Treatment of MST1-related diseases and disorders

Abstract

Disclosed herein is a composition comprising an oligonucleotide targeting MST1. The oligonucleotide may comprise a small interfering RNA (siRNA) or an antisense oligonucleotide (ASO). Also provided herein is a method for treating a condition associated with an MST1 mutant, comprising providing a subject with an oligonucleotide targeting MST1.

Description

[Technical Field]

[0001] cross reference This application claims the benefit of U.S. Provisional Patent Application No. 63 / 432,918, filed December 15, 2022, U.S. Provisional Patent Application No. 63 / 582,783, filed September 14, 2023, and U.S. Provisional Patent Application No. 63 / 584,461, filed September 21, 2023, all of which are incorporated herein by reference in their entirety.

[0002] INCORPORATION BY REFERENCE OF SEQUENCE LISTING This application is filed with an electronic Sequence Listing, which is provided as a file titled 54462-747_601_SL.xml, created November 10, 2023, and 12,534,167 bytes in size. The information in the electronic format of the Sequence Listing is incorporated herein by reference in its entirety. [Background technology]

[0003] Pulmonary disorders are a common problem that can affect a wide variety of individuals. Improved therapies are needed to treat these disorders. Summary of the Invention

[0004] In certain aspects herein, a composition is disclosed comprising an siRNA targeting MST1, wherein the siRNA comprises a sense strand and an antisense strand, and the siRNA comprises a sense strand comprising any one of SEQ ID NOs: 6600 to 6631 or 6696 to 6707, or an antisense strand comprising any one of SEQ ID NOs: 6632 to 6683 or 6708 to 6719. In some embodiments, the sense sequence comprises SEQ ID NO: 6616, 6446, 6602, 6448, 6476, 6603, 6611, 6612, or 6707, and the antisense sequence comprises SEQ ID NO: 6648, 6505, 6635, 6507, 6535, 6634, 6643, 6644, or 6719. In some embodiments, the sense sequence comprises a sequence selected from the group consisting of 6552, 6214, 6539, 6216, 6244, 6538, 6547, 6548, and 6683. In some embodiments, the antisense sequence comprises a sequence selected from the group consisting of 6584, 6273, 6571, 6275, 6303, 6570, 6579, 6580, and 6695. In some embodiments, the oligonucleotide comprises a modified internucleoside linkage. In some embodiments, the modified internucleoside linkage comprises an alkyl phosphonate, phosphorothioate, methyl phosphonate, phosphorodithioate, alkyl phosphonothioate, phosphoramidate, carbamate, carbonate, phosphate triester, acetamidate, or carboxymethyl ester, or a combination thereof. In some embodiments, the modified internucleoside linkage comprises one or more phosphorothioate linkages. In some embodiments, the oligonucleotide comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 modified internucleoside linkages. In some embodiments, the oligonucleotide comprises a modified nucleoside. In some embodiments, the modified nucleoside comprises a locked nucleic acid (LNA), a hexitol nucleic acid (HNA), a cyclohexene nucleic acid (CeNA), a 2'-methoxyethyl, a 2'-O-alkyl, a 2'-O-allyl, a 2'-O-allyl, a 2'-fluoro, or a 2'-deoxy, or a combination thereof. In some embodiments, the modified nucleoside comprises an LNA.In some embodiments, the modified nucleoside comprises a 2',4' constrained ethyl nucleic acid. In some embodiments, the modified nucleoside comprises a 2'-O-methyl nucleoside, a 2'-deoxyfluoro nucleoside, a 2'-ON-methylacetamide (2'-O-NMA) nucleoside, a 2'-O-dimethylaminoethoxyethyl (2'-O-DMAEOE) nucleoside, a 2'-O-aminopropyl (2'-O-AP) nucleoside, or 2'-ara-F, or a combination thereof. In some embodiments, the modified nucleoside comprises one or more 2'-fluoro modified nucleosides. In some embodiments, the modified nucleoside comprises a 2'-O-alkyl modified nucleoside. In some embodiments, the oligonucleotide comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 modified nucleosides. In some embodiments, the oligonucleotide comprises a lipid attached at the 3' or 5' end of the oligonucleotide. In some embodiments, the lipid comprises cholesterol, myristoyl, palmitoyl, stearoyl, lithocholoyl, docosanoyl, docosahexaenoyl, myristyl, palmitylstearyl, or α-tocopherol, or a combination thereof. In some embodiments, the oligonucleotide comprises a sugar moiety attached at the 3' or 5' end of the oligonucleotide. In some embodiments, the sugar comprises N-acetylgalactosamine (GalNAc), N-acetylglucosamine (GlcNAc), or mannose. In some embodiments, the sugar moiety

[0005] [ka] wherein J is an oligonucleotide and J comprises an optional phosphate or phosphorothioate linked to the oligonucleotide. In some embodiments, the oligonucleotide comprises an integrin targeting ligand attached at the 3' or 5' end of the oligonucleotide. In some embodiments, the integrin comprises integrin α-v-β-6. In some embodiments, the integrin targeting ligand comprises an arginine-glycine-aspartic acid (RGD) peptide. In some embodiments, with respect to the sense strand, any one of the following is true: all purines comprise 2'-fluoro modified purines and all pyrimidines comprise a mixture of 2'-fluoro and 2'-methyl modified pyrimidines; all purines comprise 2'-methyl modified purines and all pyrimidines comprise a mixture of 2'-fluoro and 2'-methyl modified pyrimidines; all purines comprise 2'-fluoro modified purines and all pyrimidines comprise 2'-methyl modified pyrimidines; all pyrimidines comprise 2'-fluoro modified pyrimidines and all purines comprise a mixture of 2'-fluoro and 2'-methyl modified purines; all pyrimidines comprise 2'-methyl modified pyrimidines and all purines comprise a mixture of 2'-fluoro and 2'-methyl modified purines; or all pyrimidines comprise 2'-fluoro modified pyrimidines and all purines comprise 2'-methyl modified purines. In some embodiments, with respect to the sense strand, (a) all purines comprise fluoro-modified purines and all pyrimidines comprise (i) a mixture of 2'-O-methyl and 2'-O-methoxyethyl modified pyrimidines, or (ii) a mixture of 2'-fluoro, 2'-O-methyl and 2'-O-methoxyethyl modified pyrimidines; (b) all purines comprise 2'-O-methyl modified purines and all pyrimidines comprise (i) a mixture of 2'-fluoro and 2'-O-methoxyethyl modified pyrimidines, or (ii) a mixture of 2'-fluoro, 2'-O-methyl and 2'-O-methoxyethyl modified pyrimidines; (c) all purines comprise 2'-O-methoxyethyl modified purines and all pyrimidines comprise (i) a mixture of 2'-fluoro and 2'-O-methyl modified pyrimidines;or (ii) a mixture of 2'-fluoro, 2'-O-methyl, and 2'-O-methoxyethyl modified pyrimidines; (d) a mixture of all purines and all pyrimidines are (i) 2'-O-methoxyethyl modified pyrimidines, (ii) a mixture of 2'-O-methyl and 2'-O-methoxyethyl modified pyrimidines, (iii) a mixture of 2'-fluoro and 2'-O-methoxyethyl modified pyrimidines, or (iv) a mixture of 2'-fluoro, 2'-O-methyl, and 2'-O-methoxyethyl modified pyrimidines. (e) all purines comprise a mixture of 2'-fluoro and 2'-O-methoxyethyl modified purines and all pyrimidines in the sense strand comprise (i) 2'-O-methyl modified pyrimidines, (ii) a mixture of 2'-fluoro and 2'-O-methyl modified pyrimidines, (iii) a mixture of 2'-O-methyl and 2'-O-methoxyethyl modified pyrimidines, or (iv) a mixture of 2'-fluoro, 2'-O-methyl, and 2'-O-methoxyethyl modified pyrimidines; (f) all purines comprise a mixture of 2'-O-methyl and 2'-O-methoxyethyl modified pyrimidines. (ii) a mixture of 2'-fluoro and 2'-O-methyl modified pyrimidines, (iii) a mixture of 2'-fluoro and 2'-O-methoxyethyl modified pyrimidines, or (iv) a mixture of 2'-fluoro, 2'-O-methyl, and 2'-O-methoxyethyl modified pyrimidines; or (g) a mixture of all purines, 2'-fluoro, 2'-O-methyl, and 2'-O-methoxyethyl modified purines, and all pyrimidines are (i) 2'-fluoro (ii) a 2'-O-methyl modified pyrimidine, (iii) a 2'-O-methoxyethyl modified pyrimidine, (iv) a mixture of 2'-fluoro and 2'-O-methyl modified pyrimidines, (v) a mixture of 2'-O-methyl and 2'-O-methoxyethyl modified pyrimidines, (vi) a mixture of 2'-fluoro and 2'-O-methoxyethyl modified pyrimidines, or (vii) a mixture of 2'-fluoro, 2'-O-methyl and 2'-O-methoxyethyl modified pyrimidines, and in any of the foregoingIt is assumed that the sense strand may contain 2'-deoxynucleosides. In some embodiments, the antisense strand is one of the following: all purines are 2'-fluoro-modified purines and all pyrimidines are a mixture of 2'-fluoro and 2'-methyl-modified pyrimidines; all purines are 2'-methyl-modified purines and all pyrimidines are a mixture of 2'-fluoro and 2'-methyl-modified pyrimidines; all purines are 2'-methyl-modified purines and all pyrimidines are 2'-fluoro-modified pyrimidines; all pyrimidines are 2'-fluoro-modified pyrimidines and all purines are a mixture of 2'-fluoro and 2'-methyl-modified purines; all pyrimidines are 2'-methyl-modified pyrimidines and all purines are a mixture of 2'-fluoro and 2'-methyl-modified purines; all pyrimidines are 2'-methyl-modified pyrimidines and all purines are a mixture of 2'-fluoro and 2'-methyl-modified purines; or all pyrimidines are 2'-methyl-modified pyrimidines and all purines are 2'-fluoro-modified purines.

[0006] In a specific embodiment herein, a composition is disclosed comprising an siRNA targeting MST1, wherein the siRNA comprises a sense strand and an antisense strand, and the sense strand comprises a modification pattern selected from the group consisting of 36S, 37S, 38S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, and 48S, or the antisense strand comprises a modification pattern selected from the group consisting of 2AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, and 37AS. In some embodiments, the composition further comprises a sense strand comprising any one of SEQ ID NOs: 1-3024, 6317, 6358-6387, 6418-6476, 6600-6631, or 6696-6707, or an antisense strand comprising any one of SEQ ID NOs: 3025-6048, 6318, 6388-6417, 6477-6535, 6632-6683, or 6708-6719.

[0007] In certain aspects herein, a composition is described comprising an siRNA targeting MST1, wherein the siRNA comprises a sense strand and an antisense strand, and the siRNA comprises a sense strand comprising any one of SEQ ID NOs: 6672 to 6683 or 6526 to 6567, or an antisense strand comprising any one of SEQ ID NOs: 6568 to 6599 or 6684 to 6695. In some embodiments, the sense sequence comprises SEQ ID NO: 6616, 6446, 6602, 6448, 6476, 6603, 6611, 6612, or 6707, and the antisense sequence comprises SEQ ID NO: 6648, 6505, 6635, 6507, 6535, 6634, 6643, 6644, or 6719. In some embodiments, the sense sequence comprises a sequence selected from the group consisting of 6552, 6214, 6539, 6216, 6244, 6538, 6547, 6548, and 6683. In some embodiments, the antisense sequence comprises a sequence selected from the group consisting of 6584, 6273, 6571, 6275, 6303, 6570, 6579, 6580, and 6695. Disclosed herein in some embodiments is a composition comprising an oligonucleotide as described herein, which, when administered to a subject in an effective amount, increases a pulmonary function measurement. In some embodiments, the pulmonary function measurement comprises a forced expiratory volume in one second (FEV1) measurement, a predicted forced expiratory volume fraction in one second (FEV1pp) measurement, a forced vital capacity (FVC) measurement, an FEV1 / FVC ratio measurement, a forced expiratory volume, or a peak expiratory flow measurement. In some embodiments, the pulmonary function measurement increases by about 10% or more compared to before administration. Some embodiments described herein provide compositions comprising an oligonucleotide described herein that, when administered to a subject in an effective amount, reduce white blood cell counts. In some embodiments, the white blood cell counts include lung white blood cell counts. In some embodiments, the white blood cell counts include circulating white blood cell counts. In some embodiments, the white blood cell counts include neutrophil counts, eosinophil counts, basophil counts, monocyte counts, macrophages counts, lymphocyte counts, or neutrophil-lymphocyte ratio counts, or combinations thereof. In some embodiments, the white blood cell counts are reduced by about 10% or more compared to pre-administration levels.Some embodiments described herein provide compositions comprising an oligonucleotide described herein, which, when administered to a subject in an effective amount, reduce a measure of chronic obstructive pulmonary disease (COPD) or asthma exacerbation or symptom. In some embodiments, the measure of COPD or asthma exacerbation or symptom is reduced by about 10% or more compared to before administration. In some embodiments, the composition further comprises a pharmaceutically acceptable carrier. In some embodiments, the composition, when administered to a subject, does not affect safety or toxicity measures in the subject. Some embodiments described herein provide methods for treating a subject suffering from a pulmonary disorder, comprising administering to the subject an effective amount of a composition described herein. In some embodiments, the pulmonary disorder includes COPD, acute exacerbation of COPD, emphysema, chronic bronchitis, asthma, status asthmaticus, asthma-COPD overlap syndrome (ACOS), bronchiectasis, cough, dyspnea, mucus hypersecretion, lung cancer, interstitial lung disease, or pulmonary fibrosis. [Brief explanation of the drawings]

[0008] The novel features of the present disclosure are set forth with particularity in the appended claims. The features and advantages of the present disclosure will be better understood by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the disclosure are utilized, and the accompanying drawings.

