367] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCmUmAmAmUi2FGmAmGmUmU-3' (SEQ ID NO: 182)

[0368] Antisense strand: 5'-mA*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAmGmGmUmG*i2FG*mG-3' (SEQ ID NO: 180);

[0369] Modified duplex 89

[0370] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCmUmAmAmUmGmAi2FGmUmU-3' (SEQ ID NO: 183)

[0371] Antisense strand: 5'-mA*i2FA*mCi2FUmCi2FAmUmUmUmAmGmAmAmGi2FAmAi2FAmAmGmGmUmG*mG*mG-3' (SEQ ID NO: 175);

[0372] Modified duplex 90

[0373] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCmUmAmAmUmGmAi2FGmUmU-3' (SEQ ID NO: 183)

[0374] Antisense strand: 5'-mA*i2FA*mCmUmCi2FAmUi2FUmAmGmAmAmGi2FAmAi2FAmAmGmGmUmG*mG*mG-3' (SEQ ID NO: 176);

[0375] Modified duplex 91

[0376] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCmUmAmAmUmGmAi2FGmUmU-3' (SEQ ID NO: 183)

[0377] Antisense strand: 5′-mA*i2FA*mCmUmCi2FAmUmUmAi2FGmAmAmGi2FAmAi2FAmAmGmGmUmG*mG*mG-3′ (SEQ ID NO: 177);

[0378] Modified duplex 92

[0379] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCmUmAmAmUmGmAi2FGmUmU-3'(SE Q ID NO:183)

[0380] Antisense strand: 5′-mA*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAi2FGmGmUmG*mG*mG-3′ (SEQ ID NO: 178);

[0381] Modified duplex 93

[0382] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCmUmAmAmUmGmAi2FGmUmU-3' (SEQ ID NO: 183)

[0383] Antisense strand: 5′-mA*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAmGmGi2FUmG*mG*mG-3′ (SEQ ID NO: 179);

[0384] Modified duplex 94

[0385] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCmUmAmAmUmGmAi2FGmUmU-3' (SEQ ID NO: 183)

[0386] Antisense strand: 5'-mA*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAmGmGmUmG*i2FG*mG-3' (SEQ ID NO: 180);

[0387] Modified duplex 95

[0388] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCmUmAmAmUmGmAmGmUi2FU-3' (SEQ ID NO: 184)

[0389] Antisense strand: 5'-mA*i2FA*mCi2FUmCi2FAmUmUmUmAmGmAmAmGi2FAmAi2FAmAmGmGmUmG*mG*mG-3' (SEQ ID NO: 175);

[0390] Modified duplex 96

[0391] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCmUmAmAmUmGmAmGmUi2FU-3' (SEQ ID NO: 184)

[0392] Antisense strand: 5'-mA*i2FA*mCmUmCi2FAmUi2FUmAmGmAmAmGi2FAmAi2FAmAmGmGmUmG*mG*mG-3' (SEQ ID NO: 176);

[0393] Modified duplex 97

[0394] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCmUmAmAmUmGmAmGmUi2FU-3' (SEQ ID NO: 184)

[0395] Antisense strand: 5′-mA*i2FA*mCmUmCi2FAmUmUmAi2FGmAmAmGi2FAmAi2FAmAmGmGmUmG*mG*mG-3′ (SEQ ID NO: 177);

[0396] Modified duplex 98

[0397] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCmUmAmAmUmGmAmGmUi2FU-3' (SEQ ID NO: 184)

[0398] Antisense strand: 5′-mA*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAi2FGmGmUmG*mG*mG-3′ (SEQ ID NO: 178);

[0399] Modified duplex 99

[0400] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCmUmAmAmUmGmAmGmUi2FU-3' (SEQ ID NO: 184)

[0401] Antisense strand: 5′-mA*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAmGmGi2FUmG*mG*mG-3′ (SEQ ID NO: 179);

[0402] Modified duplex 100

[0403] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCmUmAmAmUmGmAmGmUi2FU-3' (SEQ ID NO: 184)

[0404] Antisense strand: 5'-mA*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAmGmGmUmG*i2FG*mG-3' (SEQ ID NO: 180);

[0405] Modifying Duplexes 101

[0406] Sense strand: 5'-mG*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmU-3' (SEQ ID NO: 185)

[0407] Antisense strand: 5'-mA*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAmGmGmUmC*i2FG*mG-3' (SEQ ID NO: 186);

[0408] Modified duplex 102

[0409] Sense strand: 5'-mC*mU*mCmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmU-3' (SEQ ID NO: 187)

[0410] Antisense strand: 5'-mA*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAmGmGmAmG*i2FG*mG-3' (SEQ ID NO: 188);

[0411] Modified duplex 103

[0412] Sense strand: 5'-mC*mA*mGmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmU-3' (SEQ ID NO: 189)

[0413] Antisense strand: 5'-mA*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAmGmCmUmG*i2FG*mG-3' (SEQ ID NO: 190);

[0414] Modified duplex 104

[0415] Sense strand: 5'-mC*mA*mCmGmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmU-3' (SEQ ID NO: 191)

[0416] Antisense strand: 5'-mA*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAmCmGmUmG*i2FG*mG-3' (SEQ ID NO: 192);

[0417] Modified duplex 105

[0418] Sense strand: 5'-mC*mA*mCmCmAmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmU-3' (SEQ ID NO: 193)

[0419] Antisense strand: 5'-mA*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmUmGmGmUmG*i2FG*mG-3' (SEQ ID NO: 194);

[0420] Modified duplex 106

[0421] Sense strand: 5'-mC*mA*mCmCmUmAi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmU-3' (SEQ ID NO: 195)

[0422] Antisense strand: 5'-mA*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FUmAmGmGmUmG*i2FG*mG-3' (SEQ ID NO: 196);

[0423] Modified duplex 107

[0424] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmU-3' (SEQ ID NO: 174)

[0425] Antisense strand: 5'-mA*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAmGmGi2FUmG*i2FG*mG-3' (SEQ ID NO: 197);

[0426] Modified duplex 108

[0427] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmU-3' (SEQ ID NO: 174)

[0428] Antisense strand: 5'-mA*i2FA*mCmUmCi2FAmUi2FUmAmGmAmAmGi2FAmAi2FAmAmGmGmUmG*i2FG*mG-3' (SEQ ID NO: 198);

[0429] Modified duplex 109

[0430] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmU-3' (SEQ ID NO: 174)

[0431] Antisense strand: 5'-mA*i2FA*mCi2FUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAmGmGmUmG*i2FG*mG-3' (SEQ ID NO: 199);

[0432] Modified duplex 110

[0433] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUi2FGmAmGmUmU-3' (SEQ ID NO: 200)

[0434] Antisense strand: 5'-mA*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAmGmGmUmG*i2FG*mG-3' (SEQ ID NO: 180);

[0435] Modified duplex 111

[0436] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUi2FU-3' (SEQ ID NO: 201)

[0437] Antisense strand: 5'-mA*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAmGmGmUmG*i2FG*mG-3' (SEQ ID NO: 180);

[0438] Modified duplex 112

[0439] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCmUi2FUmCmUmAmAmUmGmAmGmUmU-3' (SEQ ID NO: 202)

[0440] Antisense strand: 5'-mA*i2FA*mCmUmCi2FAmUmUmAmGmAi2FAmGi2FAmAi2FAmAmGmGmUmG*i2FG*mG-3' (SEQ ID NO: 203);

[0441] Modified duplex 113

[0442] Sense strand: 5'-mC*mA*mCmCmUmUmUmUi2FCmUi2FUmCi2FUmAmAmUmGmAmGmUmU-3' (SEQ ID NO: 204)

[0443] Antisense strand: 5'-mA*i2FA*mCmUmCi2FAmUmUmAmGmAi2FAmGi2FAmAi2FAmAmGmGmUmG*i2FG*mG-3' (SEQ ID NO: 203);

[0444] Modified duplex 114

[0445] Sense strand: 5'-mC*mA*mCmCmUmUmUmUi2FCmUi2FUmCmUmAmAmUi2FGmAmGmUmU-3' (SEQ ID NO: 205)

[0446] Antisense strand: 5'-mA*i2FA*mCmUmCi2FAmUmUmAmGmAi2FAmGi2FAmAi2FAmAmGmGmUmG*i2FG*mG-3' (SEQ ID NO: 203);

[0447] Modified duplex 115

[0448] Sense strand: 5'-mC*mA*mCmCmUmUmUmUi2FCmUi2FUmCmUmAmAmUi2FGmAmGmUmU-3' (SEQ ID NO: 205)

[0449] Antisense strand: 5'-mA*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAmGmGmUmG*i2FG*mG-3' (SEQ ID NO: 180);

[0450] Modified duplex 116

[0451] Sense strand: 5'-mC*mA*mCmCmUmUmUmUi2FCi2FUi2FUmCmUmAmAmUmGmAmGmUmU-3' (SEQ ID NO: 206)

[0452] Antisense strand: 5'-mA*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAmGmGmUmG*i2FG*mG-3' (SEQ ID NO: 180);

[0453] Modified duplex 117

[0454] Sense strand: 5'-mG*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUi2FGmAmGmUmU-3' (SEQ ID NO: 207)

[0455] Antisense strand: 5'-mA*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAmGmGmUmC*i2FG*mG-3' (SEQ ID NO: 186);

[0456] Modified duplex 118

[0457] Sense strand: 5'-mC*mU*mCmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUi2FGmAmGmUmU-3' (SEQ ID NO: 208)

[0458] Antisense strand: 5'-mA*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAmGmGmAmG*i2FG*mG-3' (SEQ ID NO: 188);

[0459] Modified duplex 119

[0460] Sense strand: 5'-mC*mA*mGmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUi2FGmAmGmUmU-3' (SEQ ID NO: 209)

[0461] Antisense strand: 5'-mA*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAmGmCmUmG*i2FG*mG-3' (SEQ ID NO: 190);

[0462] Modified duplex 120

[0463] Sense strand: 5'-mG*mU*mCmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUi2FGmAmGmUmU-3' (SEQ ID NO: 210)

[0464] Antisense strand: 5'-mA*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAmGmGmAmC*i2FG*mG-3' (SEQ ID NO: 211);

[0465] Modified duplex 121

[0466] Sense strand: 5'-mG*mA*mGmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUi2FGmAmGmUmU-3' (SEQ ID NO: 212)

[0467] Antisense strand: 5'-mA*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAmGmCmUmC*i2FG*mG-3' (SEQ ID NO: 213);

[0468] Modified duplex 122

[0469] Sense strand: 5'-mC*mU*mGmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUi2FGmAmGmUmU-3' (SEQ ID NO: 214)

[0470] Antisense strand: 5'-mA*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAmGmCmAmG*i2FG*mG-3' (SEQ ID NO: 215);

[0471] Modified duplex 123

[0472] Sense strand: 5'-mG*mU*mGmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUi2FGmAmGmUmU-3' (SEQ ID NO: 216)

[0473] Antisense strand: 5'-mA*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAmGmCmAmC*i2FG*mG-3' (SEQ ID NO: 217);

[0474] Modified duplex 124

[0475] Sense chain: 5'-mG*mU*mCmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmU-3' (SEQ ID NO: 218)

[0476] Antisense strand: 5'-mA*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAmGmGmAmC*i2FG*mG-3' (SEQ ID NO: 211);

[0477] Modified duplex 125

[0478] Sense chain: 5'-mG*mU*mGmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmU-3' (SEQ ID NO: 219)

[0479] Antisense strand: 5'-mA*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAmGmCmAmC*i2FG*mG-3' (SEQ ID NO: 217);

[0480] Modified duplex 129

[0481] Sense strand: 5'-mU*mC*mCmCmAmCi2FCmUi2FUi2FUi2FUmCi2FUmUmCmUi2FAmAmUmGmA-3' (SEQ ID NO: 220)

[0482] Antisense strand: 5'-mU*i2FC*mAmUmUi2FAmGmAmAmGmAmAmAi2FAmGi2FGmUmGmGmGmA*i2FG*mA-3' (SEQ ID NO: 221);

[0483] Modified duplex 130

[0484] Sense strand: 5'-mA*mC*mCmCmAmCi2FCmUi2FUi2FUi2FUmCi2FUmUmCmUi2FAmAmUmGmA-3' (SEQ ID NO: 222)

[0485] Antisense strand: 5'-mU*i2FC*mAmUmUi2FAmGmAmAmGmAmAmAi2FAmGi2FGmUmGmGmGmU*i2FG*mA-3' (SEQ ID NO: 223);

[0486] Modified duplex 133

[0487] Sense strand: 5'-mA*mG*mGmCmAmCi2FCmUi2FUi2FUi2FUmCi2FUmUmCmUi2FAmAmUmGmA-3' (SEQ ID NO: 224)

[0488] Antisense strand: 5'-mU*i2FC*mAmUmUi2FAmGmAmAmGmAmAmAi2FAmGi2FGmUmGmCmCmU*i2FG*mA-3' (SEQ ID NO: 225);

[0489] Modified duplex 134

[0490] Sense strand: 5'-mA*mC*mCmGmAmCi2FCmAi2FGi2FCi2FUmUi2FGmUmUmUi2FGmUmGmAmA-3' (SEQ ID NO: 226)

[0491] Antisense strand: 5'-mU*i2FU*mCmAmCi2FAmAmAmCmAmAmGmCi2FUmGi2FGmUmCmGmGmU*i2FU*mG-3' (SEQ ID NO: 227);

[0492] Modified duplex 135

[0493] Sense strand: 5'-mU*mC*mCmGmAmCi2FCmAi2FGi2FCi2FUmUi2FGmUmUmUi2FGmUmGmAmA-3' (SEQ ID NO: 228)

[0494] Antisense strand: 5'-mU*i2FU*mCmAmCi2FAmAmAmCmAmAmGmCi2FUmGi2FGmUmCmGmGmA*i2FU*mG-3' (SEQ ID NO: 229);

[0495] Modified duplex 136

[0496] Sense strand: 5'-mU*mG*mGmGmAmCi2FCmAi2FGi2FCi2FUmUi2FGmUmUmUi2FGmUmGmAmA-3' (SEQ ID NO: 230)

[0497] Antisense strand: 5'-mU*i2FU*mCmAmCi2FAmAmAmCmAmAmGmCi2FUmGi2FGmUmCmCmCmA*i2FU*mG-3' (SEQ ID NO: 231);

[0498] Modified duplex 137

[0499] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmU-3' (SEQ ID NO: 174)

[0500] Antisense strand: 5'-mA*mA*mCi2FUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAmGmGmUmG*i2FG*mG-3' (SEQ ID NO: 232);

[0501] Modified duplex 138

[0502] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmU-3' (SEQ ID NO: 174)

[0503] Antisense strand: 5'-mA*i2FA*mCi2FUmCi2FAmUmUmAmGmAmAmGi2FAmAmAmAmGmGmUmG*i2FG*mG-3' (SEQ ID NO: 233);

[0504] Modified duplex 139

[0505] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmU-3' (SEQ ID NO: 174)

[0506] Antisense strand: 5'-mA*mA*mCmUmCi2FAmUi2FUmAmGmAmAmGi2FAmAi2FAmAmGmGmUmG*i2FG*mG -3' (SEQ ID NO: 234);

[0507] Modified duplex 140

[0508] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmU-3' (SEQ ID NO: 174)

[0509] Antisense strand: 5'-mA*i2FA*mCmUmCi2FAmUi2FUmAmGmAmAmGi2FAmAmAmAmGmGmUmG*i2FG*mG-3' (SEQ ID NO: 235);

[0510] Modified duplex 141

[0511] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmU-3' (SEQ ID NO: 174)

[0512] Antisense strand: 5'-mA*mA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAi2FGmGmUmG*i2FG*mG-3' (SEQ ID NO: 236);

[0513] Modified duplex 142

[0514] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmU-3' (SEQ ID NO: 174)

[0515] Antisense strand: 5'-mA*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAmAmAi2FGmGmUmG*i2FG*mG-3' (SEQ ID NO: 237);

[0516] Modified duplex 143

[0517] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmU-3' (SEQ ID NO: 174)

[0518] Antisense strand: 5'-mA*i2FA*mCmUmCmAmUi2FUmAmGmAmAmGi2FAmAi2FAmAmGmGmUmG*i2FG*mG-3' (SEQ ID NO: 238);

[0519] Modified duplex 144

[0520] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmU-3' (SEQ ID NO: 174)

[0521] Antisense strand: 5'-mA*i2FA*mCi2FUmCmAmUmUmAmGmAmAmGi2FAmAi2FAmAmGmGmUmG*i2FG*mG-3' (SEQ ID NO: 239);

[0522] Modified duplex 145

[0523] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmU-3' (SEQ ID NO: 174)

[0524] Antisense strand: 5'-mA*mA*mCmUmCi2FAmUmUi2FAmGmAmAmGi2FAmAi2FAmAmGmGmUmG*i2FG*mG-3' (SEQ ID NO: 240);

[0525] Modified duplex 146

[0526] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmU-3' (SEQ ID NO: 174)

[0527] Antisense strand: 5'-mA*i2FA*mCmUmCmAmUmUi2FAmGmAmAmGi2FAmAi2FAmAmGmGmUmG*i2FG*mG-3' (SEQ ID NO: 241);

[0528] Modified duplex 147

[0529] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmU-3' (SEQ ID NO: 174)

[0530] Antisense strand: 5'-mA*i2FA*mCmUmCi2FAmUmUi2FAmGmAmAmGi2FAmAmAmAmGmGmUmG*i2FG*mG-3' (SEQ ID NO: 242);

[0531] Modified duplex 148

[0532] Sense strand: 5'-mC*mC*mUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmU-3' (SEQ ID NO: 243)

[0533] Antisense strand: 5'-mA*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAmGmG*mU*mG-3' (SEQ ID NO: 244);

[0534] Modified duplex 149

[0535] Sense strand: 5'-mC*mC*mUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmU-3' (SEQ ID NO: 243)

[0536] Antisense strand: 5'-mA*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAmGmG*i2FU*mG-3' (SEQ ID NO: 245);

[0537] Modified duplex 152

[0538] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCmUmAmAmUmGmAmGmUmU-3' (SEQ ID NO: 170)

[0539] Antisense strand: 5′-mA*i2FA*mCmUmCi2FAmUi2FUi2FAmGmAmAmGi2FAmAi2FAmAmGmGmUmG*mG*mG-3′ (SEQ ID NO: 246);

[0540] Modified duplex 153

[0541] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmU-3' (SEQ ID NO: 174)

[0542] Antisense strand: 5'-mA*i2FA*mCmUmCi2FAmUi2FUi2FAmGmAmAmGi2FAmAi2FAmAmGmGmUmG*i2FG*mG-3' (SEQ ID NO: 247);

[0543] Modified duplex 154

[0544] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUi2FGmAmGmUmU-3' (SEQ ID NO: 200)

[0545] Antisense strand: 5'-mA*i2FA*mCmUmCi2FAmUi2FUi2FAmGmAmAmGi2FAmAi2FAmAmGmGmUmG*i2FG*mG-3' (SEQ ID NO: 247);

[0546] Modified duplex 155

[0547] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmA-3' (SEQ ID NO: 248)

[0548] Antisense strand: 5'-(E)-VPmU*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAmGmGmUmG*i2FG*mG-3' (SEQ ID NO: 249);

[0549] Modified duplex 156

[0550] Sense strand: 5'-mC*mU*mCmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmA-3' (SEQ ID NO: 250)

[0551] Antisense strand: 5'-(E)-VPmU*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAmGmGmAmG*i2FG*mG-3' (SEQ ID NO: 251);

[0552] Modified duplex 157

[0553] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmA-3' (SEQ ID NO: 248)

[0554] Antisense strand: 5'-(E)-VPmU*i2FA*mCmUmCi2FAmUmUmAi2FGmAmAmGi2FAmAi2FAmAmGmGmUmG*i2FG*mG-3' (SEQ ID NO: 252);

[0555] Modified duplex 158

[0556] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmA-3' (SEQ ID NO: 248)

[0557] Antisense strand: 5'-(E)-VPmU*i2FA*mCmUmCi2FAmUi2FUmAmGmAmAmGi2FAmAi2FAmAmGmGmUmG*i2FG*mG-3' (SEQ ID NO: 253);

[0558] Modified duplex 159

[0559] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmA-3' (SEQ ID NO: 248)

[0560] Antisense strand: 5'-(E)-VPmU*i2FA*mCi2FUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAmGmGmUmG*i2FG*mG-3' (SEQ ID NO: 254);

[0561] Modified duplex 160

[0562] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmA-3' (SEQ ID NO: 248)

[0563] Antisense strand: 5'-(E)-VPmU*i2FA*i2FCmUmCi2FAmUmUmAi2FGmAmAmGi2FAmAi2FAmAmGmGmUmG*i2FG*mG-3' (SEQ ID NO: 255);

[0564] Modified duplex 161

[0565] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmA-3' (SEQ ID NO: 248)

[0566] Antisense strand: 5'-(E)-VPmU*i2FA*mCmUi2FCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAmGmGmUmG*i2FG*mG-3' (SEQ ID NO: 256);

[0567] Modified duplex 162

[0568] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmA-3' (SEQ ID NO: 248)

[0569] Antisense strand: 5'-(E)-VPmU*i2FA*mCmUmCi2FAi2FUmUmAmGmAmAmGi2FAmAi2FAmAmGmGmUmG*i2FG*mG-3' (SEQ ID NO: 257);

[0570] Modified duplex 163

[0571] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmA-3' (SEQ ID NO: 248)

[0572] Antisense strand: 5'-(E)-VPmU*i2FA*mCmUmCi2FAmUi2FUi2FAmGmAmAmGi2FAmAi2FAmAmGmGmUmG*i2FG*mG-3' (SEQ ID NO: 258);

[0573] Modified duplex 164

[0574] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmA-3' (SEQ ID NO: 248)

[0575] Antisense strand: 5'-(E)-VPmU*i2FA*mCmUmCi2FAmUmUi2FAi2FGmAmAmGi2FAmAi2FAmAmGmGmUmG*i2FG*mG-3' (SEQ ID NO: 259);

[0576] Modified duplex 165

[0577] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCmUmAmAmUi2FGmAmGmUmA-3' (SEQ ID NO: 260)

[0578] Antisense strand: 5'-(E)-VPmU*i2FA*mCmUmCi2FAmUmUi2FAi2FGmAmAmGi2FAmAi2FAmAmGmGmUmG*i2FG*mG-3' (SEQ ID NO: 259);

[0579] Modified duplex 166

[0580] Sense strand: 5'-mC*mG*mCmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmA-3' (SEQ ID NO: 261)

[0581] Antisense strand: 5′-(E)-VPmU*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAmGmGmCmG*i2FG*mG-3′ (SEQ ID NO: 262);

[0582] Modified duplex 167

[0583] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGTmA-3'(SEQID NO:263)

[0584] Antisense strand: 5'-(E)-VPmU*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAmGmGmUmG*i2FG*mG-3' (SEQ ID NO: 249);

[0585] Modified duplex 168

[0586] Sense strand: 5'-mC*mU*mCmCmCmAmCmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmA-3' (SEQ ID NO: 264)

[0587] Antisense strand: 5'-(E)-VPmU*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAmGmGmUmGmGmGmAmG*i2FA*mC-3' (SEQ ID NO: 265);

[0588] Modified duplex 169

[0589] Sense strand: 5'-mU*mC*mCmCmAmCmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmA-3' (SEQ ID NO: 266)

[0590] Antisense strand: 5'-(E)-VPmU*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAmGmGmUmGmGmGmA*i2FG*mA-3' (SEQ ID NO: 267);

[0591] Modified duplex 170

[0592] Sense strand: 5'-mC*mC*mCmAmCmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmA-3' (SEQ ID NO: 268)

[0593] Antisense strand: 5'-(E)-VPmU*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAmGmGmUmGmGmG*i2FA*mG-3' (SEQ ID NO: 269);

[0594] Modified duplex 171

[0595] Sense strand: 5'-mC*mC*mAmCmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmA-3' (SEQ ID NO: 270)

[0596] Antisense strand: 5'-(E)-VPmU*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAmGmGmUmGmG*i2FG*mA-3' (SEQ ID NO: 271);

[0597] Modified duplex 172

[0598] Sense strand: 5'-mA*mC*mCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmA-3' (SEQ ID NO: 272)

[0599] Antisense strand: 5'-(E)-VPmU*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAmGmGmU*i2FG*mG-3' (SEQ ID NO: 273);

[0600] Modified duplex 173

[0601] Sense strand: 5'-mC*mC*mUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmA-3' (SEQ ID NO: 274)

[0602] Antisense strand: 5'-(E)-VPmU*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAmGmG*i2FU*mG-3' (SEQ ID NO: 275);

[0603] Modified duplex 174

[0604] Sense chain: 5'-mU*i2FU*mUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmA-3' (SEQ ID NO: 276)

[0605] Antisense strand: 5'-(E)-VPmU*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAmGmG*i2FU*mG-3' (SEQ ID NO: 275);

[0606] Modified duplex 175

[0607] Justice strand: 5'-mU*mU*i2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmA-3' (SEQ ID NO: 277)

[0608] Antisense strand: 5'-(E)-VPmU*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAmGmG*i2FU*mG-3' (SEQ ID NO: 275);

[0609] Modified duplex 176

[0610] Justice strand: 5'-mU*mU*i2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmA-3' (SEQ ID NO: 277)

[0611] Antisense strand: 5'-(E)-VPmU*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAmGmGmUmG*i2FG*mG-3' (SEQ ID NO: 249);

[0612] Modified duplex 177

[0613] Sense strand: 5'-mC*mU*mUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmA-3' (SEQ ID NO: 278)

[0614] Antisense strand: 5'-(E)-VPmU*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAmGmGmUmG*i2FG*mG-3' (SEQ ID NO: 249);

[0615] Modified duplex 178

[0616] Sense strand: 5'-mC*mC*mUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmA-3' (SEQ ID NO: 274)

[0617] Antisense strand: 5'-(E)-VPmU*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAmGmGmUmG*i2FG*mG-3' (SEQ ID NO: 249);

[0618] Modified duplex 179

[0619] Sense chain: 5'-mU*i2FU*mUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmA-3' (SEQ ID NO: 276)

[0620] Antisense strand: 5′-(E)-VPmU*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmA*i2FG*mG-3′ (SEQ ID NO: 279);

[0621] Modified duplex 180

[0622] Justice strand: 5'-mU*mU*i2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmA-3' (SEQ ID NO: 277)

[0623] Antisense strand: 5′-(E)-VPmU*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmA*i2FG*mG-3′ (SEQ ID NO: 279);

[0624] Modified duplex 181

[0625] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmA-3' (SEQ ID NO: 248)

[0626] Antisense strand: 5'-(E)-VPmU*i2FA*mCmUmCi2FAi2FUmUmAi2FGmAmAmGi2FAmAi2FAmAmGmGmUmG*i2FG*mG-3' (SEQ ID NO: 280);

[0627] Modified duplex 182

[0628] Sense strand: 5'-mC*mU*mCmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmA-3' (SEQ ID NO: 250)

[0629] Antisense strand: 5'-(E)-VPmU*i2FA*mCmUmCi2FAi2FUmUmAmGmAmAmGi2FAmAi2FAmAmGmGmAmG*i2FG*mG-3' (SEQ ID NO: 281);

[0630] Modified duplex 183

[0631] Sense strand: 5'-mC*mG*mCmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmA-3' (SEQ ID NO: 261)

[0632] Antisense strand: 5'-(E)-VPmU*i2FA*mCmUmCi2FAi2FUmUmAmGmAmAmGi2FAmAi2FAmAmGmGmCmG*i2FG*mG-3' (SEQ ID NO: 282);

[0633] Modified duplex 184

[0634] Sense strand: 5'-mC*mU*mCmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmA-3' (SEQ ID NO: 250)

[0635] Antisense strand: 5'-(E)-VPmU*i2FA*mCmUmCi2FAi2FUmUmAi2FGmAmAmGi2FAmAi2FAmAmGmGmAmG*i2FG*mG-3' (SEQ ID NO: 283);

[0636] Modified duplex 185

[0637] Sense strand: 5'-mC*mG*mCmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmA-3' (SEQ ID NO: 261)

[0638] Antisense strand: 5'-(E)-VPmU*i2FA*mCmUmCi2FAi2FUmUmAi2FGmAmAmGi2FAmAi2FAmAmGmGmCmG*i2FG*mG-3' (SEQ ID NO: 284);

[0639] Modified duplex 186

[0640] Justice strand: 5'-mU*mU*i2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmA-3' (SEQ ID NO: 277)

[0641] Antisense strand: 5'-(E)-VPmU*i2FA*mCmUmCi2FAmUmUmAi2FGmAmAmGi2FAmAi2FAmGmG*i2FU*mG-3' (SEQ ID NO: 285);

[0642] Modified duplex 187

[0643] Justice strand: 5'-mU*mU*i2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmA-3' (SEQ ID NO: 277)

[0644] Antisense strand: 5'-(E)-VPmU*i2FA*mCmUmCi2FAi2FUmUmAmGmAmAmGi2FAmAi2FAmAmGmG*i2FU*mG-3' (SEQ ID NO: 286);

[0645] Modified duplex 188

[0646] Justice strand: 5'-mU*mU*i2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmA-3' (SEQ ID NO: 277)

[0647] Antisense strand: 5'-(E)-VPmU*i2FA*mCmUmCi2FAi2FUmUmAi2FGmAmAmGi2FAmAi2FAmAmGmG*i2FU*mG-3' (SEQ ID NO: 287);

[0648] Modified duplex 189

[0649] Sense strand: 5'-mA*mC*mCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmA-3' (SEQ ID NO: 272)

[0650] Antisense strand: 5'-(E)-VPmU*i2FA*mCmUmCi2FAi2FUmUmAmGmAmAmGi2FAmAi2FAmAmGmGmU*i2FG*mG-3' (SEQ ID NO: 288);

[0651] Modified duplex 190

[0652] Sense strand: 5'-mU*mC*mCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmA-3' (SEQ ID NO: 289)

[0653] Antisense strand: 5'-(E)-VPmU*i2FA*mCmUmCi2FAi2FUmUmAmGmAmAmGi2FAmAi2FAmAmGmGmA*i2FG*mG-3' (SEQ ID NO: 290);

[0654] Modified duplex 191

[0655] Sense strand: 5'-mA*mG*mCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmA-3' (SEQ ID NO: 291)

[0656] Antisense strand: 5'-(E)-VPmU*i2FA*mCmUmCi2FAi2FUmUmAmGmAmAmGi2FAmAi2FAmAmGmCmU*i2FG*mG-3' (SEQ ID NO: 292);

[0657] Modified duplex 192

[0658] Sense strand: 5'-mA*mC*mGmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmA-3' (SEQ ID NO: 293)

[0659] Antisense strand: 5'-(E)-VPmU*i2FA*mCmUmCi2FAi2FUmUmAmGmAmAmGi2FAmAi2FAmAmCmGmU*i2FG*mG-3' (SEQ ID NO: 294);

[0660] Modified duplex 193

[0661] Sense strand: 5'-mG*mC*mCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmA-3' (SEQ ID NO: 295)

[0662] Antisense strand: 5′-(E)-VPmU*i2FA*mCmUmCi2FAi2FUmUmAmGmAmAmGi2FAmAi2FAmAmGmGmC*i2FG*mG-3′ (SEQ ID NO: 296);

[0663] Modified duplex 194

[0664] Sense strand: 5'-mC*mC*mAmCmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmA-3' (SEQ ID NO: 271)

[0665] Antisense strand: 5'-(E)-VPmU*i2FA*mCmUmCi2FAi2FUmUmAmGmAmAmGi2FAmAi2FAmAmGmGmUmGmG*i2FG*mA-3' (SEQ ID NO: 297);

[0666] Modified duplex 195

[0667] Sense strand: 5'-mG*mC*mAmCmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmA-3' (SEQ ID NO: 298)

[0668] Antisense strand: 5'-(E)-VPmU*i2FA*mCmUmCi2FAi2FUmUmAmGmAmAmGi2FAmAi2FAmAmGmGmUmGmC*i2FG*mA-3' (SEQ ID NO: 299);

[0669] Modified duplex 196

[0670] Sense strand: 5'-mC*mG*mAmCmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmA-3' (SEQ ID NO: 300)

[0671] Antisense strand: 5'-(E)-VPmU*i2FA*mCmUmCi2FAi2FUmUmAmGmAmAmGi2FAmAi2FAmAmGmGmUmCmG*i2FG*mA-3' (SEQ ID NO: 301);

[0672] Modified duplex 197

[0673] Sense strand: 5'-mC*mC*mUmCmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmA-3' (SEQ ID NO: 302)

[0674] Antisense strand: 5'-(E)-VPmU*i2FA*mCmUmCi2FAi2FUmUmAmGmAmAmGi2FAmAi2FAmAmGmGmAmGmG*i2FG*mA-3' (SEQ ID NO: 303);

[0675] Modified duplex 198

[0676] Sense strand: 5'-mC*mC*mGmCmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmA-3' (SEQ ID NO: 304)

[0677] Antisense strand: 5'-(E)-VPmU*i2FA*mCmUmCi2FAi2FUmUmAmGmAmAmGi2FAmAi2FAmAmGmGmCmGmG*i2FG*mA-3' (SEQ ID NO: 305);

[0678] Modified duplex 199

[0679] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUi2FGmAmGmUmA-3' (SEQ ID NO: 306)

[0680] Antisense strand: 5'-(E)-VPmU*i2FA*mCmUmCi2FAmUi2FUi2FAmGmAmAmGi2FAmAi2FAmAmGmGmUmG*i2FG*mG-3' (SEQ ID NO: 258);

[0681] Modified duplex 200

[0682] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUi2FGmAmGmUmA-3' (SEQ ID NO: 306)

[0683] Antisense strand: 5'-(E)-VPmU*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAmGmGmUmG*i2FG*mG-3' (SEQ ID NO: 249);

[0684] Modified duplex 201

[0685] Sense strand: 5'-mC*mA*mGmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUi2FGmAmGmUmA-3' (SEQ ID NO: 307)

[0686] Antisense strand: 5′-(E)-VPmU*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAmGmCmUmG*i2FG*mG-3′ (SEQ ID NO: 308).