[0009] [Figure 1A] FIG. 1 shows a Western blot for MST1 protein. [Figure 1B] Figure 1 shows secreted MST1 protein by ELISA assay. DETAILED DESCRIPTION OF THE INVENTION

[0010] Large-scale human genetic data has the potential to improve the success rate of pharmaceutical discovery and development. Genome-wide association studies (GWAS) can identify associations between genetic variants and traits in population samples. GWAS can enable a better understanding of disease biology and may inform applicable treatments. GWAS can utilize genotyping and / or sequencing data and often involve the evaluation of millions of genetic variants that are relatively evenly distributed across the genome. The most common GWAS design is a case-control study, which involves comparing variant frequencies in cases and controls. If the frequency of a variant differs significantly between cases and controls, the variant is said to be associated with disease. Association statistics that can be used in GWAS include the p-value, which is a measure of statistical significance; the odds ratio (OR), which is a measure of effect size; or the beta coefficient (beta), which is also a measure of effect size. Researchers often calculate allelic odds ratios assuming an additive genetic model, which are the increased (or decreased) disease risk conferred by each additional copy of an allele (compared to having no copies of that allele). An additional concept in the design and interpretation of GWAS is that of linkage disequilibrium, the selective association of alleles. The presence of linkage disequilibrium can obscure which variants are "causative."

[0011] Functional annotation of variants and / or wet-lab experiments can identify causative gene variants identified through GWAS, often leading to the identification of disease-causing genes. In particular, understanding the functional effect of the causative gene variant (e.g., loss of protein function, gain of protein function, increased gene expression, or decreased gene expression) can enable the variant to be used instead for therapeutic modulation of a target gene or to gain insight into the potential therapeutic efficacy and safety of treatments that modulate that target.

[0012] Identifying such gene-disease associations provides insights into disease biology, which can be used to identify novel therapeutic targets for the pharmaceutical industry. To translate therapeutic insights derived from human genetics, a patient's disease biology can be exogenously "programmed" to replicate observations from human genetics. There are several potential therapeutic modalities that can be utilized in translating therapeutic targets identified through human genetics into novel medicines. These may include well-established therapeutic modalities such as small molecules and monoclonal antibodies, mature modalities such as oligonucleotides, and emerging modalities such as gene therapy and gene editing. The choice of therapeutic modality may depend on several factors, including the location of the target (e.g., intracellular, extracellular, or secreted), the relevant tissue (e.g., lung or liver), and the relevant indication.

[0013] The MST1 (macrophage-stimulating 1) gene is located on chromosome 3 and encodes macrophage-stimulating protein (MSP), also known as hepatocyte growth factor-like protein (HLP, HGFL, or HGFLP). MSP is also sometimes referred to as MST1 protein. The MST1 gene can encode various transcripts or splice variants. MSP can contain 711 amino acids and have a mass of approximately 80.3 kDa. MSP can be cleaved into alpha and beta chains. MSP can be cytoplasmic. MSP can be secreted. MSP can interact with the macrophage-stimulating protein receptor, encoded by MST1R (macrophage-stimulating 1 receptor). MST1 can be expressed in liver cells, such as hepatocytes. Secreted MSP can bind to or interact with the macrophage-stimulating protein receptor in the lung. MSP can stimulate pulmonary cilia motility. MST1 can be expressed in lung cells. An example MSP amino acid sequence, and further description of MSP, is included at uniprot.org under accession number P26927 (last revised May 15, 2007).

[0014] Here, we show that genetic variants that can result in loss of function of the MST1 gene in humans are associated with a reduced risk of chronic obstructive pulmonary disease (COPD), a family history of COPD, asthma, and the use of inhaled beta-agonist medications. Therefore, inhibition of MST1 or MST1 may serve as a therapeutic strategy for treating pulmonary disorders such as COPD, acute exacerbations of COPD, emphysema, chronic bronchitis, asthma, status asthmaticus, asthma-COPD overlap syndrome (ACOS), bronchiectasis, cough, dyspnea, mucus hypersecretion, lung cancer, interstitial lung disease, or pulmonary fibrosis.

[0015] Disclosed herein are methods or compositions for inhibiting or targeting MST1 or MSP. Where inhibition or targeting of MST1 is disclosed, it is contemplated that some embodiments may include inhibiting or targeting MSP, and vice versa. For example, by inhibiting or targeting RNA (e.g., mRNA) encoded by the MST1 gene using the oligonucleotides described herein, MSP can be inhibited or targeted as a result of less MSP being produced by translation of MST1 RNA, or MSP can be targeted or inhibited by an oligonucleotide that binds to or interacts with MST1 RNA to reduce the production of MSP from MST1 RNA. Thus, targeting MST1 can refer to binding to MST1 RNA and reducing MST1 RNA or MSP levels. The oligonucleotide may comprise a small interfering RNA (siRNA) or an antisense oligonucleotide (ASO). Also provided herein is a method for treating a lung disorder by providing an oligonucleotide targeting MST1 to a subject in need of such treatment.

[0016] This paper discloses the results that show that MST1 siRNA treatment in mouse inflammatory disease model reduces inflammation.Also disclosed is the primate test that shows safety and tolerability in healthy subjects.Therefore, the compositions described herein can be useful for treating inflammatory disorders without causing toxicity to the subjects suffering from disorders.

[0017] I. Composition 1. Some embodiments disclosed herein include compositions comprising oligonucleotides. In some embodiments, the compositions include an oligonucleotide targeting MST1. In some embodiments, the compositions consist of an oligonucleotide targeting MST1. In some embodiments, the oligonucleotide reduces expression of MST1 mRNA in a subject. In some embodiments, the oligonucleotide reduces expression of MSP in a subject. The oligonucleotide may comprise a small interfering RNA (siRNA) described herein. The oligonucleotide may comprise an antisense oligonucleotide (ASO) described herein. In some embodiments, the compositions described herein are used in a method of treating a disorder in a subject in need thereof. Some embodiments relate to compositions comprising oligonucleotides for use in a method of treating a disorder described herein. Some embodiments relate to the use of a composition comprising an oligonucleotide in a method of treating a disorder described herein. In some embodiments, the siRNA comprises a sense strand comprising any one of SEQ ID NOs: 6600-6631 or 6696-6707, or an antisense strand comprising any one of SEQ ID NOs: 6632-6683 or 6708-6719. In some embodiments, the sense strand comprises a modification pattern selected from the group consisting of 36S, 37S, 38S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, and 48S, or the antisense strand comprises a modification pattern selected from the group consisting of 2AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, and 37AS. In some embodiments, the sense strand comprises a modification pattern selected from the group consisting of 36S, 37S, 38S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, and 48S, or the antisense strand comprises a modification pattern selected from the group consisting of 2AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, and 37AS.

[0018] Some embodiments include compositions comprising an oligonucleotide that targets MST1 and, when administered to a subject in an effective amount, reduces MST1 mRNA or MSP levels in a cell, fluid, or tissue. In some embodiments, the compositions comprise an oligonucleotide that targets MST1 and, when administered to a subject in an effective amount, reduces MST1 mRNA levels in a cell or tissue. In some embodiments, the cell is a liver cell or hepatocyte. In some embodiments, the cell is a lung cell, a lung epithelial cell, a type I or II pneumocyte, a macrophage, an alveolar macrophage, a goblet cell, a club cell, or a fibroblast. In some embodiments, the tissue is liver tissue. In some embodiments, the tissue is lung tissue. In some embodiments, the MST1 mRNA level is reduced by about 2.5% or more, about 5% or more, or about 7.5% or more compared to before administration. In some embodiments, the MST1 mRNA level is reduced by about 10% or more compared to before administration. In some embodiments, the MST1 mRNA level is reduced by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100% compared to before administration. In some embodiments, the MST1 mRNA level is reduced by up to about 2.5%, up to about 5%, or up to about 7.5% compared to before administration. In some embodiments, the MST1 mRNA level is reduced by up to about 10% compared to before administration. In some embodiments, the MST1 mRNA level is reduced by up to about 20%, up to about 30%, up to about 40%, up to about 50%, up to about 60%, up to about 70%, up to about 80%, or up to about 90% compared to before administration. In some embodiments, MST1 mRNA levels are reduced by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, or a range defined by any two of the foregoing percentages.

[0019] In some embodiments, the composition comprises an oligonucleotide that targets MST1 and, when administered to a subject in an effective amount, reduces MSP levels in a cell, fluid, or tissue. In some embodiments, the cell is a liver cell or hepatocyte. In some embodiments, the cell is a lung cell, a lung epithelial cell, a type I or II pneumocyte, a macrophage, an alveolar macrophage, a goblet cell, a club cell, or a fibroblast. In some embodiments, the tissue is liver tissue. In some embodiments, the tissue is lung tissue. In some embodiments, the fluid is a blood, serum, or plasma sample. In some embodiments, the fluid is a lung fluid, such as bronchoalveolar fluid. In some embodiments, the MSP level is reduced by about 2.5% or more, about 5% or more, or about 7.5% or more compared to before administration. In some embodiments, the MSP level is reduced by about 10% or more compared to before administration. In some embodiments, MSP levels are reduced by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100% compared to before administration. In some embodiments, MSP levels are reduced by up to about 2.5%, up to about 5%, or up to about 7.5% compared to before administration. In some embodiments, MSP levels are reduced by up to about 10% compared to before administration. In some embodiments, MSP levels are reduced by up to about 20%, up to about 30%, up to about 40%, up to about 50%, up to about 60%, up to about 70%, up to about 80%, or up to about 90% compared to before administration. In some embodiments, MSP levels are reduced by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, or a range defined by any two of the foregoing percentages.

[0020] In some embodiments, the composition comprises an oligonucleotide that targets MST1 and, when administered to a subject in an effective amount, reduces a detrimental phenotype of a pulmonary disorder in the subject. The pulmonary disorder may include chronic obstructive pulmonary disease (COPD), acute exacerbation of COPD, emphysema, chronic bronchitis, asthma, status asthmaticus, asthma-COPD overlap syndrome (ACOS), bronchiectasis, cough, dyspnea, mucus hypersecretion, lung cancer, interstitial lung disease, or pulmonary fibrosis. In some embodiments, the detrimental phenotype is reduced by at least about 2.5%, at least about 5%, or at least about 7.5% compared to pre-administration. In some embodiments, the detrimental phenotype is reduced by at least about 10% compared to pre-administration. In some embodiments, the detrimental phenotype is reduced by at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or at least about 100% compared to pre-administration. In some embodiments, the adverse phenotype is reduced by up to about 2.5%, up to about 5%, or up to about 7.5% compared to before administration. In some embodiments, the adverse phenotype is reduced by up to about 10% compared to before administration. In some embodiments, the adverse phenotype is reduced by up to about 20%, up to about 30%, up to about 40%, up to about 50%, up to about 60%, up to about 70%, up to about 80%, or up to about 90% compared to before administration. In some embodiments, the adverse phenotype is reduced by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, or a range defined by any two of the foregoing percentages.

[0021] In some embodiments, the composition comprises an oligonucleotide that targets MST1 and, when administered to a subject in an effective amount, enhances a protective phenotype in a pulmonary disorder. The pulmonary disorder may include chronic obstructive pulmonary disease (COPD), acute exacerbation of COPD, emphysema, chronic bronchitis, asthma, status asthmaticus, asthma-COPD overlap syndrome (ACOS), bronchiectasis, cough, dyspnea, mucus hypersecretion, lung cancer, interstitial lung disease, or pulmonary fibrosis. In some embodiments, the protective phenotype is increased by about 2.5% or more, about 5% or more, or about 7.5% or more compared to pre-administration. In some embodiments, the protective phenotype is increased by about 10% or more compared to pre-administration. In some embodiments, the protective phenotype is increased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100% or more compared to pre-administration. In some embodiments, the protective phenotype is increased by about 200% or more, about 300% or more, about 400% or more, about 500% or more, about 600% or more, about 700% or more, about 800% or more, about 900% or more, or about 1000% or more compared to before administration. In some embodiments, the protective phenotype is increased by up to about 2.5%, up to about 5%, or up to about 7.5% compared to before administration. In some embodiments, the protective phenotype is increased by up to about 10% compared to before administration. In some embodiments, the protective phenotype is increased by up to about 20%, up to about 30%, up to about 40%, up to about 50%, up to about 60%, up to about 70%, up to about 80%, up to about 90%, or up to about 100% compared to before administration. In some embodiments, the protective phenotype is increased by up to about 200%, up to about 300%, up to about 400%, up to about 500%, up to about 600%, up to about 700%, up to about 800%, up to about 900%, or up to about 1000% compared to before administration. In some embodiments, the protective phenotype is increased by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 250%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, or 1000%, or a range defined by any two of the foregoing percentages.