[0687] In some embodiments of the present disclosure, the siRNA is at least one selected from modified duplex 46, modified duplex 61 to modified duplex 64 and modified duplex 66 to modified duplex 116, modified duplex 117 to modified duplex 125, modified duplex 129 to modified duplex 130, modified duplex 133 to modified duplex 136, modified duplex 155 to modified duplex 201 (for example, modified duplex 155 to modified duplex 157, modified duplex 162, modified duplex 166, modified duplex 171 to modified duplex 172, modified duplex 181 to modified duplex 198).

[0688] In some embodiments of the present disclosure, the siRNA is at least one selected from the modified duplexes 156 , 182 , and 184 .

[0689] In some embodiments of the present disclosure, the siRNA comprises a sense strand and an antisense strand, wherein the antisense strand comprises a strand selected from the group consisting of SEQ ID NO: 145, 155, 157, 159, 161, 165, 167, 169, 171, 173, 175, 176, 177, 178, 179, 180, 186, 188, 190, 192, 194, 196, 197, 198, 199, 203, 211, 213, 215, 217, 221, 223, 225, 227, 229, 231, 249, 251, 252, 253, 254, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285 52, 253, 254, 255, 256, 257, 258, 259, 262, 265, 267, 269, 271, 273, 275, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 290, 292, 294, 296, 297, 299, 301, 303, 305 or 308 (e.g., selected from SEQ ID NO:145, 155, 157, 159, 161, 165, 167, 169, 171, 173, 175, 176, 177, 178, 179, 18 0, 186, 188, 190, 192, 194, 196, 197, 198, 199, 203, 211, 213, 215, 217, 221, 223, 225, 227, 229, 231, 249, 251, 252, 257, 262, 271, 273, 280, 281, 282, 283, 284, 285, 286, 287, 288, 290, 292, 294, 296, 297, 299, 301, 303, 305 or 308).

[0690] It is known to those skilled in the art that the siRNA described in the present disclosure can be obtained by conventional siRNA preparation methods in the art (e.g., solid phase synthesis and liquid phase synthesis), wherein both solid phase synthesis and liquid phase synthesis have commercial custom services. It is also clear to those skilled in the art that modified nucleotide groups can be introduced into the siRNA described in the present disclosure by using nucleotide monomers with corresponding modifications. Methods for preparing nucleotide monomers with corresponding modifications are well known to those skilled in the art, and commercial monomers are also available on the market.

[0691] 2. siRNA conjugates disclosed herein

[0692] The siRNA conjugates disclosed herein are obtained by conjugating the siRNA disclosed herein to a pharmaceutically acceptable conjugated molecule, wherein the conjugated molecule comprises a pharmaceutically acceptable targeting ligand and a linker.

[0693] "Linker" means an organic moiety that connects two parts of a compound, such as covalently attaching two parts of a compound. Linkers typically include a direct bond or an atom such as oxygen or sulfur, a unit such as NR, C(O), C(O)NH, SO, SO2, SO2NH or a chain of atoms such as, but not limited to, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heterocycloalkyl, heterocycloalkenyl, heterocycloalkynyl, aryl, heteroaryl, heterocyclo, cycloalkyl, cycloalkenyl, alkylarylalkyl, alkylarylalkenyl, alkylarylalkynyl, alkenylarylalkyl, alkenylarylalkenyl, alkenylarylalkynyl, alkynylarylalkyl, alkynylarylalkenyl, alkynylarylalkynyl, alkylheteroarylalkyl, alkylheteroarylalkenyl, alkylheteroarylalkynyl, alkenylheteroarylalkyl, alkenylheteroarylalkenyl, alkenylheteroarylalkynyl wherein one or more methylene groups may be interrupted or terminated by O, S, S(O), SO2, N(R), C(O), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl; and wherein R is hydrogen, acyl, aliphatic or substituted aliphatic. In some embodiments of the disclosure, the linker is between about 1-24 atoms, 2-24, 3-24, 4-24, 5-24, 6-24, 6-18, 7-18, 8-18, 7-17, 8-17, 6-16, 7-16, or 8-16 atoms.

[0694] In some embodiments of the present disclosure, the siRNA is covalently conjugated to the conjugate molecule. To reduce the potential impact of conjugation on siRNA activity, the conjugation site between the siRNA and the conjugate molecule can be at the 3' or 5' end of the sense strand of the siRNA, or at the 5' end of the antisense strand. In some embodiments, the conjugation site between the siRNA and the conjugate molecule can also be within the internal sequence of the siRNA.

[0695] Pharmaceutically acceptable targeting ligands can be targeting ligands conventionally used in the field of siRNA administration. In some embodiments of the present disclosure, the targeting ligand may include, but is not limited to, one or more of the following targeting ligands or their derivatives: lipophilic molecules, polymers, polypeptides, aptamers, antibodies, chimeric antigen receptors, quantum dots, carbohydrates, folic acid (folate) or receptor ligands expressed by hepatocytes. In some embodiments of the present disclosure, the lipophilic molecule may include at least one of cholesterol, bile acid, vitamins (e.g., vitamin E), lipid molecules of different chain lengths (e.g., phospholipids, phospholipid ethers (PLE)). In some embodiments of the present disclosure, the polymer may include polyethylene glycol. In some embodiments of the present disclosure, the polypeptide may include a membrane-permeable peptide. In some embodiments of the present disclosure, the carbohydrate may include at least one of lactose, polylactose, mannose, galactose, N-acetylgalactosamine (GalNAc), and CMM (Chemically Modified Mannose). In some embodiments of the present disclosure, the receptor ligand expressed by hepatic parenchymal cells may include at least one of desialoglycoprotein, desialosugar residues, lipoproteins (such as high-density lipoprotein, low-density lipoprotein, etc.), glucagon, neurotransmitters (such as adrenaline), growth factors, and transferrin.

[0696] In some embodiments of the present disclosure, the targeting ligand is N-acetylgalactosamine or CMM. In some embodiments of the present disclosure, the targeting ligand is N-acetylgalactosamine.

[0697] In some embodiments of the present disclosure, the targeting ligand can be directly linked to the 3' end of the siRNA sense strand. In some embodiments of the present disclosure, the targeting ligand can be linked to the 3' end of the siRNA sense strand via a linker.

[0698] In some embodiments of the present disclosure, the Linker-Targeting Ligand portion has the following structure:

[0699] In some embodiments of the present disclosure, the structure of the siRNA conjugate may be as follows:

[0700] Wherein, the conjugate molecule described herein is combined with The 3' end of the sense strand of the siRNA shown is covalently conjugated.

[0701] In some embodiments of the present disclosure, the siRNA conjugate can be selected from at least one of conjugates 46 to 50, conjugates 60 to 125, conjugates 129 to 130, conjugates 133 to 136, conjugates 150 to 151, and conjugates 155 to 204, wherein the structure of the conjugate is as follows:

[0702] in, represents siRNA;

[0703] Conjugate 46

[0704] Sense strand: 5'-mU*mC*mCmCmAmCi2FCmUi2FUi2FUi2FUmCmUmUmCmUmAmAmUmGmAGalNAc(L96)-3' (SEQ ID NO: 309)

[0705] Antisense strand: 5'-mU*i2FC*mAmUmUi2FAmGmAmAmGmAmAmAi2FAmGi2FGmUmGmGmGmA*mG*mA-3' (SEQ ID NO: 145);

[0706] Conjugate 47

[0707] Sense strand: 5'-mU*mC*mCmCmAmCi2FCmUi2FUi2FUi2FUmCi2FUmUmCmUmAmAmUmGmAGalNAc(L96)-3' (SEQ ID NO: 310)

[0708] Antisense strand: 5'-mU*i2FC*mAi2FUmUi2FAmGmAmAmGmAmAmAi2FAmGi2FGmUmGmGmGmA*mG*mA-3' (SEQ ID NO: 147);

[0709] Conjugate 48

[0710] Sense strand: 5'-mU*mC*mCmCmAmCi2FCmUi2FUi2FUi2FUmCmUmUi2FCmUmAmAmUmGmAGalNAc(L96)-3' (SEQ ID NO: 311)

[0711] Antisense strand: 5'-mU*i2FC*mAi2FUmUi2FAmGmAmAmGmAmAmAi2FAmGi2FGmUmGmGmGmA*mG*mA-3' (SEQ ID NO: 147);

[0712] Conjugate 49

[0713] Sense strand: 5'-mU*mC*mCmCmAmCi2FCmUi2FUi2FUi2FUmCmUmUmCmUi2FAmAmUmGmAGalNAc(L96)-3' (SEQ ID NO: 312)

[0714] Antisense strand: 5'-mU*i2FC*mAmUmUi2FAmGmAmAmGmAmAmAi2FAmGi2FGmUmGmGi2FGmA*mG*mA-3' (SEQ ID NO: 150);

[0715] Conjugate 50

[0716] Sense strand: 5'-mU*mC*i2FCmCmAmCi2FCmUi2FUi2FUi2FUmCmUmUmCmUmAmAmUmGmAGalNAc(L96)-3' (SEQ ID NO: 313)

[0717] Antisense strand: 5'-mU*i2FC*mAmUmUi2FAmGmAmAi2FGmAmAmAi2FAmGi2FGmUmGmGmGmA*mG*mA-3' (SEQ ID NO: 152);

[0718] Conjugate 60

[0719] Sense strand: 5'-mU*mC*mCmCmAmCi2FCmUi2FUi2FUi2FUmCmUmUmCi2FUmAmAmUmGmAGalNAc(L96)-3' (SEQ ID NO: 314)

[0720] Antisense strand: 5'-mU*i2FC*mAi2FUmUi2FAmGmAmAmGmAmAmAi2FAmGi2FGmUmGmGmGmA*mG*mA-3' (SEQ ID NO: 147)

[0721] Conjugate 61

[0722] Sense strand: 5'-mC*mC*mAmGmUmCi2FUmCi2FCi2FCi2FAmCmCmUmUmUmCmUmUmUGalNAc(L96)-3' (SEQ ID NO: 315)

[0723] Antisense strand: 5'-mA*i2FA*mAmGmAi2FAmAmAmGmGmUmGmGi2FGmAi2FGmAmCmUmGmG*mG*mG-3' (SEQ ID NO: 155);

[0724] Conjugate 62

[0725] Sense strand: 5'-mC*mA*mGmUmCmUi2FCmCi2FCi2FAi2FCmCmUmUmUmUmCmUmUmCmUGalNAc(L96)-3' (SEQ ID NO: 316)

[0726] Antisense strand: 5′-mA*i2FG*mAmAmGi2FAmAmAmAmGmGmUmGi2FGmGi2FAmGmAmCmUmG*mG*mG-3′ (SEQ ID NO: 157);

[0727] Conjugate 63

[0728] Sense strand: 5'-mA*mG*mUmCmUmCi2FCmCi2FAi2FCi2FCmUmUmUmUmCmUmUmCmUmAGalNAc(L96)-3' (SEQ ID NO: 317)

[0729] Antisense strand: 5'-mU*i2FA*mGmAmAi2FGmAmAmAmAmGmGmUi2FGmGi2FGmAmGmAmCmU*mG*mG-3' (SEQ ID NO: 159);

[0730] Conjugate 64

[0731] Sense strand: 5'-mG*mU*mCmUmCmCi2FCmAi2FCi2FCi2FUmUmUmUmCmUmUmCmUmAmAGalNAc(L96)-3' (SEQ ID NO: 318)

[0732] Antisense strand: 5'-mU*i2FU*mAmGmAi2FAmGmAmAmAmAmGmGi2FUmGi2FGmGmAmGmAmC*mU*mG-3' (SEQ ID NO: 161);

[0733] Conjugate 65

[0734] Sense strand: 5'-mU*mC*mUmCmCmCi2FAmCi2FCi2FUi2FUmUmUmCmUmUmCmUmAmAmUGalNAc(L96)-3' (SEQ ID NO: 319)

[0735] Antisense strand: 5'-mA*i2FU*mUmAmGi2FAmAmGmAmAmAmAmGi2FGmUi2FGmGmGmAmGmA*mC*mU-3' (SEQ ID NO: 163);

[0736] Conjugate 66

[0737] Sense strand: 5'-mC*mU*mCmCmCmAi2FCmCi2FUi2FUi2FUmUmCmUmUmCmUmAmAmUmUGalNAc(L96)-3' (SEQ ID NO: 320)

[0738] Antisense strand: 5'-mA*i2FA*mUmUmAi2FGmAmAmGmAmAmAmAi2FGmGi2FUmGmGmGmAmG*mA*mC-3' (SEQ ID NO: 165);

[0739] Conjugate 67

[0740] Sense strand: 5'-mC*mC*mCmAmCmCi2FUmUi2FUi2FUi2FCmUmUmCmUmAmAmUmGmAmUGalNAc(L96)-3' (SEQ ID NO: 321)

[0741] Antisense strand: 5'-mA*i2FU*mCmAmUi2FUmAmGmAmAmGmAmAi2FAmAi2FGmGmUmGmGmG*mA*mG-3' (SEQ ID NO: 167);

[0742] Conjugate 68

[0743] Sense strand: 5'-mC*mC*mAmCmCmUi2FUmUi2FUi2FCi2FUmUmCmUmAmAmUmGmAmGmUGalNAc(L96)-3' (SEQ ID NO: 322)

[0744] Antisense strand: 5'-mA*i2FC*mUmCmAi2FUmUmAmGmAmAmGmAi2FAmAi2FAmGmGmUmGmG*mG*mA-3' (SEQ ID NO: 169);

[0745] Conjugate 69

[0746] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCmUmAmAmUmGmAmGmUmUGalNAc(L96)-3' (SEQ ID NO: 323)

[0747] Antisense strand: 5'-mA*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAmGmGmUmG*mG*mG-3' (SEQ ID NO: 171);

[0748] Conjugate 70

[0749] Sense strand: 5'-mA*mC*mCmUmUmUi2FUmCi2FUi2FUi2FCmUmAmAmUmGmAmGmUmCmUGalNAc(L96)-3' (SEQ ID NO: 324)

[0750] Antisense strand: 5′-mA*i2FG*mAmCmUi2FCmAmUmUmAmGmAmAi2FGmAi2FAmAmAmGmGmU*mG*mG-3′ (SEQ ID NO: 173);

[0751] Conjugate 71

[0752] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmUGalNAc(L96)-3' (SEQ ID NO: 325)

[0753] Antisense strand: 5'-mA*i2FA*mCi2FUmCi2FAmUmUmUmAmGmAmAmGi2FAmAi2FAmAmGmGmUmG*mG*mG-3' (SEQ ID NO: 175);

[0754] Conjugate 72

[0755] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmUGalNAc(L96)-3' (SEQ ID NO: 325)

[0756] Antisense strand: 5'-mA*i2FA*mCmUmCi2FAmUi2FUmAmGmAmAmGi2FAmAi2FAmAmGmGmUmG*mG*mG-3' (SEQ ID NO: 176);

[0757] Conjugate 73

[0758] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmUGalNAc(L96)-3' (SEQ ID NO: 325)

[0759] Antisense strand: 5′-mA*i2FA*mCmUmCi2FAmUmUmAi2FGmAmAmGi2FAmAi2FAmAmGmGmUmG*mG*mG-3′ (SEQ ID NO: 177);

[0760] Conjugate 74

[0761] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmUGalNAc(L96)-3' (SEQ ID NO: 325)

[0762] Antisense strand: 5′-mA*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAi2FGmGmUmG*mG*mG-3′ (SEQ ID NO: 178);

[0763] Conjugate 75

[0764] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmUGalNAc(L96)-3' (SEQ ID NO: 325)

[0765] Antisense strand: 5′-mA*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAmGmGi2FUmG*mG*mG-3′ (SEQ ID NO: 179);

[0766] Conjugate 76

[0767] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmUGalNAc(L96)-3' (SEQ ID NO: 325)

[0768] Antisense strand: 5'-mA*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAmGmGmUmG*i2FG*mG-3' (SEQ ID NO: 180);

[0769] Conjugate 77

[0770] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCmUmAi2FAmUmGmAmGmUmUGalNAc(L96)-3' (SEQ ID NO: 326)

[0771] Antisense strand: 5'-mA*i2FA*mCi2FUmCi2FAmUmUmUmAmGmAmAmGi2FAmAi2FAmAmGmGmUmG*mG*mG-3' (SEQ ID NO: 175);

[0772] Conjugate 78

[0773] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCmUmAi2FAmUmGmAmGmUmUGalNAc(L96)-3' (SEQ ID NO: 326)

[0774] Antisense strand: 5'-mA*i2FA*mCmUmCi2FAmUi2FUmAmGmAmAmGi2FAmAi2FAmAmGmGmUmG*mG*mG-3' (SEQ ID NO: 176);

[0775] Conjugate 79

[0776] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCmUmAi2FAmUmGmAmGmUmUGalNAc(L96)-3' (SEQ ID NO: 326)

[0777] Antisense strand: 5′-mA*i2FA*mCmUmCi2FAmUmUmAi2FGmAmAmGi2FAmAi2FAmAmGmGmUmG*mG*mG-3′ (SEQ ID NO: 177);

[0778] Conjugate 80

[0779] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCmUmAi2FAmUmGmAmGmUmUGalNAc(L96)-3' (SEQ ID NO: 326)

[0780] Antisense strand: 5′-mA*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAi2FGmGmUmG*mG*mG-3′ (SEQ ID NO: 178);

[0781] Conjugate 81

[0782] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCmUmAi2FAmUmGmAmGmUmUGalNAc(L96)-3' (SEQ ID NO: 326)

[0783] Antisense strand: 5′-mA*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAmGmGi2FUmG*mG*mG-3′ (SEQ ID NO: 179);

[0784] Conjugate 82

[0785] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCmUmAi2FAmUmGmAmGmUmUGalNAc(L96)-3' (SEQ ID NO: 326)

[0786] Antisense strand: 5'-mA*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAmGmGmUmG*i2FG*mG-3' (SEQ ID NO: 180);

[0787] Conjugate 83

[0788] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCmUmAmAmUi2FGmAmGmUmUGalNAc(L96)-3' (SEQ ID NO: 327)

[0789] Antisense strand: 5'-mA*i2FA*mCi2FUmCi2FAmUmUmUmAmGmAmAmGi2FAmAi2FAmAmGmGmUmG*mG*mG-3' (SEQ ID NO: 175);

[0790] Conjugate 84

[0791] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCmUmAmAmUi2FGmAmGmUmUGalNAc(L96)-3' (SEQ ID NO: 327)

[0792] Antisense strand: 5′-mA*i2FA*mCmUmCi2FAmUi2FUmAmGmAmAmGi2FAmAi2FAmAmGmGmUmG*mG*mG-3′ (SEQ ID NO: 176);

[0793] Conjugate 85

[0794] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCmUmAmAmUi2FGmAmGmUmUGalNAc(L96)-3' (SEQ ID NO: 327)

[0795] Antisense strand: 5′-mA*i2FA*mCmUmCi2FAmUmUmAi2FGmAmAmGi2FAmAi2FAmAmGmGmUmG*mG*mG-3′ (SEQ ID NO: 177);

[0796] Conjugate 86

[0797] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCmUmAmAmUi2FGmAmGmUmUGalNAc(L96)-3' (SEQ ID NO: 327)

[0798] Antisense strand: 5′-mA*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAi2FGmGmUmG*mG*mG-3′ (SEQ ID NO: 178);

[0799] Conjugate 87

[0800] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCmUmAmAmUi2FGmAmGmUmUGalNAc(L96)-3' (SEQ ID NO: 327)

[0801] Antisense strand: 5′-mA*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAmGmGi2FUmG*mG*mG-3′ (SEQ ID NO: 179);

[0802] Conjugate 88

[0803] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCmUmAmAmUi2FGmAmGmUmUGalNAc(L96)-3' (SEQ ID NO: 327)

[0804] Antisense strand: 5'-mA*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAmGmGmUmG*i2FG*mG-3' (SEQ ID NO: 180);

[0805] Conjugate 89

[0806] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCmUmAmAmUmGmAi2FGmUmUGalNAc(L96)-3' (SEQ ID NO: 328)

[0807] Antisense strand: 5'-mA*i2FA*mCi2FUmCi2FAmUmUmUmAmGmAmAmGi2FAmAi2FAmAmGmGmUmG*mG*mG-3' (SEQ ID NO: 175);

[0808] Conjugate 90

[0809] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCmUmAmAmUmGmAi2FGmUmUGalNAc(L96)-3' (SEQ ID NO: 328)

[0810] Antisense strand: 5'-mA*i2FA*mCmUmCi2FAmUi2FUmAmGmAmAmGi2FAmAi2FAmAmGmGmUmG*mG*mG-3' (SEQ ID NO: 176);

[0811] Conjugate 91

[0812] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCmUmAmAmUmGmAi2FGmUmUGalNAc(L96)-3' (SEQ ID NO: 328)

[0813] Antisense strand: 5′-mA*i2FA*mCmUmCi2FAmUmUmAi2FGmAmAmGi2FAmAi2FAmAmGmGmUmG*mG*mG-3′ (SEQ ID NO: 177);

[0814] Conjugate 92

[0815] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCmUmAmAmUmGmAi2FGmUmUGalNAc(L96)-3' (SEQ ID NO: 328)

[0816] Antisense strand: 5′-mA*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAi2FGmGmUmG*mG*mG-3′ (SEQ ID NO: 178);

[0817] Conjugate 93

[0818] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCmUmAmAmUmGmAi2FGmUmUGalNAc(L96)-3' (SEQ ID NO: 328)

[0819] Antisense strand: 5′-mA*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAmGmGi2FUmG*mG*mG-3′ (SEQ ID NO: 179);

[0820] Conjugate 94

[0821] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCmUmAmAmUmGmAi2FGmUmUGalNAc(L96)-3' (SEQ ID NO: 328)

[0822] Antisense strand: 5'-mA*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAmGmGmUmG*i2FG*mG-3' (SEQ ID NO: 180);

[0823] Conjugate 95

[0824] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCmUmAmAmUmGmAmGmUi2FUGalNAc(L 96)-3' (SEQ ID NO: 329)

[0825] Antisense strand: 5'-mA*i2FA*mCi2FUmCi2FAmUmUmUmAmGmAmAmGi2FAmAi2FAmAmGmGmUmG*mG*mG-3' (SEQ ID NO: 175);

[0826] Conjugate 96

[0827] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCmUmAmAmUmGmAmGmUi2FUGalNAc(L96)-3' (SEQ ID NO: 329)

[0828] Antisense strand: 5'-mA*i2FA*mCmUmCi2FAmUi2FUmAmGmAmAmGi2FAmAi2FAmAmGmGmUmG*mG*mG-3' (SEQ ID NO: 176);

[0829] Conjugate 97

[0830] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCmUmAmAmUmGmAmGmUi2FUGalNAc(L96)-3' (SEQ ID NO: 329)

[0831] Antisense strand: 5′-mA*i2FA*mCmUmCi2FAmUmUmAi2FGmAmAmGi2FAmAi2FAmAmGmGmUmG*mG*mG-3′ (SEQ ID NO: 177);

[0832] Conjugate 98

[0833] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCmUmAmAmUmGmAmGmUi2FUGalNAc(L96)-3' (SEQ ID NO: 329)

[0834] Antisense strand: 5′-mA*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAi2FGmGmUmG*mG*mG-3′ (SEQ ID NO: 178);

[0835] Conjugate 99

[0836] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCmUmAmAmUmGmAmGmUi2FUGalNAc(L96)-3' (SEQ ID NO: 329)

[0837] Antisense strand: 5′-mA*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAmGmGi2FUmG*mG*mG-3′ (SEQ ID NO: 179);

[0838] Conjugate 100

[0839] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCmUmAmAmUmGmAmGmUi2FUGalNAc(L96)-3' (SEQ ID NO: 329)

[0840] Antisense strand: 5'-mA*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAmGmGmUmG*i2FG*mG-3' (SEQ ID NO: 180);

[0841] Conjugate 101

[0842] Sense strand: 5'-mG*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmUGalNAc(L96)-3' (SEQ ID NO: 330)

[0843] Antisense strand: 5'-mA*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAmGmGmUmC*i2FG*mG-3' (SEQ ID NO: 186);

[0844] Conjugate 102

[0845] Sense strand: 5'-mC*mU*mCmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmUGalNAc(L96)-3' (SEQ ID NO: 331)

[0846] Antisense strand: 5'-mA*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAmGmGmAmG*i2FG*mG-3' (SEQ ID NO: 188);

[0847] Conjugate 103

[0848] Sense strand: 5'-mC*mA*mGmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmUGalNAc(L96)-3' (SEQ ID NO: 332)

[0849] Antisense strand: 5'-mA*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAmGmCmUmG*i2FG*mG-3' (SEQ ID NO: 190);

[0850] Conjugate 104

[0851] Sense strand: 5'-mC*mA*mCmGmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmUGalNAc(L96)-3' (SEQ ID NO: 333)

[0852] Antisense strand: 5'-mA*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAmCmGmUmG*i2FG*mG-3' (SEQ ID NO: 192);

[0853] Conjugate 105

[0854] Sense strand: 5'-mC*mA*mCmCmAmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmUGalNAc(L96)-3' (SEQ ID NO: 334)

[0855] Antisense strand: 5'-mA*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmUmGmGmUmG*i2FG*mG-3' (SEQ ID NO: 194);

[0856] Conjugate 106

[0857] Sense strand: 5'-mC*mA*mCmCmUmAi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmUGalNAc(L96)-3' (SEQ ID NO: 335)

[0858] Antisense strand: 5'-mA*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FUmAmGmGmUmG*i2FG*mG-3' (SEQ ID NO: 196);

[0859] Conjugate 107

[0860] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmUGalNAc(L96)-3' (SEQ ID NO: 325)

[0861] Antisense strand: 5'-mA*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAmGmGi2FUmG*i2FG*mG-3' (SEQ ID NO: 197);

[0862] Conjugate 108

[0863] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmUGalNAc(L96)-3' (SEQ ID NO: 325)

[0864] Antisense strand: 5'-mA*i2FA*mCmUmCi2FAmUi2FUmAmGmAmAmGi2FAmAi2FAmAmGmGmUmG*i2FG*mG-3' (SEQ ID NO: 198);

[0865] Conjugate 109

[0866] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmUGalNAc(L96)-3' (SEQ ID NO: 325)

[0867] Antisense strand: 5'-mA*i2FA*mCi2FUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAmGmGmUmG*i2FG*mG-3' (SEQ ID NO: 199);

[0868] Conjugate 110

[0869] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUi2FGmAmGmUmUGalNAc(L96)-3' (SEQ ID NO: 336)

[0870] Antisense strand: 5'-mA*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAmGmGmUmG*i2FG*mG-3' (SEQ ID NO: 180);

[0871] Conjugate 111

[0872] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUi2FUGalNAc(L96)-3' (SEQ ID NO: 337)

[0873] Antisense strand: 5'-mA*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAmGmGmUmG*i2FG*mG-3' (SEQ ID NO: 180);

[0874] Conjugate 112

[0875] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCmUi2FUmCmUmAmAmUmGmAmGmUmUGalNAc(L96)-3' (SEQ ID NO: 338)

[0876] Antisense strand: 5'-mA*i2FA*mCmUmCi2FAmUmUmAmGmAi2FAmGi2FAmAi2FAmAmGmGmUmG*i2FG*mG-3' (SEQ ID NO: 203);

[0877] Conjugate 113

[0878] Sense strand: 5'-mC*mA*mCmCmUmUmUmUi2FCmUi2FUmCi2FUmAmAmUmGmAmGmUmUGalNAc(L96)-3' (SEQ ID NO: 339)

[0879] Antisense strand: 5'-mA*i2FA*mCmUmCi2FAmUmUmAmGmAi2FAmGi2FAmAi2FAmAmGmGmUmG*i2FG*mG-3' (SEQ ID NO: 203);

[0880] Conjugate 114

[0881] Sense strand: 5'-mC*mA*mCmCmUmUmUmUi2FCmUi2FUmCmUmAmAmUi2FGmAmGmUmUGalNAc(L96)-3' (SEQ ID NO: 340)

[0882] Antisense strand: 5'-mA*i2FA*mCmUmCi2FAmUmUmAmGmAi2FAmGi2FAmAi2FAmAmGmGmUmG*i2FG*mG-3' (SEQ ID NO: 203);

[0883] Conjugate 115

[0884] Sense strand: 5'-mC*mA*mCmCmUmUmUmUi2FCmUi2FUmCmUmAmAmUi2FGmAmGmUmUGalNAc(L96)-3' (SEQ ID NO: 340)

[0885] Antisense strand: 5'-mA*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAmGmGmUmG*i2FG*mG-3' (SEQ ID NO: 180);

[0886] Conjugate 116

[0887] Sense strand: 5'-mC*mA*mCmCmUmUmUmUi2FCi2FUi2FUmCmUmAmAmUmGmAmGmUmUGalNAc(L96)-3' (SEQ ID NO: 341)

[0888] Antisense strand: 5'-mA*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAmGmGmUmG*i2FG*mG-3' (SEQ ID NO: 180);

[0889] Conjugate 117

[0890] Sense strand: 5'-mG*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUi2FGmAmGmUmUGalNAc(L96)-3'(SEQ ID NO:342)

[0891] Antisense strand: 5'-mA*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAmGmGmUmC*i2FG*mG-3' (SEQ ID NO: 186);

[0892] Conjugate 118

[0893] Sense strand: 5'-mC*mU*mCmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUi2FGmAmGmUmUGalNAc(L96)-3'(SEQ ID NO:343)

[0894] Antisense strand: 5'-mA*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAmGmGmAmG*i2FG*mG-3' (SEQ ID NO: 188);

[0895] Conjugate 119

[0896] Sense strand: 5'-mC*mA*mGmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUi2FGmAmGmUmUGalNAc(L96)-3' (SEQ ID NO: 344)

[0897] Antisense strand: 5'-mA*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAmGmCmUmG*i2FG*mG-3' (SEQ ID NO: 190);

[0898] Conjugate 120

[0899] Sense strand: 5'-mG*mU*mCmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUi2FGmAmGmUmUGalNAc(L96)-3'(SEQ ID NO:345)

[0900] Antisense strand: 5'-mA*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAmGmGmAmC*i2FG*mG-3' (SEQ ID NO: 211);

[0901] Conjugate 121

[0902] Sense strand: 5'-mG*mA*mGmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUi2FGmAmGmUmUGalNAc(L96)-3'(SEQ ID NO:346)

[0903] Antisense strand: 5'-mA*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAmGmCmUmC*i2FG*mG-3' (SEQ ID NO: 213);

[0904] Conjugate 122

[0905] Sense strand: 5'-mC*mU*mGmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUi2FGmAmGmUmUGalNAc(L96)-3' (SEQ ID NO: 347)