[0022] In some embodiments, the composition comprises an oligonucleotide that targets MST1 and, when administered to a subject in an effective amount, improves (i.e., increases) a pulmonary function measure. The pulmonary function measure may include a measure of forced expiratory volume in 1 second (FEV1), predicted forced expiratory volume in 1 second (FEV1pp), forced vital capacity (FVC), FEV1 / FVC ratio, forced expiratory volume, or peak expiratory flow. In some embodiments, the pulmonary function measure improves by about 2.5% or more, about 5% or more, or about 7.5% or more compared to before administration. In some embodiments, the pulmonary function measure improves by about 10% or more compared to before administration. In some embodiments, the pulmonary function measure improves by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100% or more compared to before administration. In some embodiments, pulmonary function measurements improve by about 200% or more, about 300% or more, about 400% or more, about 500% or more, about 600% or more, about 700% or more, about 800% or more, about 900% or more, or about 1000% or more compared to before administration. In some embodiments, pulmonary function measurements improve by up to about 2.5%, up to about 5%, or up to about 7.5% compared to before administration. In some embodiments, pulmonary function measurements improve by up to about 10% compared to before administration. In some embodiments, pulmonary function measurements improve by up to about 20%, up to about 30%, up to about 40%, up to about 50%, up to about 60%, up to about 70%, up to about 80%, up to about 90%, or up to about 100% compared to before administration. In some embodiments, pulmonary function measurements improve by up to about 200%, up to about 300%, up to about 400%, up to about 500%, up to about 600%, up to about 700%, up to about 800%, up to about 900%, or up to about 1000% compared to before administration. In some embodiments, the pulmonary function measurement improves by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 250%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, or 1000%, or a range defined by any two of the foregoing percentages.

[0023] White blood cell counts can be affected by lung disorders. For example, some inflammatory lung disorders, which may include chronic obstructive pulmonary disease (COPD) or asthma, can result in inflammation and an increase in circulating white blood cell counts, which can be treated using a composition comprising an oligonucleotide, or the lung inflammation associated with a lung disorder can include an increase in white blood cells in lung tissue or lung fluid (e.g., bronchoalveolar fluid). In some embodiments, the composition comprises an oligonucleotide that targets MST1 and, when administered to a subject in an effective amount, alters white blood cell counts in the subject's cells, fluid, or tissue. In some embodiments, the cell is a liver cell or hepatocyte. In some embodiments, the cell is a lung cell, a lung epithelial cell, a type I or II pneumocyte, a macrophage, an alveolar macrophage, a goblet cell, a club cell, or a fibroblast. In some embodiments, the tissue is liver tissue. In some embodiments, the tissue is lung tissue. In some embodiments, the fluid is a blood, serum, or plasma sample. In some embodiments, the fluid is a lung fluid, such as bronchoalveolar fluid. The change can be a decrease (e.g., when circulating levels of white blood cells or white blood cell levels in the lungs are elevated due to an inflammatory lung disorder). The change can be an increase, in some embodiments. In some embodiments, the white blood cell measurement changes by about 2.5% or more, about 5% or more, or about 7.5% or more compared to before administration. In some embodiments, the white blood cell measurement changes by about 10% or more compared to before administration. In some embodiments, the white blood cell measurement changes by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, or about 80% or more compared to before administration. In some embodiments, the white blood cell measurement changes by up to about 2.5%, up to about 5%, or up to about 7.5% compared to before administration. In some embodiments, the white blood cell measurement changes by up to about 10% compared to before administration. In some embodiments, the white blood cell measurement changes by up to about 20%, up to about 30%, up to about 40%, up to about 50%, up to about 60%, up to about 70%, up to about 80%, or up to about 90% compared to before administration.In some embodiments, the white blood cell measurement changes by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90%, or a range defined by any two of the foregoing percentages.

[0024] In some embodiments, the composition comprises an oligonucleotide that targets MST1 and, when administered to a subject in an effective amount, reduces exacerbations of chronic obstructive pulmonary disease (COPD) in the subject. In some embodiments, COPD exacerbations are reduced by about 2.5% or more, about 5% or more, or about 7.5% or more compared to pre-administration. In some embodiments, COPD exacerbations are reduced by about 10% or more compared to pre-administration. In some embodiments, COPD exacerbations are reduced by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100% compared to pre-administration. In some embodiments, COPD exacerbations are reduced by up to about 2.5%, up to about 5%, or up to about 7.5% compared to pre-administration. In some embodiments, COPD exacerbations are reduced by up to about 10% compared to pre-administration. In some embodiments, COPD exacerbations are reduced by up to about 20%, up to about 30%, up to about 40%, up to about 50%, up to about 60%, up to about 70%, up to about 80%, or up to about 90% compared to before administration. In some embodiments, COPD exacerbations are reduced by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, or a range defined by any two of the foregoing percentages.

[0025] In some embodiments, the composition comprises an oligonucleotide that targets MST1 and, when administered to a subject in an effective amount, reduces asthma exacerbations in the subject. In some embodiments, asthma exacerbations are reduced by about 2.5% or more, about 5% or more, or about 7.5% or more compared to before administration. In some embodiments, asthma exacerbations are reduced by about 10% or more compared to before administration. In some embodiments, asthma exacerbations are reduced by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100% compared to before administration. In some embodiments, asthma exacerbations are reduced by up to about 2.5%, up to about 5%, or up to about 7.5% compared to before administration. In some embodiments, asthma exacerbations are reduced by up to about 10% compared to before administration. In some embodiments, asthma exacerbations are reduced by up to about 20%, up to about 30%, up to about 40%, up to about 50%, up to about 60%, up to about 70%, up to about 80%, or up to about 90% compared to before administration, hi some embodiments, asthma exacerbations are reduced by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, or a range defined by any two of the foregoing percentages.

[0026] A. siRNA In some embodiments, the composition comprises an oligonucleotide targeting MST1, wherein the oligonucleotide comprises a small interfering RNA (siRNA). In some embodiments, the composition comprises an oligonucleotide targeting MST1, wherein the oligonucleotide comprises a small interfering RNA (siRNA) comprising a sense strand and an antisense strand.

[0027] In some embodiments, the composition comprises an oligonucleotide that inhibits MST1 expression, the oligonucleotide comprising an siRNA comprising a sense strand and an antisense strand, the sense strand being 12-30 nucleosides in length. In some embodiments, the composition comprises a sense strand that is 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleosides in length, or a range defined by any two of the foregoing numbers. The sense strand can be 14-30 nucleosides in length. In some embodiments, the composition comprises an antisense strand that is 12-30 nucleosides in length. In some embodiments, the composition comprises an antisense strand that is 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleosides in length, or a range defined by any two of the foregoing numbers. The antisense strand can be 14 to 30 nucleosides in length.

[0028] In some embodiments, the compositions comprise oligonucleotides that inhibit expression of MST1, wherein the oligonucleotides comprise siRNAs comprising a sense strand and an antisense strand, each strand independently being about 12-30 nucleosides in length, and at least one of the sense and antisense strands comprises a nucleoside sequence comprising about 12-30 contiguous nucleosides of a full-length human MST1 mRNA sequence, such as SEQ ID NO: 6163. In some embodiments, at least one of the sense and antisense strands comprises a nucleoside sequence comprising at least about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or more contiguous nucleosides of one of SEQ ID NO: 6163.

[0029] In some embodiments, the compositions comprise oligonucleotides that inhibit expression of MST1, wherein the oligonucleotides comprise siRNAs comprising a sense strand and an antisense strand, each strand independently being about 12-30 nucleosides in length, and at least one of the sense and antisense strands comprises a nucleoside sequence comprising about 12-30 contiguous nucleosides of a full-length human MST1 mRNA sequence, such as SEQ ID NO: 6185. In some embodiments, at least one of the sense and antisense strands comprises a nucleoside sequence comprising at least about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or more contiguous nucleosides of one of SEQ ID NO: 6185.

[0030] In some embodiments, the composition comprises the oligonucleotide that inhibits the expression of MST1, wherein the oligonucleotide comprises siRNA that comprises sense strand and antisense strand, and the sense strand and antisense strand form double-stranded RNA duplex.In some embodiments, the first base pair of the double-stranded RNA duplex is AU base pair.

[0031] In some embodiments, the sense strand further comprises a 3' overhang. In some embodiments, the 3' overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range defined by any two of the foregoing numbers. In some embodiments, the 3' overhang comprises 1, 2, or more nucleosides. In some embodiments, the 3' overhang comprises 2 nucleosides. In some embodiments, the sense strand further comprises a 5' overhang. In some embodiments, the 5' overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range defined by any two of the foregoing numbers. In some embodiments, the 5' overhang comprises 1, 2, or more nucleosides. In some embodiments, the 5' overhang comprises 2 nucleosides.

[0032] In some embodiments, the antisense strand further comprises a 3' overhang. In some embodiments, the 3' overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range defined by any two of the foregoing numbers. In some embodiments, the 3' overhang comprises 1, 2, or more nucleosides. In some embodiments, the 3' overhang comprises 2 nucleosides. In some embodiments, the antisense strand further comprises a 5' overhang. In some embodiments, the 5' overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range defined by any two of the foregoing numbers. In some embodiments, the 5' overhang comprises 1, 2, or more nucleosides. In some embodiments, the 5' overhang comprises 2 nucleosides.

[0033] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of MST1, the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, and the siRNA binds to the 19-mer of human MST1 mRNA.In some embodiments, the siRNA binds to the 12-mer, 13-mer, 14-mer, 15-mer, 16-mer, 17-mer, 18-mer, 19-mer, 20-mer, 21-mer, 22-mer, 23-mer, 24-mer or 25-mer of human MST1 mRNA.

[0034] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of MST1, the oligonucleotide comprises an siRNA that comprises a sense strand and an antisense strand, and the siRNA binds to the 17-mer of non-human primate MST1 mRNA.In some embodiments, the siRNA binds to the 12-mer, 13-mer, 14-mer, 15-mer, 16-mer, 17-mer, 18-mer, 19-mer, 20-mer, 21-mer, 22-mer, 23-mer, 24-mer or 25-mer of non-human primate MST1 mRNA.

[0035] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of MST1, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the siRNA binds to human MST1 mRNA and 20 or fewer human off-targets, with no more than two mismatches in the antisense strand. In some embodiments, the siRNA binds to human MST1 mRNA and 10 or fewer human off-targets, with no more than two mismatches in the antisense strand. In some embodiments, the siRNA binds to human MST1 mRNA and 30 or fewer human off-targets, with no more than two mismatches in the antisense strand. In some embodiments, the siRNA binds to human MST1 mRNA and 40 or fewer human off-targets, with no more than two mismatches in the antisense strand. In some embodiments, the siRNA binds to human MST1 mRNA and 50 or fewer human off-targets, with no more than two mismatches in the antisense strand. In some embodiments, the siRNA binds to human MST1 mRNA and 10 or fewer human off-targets, with no more than three mismatches in the antisense strand. In some embodiments, the siRNA binds to human MST1 mRNA and 20 or fewer human off-targets with no more than 3 mismatches in the antisense strand. In some embodiments, the siRNA binds to human MST1 mRNA and 30 or fewer human off-targets with no more than 3 mismatches in the antisense strand. In some embodiments, the siRNA binds to human MST1 mRNA and 40 or fewer human off-targets with no more than 3 mismatches in the antisense strand. In some embodiments, the siRNA binds to human MST1 mRNA and 50 or fewer human off-targets with no more than 3 mismatches in the antisense strand.

[0036] In some embodiments, the composition comprises an oligonucleotide that inhibits MST1 expression, the oligonucleotide comprising an siRNA comprising a sense strand and an antisense strand, the siRNA binding to a human MST1 mRNA target site that does not contain a single nucleotide polymorphism (SNP), and the minor allele frequency (MAF) is 1% or greater (pos. 2-18). In some embodiments, the MAF is about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20% or greater.

[0037] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of MST1, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises a nucleoside sequence comprising or consisting of any one of SEQ ID NOs: 1-3024, or a nucleic acid sequence thereof having one or two nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises a nucleoside sequence comprising or consisting of any one of SEQ ID NOs: 1-3024, or a nucleic acid sequence thereof having three or four nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand further comprises a 3' overhang. In some embodiments, the 3' overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range defined by any two of the foregoing numbers. In some embodiments, the 3' overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides. In some embodiments, the 3' overhang comprises two nucleosides. In some embodiments, the sense strand further comprises a 5' overhang. In some embodiments, the 5' overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range defined by any two of the foregoing numbers. In some embodiments, the 5' overhang comprises one, two, or more nucleosides. In some embodiments, the 5' overhang comprises two nucleosides. In some embodiments, the sense strand comprises a nucleoside sequence comprising or consisting of any one of SEQ ID NOs: 1-3024, or a nucleic acid sequence thereof having one or two additional nucleosides at the 3' end. In some embodiments, the composition comprises an oligonucleotide that inhibits expression of MST1, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, and the sense strand comprises a nucleoside sequence comprising or consisting of any one of SEQ ID NOs: 1-3024. The sense or antisense strand can include any of the modifications described herein. The sense or antisense strand can include a lipid moiety or a GalNAc moiety.

[0038] In some embodiments, the composition comprises an oligonucleotide that inhibits expression of MST1, the oligonucleotide comprising an siRNA comprising a sense strand and an antisense strand, wherein the antisense strand comprises a nucleoside sequence comprising or consisting of any one of SEQ ID NOs: 3025-6048, or a nucleic acid sequence thereof having one or two nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises a nucleoside sequence comprising or consisting of any one of SEQ ID NOs: 3025-6048, or a nucleic acid sequence thereof having three or four nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand further comprises a 3' overhang. In some embodiments, the 3' overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range defined by any two of the foregoing numbers. In some embodiments, the 3' overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides. In some embodiments, the 3' overhang comprises two nucleosides. In some embodiments, the antisense strand further comprises a 5' overhang. In some embodiments, the 5' overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range defined by any two of the foregoing numbers. In some embodiments, the 5' overhang comprises one, two, or more nucleosides. In some embodiments, the 5' overhang comprises two nucleosides. In some embodiments, the antisense strand comprises a nucleoside sequence comprising or consisting of any one of SEQ ID NOs: 3025-6048, or a nucleic acid sequence thereof having one or two additional nucleosides at the 3' end. In some embodiments, the composition comprises an oligonucleotide that inhibits expression of MST1, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, and the antisense strand comprises a nucleoside sequence comprising or consisting of any one of SEQ ID NOs: 3025 to 6048. The sense strand or the antisense strand can include any modification described herein.The sense or antisense strand can include a lipid moiety or a GalNAc moiety.

[0039] In some embodiments, the composition comprises an oligonucleotide that inhibits expression of MST1, the oligonucleotide comprising an siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises a nucleoside sequence comprising or consisting of any one of SEQ ID NOs: 6358-6397, or a nucleic acid sequence thereof having one or two nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises a nucleoside sequence comprising or consisting of any one of SEQ ID NOs: 6358-6397, or a nucleic acid sequence thereof having three or four nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand further comprises a 3' overhang. In some embodiments, the 3' overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range defined by any two of the foregoing numbers. In some embodiments, the 3' overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides. In some embodiments, the 3' overhang comprises two nucleosides. In some embodiments, the sense strand further comprises a 5' overhang. In some embodiments, the 5' overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range defined by any two of the foregoing numbers. In some embodiments, the 5' overhang comprises one, two, or more nucleosides. In some embodiments, the 5' overhang comprises two nucleosides. In some embodiments, the sense strand comprises a nucleoside sequence comprising or consisting of any one of SEQ ID NOs: 6358-6397, or a nucleic acid sequence thereof having one or two nucleoside additions at the 3' end. In some embodiments, the composition comprises an oligonucleotide that inhibits expression of MST1, the oligonucleotide comprising an siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises a nucleoside sequence comprising or consisting of any one of SEQ ID NOs: 6358-6397. The sense strand or antisense strand may comprise any modification described herein. The sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety.

[0040] In some embodiments, the composition comprises an oligonucleotide that inhibits expression of MST1, the oligonucleotide comprising an siRNA comprising a sense strand and an antisense strand, wherein the antisense strand comprises a nucleoside sequence comprising or consisting of any one of SEQ ID NOs: 6398-6417, or a nucleic acid sequence thereof having one or two nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises a nucleoside sequence comprising or consisting of any one of SEQ ID NOs: 6398-6417, or a nucleic acid sequence thereof having three or four nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand further comprises a 3' overhang. In some embodiments, the 3' overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range defined by any two of the foregoing numbers. In some embodiments, the 3' overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides. In some embodiments, the 3' overhang comprises two nucleosides. In some embodiments, the antisense strand further comprises a 5' overhang. In some embodiments, the 5' overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range defined by any two of the foregoing numbers. In some embodiments, the 5' overhang comprises one, two, or more nucleosides. In some embodiments, the 5' overhang comprises two nucleosides. In some embodiments, the antisense strand comprises a nucleoside sequence comprising or consisting of any one of SEQ ID NOs: 6398-6417, or a nucleic acid sequence thereof having one or two additional nucleosides at the 3' end. In some embodiments, the composition comprises an oligonucleotide that inhibits expression of MST1, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the antisense strand comprises a nucleoside sequence comprising or consisting of any one of SEQ ID NOs: 6398 to 6417. The sense strand or the antisense strand can include any modification described herein.The sense or antisense strand can include a lipid moiety or a GalNAc moiety.

[0041] In some embodiments, the siRNA comprises the sense and / or antisense strand sequence of an siRNA in any one of Tables 3-8, or a nucleic acid sequence thereof having three or four nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense and / or antisense strand sequence of an siRNA in any one of Tables 3-8, or a nucleic acid sequence thereof having one or two nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense and / or antisense strand sequence of an siRNA in any one of Tables 3-8. In some embodiments, the siRNA is cross-reactive with non-human primate (NHP) MST1 mRNA. The sense or antisense strand may comprise any modification described herein. The sense or antisense strand may comprise a lipid moiety or a GalNAc moiety.

[0042] In some embodiments, the siRNA comprises a sense strand sequence in Table 24B or a nucleic acid sequence thereof with three or four nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises a sense strand sequence in Table 24B or a nucleic acid sequence thereof with one or two nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises a sense strand sequence in Table 24B. The sense strand comprises any of these sequences and may include an overhang, such as a 3'UU overhang. The sense strand may include any modification described herein. The sense strand may include a lipid moiety or a GalNAc moiety. In some embodiments, the siRNA comprises an antisense strand sequence in Table 24B or a nucleic acid sequence thereof with three or four nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises an antisense strand sequence in Table 24B or a nucleic acid sequence thereof with one or two nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sequence of the antisense strand in Table 24B. The antisense strand may comprise any of these sequences and may comprise an overhang, such as a 3'UU overhang. The antisense strand may comprise any modification described herein. The antisense strand may comprise a lipid moiety or a GalNAc moiety.

[0043] In some embodiments, the siRNA comprises a sense strand sequence in Table 24D, or a nucleic acid sequence thereof with three or four nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises a sense strand sequence in Table 24D, or a nucleic acid sequence thereof with one or two nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises a sense strand sequence in Table 24D. The sense strand comprises any of these sequences and may include an overhang, such as a 3'UU overhang. The sense strand may include any modification described herein. The sense strand may include a lipid moiety or a GalNAc moiety. In some embodiments, the siRNA comprises an antisense strand sequence in Table 24D, or a nucleic acid sequence thereof with three or four nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises an antisense strand sequence in Table 24D, or a nucleic acid sequence thereof with one or two nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sequence of the antisense strand in Table 24D. The antisense strand may comprise any of these sequences and may comprise an overhang, such as a 3'UU overhang. The antisense strand may comprise any modification described herein. The antisense strand may comprise a lipid moiety or a GalNAc moiety.

[0044] In some embodiments, the siRNA comprises a sense strand sequence in Table 33B or a nucleic acid sequence thereof with three or four nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises a sense strand sequence in Table 33B or a nucleic acid sequence thereof with one or two nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises a sense strand sequence in Table 33B. The sense strand comprises any of these sequences and may include an overhang, such as a 3'UU overhang. The sense strand may include any modification described herein. The sense strand may include a lipid moiety or a GalNAc moiety. In some embodiments, the siRNA comprises an antisense strand sequence in Table 33B or a nucleic acid sequence thereof with three or four nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises an antisense strand sequence in Table 33B or a nucleic acid sequence thereof with one or two nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sequence of the antisense strand in Table 33B. The antisense strand may comprise any of these sequences and may include an overhang, such as a 3'UU overhang. The antisense strand may include any modification described herein. The antisense strand may include a lipid moiety or a GalNAc moiety.

[0045] In some embodiments, the siRNA comprises a sense strand sequence in Table 36B or a nucleic acid sequence thereof with three or four nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises a sense strand sequence in Table 36B or a nucleic acid sequence thereof with one or two nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises a sense strand sequence in Table 36B. The sense strand comprises any of these sequences and may include an overhang, such as a 3'UU overhang. The sense strand may include any modification described herein. The sense strand may include a lipid moiety or a GalNAc moiety. In some embodiments, the siRNA comprises an antisense strand sequence in Table 36B or a nucleic acid sequence thereof with three or four nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises an antisense strand sequence in Table 36B or a nucleic acid sequence thereof with one or two nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sequence of the antisense strand in Table 36B. The antisense strand may comprise any of these sequences and may include an overhang, such as a 3'UU overhang. The antisense strand may include any modification described herein. The antisense strand may include a lipid moiety or a GalNAc moiety.

[0046] In some embodiments, the siRNA comprises a sense strand sequence in Table 39B or a nucleic acid sequence thereof with three or four nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises a sense strand sequence in Table 39B or a nucleic acid sequence thereof with one or two nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises a sense strand sequence in Table 39B. The sense strand comprises any of these sequences and may include an overhang, such as a 3'UU overhang. The sense strand may include any modification described herein. The sense strand may include a lipid moiety or a GalNAc moiety. In some embodiments, the siRNA comprises an antisense strand sequence in Table 39B or a nucleic acid sequence thereof with three or four nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises an antisense strand sequence in Table 39B or a nucleic acid sequence thereof with one or two nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sequence of the antisense strand in Table 39B. The antisense strand may comprise any of these sequences and may include an overhang, such as a 3'UU overhang. The antisense strand may include any modification described herein. The antisense strand may include a lipid moiety or a GalNAc moiety.

[0047] In some embodiments, the siRNA comprises a sense strand sequence in Table 42B or a nucleic acid sequence thereof with three or four nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises a sense strand sequence in Table 42B or a nucleic acid sequence thereof with one or two nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises a sense strand sequence in Table 42B. The sense strand comprises any of these sequences and may include an overhang, such as a 3'UU overhang. The sense strand may include any modification described herein. The sense strand may include a lipid moiety or a GalNAc moiety. In some embodiments, the siRNA comprises an antisense strand sequence in Table 42B or a nucleic acid sequence thereof with three or four nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises an antisense strand sequence in Table 42B or a nucleic acid sequence thereof with one or two nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sequence of the antisense strand in Table 42B. The antisense strand may comprise any of these sequences and may include an overhang, such as a 3'UU overhang. The antisense strand may include any modification described herein. The antisense strand may include a lipid moiety or a GalNAc moiety.

[0048] In some embodiments, the siRNA comprises a sense strand sequence in Table 57B or a nucleic acid sequence thereof with three or four nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises a sense strand sequence in Table 57B or a nucleic acid sequence thereof with one or two nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises a sense strand sequence in Table 57B. The sense strand comprises any of these sequences and may include an overhang, such as a 3'UU overhang. The sense strand may include any modification described herein. The sense strand may include a lipid moiety or a GalNAc moiety. In some embodiments, the siRNA comprises an antisense strand sequence in Table 57B or a nucleic acid sequence thereof with three or four nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises an antisense strand sequence in Table 57B or a nucleic acid sequence thereof with one or two nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sequence of the antisense strand in Table 57B. The antisense strand may comprise any of these sequences and may include an overhang, such as a 3'UU overhang. The antisense strand may include any modification described herein. The antisense strand may include a lipid moiety or a GalNAc moiety.

[0049] In some embodiments, the siRNA comprises a sense strand sequence in Table 71B or a nucleic acid sequence thereof with three or four nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises a sense strand sequence in Table 71B or a nucleic acid sequence thereof with one or two nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises a sense strand sequence in Table 71B. The sense strand comprises any of these sequences and may include an overhang, such as a 3'UU overhang. The sense strand may include any modification described herein. The sense strand may include a lipid moiety or a GalNAc moiety. In some embodiments, the siRNA comprises an antisense strand sequence in Table 71B or a nucleic acid sequence thereof with three or four nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises an antisense strand sequence in Table 71B or a nucleic acid sequence thereof with one or two nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sequence of the antisense strand in Table 71B. The antisense strand may comprise any of these sequences and may include an overhang, such as a 3'UU overhang. The antisense strand may include any modification described herein. The antisense strand may include a lipid moiety or a GalNAc moiety.

[0050] In some embodiments, the siRNA comprises the sense and / or antisense strand sequences of the siRNA in Table 84B or Table 84C, or nucleic acid sequences thereof with three or four nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense and / or antisense strand sequences of the siRNA in Table 84B or Table 84C, or nucleic acid sequences thereof with one or two nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense and / or antisense strand sequences of the siRNA in Table 84B or Table 84C. In some embodiments, the siRNA is cross-reactive with non-human primate (NHP) MST1 mRNA. The sense or antisense strand may comprise any modification described herein. The sense or antisense strand may comprise a lipid moiety or a GalNAc moiety.

[0051] The siRNA may comprise the sense strand and / or antisense strand base sequence of the siRNA in any of the tables contained herein (e.g., unmodified sequence or base sequence with other modifications), or may comprise the nucleic acid sequence with one or two nucleoside substitutions, additions, or deletions, or may comprise the nucleic acid sequence with three or four nucleoside substitutions, additions, or deletions. In some cases, the sequence does not comprise the overhang (e.g., UU) contained in the table.

[0052] In some embodiments, the siRNA comprises the sense and / or antisense strand sequences of siRNAs of subset A, or nucleic acid sequences thereof with 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense and / or antisense strand sequences of siRNAs of subset A, or nucleic acid sequences thereof with 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense and / or antisense strand sequences of siRNAs of subset A. In some embodiments, the siRNA is cross-reactive with non-human primate (NHP) MST1 mRNA. The sense or antisense strand may comprise any modification described herein. The sense or antisense strand may comprise a lipid moiety or a GalNAc moiety.