[0906] Antisense strand: 5'-mA*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAmGmCmAmG*i2FG*mG-3' (SEQ ID NO: 215);

[0907] Conjugate 123

[0908] Sense strand: 5'-mG*mU*mGmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUi2FGmAmGmUmUGalNAc(L96)-3'(SEQ ID NO:348)

[0909] Antisense strand: 5'-mA*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAmGmCmAmC*i2FG*mG-3' (SEQ ID NO: 217);

[0910] Conjugate 124

[0911] Sense strand: 5'-mG*mU*mCmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmUGalNAc(L96)-3' (SEQ ID NO: 349)

[0912] Antisense strand: 5'-mA*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAmGmGmAmC*i2FG*mG-3' (SEQ ID NO: 211);

[0913] Conjugate 125

[0914] Sense strand: 5'-mG*mU*mGmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmUGalNAc(L96)-3' (SEQ ID NO: 350)

[0915] Antisense strand: 5'-mA*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAmGmCmAmC*i2FG*mG-3' (SEQ ID NO: 217);

[0916] Conjugate 129

[0917] Sense strand: 5'-mU*mC*mCmCmAmCi2FCmUi2FUi2FUi2FUmCi2FUmUmCmUi2FAmAmUmGmAGalNAc(L96)-3' (SEQ ID NO: 351)

[0918] Antisense strand: 5'-mU*i2FC*mAmUmUi2FAmGmAmAmGmAmAmAi2FAmGi2FGmUmGmGmGmA*i2FG*mA-3' (SEQ ID NO: 221);

[0919] Conjugate 130

[0920] Sense strand: 5'-mA*mC*mCmCmAmCi2FCmUi2FUi2FUi2FUmCi2FUmUmCmUi2FAmAmUmGmAGalNAc(L96)-3' (SEQ ID NO: 352)

[0921] Antisense strand: 5'-mU*i2FC*mAmUmUi2FAmGmAmAmGmAmAmAi2FAmGi2FGmUmGmGmGmU*i2FG*mA-3' (SEQ ID NO: 223);

[0922] Conjugate 133

[0923] Sense strand: 5'-mA*mG*mGmCmAmCi2FCmUi2FUi2FUi2FUmCi2FUmUmCmUi2FAmAmUmGmAGalNAc(L96)-3' (SEQ ID NO: 353)

[0924] Antisense strand: 5'-mU*i2FC*mAmUmUi2FAmGmAmAmGmAmAmAi2FAmGi2FGmUmGmCmCmU*i2FG*mA-3' (SEQ ID NO: 225);

[0925] Conjugate 134

[0926] Sense strand: 5'-mA*mC*mCmGmAmCi2FCmAi2FGi2FCi2FUmUi2FGmUmUmUi2FGmUmGmAmAGalNAc(L96)-3' (SEQ ID NO: 354)

[0927] Antisense strand: 5'-mU*i2FU*mCmAmCi2FAmAmAmCmAmAmGmCi2FUmGi2FGmUmCmGmGmU*i2FU*mG-3' (SEQ ID NO: 227);

[0928] Conjugate 135

[0929] Sense strand: 5'-mU*mC*mCmGmAmCi2FCmAi2FGi2FCi2FUmUi2FGmUmUmUi2FGmUmGmAmAGalNAc(L96)-3' (SEQ ID NO: 355)

[0930] Antisense strand: 5'-mU*i2FU*mCmAmCi2FAmAmAmCmAmAmGmCi2FUmGi2FGmUmCmGmGmA*i2FU*mG-3' (SEQ ID NO: 229);

[0931] Conjugate 136

[0932] Sense strand: 5'-mU*mG*mGmGmAmCi2FCmAi2FGi2FCi2FUmUi2FGmUmUmUi2FGmUmGmAmAGalNAc(L96)-3' (SEQ ID NO: 356)

[0933] Antisense strand: 5'-mU*i2FU*mCmAmCi2FAmAmAmCmAmAmGmCi2FUmGi2FGmUmCmCmCmA*i2FU*mG-3' (SEQ ID NO: 231);

[0934] Conjugate 150

[0935] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUi2FGmAmGmUmAGalNAc(L96)-3'(SEQ ID NO:357)

[0936] Antisense strand: 5'-(E)-VPmU*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAmGmGmUmG*i2FG*mG-3' (SEQ ID NO: 249);

[0937] Conjugate 151

[0938] Sense strand: 5'-mC*mA*mGmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUi2FGmAmGmUmAGalNAc(L96)-3'(SEQ ID NO:358)

[0939] Antisense strand: 5′-(E)-VPmU*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAmGmCmUmG*i2FG*mG-3′ (SEQ ID NO: 308);

[0940] Conjugate 155

[0941] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmAGalNAc(L96)-3' (SEQ ID NO: 359)

[0942] Antisense strand: 5'-(E)-VPmU*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAmGmGmUmG*i2FG*mG-3' (SEQ ID NO: 249);

[0943] Conjugate 156

[0944] Sense strand: 5'-mC*mU*mCmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmAGalNAc(L96)-3' (SEQ ID NO: 360)

[0945] Antisense strand: 5'-(E)-VPmU*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAmGmGmAmG*i2FG*mG-3' (SEQ ID NO: 251);

[0946] Conjugate 157

[0947] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmAGalNAc(L96)-3' (SEQ ID NO: 359)

[0948] Antisense strand: 5'-(E)-VPmU*i2FA*mCmUmCi2FAmUmUmAi2FGmAmAmGi2FAmAi2FAmAmGmGmUmG*i2FG*mG-3' (SEQ ID NO: 252);

[0949] Conjugate 158

[0950] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmAGalNAc(L96)-3' (SEQ ID NO: 359)

[0951] Antisense strand: 5'-(E)-VPmU*i2FA*mCmUmCi2FAmUi2FUmAmGmAmAmGi2FAmAi2FAmAmGmGmUmG*i 2FG*mG-3' (SEQ ID NO: 253);

[0952] Conjugate 159

[0953] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmAGalNAc(L96)-3' (SEQ ID NO: 359)

[0954] Antisense strand: 5'-(E)-VPmU*i2FA*mCi2FUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAmGmGmUmG*i2FG*mG-3' (SEQ ID NO: 254);

[0955] Conjugate 160

[0956] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmAGalNAc(L96)-3' (SEQ ID NO: 359)

[0957] Antisense strand: 5'-(E)-VPmU*i2FA*i2FCmUmCi2FAmUmUmAi2FGmAmAmGi2FAmAi2FAmAmGmGmUmG*i2FG*mG-3' (SEQ ID NO: 255);

[0958] Conjugate 161

[0959] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmAGalNAc(L96)-3' (SEQ ID NO: 359)

[0960] Antisense strand: 5'-(E)-VPmU*i2FA*mCmUi2FCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAmGmGmUmG*i2FG*mG-3' (SEQ ID NO: 256);

[0961] Conjugate 162

[0962] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmAGalNAc(L96)-3' (SEQ ID NO: 359)

[0963] Antisense strand: 5'-(E)-VPmU*i2FA*mCmUmCi2FAi2FUmUmAmGmAmAmGi2FAmAi2FAmAmGmGmUmG*i2FG*mG-3' (SEQ ID NO: 257);

[0964] Conjugate 163

[0965] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmAGalNAc(L96)-3' (SEQ ID NO: 359)

[0966] Antisense strand: 5'-(E)-VPmU*i2FA*mCmUmCi2FAmUi2FUi2FAmGmAmAmGi2FAmAi2FAmAmGmGmUmG*i2FG*mG-3' (SEQ ID NO: 258);

[0967] Conjugate 164

[0968] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmAGalNAc(L96)-3' (SEQ ID NO: 359)

[0969] Antisense strand: 5'-(E)-VPmU*i2FA*mCmUmCi2FAmUmUi2FAi2FGmAmAmGi2FAmAi2FAmAmGmGmUmG*i2FG*mG-3' (SEQ ID NO: 259);

[0970] Conjugate 165

[0971] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCmUmAmAmUi2FGmAmGmUmAGalNAc(L96)-3' (SEQ ID NO: 361)

[0972] Antisense strand: 5'-(E)-VPmU*i2FA*mCmUmCi2FAmUmUi2FAi2FGmAmAmGi2FAmAi2FAmAmGmGmUmG*i2FG*mG-3' (SEQ ID NO: 259);

[0973] Conjugate 166

[0974] Sense strand: 5'-mC*mG*mCmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmAGalNAc(L96)-3' (SEQ ID NO: 362)

[0975] Antisense strand: 5′-(E)-VPmU*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAmGmGmCmG*i2FG*mG-3′ (SEQ ID NO: 262);

[0976] Conjugate 167

[0977] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGTmAGalNAc(L96)-3' (SEQ ID NO: 363)

[0978] Antisense strand: 5'-(E)-VPmU*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAmGmGmUmG*i2FG*mG-3' (SEQ ID NO: 249);

[0979] Conjugate 168

[0980] Sense strand: 5'-mC*mU*mCmCmCmAmCmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmAGalNAc(L96)-3' (SEQ ID NO: 364)

[0981] Antisense strand: 5'-(E)-VPmU*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAmGmGmUmGmGmGmAmG*i2FA*mC-3' (SEQ ID NO: 265);

[0982] Conjugate 169

[0983] Sense strand: 5'-mU*mC*mCmCmAmCmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmAGalNAc(L96)-3' (SEQ ID NO: 365)

[0984] Antisense strand: 5'-(E)-VPmU*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAmGmGmUmGmGmGmA*i2FG*mA-3' (SEQ ID NO: 267);

[0985] Conjugate 170

[0986] Sense strand: 5'-mC*mC*mCmAmCmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmAGalNAc(L96)-3' (SEQ ID NO: 366)

[0987] Antisense strand: 5'-(E)-VPmU*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAmGmGmUmGmGmG*i2FA*mG-3' (SEQ ID NO: 269);

[0988] Conjugate 171

[0989] Sense strand: 5'-mC*mC*mAmCmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmAGalNAc(L96)-3' (SEQ ID NO: 367)

[0990] Antisense strand: 5'-(E)-VPmU*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAmGmGmUmGmG*i2FG*mA-3' (SEQ ID NO: 271);

[0991] Conjugate 172

[0992] Sense strand: 5'-mA*mC*mCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmAGalNAc(L96)-3' (SEQ ID NO: 368)

[0993] Antisense strand: 5'-(E)-VPmU*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAmGmGmU*i2FG*mG-3' (SEQ ID NO: 273);

[0994] Conjugate 173

[0995] Sense strand: 5'-mC*mC*mUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmAGalNAc(L96)-3' (SEQ ID NO: 369)

[0996] Antisense strand: 5'-(E)-VPmU*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAmGmG*i2FU*mG-3' (SEQ ID NO: 275);

[0997] Conjugate 174

[0998] Sense strand: 5'-mU*i2FU*mUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmAGalNAc(L96)-3' (SEQ ID NO: 370)

[0999] Antisense strand: 5'-(E)-VPmU*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAmGmG*i2FU*mG-3' (SEQ ID NO: 275);

[1000] Conjugate 175

[1001] Sense strand: 5'-mU*mU*i2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmAGalNAc(L96)-3'(SEQ ID NO:371)

[1002] Antisense strand: 5'-(E)-VPmU*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAmGmG*i2FU*mG-3' (SEQ ID NO: 275);

[1003] Conjugate 176

[1004] Sense strand: 5'-mU*mU*i2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmAGalNAc(L96)-3'(SEQ ID NO:371)

[1005] Antisense strand: 5'-(E)-VPmU*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAmGmGmUmG*i2FG*mG-3' (SEQ ID NO: 249);

[1006] Conjugate 177

[1007] Sense strand: 5'-mC*mU*mUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmAGalNAc(L96)-3' (SEQ ID NO: 372)

[1008] Antisense strand: 5'-(E)-VPmU*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAmGmGmUmG*i2FG*mG-3' (SEQ ID NO: 249);

[1009] Conjugate 178

[1010] Sense strand: 5'-mC*mC*mUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmAGalNAc(L96)-3' (SEQ ID NO: 369)

[1011] Antisense strand: 5'-(E)-VPmU*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmAmGmGmUmG*i2FG*mG-3' (SEQ ID NO: 249);

[1012] Conjugate 179

[1013] Sense strand: 5'-mU*i2FU*mUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmAGalNAc(L96)-3' (SEQ ID NO: 370)

[1014] Antisense strand: 5′-(E)-VPmU*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmA*i2FG*mG-3′ (SEQ ID NO: 279);

[1015] Conjugate 180

[1016] Sense strand: 5'-mU*mU*i2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmAGalNAc(L96)-3'(SEQ ID NO:371)

[1017] Antisense strand: 5′-(E)-VPmU*i2FA*mCmUmCi2FAmUmUmAmGmAmAmGi2FAmAi2FAmA*i2FG*mG-3′ (SEQ ID NO: 279);

[1018] Conjugate 181

[1019] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmAGalNAc(L96)-3' (SEQ ID NO: 359)

[1020] Antisense strand: 5'-(E)-VPmU*i2FA*mCmUmCi2FAi2FUmUmAi2FGmAmAmGi2FAmAi2FAmAmGmGmUmG*i2FG*mG-3' (SEQ ID NO: 280);

[1021] Conjugate 182

[1022] Sense strand: 5'-mC*mU*mCmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmAGalNAc(L96)-3' (SEQ ID NO: 360)

[1023] Antisense strand: 5'-(E)-VPmU*i2FA*mCmUmCi2FAi2FUmUmAmGmAmAmGi2FAmAi2FAmAmGmGmAmG*i2FG*mG-3' (SEQ ID NO: 281);

[1024] Conjugate 183

[1025] Sense strand: 5'-mC*mG*mCmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmAGalNAc(L96)-3' (SEQ ID NO: 362)

[1026] Antisense strand: 5'-(E)-VPmU*i2FA*mCmUmCi2FAi2FUmUmAmGmAmAmGi2FAmAi2FAmAmGmGmCmG*i2FG*mG-3' (SEQ ID NO: 282);

[1027] Conjugate 184

[1028] Sense strand: 5'-mC*mU*mCmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmAGalNAc(L96)-3' (SEQ ID NO: 360)

[1029] Antisense strand: 5'-(E)-VPmU*i2FA*mCmUmCi2FAi2FUmUmAi2FGmAmAmGi2FAmAi2FAmAmGmGmAmG*i2FG*mG-3' (SEQ ID NO: 283);

[1030] Conjugate 185

[1031] Sense strand: 5'-mC*mG*mCmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmAGalNAc(L96)-3' (SEQ ID NO: 362)

[1032] Antisense strand: 5'-(E)-VPmU*i2FA*mCmUmCi2FAi2FUmUmAi2FGmAmAmGi2FAmAi2FAmAmGmGmCmG*i2FG*mG-3' (SEQ ID NO: 284);

[1033] Conjugate 186

[1034] Sense strand: 5'-mU*mU*i2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmAGalNAc(L96)-3'(SEQ ID NO:371)

[1035] Antisense strand: 5'-(E)-VPmU*i2FA*mCmUmCi2FAmUmUmAi2FGmAmAmGi2FAmAi2FAmGmG*i2FU*mG-3' (SEQ ID NO: 285);

[1036] Conjugate 187

[1037] Sense strand: 5'-mU*mU*i2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmAGalNAc(L96)-3'(SEQ ID NO:371)

[1038] Antisense strand: 5'-(E)-VPmU*i2FA*mCmUmCi2FAi2FUmUmAmGmAmAmGi2FAmAi2FAmAmGmG*i2FU*mG-3' (SEQ ID NO: 286);

[1039] Conjugate 188

[1040] Sense strand: 5'-mU*mU*i2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmAGalNAc(L96)-3'(SEQ ID NO:372)

[1041] Antisense strand: 5'-(E)-VPmU*i2FA*mCmUmCi2FAi2FUmUmAi2FGmAmAmGi2FAmAi2FAmAmGmG*i2FU*mG-3' (SEQ ID NO: 287);

[1042] Conjugate 189

[1043] Sense strand: 5'-mA*mC*mCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmAGalNAc(L96)-3' (SEQ ID NO: 368)

[1044] Antisense strand: 5'-(E)-VPmU*i2FA*mCmUmCi2FAi2FUmUmAmGmAmAmGi2FAmAi2FAmAmGmGmU*i2FG*mG-3' (SEQ ID NO: 288);

[1045] Conjugate 190

[1046] Sense strand: 5'-mU*mC*mCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmAGalNAc(L96)-3' (SEQ ID NO: 373)