[0053] In some embodiments, the siRNA comprises the sense and / or antisense strand sequence of an siRNA of subset B, or a nucleic acid sequence thereof having three or four nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense and / or antisense strand sequence of an siRNA of subset B, or a nucleic acid sequence thereof having one or two nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense and / or antisense strand sequence of an siRNA of subset B. In some embodiments, the siRNA is cross-reactive with non-human primate (NHP) MST1 mRNA. The sense or antisense strand may comprise any modification described herein. The sense or antisense strand may comprise a lipid moiety or a GalNAc moiety.

[0054] In some embodiments, the siRNA comprises the sense and / or antisense strand sequence of an siRNA of subset C, or a nucleic acid sequence thereof having three or four nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense and / or antisense strand sequence of an siRNA of subset C, or a nucleic acid sequence thereof having one or two nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense and / or antisense strand sequence of an siRNA of subset C. In some embodiments, the siRNA is cross-reactive with non-human primate (NHP) MST1 mRNA. The sense or antisense strand may comprise any modification described herein. The sense or antisense strand may comprise a lipid moiety or a GalNAc moiety.

[0055] In some embodiments, the siRNA comprises the sense and / or antisense strand sequences of siRNAs of subset D, or nucleic acid sequences thereof having three or four nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense and / or antisense strand sequences of siRNAs of subset D, or nucleic acid sequences thereof having one or two nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense and / or antisense strand sequences of siRNAs of subset D. In some embodiments, the siRNA is cross-reactive with non-human primate (NHP) MST1 mRNA. The sense or antisense strand may comprise any modification described herein. The sense or antisense strand may comprise a lipid moiety or a GalNAc moiety.

[0056] In some embodiments, the siRNA comprises the sense and / or antisense strand sequences of siRNAs of subset E, or nucleic acid sequences thereof with 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense and / or antisense strand sequences of siRNAs of subset E, or nucleic acid sequences thereof with 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense and / or antisense strand sequences of siRNAs of subset E. In some embodiments, the siRNA is cross-reactive with non-human primate (NHP) MST1 mRNA. The sense or antisense strand may comprise any modification described herein. The sense or antisense strand may comprise a lipid moiety or a GalNAc moiety.

[0057] In some embodiments, the siRNA comprises the sense and / or antisense strand sequences of siRNAs of subset F, or nucleic acid sequences thereof having three or four nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense and / or antisense strand sequences of siRNAs of subset F, or nucleic acid sequences thereof having one or two nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense and / or antisense strand sequences of siRNAs of subset F. In some embodiments, the siRNA is cross-reactive with non-human primate (NHP) MST1 mRNA. The sense or antisense strand may comprise any modification described herein. The sense or antisense strand may comprise a lipid moiety or a GalNAc moiety.

[0058] In some embodiments, the siRNA comprises a sense strand having a sequence according to any of SEQ ID NOs: 6373, 6375, 6385, 6386, or 6387. In some embodiments, the sense strand sequence comprises or consists of a sequence that is at least 75% identical to any one of SEQ ID NOs: 6373, 6375, 6385, 6386, or 6387; at least 80% identical to any one of SEQ ID NOs: 6373, 6375, 6385, 6386, or 6387; at least 85% identical to any one of SEQ ID NOs: 6373, 6375, 6385, 6386, or 6387; at least 90% identical to any one of SEQ ID NOs: 6373, 6375, 6385, 6386, or 6387; or at least 95% identical to any one of SEQ ID NOs: 6373, 6375, 6385, 6386, or 6387. In some embodiments, the sense strand sequence comprises or consists of the sequence of any one of SEQ ID NOs: 6373, 6375, 6385, 6386, or 6387, or a sense strand sequence thereof with one, two, three, or four nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of the sequence of any one of SEQ ID NOs: 6373, 6375, 6385, 6386, or 6387, or a sense strand sequence thereof with one or two nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NO: 6373, 6375, 6385, 6386, or 6387. The sense strand sequence can include the first 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 nucleotides (in the 5' to 3' direction) of any of the aforementioned sequences. The sense strand sequence can include the last 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 nucleotides (in the 5' to 3' direction) of any of the aforementioned sequences. The sense strand can include a modification pattern described herein. The sense strand can include an overhang. The sense strand can include a lipid moiety. The sense strand can include a GalNAc moiety.

[0059] In some embodiments, the siRNA comprises an antisense strand having a sequence according to any of SEQ ID NOs: 6403, 6405, 6415, 6416, or 6417. In some embodiments, the antisense strand sequence comprises or consists of a sequence that is at least 75% identical to any one of SEQ ID NOs: 6403, 6405, 6415, 6416, or 6417; at least 80% identical to any one of SEQ ID NOs: 6403, 6405, 6415, 6416, or 6417; at least 85% identical to any one of SEQ ID NOs: 6403, 6405, 6415, 6416, or 6417; at least 90% identical to any one of SEQ ID NOs: 6403, 6405, 6415, 6416, or 6417; or at least 95% identical to any one of SEQ ID NOs: 6403, 6405, 6415, 6416, or 6417. In some embodiments, the antisense strand sequence comprises or consists of the sequence of any one of SEQ ID NOs: 6403, 6405, 6415, 6416, or 6417, or an antisense strand sequence thereof having one, two, three, or four nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of the sequence of any one of SEQ ID NOs: 6403, 6405, 6415, 6416, or 6417, or an antisense strand sequence thereof having one or two nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NO: 6403, 6405, 6415, 6416, or 6417. The antisense strand sequence may comprise the first 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 nucleotides (5' to 3' direction) of any of the aforementioned sequences. The antisense strand sequence may comprise the last 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 nucleotides (5' to 3' direction) of any of the aforementioned sequences. The antisense strand may comprise an overhang. The antisense strand may comprise a modification pattern described herein. The anti-antisense strand may comprise a lipid moiety or a GalNAc moiety.

[0060] In some embodiments, the siRNA comprises a sense strand having a sequence according to SEQ ID NO: 6373. In some embodiments, the sense strand sequence comprises or consists of a sequence that is at least 75% identical to SEQ ID NO: 6373, at least 80% identical to SEQ ID NO: 6373, at least 85% identical to SEQ ID NO: 6373, at least 90% identical to SEQ ID NO: 6373, or at least 95% identical to SEQ ID NO: 6373. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 6373, or a sense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 6373, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of a sequence that is 100% identical to SEQ ID NO: 6373. The sense strand may comprise a modification pattern described herein. The sense strand may comprise an overhang. The sense strand can include a lipid moiety. The sense strand can include a GalNAc moiety.

[0061] In some embodiments, the siRNA comprises a sense strand having a sequence according to SEQ ID NO: 6374. In some embodiments, the sense strand sequence comprises or consists of a sequence that is at least 75% identical to SEQ ID NO: 6374, at least 80% identical to SEQ ID NO: 6374, at least 85% identical to SEQ ID NO: 6374, at least 90% identical to SEQ ID NO: 6374, or at least 95% identical to SEQ ID NO: 6374. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 6374, or a sense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 6374, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of a sequence that is 100% identical to SEQ ID NO: 6374. The sense strand may comprise a modification pattern described herein. The sense strand may comprise an overhang. The sense strand can include a lipid moiety. The sense strand can include a GalNAc moiety.

[0062] In some embodiments, the siRNA comprises a sense strand having a sequence according to SEQ ID NO: 6385. In some embodiments, the sense strand sequence comprises or consists of a sequence that is at least 75% identical to SEQ ID NO: 6385, at least 80% identical to SEQ ID NO: 6385, at least 85% identical to SEQ ID NO: 6385, at least 90% identical to SEQ ID NO: 6385, or at least 95% identical to SEQ ID NO: 6385. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 6385, or a sense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 6385, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of a sequence that is 100% identical to SEQ ID NO: 6385. The sense strand may comprise a modification pattern described herein. The sense strand may comprise an overhang. The sense strand can include a lipid moiety. The sense strand can include a GalNAc moiety.

[0063] In some embodiments, the siRNA comprises a sense strand having a sequence according to SEQ ID NO: 6386. In some embodiments, the sense strand sequence comprises or consists of a sequence that is at least 75% identical to SEQ ID NO: 6386, at least 80% identical to SEQ ID NO: 6386, at least 85% identical to SEQ ID NO: 6386, at least 90% identical to SEQ ID NO: 6386, or at least 95% identical to SEQ ID NO: 6386. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 6386, or a sense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 6386, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of a sequence that is 100% identical to SEQ ID NO: 6386. The sense strand may comprise a modification pattern described herein. The sense strand may comprise an overhang. The sense strand can include a lipid moiety. The sense strand can include a GalNAc moiety.

[0064] In some embodiments, the siRNA comprises a sense strand having a sequence according to SEQ ID NO: 6387. In some embodiments, the sense strand sequence comprises or consists of a sequence that is at least 75% identical to SEQ ID NO: 6387, at least 80% identical to SEQ ID NO: 6387, at least 85% identical to SEQ ID NO: 6387, at least 90% identical to SEQ ID NO: 6387, or at least 95% identical to SEQ ID NO: 6387. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 6387, or a sense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 6387, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of a sequence that is 100% identical to SEQ ID NO: 6387. The sense strand may comprise a modification pattern described herein. The sense strand may comprise an overhang. The sense strand can include a lipid moiety. The sense strand can include a GalNAc moiety.

[0065] In some embodiments, the siRNA comprises an antisense strand having a sequence according to SEQ ID NO: 6403. In some embodiments, the antisense strand sequence comprises or consists of a sequence that is at least 75% identical to SEQ ID NO: 6403, at least 80% identical to SEQ ID NO: 6403, at least 85% identical to SEQ ID NO: 6403, at least 90% identical to SEQ ID NO: 6403, or at least 95% identical to SEQ ID NO: 6403. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 6403, or its antisense strand sequence having one, two, three, or four nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 6403, or its antisense strand sequence having one or two nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of a sequence that is 100% identical to SEQ ID NO: 6403. The antisense strand may contain a modification pattern described herein. The antisense strand may comprise an overhang. The antisense strand may comprise a lipid moiety. The antisense strand may comprise a GalNAc moiety.

[0066] In some embodiments, the siRNA comprises an antisense strand having a sequence according to SEQ ID NO: 6405. In some embodiments, the antisense strand sequence comprises or consists of a sequence that is at least 75% identical to SEQ ID NO: 6405, at least 80% identical to SEQ ID NO: 6405, at least 85% identical to SEQ ID NO: 6405, at least 90% identical to SEQ ID NO: 6405, or at least 95% identical to SEQ ID NO: 6405. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 6405, or its antisense strand sequence having one, two, three, or four nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 6405, or its antisense strand sequence having one or two nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of a sequence that is 100% identical to SEQ ID NO: 6405. The antisense strand may contain a modification pattern described herein. The antisense strand may comprise an overhang. The antisense strand may comprise a lipid moiety. The antisense strand may comprise a GalNAc moiety.

[0067] In some embodiments, the siRNA comprises an antisense strand having a sequence according to SEQ ID NO: 6415. In some embodiments, the antisense strand sequence comprises or consists of a sequence that is at least 75% identical to SEQ ID NO: 6415, at least 80% identical to SEQ ID NO: 6415, at least 85% identical to SEQ ID NO: 6415, at least 90% identical to SEQ ID NO: 6415, or at least 95% identical to SEQ ID NO: 6415. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 6415, or its antisense strand sequence having one, two, three, or four nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 6415, or its antisense strand sequence having one or two nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of a sequence that is 100% identical to SEQ ID NO: 6415. The antisense strand may contain a modification pattern described herein. The antisense strand may comprise an overhang. The antisense strand may comprise a lipid moiety. The antisense strand may comprise a GalNAc moiety.

[0068] In some embodiments, the siRNA comprises an antisense strand having a sequence according to SEQ ID NO: 6416. In some embodiments, the antisense strand sequence comprises or consists of a sequence that is at least 75% identical to SEQ ID NO: 6416, at least 80% identical to SEQ ID NO: 6416, at least 85% identical to SEQ ID NO: 6416, at least 90% identical to SEQ ID NO: 6416, or at least 95% identical to SEQ ID NO: 6416. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 6416, or its antisense strand sequence having one, two, three, or four nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 6416, or its antisense strand sequence having one or two nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of a sequence that is 100% identical to SEQ ID NO: 6416. The antisense strand may comprise a modification pattern described herein. The antisense strand may comprise an overhang. The antisense strand may comprise a lipid moiety. The antisense strand may comprise a GalNAc moiety.

[0069] In some embodiments, the siRNA comprises an antisense strand having a sequence according to SEQ ID NO: 6417. In some embodiments, the antisense strand sequence comprises or consists of a sequence that is at least 75% identical to SEQ ID NO: 6417, at least 80% identical to SEQ ID NO: 6417, at least 85% identical to SEQ ID NO: 6417, at least 90% identical to SEQ ID NO: 6417, or at least 95% identical to SEQ ID NO: 6417. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 6417 or its antisense strand sequence having one, two, three, or four nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 6417 or its antisense strand sequence having one or two nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of a sequence that is 100% identical to SEQ ID NO: 6417. The antisense strand may contain a modification pattern described herein. The antisense strand may comprise an overhang. The antisense strand may comprise a lipid moiety. The antisense strand may comprise a GalNAc moiety.

[0070] In some embodiments, the siRNA comprises a sense strand having a sequence according to SEQ ID NO: 6440. In some embodiments, the sense strand sequence comprises or consists of a sequence that is at least 75% identical to SEQ ID NO: 6440, at least 80% identical to SEQ ID NO: 6440, at least 85% identical to SEQ ID NO: 6440, at least 90% identical to SEQ ID NO: 6440, or at least 95% identical to SEQ ID NO: 6440. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 6440, or a sense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 6440, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of a sequence that is 100% identical to SEQ ID NO: 6440. The sense strand may comprise a modification pattern described herein. The sense strand may comprise an overhang. The sense strand may include a moiety such as a GalNAc moiety or a lipid moiety. In some embodiments, the siRNA comprises an antisense strand having a sequence according to SEQ ID NO: 6499. In some embodiments, the antisense strand sequence comprises or consists of a sequence that is at least 75% identical to SEQ ID NO: 6499, at least 80% identical to SEQ ID NO: 6499, at least 85% identical to SEQ ID NO: 6499, at least 90% identical to SEQ ID NO: 6499, or at least 95% identical to SEQ ID NO: 6499. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 6499 or its antisense strand sequence having one, two, three, or four nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 6499 or its antisense strand sequence having one or two nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of a sequence that is 100% identical to SEQ ID NO: 6499. The antisense strand may comprise a modification pattern as described herein. The antisense strand may comprise an overhang. The antisense strand may comprise a moiety such as a GalNAc moiety or a lipid moiety.

[0071] In some embodiments, the siRNA comprises a sense strand having a sequence according to SEQ ID NO: 6446. In some embodiments, the sense strand sequence comprises or consists of a sequence that is at least 75% identical to SEQ ID NO: 6446, at least 80% identical to SEQ ID NO: 6446, at least 85% identical to SEQ ID NO: 6446, at least 90% identical to SEQ ID NO: 6446, or at least 95% identical to SEQ ID NO: 6446. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 6446, or a sense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 6446, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of a sequence that is 100% identical to SEQ ID NO: 6446. The sense strand may comprise a modification pattern described herein. The sense strand may comprise an overhang. The sense strand may include a moiety such as a GalNAc moiety or a lipid moiety. In some embodiments, the siRNA comprises an antisense strand having a sequence according to SEQ ID NO: 6505. In some embodiments, the antisense strand sequence comprises or consists of a sequence that is at least 75% identical to SEQ ID NO: 6505, at least 80% identical to SEQ ID NO: 6505, at least 85% identical to SEQ ID NO: 6505, at least 90% identical to SEQ ID NO: 6505, or at least 95% identical to SEQ ID NO: 6505. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 6505, or its antisense strand sequence having one, two, three, or four nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 6505, or its antisense strand sequence having one or two nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of a sequence that is 100% identical to SEQ ID NO: 6505. The antisense strand may comprise a modification pattern as described herein. The antisense strand may comprise an overhang. The antisense strand may comprise a moiety such as a GalNAc moiety or a lipid moiety.

[0072] In some embodiments, the siRNA comprises a sense strand having a sequence according to SEQ ID NO: 6447. In some embodiments, the sense strand sequence comprises or consists of a sequence that is at least 75% identical to SEQ ID NO: 6447, at least 80% identical to SEQ ID NO: 6447, at least 85% identical to SEQ ID NO: 6447, at least 90% identical to SEQ ID NO: 6447, or at least 95% identical to SEQ ID NO: 6447. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 6447, or a sense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 6447, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of a sequence that is 100% identical to SEQ ID NO: 6447. The sense strand may comprise a modification pattern described herein. The sense strand may comprise an overhang. The sense strand can include a moiety such as a GalNAc moiety or a lipid moiety.

[0073] In some embodiments, the siRNA comprises an antisense strand having a sequence according to SEQ ID NO: 6506. In some embodiments, the antisense strand sequence comprises or consists of a sequence that is at least 75% identical to SEQ ID NO: 6506, at least 80% identical to SEQ ID NO: 6506, at least 85% identical to SEQ ID NO: 6506, at least 90% identical to SEQ ID NO: 6506, or at least 95% identical to SEQ ID NO: 6506. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 6506, or its antisense strand sequence having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 6506, or its antisense strand sequence having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of a sequence that is 100% identical to SEQ ID NO: 6506. The antisense strand may contain a modification pattern described herein. The antisense strand can include an overhang. The antisense strand can include a moiety such as a GalNAc moiety or a lipid moiety.

[0074] In some embodiments, the siRNA comprises a sense strand having a sequence according to SEQ ID NO: 6448. In some embodiments, the sense strand sequence comprises or consists of a sequence that is at least 75% identical to SEQ ID NO: 6448, at least 80% identical to SEQ ID NO: 6448, at least 85% identical to SEQ ID NO: 6448, at least 90% identical to SEQ ID NO: 6448, or at least 95% identical to SEQ ID NO: 6448. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 6448, or a sense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 6448, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of a sequence that is 100% identical to SEQ ID NO: 6448. The sense strand may comprise a modification pattern described herein. The sense strand may comprise an overhang. The sense strand may include a moiety such as a GalNAc moiety or a lipid moiety. In some embodiments, the siRNA comprises an antisense strand having a sequence according to SEQ ID NO: 6507. In some embodiments, the antisense strand sequence comprises or consists of a sequence that is at least 75% identical to SEQ ID NO: 6507, at least 80% identical to SEQ ID NO: 6507, at least 85% identical to SEQ ID NO: 6507, at least 90% identical to SEQ ID NO: 6507, or at least 95% identical to SEQ ID NO: 6507. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 6507 or its antisense strand sequence having one, two, three, or four nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 6507 or its antisense strand sequence having one or two nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of a sequence that is 100% identical to SEQ ID NO: 6507. The antisense strand may comprise a modification pattern as described herein. The antisense strand may comprise an overhang. The antisense strand may comprise a moiety such as a GalNAc moiety or a lipid moiety.

[0075] In some embodiments, the siRNA comprises a sense strand having a sequence according to SEQ ID NO: 6461. In some embodiments, the sense strand sequence comprises or consists of a sequence that is at least 75% identical to SEQ ID NO: 6461, at least 80% identical to SEQ ID NO: 6461, at least 85% identical to SEQ ID NO: 6461, at least 90% identical to SEQ ID NO: 6461, or at least 95% identical to SEQ ID NO: 6461. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 6461, or a sense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 6461, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of a sequence that is 100% identical to SEQ ID NO: 6461. The sense strand may comprise a modification pattern described herein. The sense strand may comprise an overhang. The sense strand may include a moiety such as a GalNAc moiety or a lipid moiety. In some embodiments, the siRNA comprises an antisense strand having a sequence according to SEQ ID NO: 6520. In some embodiments, the antisense strand sequence comprises or consists of a sequence that is at least 75% identical to SEQ ID NO: 6520, at least 80% identical to SEQ ID NO: 6520, at least 85% identical to SEQ ID NO: 6520, at least 90% identical to SEQ ID NO: 6520, or at least 95% identical to SEQ ID NO: 6520. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 6520, or an antisense strand sequence thereof having one, two, three, or four nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 6520, or an antisense strand sequence thereof having one or two nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of a sequence that is 100% identical to SEQ ID NO: 6520. The antisense strand may comprise a modification pattern as described herein. The antisense strand may comprise an overhang. The antisense strand may comprise a moiety such as a GalNAc moiety or a lipid moiety.

[0076] In some embodiments, the siRNA comprises a sense strand having a sequence according to SEQ ID NO: 6466. In some embodiments, the sense strand sequence comprises or consists of a sequence that is at least 75% identical to SEQ ID NO: 6466, at least 80% identical to SEQ ID NO: 6466, at least 85% identical to SEQ ID NO: 6466, at least 90% identical to SEQ ID NO: 6466, or at least 95% identical to SEQ ID NO: 6466. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 6466, or a sense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 6466, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of a sequence that is 100% identical to SEQ ID NO: 6466. The sense strand may comprise a modification pattern described herein. The sense strand may comprise an overhang. The sense strand may include a moiety such as a GalNAc moiety or a lipid moiety. In some embodiments, the siRNA comprises an antisense strand having a sequence according to SEQ ID NO: 6525. In some embodiments, the antisense strand sequence comprises or consists of a sequence that is at least 75% identical to SEQ ID NO: 6525, at least 80% identical to SEQ ID NO: 6525, at least 85% identical to SEQ ID NO: 6525, at least 90% identical to SEQ ID NO: 6525, or at least 95% identical to SEQ ID NO: 6525. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 6525 or its antisense strand sequence having one, two, three, or four nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 6525 or its antisense strand sequence having one or two nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of a sequence that is 100% identical to SEQ ID NO: 6525. The antisense strand may comprise a modification pattern as described herein. The antisense strand may comprise an overhang. The antisense strand may comprise a moiety such as a GalNAc moiety or a lipid moiety.

[0077] In some embodiments, the siRNA comprises a sense strand having a sequence according to SEQ ID NO: 6470. In some embodiments, the sense strand sequence comprises or consists of a sequence that is at least 75% identical to SEQ ID NO: 6470, at least 80% identical to SEQ ID NO: 6470, at least 85% identical to SEQ ID NO: 6470, at least 90% identical to SEQ ID NO: 6470, or at least 95% identical to SEQ ID NO: 6470. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 6470, or a sense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 6470, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of a sequence that is 100% identical to SEQ ID NO: 6470. The sense strand may comprise a modification pattern described herein. The sense strand may comprise an overhang. The sense strand may include a moiety such as a GalNAc moiety or a lipid moiety. In some embodiments, the siRNA comprises an antisense strand having a sequence according to SEQ ID NO: 6529. In some embodiments, the antisense strand sequence comprises or consists of a sequence that is at least 75% identical to SEQ ID NO: 6529, at least 80% identical to SEQ ID NO: 6529, at least 85% identical to SEQ ID NO: 6529, at least 90% identical to SEQ ID NO: 6529, or at least 95% identical to SEQ ID NO: 6529. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 6529 or its antisense strand sequence having one, two, three, or four nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 6529 or its antisense strand sequence having one or two nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of a sequence that is 100% identical to SEQ ID NO: 6529. The antisense strand may comprise a modification pattern as described herein. The antisense strand may comprise an overhang. The antisense strand may comprise a moiety such as a GalNAc moiety or a lipid moiety.

[0078] In some embodiments, the siRNA comprises a sense strand having a sequence according to SEQ ID NO: 6476. In some embodiments, the sense strand sequence comprises or consists of a sequence that is at least 75% identical to SEQ ID NO: 6476, at least 80% identical to SEQ ID NO: 6476, at least 85% identical to SEQ ID NO: 6476, at least 90% identical to SEQ ID NO: 6476, or at least 95% identical to SEQ ID NO: 6476. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 6476, or a sense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 6476, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of a sequence that is 100% identical to SEQ ID NO: 6476. The sense strand may comprise a modification pattern described herein. The sense strand may comprise an overhang. The sense strand may include a moiety such as a GalNAc moiety or a lipid moiety. In some embodiments, the siRNA comprises an antisense strand having a sequence according to SEQ ID NO: 6535. In some embodiments, the antisense strand sequence comprises or consists of a sequence that is at least 75% identical to SEQ ID NO: 6535, at least 80% identical to SEQ ID NO: 6535, at least 85% identical to SEQ ID NO: 6535, at least 90% identical to SEQ ID NO: 6535, or at least 95% identical to SEQ ID NO: 6535. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 6535, or its antisense strand sequence having one, two, three, or four nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 6535, or its antisense strand sequence having one or two nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of a sequence that is 100% identical to SEQ ID NO: 6535. The antisense strand may comprise a modification pattern as described herein. The antisense strand may comprise an overhang. The antisense strand may comprise a moiety such as a GalNAc moiety or a lipid moiety.

[0079] In some embodiments, the siRNA comprises a sense strand having a sequence according to SEQ ID NO: 6602. In some embodiments, the sense strand sequence comprises or consists of a sequence that is at least 75% identical to SEQ ID NO: 6602, at least 80% identical to SEQ ID NO: 6602, at least 85% identical to SEQ ID NO: 6602, at least 90% identical to SEQ ID NO: 6602, or at least 95% identical to SEQ ID NO: 6602. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 6602, or a sense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 6602, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of a sequence that is 100% identical to SEQ ID NO: 6602. The sense strand may comprise a modification pattern described herein. The sense strand may comprise an overhang. The sense strand may include a moiety such as a GalNAc moiety or a lipid moiety. In some embodiments, the siRNA comprises an antisense strand having a sequence according to SEQ ID NO: 6634. In some embodiments, the antisense strand sequence comprises or consists of a sequence that is at least 75% identical to SEQ ID NO: 6634, at least 80% identical to SEQ ID NO: 6634, at least 85% identical to SEQ ID NO: 6634, at least 90% identical to SEQ ID NO: 6634, or at least 95% identical to SEQ ID NO: 6634. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 6634, or an antisense strand sequence thereof having one, two, three, or four nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 6634, or an antisense strand sequence thereof having one or two nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of a sequence that is 100% identical to SEQ ID NO: 6634. The antisense strand may comprise a modification pattern as described herein. The antisense strand may comprise an overhang. The antisense strand may comprise a moiety such as a GalNAc moiety or a lipid moiety.