[1047] Antisense strand: 5'-(E)-VPmU*i2FA*mCmUmCi2FAi2FUmUmAmGmAmAmGi2FAmAi2FAmAmGmGmA*i2FG*mG-3' (SEQ ID NO: 290);

[1048] Conjugate 191

[1049] Sense strand: 5'-mA*mG*mCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmAGalNAc(L96)-3' (SEQ ID NO: 374)

[1050] Antisense strand: 5'-(E)-VPmU*i2FA*mCmUmCi2FAi2FUmUmAmGmAmAmGi2FAmAi2FAmAmGmCmU*i2FG*mG-3' (SEQ ID NO: 292);

[1051] Conjugate 192

[1052] Sense strand: 5'-mA*mC*mGmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmAGalNAc(L96)-3'(SEQ ID NO:375)

[1053] Antisense strand: 5'-(E)-VPmU*i2FA*mCmUmCi2FAi2FUmUmAmGmAmAmGi2FAmAi2FAmAmCmGmU*i2FG*mG-3' (SEQ ID NO: 294);

[1054] Conjugate 193

[1055] Sense strand: 5'-mG*mC*mCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmAGalNAc(L96)-3' (SEQ ID NO: 376)

[1056] Antisense strand: 5′-(E)-VPmU*i2FA*mCmUmCi2FAi2FUmUmAmGmAmAmGi2FAmAi2FAmAmGmGmC*i2FG*mG-3′ (SEQ ID NO: 296);

[1057] Conjugate 194

[1058] Sense strand: 5'-mC*mC*mAmCmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmAGalNAc(L96)-3' (SEQ ID NO: 367)

[1059] Antisense strand: 5'-(E)-VPmU*i2FA*mCmUmCi2FAi2FUmUmAmGmAmAmGi2FAmAi2FAmAmGmGmUmGmG*i2FG*mA-3' (SEQ ID NO: 297);

[1060] Conjugate 195

[1061] Sense strand: 5'-mG*mC*mAmCmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmAGalNAc(L96)-3' (SEQ ID NO: 377)

[1062] Antisense strand: 5'-(E)-VPmU*i2FA*mCmUmCi2FAi2FUmUmAmGmAmAmGi2FAmAi2FAmAmGmGmUmGmC*i2FG*mA-3' (SEQ ID NO: 299);

[1063] Conjugate 196

[1064] Sense strand: 5'-mC*mG*mAmCmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmAGalNAc(L96)-3' (SEQ ID NO: 378)

[1065] Antisense strand: 5'-(E)-VPmU*i2FA*mCmUmCi2FAi2FUmUmAmGmAmAmGi2FAmAi2FAmAmGmGmUmCmG*i2FG*mA-3' (SEQ ID NO: 301);

[1066] Conjugate 197

[1067] Sense strand: 5'-mC*mC*mUmCmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmAGalNAc(L96)-3' (SEQ ID NO: 379)

[1068] Antisense strand: 5'-(E)-VPmU*i2FA*mCmUmCi2FAi2FUmUmAmGmAmAmGi2FAmAi2FAmAmGmGmAmGmG*i2FG*mA-3' (SEQ ID NO: 303);

[1069] Conjugate 198

[1070] Sense strand: 5'-mC*mC*mGmCmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmAGalNAc(L96)-3' (SEQ ID NO: 380)

[1071] Antisense strand: 5'-(E)-VPmU*i2FA*mCmUmCi2FAi2FUmUmAmGmAmAmGi2FAmAi2FAmAmGmGmCmGmG*i2FG*mA-3' (SEQ ID NO: 305);

[1072] Conjugate 199

[1073] Sense strand: 5'-mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUi2FGmAmGmUmAGalNAc(L96)-3'(SEQ ID NO:357)

[1074] Antisense strand: 5'-(E)-VPmU*i2FA*mCmUmCi2FAmUi2FUi2FAmGmAmAmGi2FAmAi2FAmAmGmGmUmG*i2FG*mG-3' (SEQ ID NO: 258);

[1075] Conjugate 200

[1076] Sense strand: 5'-mG*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmAGalNAc(L96)-3'(SEQ ID NO:381)

[1077] Antisense strand: 5'-(E)-VPmU*i2FA*mCmUmCi2FAi2FUmUmAmGmAmAmGi2FAmAi2FAmAmGmGmUmC*i2FG*mG-3' (SEQ ID NO: 382);

[1078] Conjugate 201

[1079] Sense strand: 5'-mC*mA*mGmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmAGalNAc(L96)-3' (SEQ ID NO: 383)

[1080] Antisense strand: 5'-(E)-VPmU*i2FA*mCmUmCi2FAi2FUmUmAmGmAmAmGi2FAmAi2FAmAmGmCmUmG*i2FG*mG-3' (SEQ ID NO: 384);

[1081] Conjugate 202

[1082] Sense strand: 5'-mC*mA*mCmGmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmAGalNAc(L96)-3'(SEQ ID NO:385)

[1083] Antisense strand: 5'-(E)-VPmU*i2FA*mCmUmCi2FAi2FUmUmAmGmAmAmGi2FAmAi2FAmAmCmGmUmG*i2FG*mG-3' (SEQ ID NO: 386);

[1084] Conjugate 203

[1085] Sense strand: 5'-mC*mA*mCmCmAmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmAGalNAc(L96)-3' (SEQ ID NO: 387)

[1086] Antisense strand: 5'-(E)-VPmU*i2FA*mCmUmCi2FAi2FUmUmAmGmAmAmGi2FAmAi2FAmUmGmGmUmG*i2FG*mG-3' (SEQ ID NO: 388);

[1087] Conjugate 204

[1088] Sense strand: 5'-mC*mA*mCmCmUmAi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmAGalNAc(L96)-3' (SEQ ID NO: 389)

[1089] Antisense strand: 5'-(E)-VPmU*i2FA*mCmUmCi2FAi2FUmUmAmGmAmAmGi2FAmAi2FUmAmGmGmUmG*i2FG*mG-3' (SEQ ID NO: 390).

[1090] In some embodiments of the present disclosure, the siRNA conjugate can be selected from at least one of conjugates 101-103, conjugate 110, conjugates 117 to 125, conjugates 129 to 130, conjugates 133 to 136, conjugates 150 to 151, and conjugates 155 to 199 (e.g., conjugates 155 to 157, conjugate 162, conjugate 166, conjugates 171 to 172, and conjugates 181 to 198).

[1091] In some embodiments of the present disclosure, the siRNA comprises a sense strand and an antisense strand, wherein the antisense strand comprises a strand selected from the group consisting of SEQ ID 186, 188, 190, 180, 211, 213, 215, 217, 221, 223, 225, 227, 229, 231, 249, 308, 251, 252, 253, 254, 255, 256, 257, 258, 259, 262, 265, 267, 269, 271, 273, 275, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 290, 292, 294, 296, 297, 299, 301, 303, 305, 382, ​​384, 386, 388, or 390 (e.g., SEQ ID NO: 186, 188, 190, 180, 211, 213, 215, 217, 221, 223, 225, 227, 229, 231, 249, 308, 251, 252, 257, 262, 271, 273, 280, 281, 282, 283, 284, 285, 286, 287, 288, 290, 292, 294, 296, 297, 299, 301, 303 or 305).

[1092] In some embodiments of the present disclosure, the siRNA conjugate may be selected from at least one of conjugate 150, conjugate 151, conjugate 155, conjugate 156, conjugate 157, conjugate 162, conjugate 166, conjugate 171, conjugate 172, conjugate 175, conjugate 181, conjugate 182, conjugate 183, conjugate 184, and conjugate 185. In some embodiments of the present disclosure, the siRNA conjugate may be selected from conjugate 155, conjugate 156, conjugate 157, conjugate 162, conjugate 171, conjugate 172, conjugate 175, conjugate 182, conjugate 183, and conjugate 184 (e.g., conjugate 155, conjugate 156, conjugate 157, conjugate 162, conjugate 171, conjugate 172, conjugate 175, conjugate 182, and conjugate 183). In some embodiments of the present disclosure, the siRNA conjugate may be selected from conjugate 157, conjugate 158, conjugate 159, conjugate 160, conjugate 161, conjugate 162, conjugate 163, conjugate 164, and conjugate 165.

[1093] In some embodiments of the present disclosure, the siRNA conjugate comprises a sense strand and an antisense strand, wherein the antisense strand comprises a sequence selected from any one of SEQ ID NOs: 249, 251, 252, 257, 271, 273, 275, 281, 282, and 283 (e.g., SEQ ID NOs: 249, 251, 252, 257, 271, 273, 275, 281, and 282). In some embodiments of the present disclosure, the antisense strand comprises a sequence selected from SEQ ID NOs: 252, 253, 254, 255, 256, 257, 258, and 259.

[1094] In some embodiments of the present disclosure, the siRNA conjugate may be selected from conjugate 155, conjugate 156, conjugate 162, conjugate 182, and conjugate 184. In further embodiments, the siRNA conjugate may be selected from conjugate 156, conjugate 182, and conjugate 184.

[1095] In some embodiments of the present disclosure, the siRNA conjugate comprises a sense strand and an antisense strand, wherein the antisense strand comprises the following sequence in which all nucleotides are modified nucleotides:

[1096] UACUCAUUAGAAGAAAAGGX1GGG(SEQ ID NO:396)

[1097] Where X1 is A or U,

[1098] The nucleotides at positions 2, 6, 14, 16, and 22 from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides; the nucleotides at positions 7 or 7 and 10 from the 5' end to the 3' end of the antisense strand may further be 2'-fluoro nucleotides; the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides;

[1099] The first nucleotide from the 5' end to the 3' end of the antisense strand further has an (E)-VP modification;

[1100] There are phosphorothioate groups between the first and second nucleotides and between the second and third nucleotides at the 5' end of the antisense strand, and between the first and second nucleotides and between the second and third nucleotides at the 3' end.

[1101] In some embodiments of the present disclosure, the siRNA conjugate comprises a sense strand and an antisense strand, wherein the antisense strand comprises the following sequence in the 5' to 3' direction:

[1102] (E)-VPmU*i2FA*mCmUmCi2FAX2mUmAX3mAmAmGi2FAmAi2FAmAmGmGmX4mG*i2FG*mG(SEQ ID NO:397)

[1103] Wherein, X2 is mU or i2FU, X3 is mG or i2FG, and X4 is A or U.

[1104] In a further embodiment, the sense strand comprises the following sequence in the 5' to 3' direction:

[1105] mC*mX5*mCmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmAGalNAc(L96) (SEQ ID NO: 398), wherein X5 is A or U.

[1106] In some embodiments of the present disclosure, the siRNA conjugate comprises a sense strand and an antisense strand, wherein the antisense strand comprises a sequence selected from any one of SEQ ID NOs: 249, 251, 257, 281, and 283. In further embodiments, the sense strand comprises a sequence selected from SEQ ID NO: 359 and SEQ ID NO: 360; in still further embodiments, the sense strand comprises a sequence selected from SEQ ID NO: 360.

[1107] In some embodiments of the present disclosure, the siRNA conjugate may be conjugate 156 or conjugate 182 .

[1108] In some embodiments of the present disclosure, the siRNA conjugate comprises a sense strand and an antisense strand, wherein the antisense strand comprises the sequence shown in SEQ ID NO: 399:

[1109] 5'-(E)-VPmU*i2FA*mCmUmCi2FAX6mUmAmGmAmAmGi2FAmAi2FAmAmGmGmAmG*i2FG*mG-3' (SEQ ID NO: 399),

[1110] Among them, X6 is i2FU or mU.

[1111] In some embodiments of the present disclosure, the siRNA comprises a sense strand and an antisense strand, wherein the antisense strand comprises the sequence set forth in SEQ ID NO: 251 or 281. In further embodiments, the sense strand comprises the sequence set forth in SEQ ID NO: 360.

[1112] In some embodiments of the present disclosure, the siRNA conjugate comprises a sense strand and an antisense strand, wherein the antisense strand comprises the following sequence in the 5' to 3' direction:

[1113] (E)-VPmU*i2FA*X7X8X9i2FAX 10 X 11 X 12 X 13 mAmAmGi2FAmAi2FAmAmGmGmUmG*i2FG*mG(SEQ ID NO:400)

[1114] Among them, X7 is mC or i2FC, X8, X 10 、X 11 is mU or i2FU, X9 is mC or i2FC, X 12 is mA or i2FA, and X 13 mG or i2FG.

[1115] In a further embodiment, the sense strand comprises the following sequence in the 5' to 3' direction:

[1116] mC*mA*mCmCmUmUi2FUmUi2FCi2FUi2FUmCX 14 mAmAmUX 15 mAmGmUmAGalNAc(L96) (SEQ ID NO:401), wherein X 14 For i2FU or mU, X 15 mG or i2FG.

[1117] In some embodiments of the present disclosure, the siRNA comprises a sense strand and an antisense strand, the antisense strand comprising the sequence set forth in any one of SEQ ID NOs: 252, 253, 254, 255, 256, 257, 258, and 259. In further embodiments, the sense strand comprises the sequence set forth in SEQ ID NO: 359 or 361.

[1118] The present disclosure also provides siRNA or its conjugates whose sense chain and antisense chain have at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with the full-length nucleotide sequences of the sense chain and antisense chain mentioned above, respectively, and the siRNA or its conjugates can effectively inhibit the expression of the AGT gene.

[1119] In some embodiments of the present disclosure, a duplex in which the nucleotide at position 19, 20 or 21 in the direction from the 5' end to the 3' end of the antisense strand is mismatched with the target sequence, preferably a duplex in which the nucleotide at position 20 in the direction from the 5' end to the 3' end of the antisense strand is mismatched with the target sequence, and at the site of mismatch between the antisense strand and the target sequence, the nucleotides of the antisense strand and the target sequence are the same (e.g., duplex 22, duplex 26). When a preferred modification is selected, for example, the nucleotides at positions 9, 11, 12, 13, and 15 in the direction from the 3' end to the 5' end of the sense strand are 2 '-fluoro nucleotides, the nucleotides at other sites of the sense chain are 2'-methoxy nucleotides, the nucleotides at positions 2, 6, 7, 14, 16, and 22 in the direction from the 5' end to the 3' end of the antisense chain are 2'-fluoro nucleotides, and the nucleotides at other sites of the antisense chain are 2'-methoxy nucleotides. The modified duplex or the further obtained conjugate obtained has an improved gene silencing effect compared to the duplexes without mismatches at the above-mentioned sites (e.g., duplex 21 and duplex 24) obtained by the same modification method.

[1120] In some embodiments of the present disclosure, in a duplex 26 in which the nucleotide at position 20 from the 5' end to the 3' end of the antisense chain is mismatched with the target sequence, when a preferred modification method is selected, for example, the nucleotides at positions 9, 11, 12, 13, and 15 from the 3' end to the 5' end of the sense chain are 2'-fluoro nucleotides, and the nucleotides at other positions of the sense chain are 2'-methoxy nucleotides, and the nucleotides at positions 2, 6, 7, 14, 16, and 22 from the 5' end to the 3' end of the antisense chain are 2'-fluoro nucleotides, and the nucleotides at other positions of the antisense chain are 2'-methoxy nucleotides, the resulting modified duplex or the further obtained conjugate has a significantly improved gene silencing effect compared to the same modification method of a duplex without mismatches at the above-mentioned positions.

[1121] In some embodiments of the present disclosure, the conjugate 182 using a special mismatch pattern (the nucleotide at position 20 from the 5' end to the 3' end of the antisense chain is the same as the nucleotide of the target sequence) has an improved gene silencing effect compared to the conjugate 162 with the same modification pattern in which the nucleotide at position 20 from the 5' end to the 3' end of the antisense chain is not mismatched with the target sequence.

[1122] 3. siRNA pharmaceutical compositions disclosed herein

[1123] The present disclosure also provides a pharmaceutical composition, which contains the siRNA or siRNA conjugate described in any embodiment of the present disclosure as an active ingredient and a pharmaceutically acceptable carrier.

[1124] In some embodiments of the present disclosure, the pharmaceutical composition contains one siRNA or siRNA conjugate as described in any embodiment of the present disclosure. In other embodiments of the present disclosure, the pharmaceutical composition contains at least two siRNAs or siRNA conjugates as described in any embodiment of the present disclosure (including but not limited to two, three, four, five, six, seven, eight, nine, ten or more) as active ingredients. In some embodiments of the present disclosure, the at least two siRNAs or siRNA conjugates as described in any embodiment of the present disclosure each target a different target sequence in the AGT gene, thereby expecting a synergistic effect brought about by acting simultaneously on different target sequences. Here, the "different target sequences" refers to the target sequences having no overlap or the number of overlapping consecutive nucleotides between the target sequences being less than 5 (for example, the number of overlapping consecutive nucleotides is 4, 3, 2, 1 or 0). In this case, the at least two siRNAs or siRNA conjugates as described in any embodiment of the present disclosure can be present in any different ratios. In some embodiments of the present disclosure, the at least two siRNAs or siRNA conjugates according to the first aspect may be present in a molar ratio of 1:100 to 100:1. In some embodiments of the present disclosure, the at least two siRNAs or siRNA conjugates according to the first aspect may be present in a molar ratio of 1:70 to 70:1. In some embodiments of the present disclosure, the at least two siRNAs according to the first aspect or the siRNA conjugates according to the second aspect may be present in a molar ratio of 1:50 to 50:1. In some embodiments of the present disclosure, the at least two siRNAs according to the first aspect or the siRNA conjugates according to the second aspect may be present in a molar ratio of 1:10 to 10:1. In some embodiments of the present disclosure, the at least two siRNAs according to the first aspect or the siRNA conjugates according to the second aspect may be present in a molar ratio of 1:5 to 5:1. In some embodiments of the present disclosure, the at least two siRNAs according to the first aspect or the siRNA conjugates according to the second aspect may be present in a molar ratio of 1:2 to 2:1. In some embodiments of the present disclosure, the at least two siRNAs according to the first aspect or the siRNA conjugates according to the second aspect are present in a molar ratio of 1:1.

[1125] In some embodiments of the present disclosure, the pharmaceutically acceptable carrier may include, but is not limited to, magnetic nanoparticles (such as Fe3O4, Fe2O3), gold nanoparticles, quantum dots, silica nanoparticles, carbon nanotubes, mesoporous silica, calcium phosphate nanoparticles, polyethyleneimine, polyamidoamine dendrimers, poly-L-lysine, chitosan, 1,2-dioleoyl-3-trimethylammonium propane, poly-D- or L-lactic acid / glycolic acid copolymers, poly(2-aminoethyl ethylene phosphate) and poly(methacrylic acid-N,N-dimethylaminoethyl ester) and one or more of their derivatives. In the pharmaceutical composition of the present disclosure, there is no particular requirement for the content of the pharmaceutically acceptable carrier. In some embodiments of the present disclosure, the ratio of the total weight of the siRNA contained in the pharmaceutical composition to the total weight of the pharmaceutically acceptable carrier may be 1:(1-500). In some embodiments of the present disclosure, the ratio of the total weight of the siRNA contained in the pharmaceutical composition to the total weight of the pharmaceutically acceptable carrier may be 1:(1-300). In some embodiments of the present disclosure, the ratio of the total weight of the siRNA contained in the pharmaceutical composition to the total weight of the pharmaceutically acceptable carrier can be 1:(1-100). In some embodiments of the present disclosure, the ratio of the total weight of the siRNA or siRNA conjugate contained in the pharmaceutical composition to the total weight of the pharmaceutically acceptable carrier can be 1:(1-50).

[1126] In some embodiments of the present disclosure, the pharmaceutical composition may further comprise a cationic component to assist in the in vivo delivery of the drug. In some embodiments of the present disclosure, the cationic component may include, but is not limited to, at least one of a positively charged polypeptide or protein, a cationic lipid, a positively charged polymer, a cationic nanoemulsion (e.g., formed by mixing DOTAP with squalene, sorbitan trioleate, and polysorbate 80 in a citric acid buffer at pH 6.5). In some embodiments of the present disclosure, the positively charged polypeptide or protein may comprise at least one of oligoarginine, oligolysine, and protamine.In some embodiments of the present disclosure, the cationic lipid can be selected from dimethyldioctadecyl ammonium bromide (DDAB), 1,2-dimyristoyl-3-trimethylammonium propane, 1,2-dioleoyl-3-trimethylammonium propane (DOTAP), 1,2-dioleoyl-3-trimethylammonium propane methylsulfate, 1,2-dipalmitoyl-3-trimethylammonium propane, 1,2-distearoyl-3-trimethylammonium propane, N-(1-(2,3-dioleoyloxy)propyl)-N,N,N-trimethylammonium chloride (DOTMA), dimyristoyloxypropyl dimethylhydroxyethylammonium bromide (DMRIE), dioleoyloxypropyl dimethylhydroxyethylammonium bromide ( DORIE), dimethyldi(dodecyl)ammonium bromide, N-(a-trimethylammonioacetyl)-di(dodecyl)-D-glutamine hydrochloride, N-(a-trimethylammonioacetyl)-O,O'-bis-(1H,1H,2H,2H-perfluorodecyl)-L-glutamine hydrochloride, O,O'-di(dodecanoyl)-N-(a-trimethylammonioacetyl)diethanolamine hydrochloride, methylallyldi(dodecyl)ammonium bromide, N-{p-(w-trimethylammoniobutyloxy)-benzoyl}-di(dodecyl)-L-glutamine hydrochloride, 9-(w-trimethylammoniobutyl)-3,6-bis(dodecanoyl)carbazole bromide, dimethyldi(dodecyl)ammonium bromide Octadecyl)ammonium hydrochloride, Nw-trimethylammonium decanoyl-dihexadecyl-D-glutamine bromide, N-{p-(w-trimethylammonium hexyloxy)-benzoyl}-ditetradecyl-L-glutamine bromide, p-(w-trimethylammonium decyloxy)-p'-octyloxyazobenzene bromide (MC-1-0810), p-{w-(b-hydroxyethyl)dimethyl-ammonium-decyloxy}-p'-octyloxyazobenzene bromide (MC-3-0810), O,O',O"-tridodecanoyl-N-(w-trimethyl-ammonium decanoyl)-tris(hydroxymethyl)aminomethane bromide (TC-1-12), 1,2-dimethoxybenzoyl At least one of lauryl-glycero-3-ethylphosphocholine, 1,2-dimyristoyl-glycero-3-ethylphosphocholine, 1,2-dipalmitoyl-glycero-3-ethylphosphocholine, 1,2-distearoyl-glycero-3-ethylphosphocholine, 1,2-dioleoyl-glycero-3-ethylphosphocholine, 1-palmitoyl-2-oleoyl-glycero-3-ethylphosphocholine, N,N-dihydroxyethyl-N-methyl-N-2-(cholesteryloxycarbonylamino)ethylammonium bromide (BHEM-Chol), (2,3-dioleyloxypropyl)trimethylammonium chloride (DOTAP), and N-(1-(2,3-dioleyloxy)propyl)-N,N,N-trimethylammonium chloride.In some embodiments of the present disclosure, the positively charged polymer can be selected from at least one of poly L-lysine, poly L-arginine, polyethyleneimine, poly β-amino ester, chitosan, dextran (e.g., DEAE-dextran, diethylaminoethyl dextran), hyaluronic acid, and chitosan quaternary ammonium salt.

[1127] For the same purpose, the pharmaceutical composition may also include a non-cationic component. The non-cationic component may include, but is not limited to, at least one of a neutral membrane fusion lipid, an anionic lipid, and an amphiphilic polymer. In some embodiments of the present disclosure, the membrane fusion lipid may include dioleoylphosphatidylethanolamine, dioleoylphosphatidylcholine, trans-phosphatidylethanolamine, 1,2-bis(10,12-tricosane diacyl)-phosphoethanolamine, 1,2-di-anti-oleoylphosphoethanolamine, 1,2-di(hexadecyl)phosphoethanolamine, 1,2-dihexanoylphosphoethanolamine, 1,2-dilauroylphosphoethanolamine, 1,2-dilinoleoylphosphoethanolamine, 1,2-dimyristoylphosphoethanolamine, 1,2-dioleoylphosphoethanolamine, 1,2-dipalmitoleoylphosphoethanolamine, 1, 2-Dipalmitoylphosphoethanolamine, 1,2-diphytanoylphosphoethanolamine, 1,2-distearoylphosphoethanolamine, 1-palmitoyl-2-oleoylphosphoethanolamine, 1-palmitoyl-2-(10,12-tricosandioyl)phosphoethanolamine, 1,2-dioleoylphosphoethanolamine-N-hexanamide, 1,2-dipalmitoylphosphoethanolamine-N-hexanamide, N,N-dimethyl-1,2-dioleoylphosphoethanolamine, N,N-dimethyl-1,2-dipalmitoylphosphoethanolamine, N-dodecanoyl-1,2-dipalmitoylphosphoethanolamine, N-dodecanoyl- 1,2-Dioleoylphosphoethanolamine, 1,2-Dioleoylphosphoethanolamine-N-dodecylamine, 1,2-Dipalmitoylphosphoethanolamine-N-dodecylamine, 1,2-Dioleoylphosphoethanolamine-N-glutaryl, 1,2-Dipalmitoylphosphoethanolamine-N-glutaryl, 1,2-Dioleoylphosphoethanolamine-N-lactose, 1,2-Dioleoylphosphoethanolamine-N-[4-(p-maleimidomethyl)cyclohexane-carboxylate], Dipalmitoylphosphoethanolamine-N-[4-(p-maleimidomethyl)cyclohexane-carboxylate], 1,2-Dipalmitoylphosphoethanolamine -N-[4-(p-maleimidophenyl)butyramide], 1,2-dioleoylphosphoethanolamine-N-[4-(p-maleimidophenyl)butyrate], N-methyl-1,2-dioleoylphosphoethanolamine, N-methyl-dipalmitoylphosphoethanolamine, 1,2-dioleoylphosphoethanolamine-N-[3-(2-pyridyldithio)propionate, 1,2-dipalmitoylphosphoethanolamine-N-[3-(2-pyridyldithio)propionate], N-(succinyl)-1,2-dioleoylphosphoethanolamine, N-(succinyl)-1,2-dipalmitoylphosphoethanolamine. By adding the above membrane fusogenic lipids to the pharmaceutical composition of the present invention, the transport and delivery efficiency of the pharmaceutical composition in mammals can be further improved.In some embodiments of the present disclosure, the amphiphilic polymer may include at least one of a polyethylene glycol-polylactic acid diblock copolymer, a polyethylene glycol-polylactic acid triblock copolymer, a polyethylene glycol-poly(lactic acid-glycolic acid) diblock copolymer, or a polyethylene glycol-poly(lactic acid-glycolic acid) triblock copolymer, a polycaprolactone-polyphosphate diblock copolymer, a polycaprolactone-polyphosphate triblock copolymer, a polyethylene glycol-polycaprolactone diblock copolymer, and a polyethylene glycol-polycaprolactone triblock copolymer.

[1128] In some embodiments of the present disclosure, the pharmaceutical composition may further include other pharmaceutically acceptable excipients. In some embodiments of the present disclosure, the other pharmaceutically acceptable excipients may include at least one of a pH buffer, a protective agent, and an osmotic pressure regulator. In some embodiments of the present disclosure, the pH buffer may be one or both of a tris-hydroxymethylaminomethane hydrochloride buffer with a pH of 7.5-8.5 and a phosphate buffer with a pH of 5.5-8.5. In some embodiments of the present disclosure, the pH buffer may be a phosphate buffer with a pH of 5.5-8.5. In some embodiments of the present disclosure, the protective agent may be at least one of inositol, sorbitol, sucrose, trehalose, mannose, maltose, lactose, and glucose. In some embodiments of the present disclosure, the weight proportion of the protective agent may be 0.01%-30% based on the total weight of the pharmaceutical composition. In some embodiments of the present disclosure, the weight proportion of the protective agent may be 0.1%-25% based on the total weight of the pharmaceutical composition. In some embodiments of the present disclosure, the weight proportion of the protective agent may be 1%-20% based on the total weight of the pharmaceutical composition. In some embodiments of the present disclosure, the weight proportion of the protective agent may be 5%-15% based on the total weight of the pharmaceutical composition. In some embodiments of the present disclosure, the weight proportion of the protective agent may be 10%-12% based on the total weight of the pharmaceutical composition. In some embodiments of the present disclosure, the osmotic pressure regulator may be one or both of sodium chloride and potassium chloride. In some embodiments of the present disclosure, the content of the osmotic pressure regulator is such that the osmotic pressure of the pharmaceutical composition is 200-700 milliosmoles / kilogram (mOsmol / kg). In some embodiments of the present disclosure, the content of the osmotic pressure regulator is such that the osmotic pressure of the pharmaceutical composition is 300-600 milliosmoles / kilogram. In some embodiments of the present disclosure, the content of the osmotic pressure regulator is such that the osmotic pressure of the pharmaceutical composition is 400-500 milliosmoles / kilogram. According to the desired osmotic pressure, those skilled in the art can easily determine the content of the osmotic pressure regulator.

[1129] In some embodiments of the present disclosure, the pharmaceutical composition can be a liquid preparation, such as an injection. In some embodiments of the present disclosure, the pharmaceutical composition can also be a lyophilized powder injection, which is mixed with a liquid excipient during administration to form a liquid preparation. In some embodiments of the present disclosure, the liquid preparation can include but is not limited to being used for subcutaneous, intramuscular or intravenous administration. In some embodiments of the present disclosure, the liquid preparation can include but is not limited to being administered by spraying to the lungs, or being administered to other organs and tissues (such as the liver) through the lungs by spraying. In some embodiments of the present disclosure, the pharmaceutical composition is used for intravenous administration.

[1130] 4. Kits of the Present Disclosure

[1131] The kit of the present disclosure contains at least one of the siRNA, siRNA conjugate, or pharmaceutical composition described in any embodiment of the present disclosure. Where multiple siRNAs are present, each siRNA may be present alone or in the form of a mixture of two or more.

[1132] In some embodiments of the present disclosure, in addition to the siRNA, siRNA conjugate, or pharmaceutical composition, the kit may further include components necessary or beneficial for achieving one or more specific applications of the present disclosure, including but not limited to: (1) one or more components for achieving desired cell transfection; (2) one or more components for achieving diagnosis, treatment, or prevention of a specific disease, such as one or more additional therapeutic compounds or compositions, one or more diagnostic agents; (3) one or more buffers; (4) positive or negative control samples; and (5) at least one of an excipient, stabilizer, or preservative. In some embodiments of the present disclosure, the kit may further include instructions for use.

[1133] In some embodiments of the present disclosure, the components used to achieve the desired cell transfection include viruses (such as adenovirus, lentivirus, adeno-associated virus, retrovirus, herpes simplex virus) or virus-like particles (VLPs), etc.

[1134] In some embodiments of the present disclosure, the siRNA, siRNA conjugate or pharmaceutical composition in the kit can be provided in any form, such as liquid form, dry form or lyophilized form. In some embodiments of the present disclosure, the siRNA, siRNA conjugate or pharmaceutical composition in the kit is substantially pure and / or sterile.

[1135] 5. Applications of the siRNA, siRNA conjugates, and pharmaceutical compositions disclosed herein

[1136] By administering at least one of the siRNA, siRNA conjugates, and pharmaceutical compositions disclosed herein to a subject in need thereof, the expression level of the AGT gene can be effectively reduced in the subject, thereby being expected to be used to prevent and / or treat angiotensinogen disorder-related diseases in the subject, or to prepare a medicament for preventing and / or treating angiotensinogen disorder-related diseases.

[1137] In the method for preventing and / or treating angiotensinogen disorder-related diseases disclosed herein, an effective dose of the siRNA, siRNA conjugate, or pharmaceutical composition described herein is administered to a subject suffering from angiotensinogen disorder-related disease or a subject at risk of suffering from angiotensinogen disorder-related disease. In one embodiment, the subject is a human.

[1138] In one embodiment, the disease associated with angiotensinogen dysregulation is selected from hypertension or a related condition (e.g., borderline hypertension, essential hypertension, secondary hypertension, hypertensive crisis, hypertensive urgency, isolated systolic and diastolic hypertension, pregnancy-related hypertension, diabetic hypertension, resistant hypertension, refractory hypertension, paroxysmal hypertension, renovascular hypertension, Goldblatt's hypertension, ocular hypertension, pulmonary hypertension, portal hypertension, systemic venous hypertension, systolic hypertension, unstable hypertension, hypertensive heart disease, and hypertensive nephropathy).

[1139] In another embodiment, the disease associated with angiotensinogen dysregulation is selected from the group consisting of hypertension, hypertensive heart disease, and hypertensive nephropathy.