[0080] In some embodiments, the siRNA comprises a sense strand having a sequence according to SEQ ID NO: 6603. In some embodiments, the sense strand sequence comprises or consists of a sequence that is at least 75% identical to SEQ ID NO: 6603, at least 80% identical to SEQ ID NO: 6603, at least 85% identical to SEQ ID NO: 6603, at least 90% identical to SEQ ID NO: 6603, or at least 95% identical to SEQ ID NO: 6603. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 6603, or a sense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 6603, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of a sequence that is 100% identical to SEQ ID NO: 6603. The sense strand may comprise a modification pattern described herein. The sense strand may comprise an overhang. The sense strand may include a moiety such as a GalNAc moiety or a lipid moiety. In some embodiments, the siRNA comprises an antisense strand having a sequence according to SEQ ID NO: 6635. In some embodiments, the antisense strand sequence comprises or consists of a sequence that is at least 75% identical to SEQ ID NO: 6635, at least 80% identical to SEQ ID NO: 6635, at least 85% identical to SEQ ID NO: 6635, at least 90% identical to SEQ ID NO: 6635, or at least 95% identical to SEQ ID NO: 6635. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 6635, or an antisense strand sequence thereof having one, two, three, or four nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 6635, or an antisense strand sequence thereof having one or two nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of a sequence that is 100% identical to SEQ ID NO: 6635. The antisense strand may comprise a modification pattern as described herein. The antisense strand may comprise an overhang. The antisense strand may comprise a moiety such as a GalNAc moiety or a lipid moiety.

[0081] In some embodiments, the siRNA comprises a sense strand having a sequence according to SEQ ID NO: 6611. In some embodiments, the sense strand sequence comprises or consists of a sequence that is at least 75% identical to SEQ ID NO: 6611, at least 80% identical to SEQ ID NO: 6611, at least 85% identical to SEQ ID NO: 6611, at least 90% identical to SEQ ID NO: 6611, or at least 95% identical to SEQ ID NO: 6611. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 6611, or a sense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 6611, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of a sequence that is 100% identical to SEQ ID NO: 6611. The sense strand may comprise a modification pattern described herein. The sense strand may comprise an overhang. The sense strand may include a moiety such as a GalNAc moiety or a lipid moiety. In some embodiments, the siRNA comprises an antisense strand having a sequence according to SEQ ID NO: 6643. In some embodiments, the antisense strand sequence comprises or consists of a sequence that is at least 75% identical to SEQ ID NO: 6643, at least 80% identical to SEQ ID NO: 6643, at least 85% identical to SEQ ID NO: 6643, at least 90% identical to SEQ ID NO: 6643, or at least 95% identical to SEQ ID NO: 6643. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 6643, or an antisense strand sequence thereof having one, two, three, or four nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 6643, or an antisense strand sequence thereof having one or two nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of a sequence that is 100% identical to SEQ ID NO: 6643. The antisense strand may comprise a modification pattern as described herein. The antisense strand may comprise an overhang. The antisense strand may comprise a moiety such as a GalNAc moiety or a lipid moiety.

[0082] In some embodiments, the siRNA comprises a sense strand having a sequence according to SEQ ID NO: 6612. In some embodiments, the sense strand sequence comprises or consists of a sequence that is at least 75% identical to SEQ ID NO: 6612, at least 80% identical to SEQ ID NO: 6612, at least 85% identical to SEQ ID NO: 6612, at least 90% identical to SEQ ID NO: 6612, or at least 95% identical to SEQ ID NO: 6612. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 6612, or a sense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 6612, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of a sequence that is 100% identical to SEQ ID NO: 6612. The sense strand may comprise a modification pattern described herein. The sense strand may comprise an overhang. The sense strand may include a moiety such as a GalNAc moiety or a lipid moiety. In some embodiments, the siRNA comprises an antisense strand having a sequence according to SEQ ID NO: 6644. In some embodiments, the antisense strand sequence comprises or consists of a sequence that is at least 75% identical to SEQ ID NO: 6644, at least 80% identical to SEQ ID NO: 6644, at least 85% identical to SEQ ID NO: 6644, at least 90% identical to SEQ ID NO: 6644, or at least 95% identical to SEQ ID NO: 6644. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 6644, or its antisense strand sequence having one, two, three, or four nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 6644, or its antisense strand sequence having one or two nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of a sequence that is 100% identical to SEQ ID NO: 6644. The antisense strand may comprise a modification pattern as described herein. The antisense strand may comprise an overhang. The antisense strand may comprise a moiety such as a GalNAc moiety or a lipid moiety.

[0083] In some embodiments, the siRNA comprises a sense strand having a sequence according to SEQ ID NO: 6616. In some embodiments, the sense strand sequence comprises or consists of a sequence that is at least 75% identical to SEQ ID NO: 6616, at least 80% identical to SEQ ID NO: 6616, at least 85% identical to SEQ ID NO: 6616, at least 90% identical to SEQ ID NO: 6616, or at least 95% identical to SEQ ID NO: 6616. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 6616, or a sense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 6616, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of a sequence that is 100% identical to SEQ ID NO: 6616. The sense strand may comprise a modification pattern described herein. The sense strand may comprise an overhang. The sense strand may include a moiety such as a GalNAc moiety or a lipid moiety. In some embodiments, the siRNA comprises an antisense strand having a sequence according to SEQ ID NO: 6648. In some embodiments, the antisense strand sequence comprises or consists of a sequence that is at least 75% identical to SEQ ID NO: 6648, at least 80% identical to SEQ ID NO: 6648, at least 85% identical to SEQ ID NO: 6648, at least 90% identical to SEQ ID NO: 6648, or at least 95% identical to SEQ ID NO: 6648. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 6648, or an antisense strand sequence thereof having one, two, three, or four nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 6648, or an antisense strand sequence thereof having one or two nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of a sequence that is 100% identical to SEQ ID NO: 6648. The antisense strand may comprise a modification pattern as described herein. The antisense strand may comprise an overhang. The antisense strand may comprise a moiety such as a GalNAc moiety or a lipid moiety.

[0084] In some embodiments, the siRNA comprises a sense strand having a sequence according to SEQ ID NO: 6707. In some embodiments, the sense strand sequence comprises or consists of a sequence that is at least 75% identical to SEQ ID NO: 6707, at least 80% identical to SEQ ID NO: 6707, at least 85% identical to SEQ ID NO: 6707, at least 90% identical to SEQ ID NO: 6707, or at least 95% identical to SEQ ID NO: 6707. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 6707, or a sense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 6707, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of a sequence that is 100% identical to SEQ ID NO: 6707. The sense strand may comprise a modification pattern described herein. The sense strand may comprise an overhang. The sense strand may include a moiety such as a GalNAc moiety or a lipid moiety. In some embodiments, the siRNA comprises an antisense strand having a sequence according to SEQ ID NO: 6719. In some embodiments, the antisense strand sequence comprises or consists of a sequence that is at least 75% identical to SEQ ID NO: 6719, at least 80% identical to SEQ ID NO: 6719, at least 85% identical to SEQ ID NO: 6719, at least 90% identical to SEQ ID NO: 6719, or at least 95% identical to SEQ ID NO: 6719. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 6719 or its antisense strand sequence having one, two, three, or four nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 6719 or its antisense strand sequence having one or two nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of a sequence that is 100% identical to SEQ ID NO: 6719. The antisense strand may comprise a modification pattern as described herein. The antisense strand may comprise an overhang. The antisense strand may comprise a moiety such as a GalNAc moiety or a lipid moiety.

[0085] B.ASO In some embodiments, the composition comprises an oligonucleotide that inhibits expression of MST1, wherein the oligonucleotide comprises an antisense oligonucleotide (ASO). In some embodiments, the ASO is 12-30 nucleosides in length. In some embodiments, the ASO is 14-30 nucleosides in length. In some embodiments, the ASO is at least about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleosides in length, or a range defined by any two of the foregoing numbers. In some embodiments, the ASO is 15-25 nucleosides in length. In some embodiments, the ASO is 20 nucleosides in length.

[0086] In some embodiments, the composition comprises an oligonucleotide that inhibits expression of MST1, wherein the oligonucleotide is about 12-30 nucleosides in length and comprises a nucleoside sequence complementary to about 12-30 contiguous nucleosides of a full-length human MST1 mRNA sequence, such as SEQ ID NO: 6163, including an ASO, wherein (i) the oligonucleotide comprises modified nucleosides and / or modified internucleoside linkages, and / or (ii) the composition comprises a pharmaceutically acceptable carrier. In some embodiments, the ASO comprises a nucleoside sequence complementary to at least about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or more contiguous nucleosides of one of SEQ ID NO: 6163.

[0087] In some embodiments, the composition comprises an oligonucleotide that inhibits expression of MST1, wherein the oligonucleotide is about 12-30 nucleosides in length and comprises a nucleoside sequence complementary to about 12-30 contiguous nucleosides of a full-length human MST1 mRNA sequence, such as SEQ ID NO: 6185, and comprises an ASO, wherein (i) the oligonucleotide comprises modified nucleosides and / or modified internucleoside linkages, and / or (ii) the composition comprises a pharmaceutically acceptable carrier. In some embodiments, the ASO comprises a nucleoside sequence complementary to at least about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or more contiguous nucleosides of one of SEQ ID NO: 6185.

[0088] C. Modification Pattern In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of MST1, wherein the oligonucleotide comprises a modification including a modified nucleoside and / or a modified internucleoside linkage, and / or the composition comprises a pharmaceutically acceptable carrier. In some embodiments, the oligonucleotide comprises a modification including a modified nucleoside and / or a modified internucleoside linkage. In some embodiments, the oligonucleotide comprises a modified internucleoside linkage. In some embodiments, the modified internucleoside linkage comprises an alkyl phosphonate, phosphorothioate, methyl phosphonate, phosphorodithioate, alkyl phosphonothioate, phosphoramidate, carbamate, carbonate, phosphate triester, acetamidate, or carboxymethyl ester, or a combination thereof. In some embodiments, the modified internucleoside linkage comprises one or more phosphorothioate linkages. Phosphorothioates may include a non-bridging oxygen atom in the phosphate backbone of the oligonucleotide replaced with sulfur. The modified internucleoside linkage may be included in an siRNA or ASO. The benefits of modified internucleoside linkages may include reduced toxicity or improved pharmacokinetics.

[0089] In some embodiments, the composition comprises an oligonucleotide that inhibits expression of MST1, wherein the oligonucleotide comprises a modified internucleoside linkage, wherein the oligonucleotide comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 modified internucleoside linkages, or a range defined by any two of the foregoing numbers. In some embodiments, the oligonucleotide comprises 18 or fewer modified internucleoside linkages. In some embodiments, the oligonucleotide comprises 20 or fewer modified internucleoside linkages. In some embodiments, the oligonucleotide has 2 or more modified internucleoside linkages, 3 or more modified internucleoside linkages, 4 or more modified internucleoside linkages, 5 or more modified internucleoside linkages, 6 or more modified internucleoside linkages, 7 or more modified internucleoside linkages, 8 or more modified internucleoside linkages, 9 or more modified internucleoside linkages, 10 or more modified internucleoside linkages, 11 or more modified internucleoside linkages, modified internucleoside linkages, 12 or more modified internucleoside linkages, 13 or more modified internucleoside linkages, 14 or more modified internucleoside linkages, 15 or more modified internucleoside linkages, 16 or more modified internucleoside linkages, 17 or more modified internucleoside linkages, 18 or more modified internucleoside linkages, 19 or more modified internucleoside linkages, or 20 or more modified internucleoside linkages.

[0090] In some embodiments, the composition comprises an oligonucleotide that inhibits expression of MST1, wherein the oligonucleotide comprises a modified nucleoside. In some embodiments, the modified nucleoside comprises a locked nucleic acid (LNA), a hexitol nucleic acid (HNA), a cyclohexene nucleic acid (CeNA), a 2'-methoxyethyl, a 2'-O-alkyl, a 2'-O-allyl, a 2'-fluoro, a 2'-deoxy, a 2'-O-methylinosine, or a combination thereof. In some embodiments, the modified nucleoside comprises an LNA. In some embodiments, the modified nucleoside comprises a 2',4' constrained ethyl nucleic acid. In some embodiments, the modified nucleoside comprises an HNA. In some embodiments, the modified nucleoside comprises a CeNA. In some embodiments, the modified nucleoside comprises a 2'-methoxyethyl group. In some embodiments, the modified nucleoside comprises a 2'-O-alkyl group. In some embodiments, the modified nucleoside comprises a 2'-O-allyl group. In some embodiments, the modified nucleoside comprises a 2'-O-fluoro group. In some embodiments, the modified nucleoside comprises a 2'-O-deoxy group. In some embodiments, the modified nucleoside comprises a 2'-O-methyl nucleoside, a 2'-deoxyfluoro nucleoside, a 2'-ON-methylacetamide (2'-O-NMA) nucleoside, a 2'-O-dimethylaminoethoxyethyl (2'-O-DMAEOE) nucleoside, a 2'-O-aminopropyl (2'-O-AP) nucleoside, or 2'-ara-F, or a combination thereof. In some embodiments, the modified nucleoside comprises a 2'-O-methyl nucleoside. In some embodiments, the modified nucleoside comprises a 2'-O-deoxyfluoro nucleoside. In some embodiments, the modified nucleoside comprises a 2'-O-NMA nucleoside. In some embodiments, the modified nucleoside comprises a 2'-O-DMAEOE nucleoside. In some embodiments, the modified nucleoside comprises a 2'-O-aminopropyl (2'-O-AP) nucleoside. In some embodiments, the modified nucleoside comprises 2'-ara-F. In some embodiments, the modified nucleoside comprises one or more 2'-fluoro modified nucleosides.In some embodiments, the modified nucleoside comprises a 2'-O-alkyl modified nucleoside. In some embodiments, the modified nucleoside comprises a 2'-O-methylinosine nucleoside. In some embodiments, the modified nucleoside comprises a non-cyclic nucleic acid. In some embodiments, the non-cyclic nucleic acid is a glycol nucleic acid. In some embodiments, the modified nucleoside comprises a non-locked nucleic acid. The benefits of the modified nucleoside may include reduced toxicity or improved pharmacokinetics.