[1140] A subject with normal blood pressure is one with a blood pressure of approximately 90-119 mmHg (approximately 12-15.9 kPa (kN / m 2 )) systolic pressure and about 60-79 mmHg (about 8.0-10.5 kPa (kN / m 2 )) diastolic blood pressure; a subject with prehypertension is one with a diastolic blood pressure of about 120-139 mmHg (about 16.1-18.5 kPa (kN / m 2 )) systolic pressure and about 60-79 mmHg (about 8.0-10.5 kPa (kN / m 2 )) diastolic blood pressure; a subject with hypertension (e.g., stage I hypertension) is one with a diastolic blood pressure of about 140-159 mmHg (about 18.7-21.2 kPa (kN / m 2 )) systolic pressure and about 90-99 mmHg (about 12.0-13.2 kPa (kN / m 2)) diastolic blood pressure; a subject with hypertension (e.g., stage II hypertension) is one with a diastolic blood pressure of about ≥160 mmHg (about ≥21.3 kPa (kN / m 2 )) systolic blood pressure and approximately ≥100 mmHg (approximately ≥13.3 kPa (kN / m 2 )) Subjects with diastolic blood pressure greater than 130 / 80 mmHg along with type 1 or type 2 diabetes or kidney disease were considered to have hypertension.

[1141] In one embodiment, the disease associated with angiotensinogen dysregulation is essential hypertension."Essential hypertension"is the result of environmental or genetic factors (eg, the result without an obvious underlying medical cause).

[1142] In one embodiment, the angiotensinogen dysregulation-related disease is secondary hypertension. "Secondary hypertension" has an identifiable underlying disorder that can be of various etiologies, including renal, vascular, and endocrine causes, for example, renal parenchymal disease (e.g., polycystic kidney disease, glomerular or interstitial disease), renal vascular disease (e.g., renal artery stenosis, fibromuscular dysplasia), endocrine disorders (e.g., adrenocortical or mineralocorticoid excess, pheochromocytoma, hyperthyroidism or hypothyroidism, growth hormone excess, hyperparathyroidism), aortic coarctation, or oral contraceptive use.

[1143] In one embodiment, the angiotensinogen disorder-related disease is a hypertensive crisis, such as malignant hypertension and rapid hypertension. "Rapid hypertension" is a severely elevated blood pressure (i.e., a systolic blood pressure of 180 mmHg or higher or a diastolic blood pressure of 110 mmHg) that causes direct damage to one or more end organs. Blood pressure must be immediately lowered to prevent further organ damage. "Malignant hypertension" is a severely elevated blood pressure (a systolic blood pressure of 180 mmHg or higher or a diastolic blood pressure of 110 mmHg) that causes direct damage to one or more end organs and papilledema. Blood pressure must be immediately lowered to prevent further organ damage. Neurological end-organ damage due to uncontrolled blood pressure can include hypertensive encephalopathy, cerebrovascular accident / cerebral infarction; subarachnoid hemorrhage, and / or intracranial hemorrhage. Cardiovascular end-organ...

Claims

1. A siRNA for inhibiting the expression of angiotensinogen, comprising a sense strand and an antisense strand, wherein: The antisense strand comprises at least 19 consecutive nucleotides that differ from any of the antisense strand sequences shown in Table 1 by no more than 3 nucleotides.

2. The siRNA according to claim 1, wherein The antisense strand comprises a terminal overhang of 1-4 nucleotides in length at the 3' end.

3. The siRNA according to claim 1 or 2, wherein The number of nucleotides in the sense strand is 16-25.

4. The siRNA according to any one of claims 1 to 3, wherein The antisense strand has at most four mismatches with the target sequence as shown in SEQ ID NO: 1, and preferably the antisense strand has at most two mismatches with the target sequence.

5. The siRNA according to any one of claims 1 to 4, wherein The nucleotides from positions 16 to 23 in the 5' to 3' direction of the antisense strand have at most one mismatch with the target sequence, and preferably the nucleotide at position 20 in the 5' to 3' direction of the antisense strand has a mismatch with the target sequence.

6. The siRNA according to any one of claims 1 to 5, wherein The sense strand has at most one mismatch with the antisense strand, and preferably there is no mismatch with the antisense strand.

7. The siRNA of any one of claims 1-6, wherein the antisense strand in the siRNA differs from any one of SEQ ID NOs: 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74 by no more than 1 nucleotide.

8. The siRNA according to any one of claims 1 to 6, wherein The antisense strand comprises a sequence selected from any one of SEQ ID NOs: 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, 90, 92, 94, 96, 98, 100, 102, 104, 106, 109, 111, 113, 115, 117, 119, 121, 123, 125, 127, 129, 131, 133, 135, 137, 139, 141, 143.

9. The siRNA according to any one of claims 1 to 8, wherein The siRNA is an unmodified duplex selected from any one of duplexes 1 to 27.

10. The siRNA according to any one of claims 1 to 9, wherein The siRNA comprises at least one modified nucleotide or nucleotide analog.

11. The siRNA according to claim 10, wherein All nucleotides in the sense strand and / or antisense strand are modified nucleotides or nucleotide analogs, wherein the modified nucleotides are at least one selected from 2'-methoxy nucleotides, 2'-fluoro nucleotides, 2'-deoxy nucleotides, 2'-methoxyethyl nucleotides, 2'-amino nucleotides, 2'-alkyl nucleotides, 3'-methoxy nucleotides, (E)-vinyl phosphate-modified nucleotides, (Z)-vinyl phosphate-modified nucleotides, thiophosphate-modified nucleotides, Sp-configured thiophosphate-modified nucleotides, Rp-configured thiophosphate-modified nucleotides or methylsulfonylaminophosphoric acid-modified nucleotides, and the nucleotide analogs include locked nucleic acids, unlocked nucleic acids or glycerol nucleic acids.

12. The siRNA according to any one of claims 1 to 11, wherein A portion of adjacent nucleotides in the sense strand and / or antisense strand are connected by thiophosphate groups. Preferably, at least one of the nucleotides at positions 1 and 2 at the 5' end of the sense strand, the nucleotides at positions 2 and 3 at the 5' end of the sense strand, the nucleotides at positions 1 and 2 at the 3' end of the antisense strand, the nucleotides at positions 2 and 3 at the 3' end of the antisense strand, the nucleotides at positions 1 and 2 at the 5' end of the antisense strand, and the nucleotides at positions 2 and 3 at the 5' end of the antisense strand is connected by a thiophosphate group, a thiophosphate group of Rp configuration, or a thiophosphate group of Sp configuration.

13. The siRNA according to any one of claims 1 to 12, wherein The antisense strand has four, five, six or seven nucleotides that are 2'-fluoro nucleotides, and the 2'-fluoro nucleotides are selected from the 2nd, 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 14th, 16th, 18th, 20th, 21st, and optionally 22nd positions from the 5' end to the 3' end of the antisense strand, and the nucleotides at positions 2, 6, 14 and 16 are all 2'-fluoro nucleotides.

14. The siRNA according to any one of claims 1 to 12, wherein The antisense strand has the following modified nucleotides: (1) The nucleotides at positions 2, 6, 7, 14, 16, and 22 from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides; the nucleotides at other positions of the antisense strand may be 2'-methoxy nucleotides; the nucleotide at position 1 from the 5' end to the 3' end of the antisense strand further has an (E)-VP modification; (2) The nucleotides at positions 2, 6, 14, and 16 from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides; one or two of the nucleotides at positions 4, 8, 9, 10, 18, and 20 from the 5' end to the 3' end of the antisense strand may further be 2'-fluoro nucleotides; the nucleotides at other positions of the antisense strand are 2'-methoxy nucleotides; (3) The nucleotides at positions 2, 6, 14, 16 from the 5' end to the 3' end and the nucleotides at position 2 from the 3' end to the 5' end of the antisense strand are 2'-fluoro nucleotides; one or two of the nucleotides at positions 3, 4, 5, 7, 8, 9, 10, 12, and 20 from the 5' end to the 3' end of the antisense strand may further be 2'-fluoro nucleotides; the nucleotides at other positions of the antisense strand are 2'-methoxy nucleotides; the nucleotide at position 1 from the 5' end to the 3' end of the antisense strand may further have an (E)-VP modification; (4) The nucleotides at positions 2, 6, 7, 14, and 16 from the 5' end to the 3' end and the nucleotide at position 2 from the 3' end to the 5' end of the antisense strand are 2'-fluoro nucleotides; the nucleotide at position 10 from the 5' end to the 3' end of the antisense strand may further be a 2'-fluoro nucleotide; the nucleotides at other positions of the antisense strand may further be 2'-fluoro nucleotides. The nucleotide at the dot is a 2'-methoxy nucleotide; the first nucleotide from the 5' end to the 3' end of the antisense strand further has an (E)-VP modification; (5) The nucleotides at positions 2, 14, and 16 from the 5' end to the 3' end and the nucleotides at position 2 from the 3' end to the 5' end of the antisense strand are 2'-fluoro nucleotides; one of the nucleotides at positions 4, 8, and 9 from the 5' end to the 3' end of the antisense strand may further be a 2'-fluoro nucleotide; the nucleotides at other positions of the antisense strand are 2'-methoxy nucleotides; (6) The nucleotides at positions 2, 6, and 14 from the 5' end to the 3' end and the nucleotide at position 2 from the 3' end to the 5' end of the antisense strand are 2'-fluoro nucleotides; one of the nucleotides at positions 4, 8, 9, and 18 from the 5' end to the 3' end of the antisense strand may further be a 2'-fluoro nucleotide; the nucleotides at other positions of the antisense strand are 2'-methoxy nucleotides; or (7) The nucleotides at positions 6, 14, and 16 from the 5' end to the 3' end and the nucleotide at position 2 from the 3' end to the 5' end of the antisense chain are 2'-fluoro nucleotides; one of the nucleotides at positions 4, 8, 9, and 18 from the 5' end to the 3' end of the antisense chain can further be a 2'-fluoro nucleotide; the nucleotides at other positions of the antisense chain are 2'-methoxy nucleotides.

15. The siRNA according to any one of claims 1 to 14, wherein The nucleotides at positions 9, 11, 12, 13, and 15 from the 3' end to the 5' end of the sense chain are 2'-fluoro nucleotides, the nucleotides at other positions of the sense chain are 2'-methoxy nucleotides, and the nucleotides at positions 19 and 20, and the nucleotides at positions 20 and 21 from the 3' end to the 5' end of the sense chain are connected by thiophosphate groups, and the nucleotides at positions 2, 6, 7, 14, 16, and 22 from the 5' end to the 3' end of the antisense chain are 2'-fluoro nucleotides, the nucleotides at other positions of the antisense chain are 2'-methoxy nucleotides, the nucleotide at position 1 from the 5' end to the 3' end of the antisense chain further has an (E)-VP modification, and the nucleotides at positions 1 and 2, nucleotides at positions 2 and 3, nucleotides at positions 21 and 22, and nucleotides at positions 22 and 23 from the 5' end to the 3' end of the antisense chain are connected by thiophosphate groups.

16. The siRNA according to any one of claims 1 to 12, wherein The siRNA is at least one selected from modified duplex 46 to modified duplex 50, modified duplex 60 to modified duplex 125, modified duplex 129 to modified duplex 130, modified duplex 133 to modified duplex 149, and modified duplex 152 to modified duplex 201.

17. The siRNA according to claim 16, wherein The siRNA is at least one selected from modified duplex 46, modified duplex 61 to modified duplex 64 and modified duplex 66 to modified duplex 116, modified duplex 117 to modified duplex 125, modified duplex 129 to modified duplex 130, modified duplex 133 to modified duplex 136, modified duplex 155 to modified duplex 157, modified duplex 162, modified duplex 166, modified duplex 171 to modified duplex 172, and modified duplex 181 to modified duplex 198.

18. A siRNA conjugate, wherein: The siRNA conjugate is obtained by conjugating the siRNA according to any one of claims 1 to 17 with a conjugation molecule.

19. The siRNA conjugate according to claim 18, wherein The conjugate molecule comprises: Preferably, the structure of the conjugate is as follows: The conjugated molecule is covalently conjugated to the 3' end of the sense strand of the siRNA in the manner shown in the above formula.

20. The siRNA conjugate according to claim 18 or 19, wherein The siRNA conjugate is at least one selected from conjugates 46 to 50, conjugates 60 to 125, conjugates 129 to 130, conjugates 133 to 136, conjugates 150 to 151, and conjugates 155 to 204; preferably, the siRNA conjugate is at least one selected from conjugates 150, 151, 155, 156, 157, 162, and 163. More preferably, the siRNA conjugate is at least one selected from conjugate 155, conjugate 156, conjugate 157, conjugate 162, conjugate 171, conjugate 172, conjugate 175, conjugate 181, conjugate 182, conjugate 183, conjugate 184, and conjugate 185; more preferably, the siRNA conjugate is at least one selected from conjugate 155, conjugate 156, conjugate 157, conjugate 162, conjugate 171, conjugate 172, conjugate 175, conjugate 182, conjugate 183, and conjugate 184.

21. The siRNA conjugate according to claim 18 or 19, wherein The siRNA conjugate comprises a sense strand and an antisense strand, wherein the antisense strand comprises the following sequence in which all nucleotides are modified nucleotides: UACUCAUUAGAAGAAAAGGX1GGG (SEQ ID NO: 396) Where X1 is A or U, The nucleotides at positions 2, 6, 14, 16, and 22 from the 5' end to the 3' end of the antisense strand are 2'-fluoro nucleotides; the nucleotides at positions 7 or 7 and 10 from the 5' end to the 3' end of the antisense strand may further be 2'-fluoro nucleotides; the nucleotides at other positions of the antisense strand are 2'-methoxy nucleotides; The first nucleotide in the direction from the 5' end to the 3' end of the antisense strand further has an (E)-VP modification; There are phosphorothioate groups between the first and second nucleotides and between the second and third nucleotides at the 5' end of the antisense strand, and between the first and second nucleotides and between the second and third nucleotides at the 3' end.

22. The siRNA conjugate of claim 21, wherein The antisense strand comprises the following sequence in the 5' to 3' direction: (E)-VPmU*i2FA*mCmUmCi2FAX2mUmAX3mAmAmGi2FAmAi2FAmAmGmGmX4mG*i2FG*mG, wherein X2 is mU or i2FU, X3 is mG or i2FG, and X4 is A or U.

23. The siRNA conjugate of claim 22, wherein: The sense strand comprises the following sequence in the 5' to 3' direction: mC*mX5*mCmCmUmUi2FUmUi2FCi2FUi2FUmCi2FUmAmAmUmGmAmGmUmAGalNAc(L96), wherein X5 is A or U.

24. A pharmaceutical composition, wherein The pharmaceutical composition contains the siRNA according to any one of claims 1 to 17 or the siRNA conjugate according to any one of claims 18 to 23 as an active ingredient and a pharmaceutically acceptable carrier.

25. A kit, wherein: The kit contains at least one of the siRNA according to any one of claims 1 to 17, the siRNA conjugate according to any one of claims 18 to 23, and the pharmaceutical composition according to claim 24.

26. A method for preventing and / or treating angiotensinogen disorder-related diseases, the method comprising administering at least one of the siRNA according to any one of claims 1 to 17, the siRNA conjugate according to any one of claims 18 to 23, and the pharmaceutical composition according to claim 24 to a subject in need thereof, preferably, the angiotensinogen disorder-related disease is selected from hypertension or related disorders.

27. Use of at least one of the siRNA according to any one of claims 1 to 17, the siRNA conjugate according to any one of claims 18 to 23, and the pharmaceutical composition according to claim 24 in the preparation of a medicament for preventing and / or treating angiotensinogen disorder-related diseases, preferably, the angiotensinogen disorder-related diseases are selected from hypertension or related disorders.

28. The method of claim 26 or the use of claim 27, wherein The hypertension or related conditions are selected from at least one of critical hypertension, essential hypertension, secondary hypertension, hypertensive crisis, hypertensive emergency state, isolated systolic and diastolic hypertension, pregnancy-related hypertension, diabetic hypertension, resistant hypertension, refractory hypertension, paroxysmal hypertension, renovascular hypertension, Goldblatt's hypertension, ocular hypertension, pulmonary hypertension, portal hypertension, systemic venous hypertension, systolic hypertension and unstable hypertension, hypertensive heart disease, and hypertensive nephropathy.