[0091] In some embodiments, the modified nucleoside comprises a glycol nucleic acid (GNA). GNA has the following structure:

[0092] [ka] may include:

[0093] In some embodiments, the modified nucleoside comprises a non-locked nucleic acid. The non-locked nucleic acid has the following structure:

[0094] [ka] where the base can be any pyrimidine or purine.

[0095] In some embodiments, the oligonucleotide comprises modified nucleosides. In some embodiments, the modified nucleosides are locked nucleic acids and abasic sites.

[0096] [ka] wherein J and K are independently H or a 3' or 5' linkage to the nucleotide via a phosphodiester or phosphorothioate bond.

[0097] In some embodiments, the oligonucleotide comprises a phosphate mimic. In some embodiments, the phosphate mimic comprises a methylphosphonate. Examples of nucleotides that contain methylphosphonates are shown below.

[0098] [ka]

[0099] In some embodiments, the oligonucleotide comprises a duplex consisting of a single strand of 21 to 36 nucleotides that form base pairs with between 17 and 25 base pairs. In some embodiments, the duplex comprises a blunt end at the 5' or 3' end of each strand. One strand (the antisense strand) is complementary to the target mRNA. Each end of the antisense strand has one to five phosphorothioate linkages. The 5' end has an optional phosphonate mimic, such as vinyl phosphonate. In some embodiments, the oligonucleotide is used to knock down a target mRNA or target protein. In some embodiments, the sense strand has the same sequence as the target mRNA. In some embodiments, there are one to five phosphorothioates at the 5' and 3' ends.

[0100] In some embodiments, the oligonucleotide comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 modified nucleosides, or a range defined by any two of the foregoing numbers. In some embodiments, the oligonucleotide comprises 19 or fewer modified nucleosides. In some embodiments, the oligonucleotide comprises 21 or fewer modified nucleosides. In some embodiments, the oligonucleotide comprises two or more modified nucleosides, three or more modified nucleosides, four or more modified nucleosides, five or more modified nucleosides, six or more modified nucleosides, seven or more modified nucleosides, eight or more modified nucleosides, nine or more modified nucleosides, ten or more modified nucleosides, eleven or more modified nucleosides, twelve or more modified nucleosides, thirteen or more modified nucleosides, fourteen or more modified nucleosides, fifteen or more modified nucleosides, sixteen or more modified nucleosides, seventeen or more modified nucleosides, eighteen or more modified nucleosides, nineteen or more modified nucleosides, twenty or more modified nucleosides, or twenty one or more modified nucleosides.

[0101] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of MST1, wherein the oligonucleotide comprises a moiety attached at the 3' or 5' end of the oligonucleotide. Exemplary moieties include an integrin targeting ligand, a hydrophobic moiety, a sugar moiety, or a combination thereof. In some embodiments, the oligonucleotide is an siRNA having a sense strand, wherein the moiety is attached at the 5' end of the sense strand. In some embodiments, the oligonucleotide is an siRNA having a sense strand, wherein the moiety is attached at the 3' end of the sense strand. In some embodiments, the oligonucleotide is an siRNA having an antisense strand, wherein the moiety is attached at the 5' end of the antisense strand. In some embodiments, the oligonucleotide is an siRNA having an antisense strand, wherein the moiety is attached at the 3' end of the antisense strand. In some embodiments, the oligonucleotide is an ASO, wherein the moiety is attached at the 5' end of the ASO. In some embodiments, the oligonucleotide is an ASO, wherein the moiety is attached at the 3' end of the ASO.

[0102] In some embodiments, the sense strand comprises at least three modified nucleosides, the three modifications comprising a 2'-fluoro-modified nucleoside, a 2'-O-methyl-modified nucleoside, and a 2'-O-methoxyethyl. In some embodiments, the sense strand comprises at least two modified nucleosides, the two modifications comprising a 2'-fluoro-modified nucleoside, a 2'-O-methyl-modified nucleoside, and a 2'-O-methoxyethyl. In some embodiments, each nucleoside in the sense strand comprises a modified nucleoside, the modified nucleoside being selected from the group consisting of a 2'-fluoro-modified nucleoside, a 2'-O-methyl-modified nucleoside, and a 2'-O-methoxyethyl. In some embodiments, the sense strand comprises at least a 2'-fluoro-modified nucleoside, a 2'-O-methyl-modified nucleoside, and a 2'-O-methoxyethyl.

[0103] In some embodiments, antisense strand is a combination of 2'-fluoro and 2'-O-methyl modified.In some embodiments, each nucleoside of antisense strand comprises modified nucleoside, and modified nucleoside is selected from the group consisting of 2'-fluoro modified nucleoside and 2'-O-methyl modified nucleoside.In some embodiments, sense strand comprises at least 2'-fluoro modified nucleoside and 2'-O-methyl modified nucleoside.

[0104] The oligonucleotide may contain purines. Examples of purines include adenine (A), inosine (I), or guanine (G), or modified versions thereof. The oligonucleotide may contain pyrimidines. Examples of pyrimidines include cytosine (C), thymine (T), or uracil (U), or modified versions thereof.

[0105] In some embodiments, the sense strand comprises purines and pyrimidines. In some embodiments, all purine nucleosides comprise 2'-fluoro and all pyrimidine nucleosides are modified with a mixture of 2'-O-methyl and 2'-O-methoxyethyl. In some embodiments, all purine nucleosides comprise 2'-O-methyl and all pyrimidine nucleosides are modified with a mixture of 2'-fluoro and 2'-O-methoxyethyl. In some embodiments, all purine nucleosides comprise 2'-O-methoxyethyl and all pyrimidine nucleosides are modified with a mixture of 2'-fluoro and 2'-O-methyl. In some embodiments, all pyrimidine nucleosides comprise 2'-fluoro and all purine nucleosides are modified with a mixture of 2'-O-methyl and 2'-O-methoxyethyl. In some embodiments, all pyrimidine nucleosides comprise 2'-O-methyl and all purine nucleosides are modified with a mixture of 2'-fluoro and 2'-O-methoxyethyl. In some embodiments, all pyrimidine nucleosides contain 2'-O-methoxyethyl and all purine nucleosides are modified with a mixture of 2'-fluoro and 2'-O-methyl. In some embodiments, the sense strand can contain 2'-deoxynucleosides.

[0106] In some embodiments, at least one nucleotide at positions 4 or 5 of the sense strand comprises a 2'-O-methoxyethyl modified nucleoside. In some embodiments, at least one nucleotide at positions 6 through 9 of the sense strand comprises a 2'-fluoro modified nucleoside. In some embodiments, at least two nucleotides at positions 6 through 9 of the sense strand comprise a 2'-fluoro modified nucleoside. In some embodiments, at least three nucleotides at positions 6 through 9 of the sense strand comprise a 2'-fluoro modified nucleoside. In some embodiments, each nucleotide at positions 6 through 9 of the sense strand comprises a 2'-fluoro modified nucleoside. In some embodiments, at least one nucleotide at positions 16 through 20 of the sense strand comprises a 2'-O-methyl modified nucleoside. In some embodiments, at least two nucleotides at positions 16 through 20 of the sense strand comprise a 2'-O-methyl modified nucleoside. In some embodiments, at least three nucleotides in positions 16-20 of the sense strand comprise 2'-O-methyl modified nucleosides. In some embodiments, at least four nucleotides in positions 16-20 of the sense strand comprise 2'-O-methyl modified nucleosides. In some embodiments, all nucleotides in positions 16-20 of the sense strand comprise 2'-O-methyl modified nucleosides.

[0107] In some embodiments, with respect to the antisense strand, any one of the following is true: all purine nucleosides contain 2'-fluoro and all pyrimidine nucleosides are modified with a mixture of 2'-fluoro and 2'-O-methyl; all purine nucleosides contain 2'-O-methyl and all pyrimidine nucleosides are modified with a mixture of 2'-fluoro and 2'-O-methyl; all purine nucleosides contain 2'-O-methyl and all pyrimidine nucleosides contain 2'-fluoro; all pyrimidine nucleosides contain 2'-fluoro and all purine nucleosides are modified with a mixture of 2'-fluoro and 2'-O-methyl; all pyrimidine nucleosides contain 2'-O-methyl and all purine nucleosides are modified with a mixture of 2'-fluoro and 2'-O-methyl; or all pyrimidine nucleosides contain 2'-O-methyl and all purine nucleosides contain 2'-fluoro. In some embodiments, all purine nucleosides contain 2'-fluoro and all pyrimidine nucleosides are modified with a mixture of 2'-fluoro and 2'-O-methyl. In some embodiments, all purine nucleosides contain 2'-O-methyl and all pyrimidine nucleosides are modified with a mixture of 2'-fluoro and 2'-O-methyl, all purine nucleosides contain 2'-O-methyl and all pyrimidine nucleosides contain 2'-fluoro. In some embodiments, all pyrimidine nucleosides contain 2'-fluoro and all purine nucleosides are modified with a mixture of 2'-fluoro and 2'-O-methyl, all pyrimidine nucleosides contain 2'-O-methyl and all purine nucleosides are modified with a mixture of 2'-fluoro and 2'-O-methyl. In some embodiments, all pyrimidine nucleosides contain 2'-O-methyl and all purine nucleosides contain 2'-fluoro.

[0108] In some embodiments, the oligonucleotide is delivered to a cell or tissue by linking the oligonucleotide to a targeting group. In some embodiments, the targeting group comprises a cell receptor ligand, such as an integrin targeting ligand. Integrins may comprise a family of transmembrane receptors that promote binding to the extracellular matrix (ECM). In some embodiments, the moiety comprises an epithelial-specific integrin. Integrin alpha-v-beta-6 (αvβ6) is an example of an epithelial-specific integrin αvβ6 that may be a receptor for ECM proteins or TGF-β latency-associated peptide (LAP). Integrin αvβ6 may be expressed in a cell or tissue. Integrin αvβ6 may be expressed or upregulated in damaged lung epithelium.

[0109] In some embodiments, the oligonucleotide is linked to an integrin targeting ligand having affinity for integrin αvβ6. The integrin targeting ligand may include a compound having affinity for integrin αvβ6 or integrin α-v-β-3 (αvβ3), and may be useful as a ligand that enhances targeting or delivery of the bound oligonucleotide to a specific cell type or tissue (e.g., to cells expressing integrin αvβ3 or αvβ6). In some embodiments, multiple integrin targeting ligands are linked to the oligonucleotide. In some embodiments, the conjugate of the oligonucleotide and the integrin targeting ligand is selectively internalized by lung epithelial cells by receptor-mediated endocytosis or other means.

[0110] Examples of targeting groups useful for delivering oligonucleotides comprising integrin-targeting ligands may be based on peptides or peptidomimetics containing arginine-glycine-aspartic acid (RGD) peptides. In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of MST1, wherein the oligonucleotide comprises an RGD peptide. In some embodiments, the composition comprises an RGD peptide. In some embodiments, the composition comprises an RGD peptide derivative. In some embodiments, the RGD peptide is attached to the 3' end of the oligonucleotide. In some embodiments, the RGD peptide is attached to the 5' end of the oligonucleotide. In some embodiments, the composition comprises a sense strand, wherein the RGD peptide is attached to the sense strand (e.g., attached to the 5' end of the sense strand or attached to the 3' end of the sense strand). In some embodiments, the composition comprises an antisense strand, wherein the RGD peptide is attached to the antisense strand (e.g., attached to the 5' end of the antisense strand or attached to the 3' end of the antisense strand). In some embodiments, the composition comprises an RGD peptide attached to the 3' or 5' end of the oligonucleotide. In some embodiments, the oligonucleotide comprises an RGD peptide and a lipid attached at the 3' or 5' end of the oligonucleotide. The RGD peptide can be linear. The RGD peptide can be cyclic. The RGD peptide can comprise D amino acids. In some embodiments, the RGD peptide comprises cyclo(-Arg-Gly-Asp-D-Phe-Cys) (SEQ ID NO: 6182). In some embodiments, the RGD peptide comprises cyclo(-Arg-Gly-Asp-D-Phe-Lys) (SEQ ID NO: 6183). In some embodiments, the RGD peptide comprises cyclo(-Arg-Gly-Asp-D-Phe-azide) (SEQ ID NO: 6184). In some embodiments, the RGD peptide comprises an RGD derived from aminobenzoic acid. In some embodiments, the RGD peptide comprises cyclo(-Arg-Gly-Asp-D-Phe-Cys) (SEQ ID NO: 6182), cyclo(-Arg-Gly-Asp-D-Phe-Lys) (SEQ ID NO: 6183), cyclo(-Arg-Gly-Asp-D-Phe-azide) (SEQ ID NO: 6184), or a combination thereof.In some embodiments, the RGD peptide comprises a plurality of such RGD peptides. For example, the RGD peptide may comprise 2, 3, or 4 RGD peptides. Some embodiments comprise an arginine-glycine-glutamic acid peptide.

[0111] The oligonucleotide may contain purines. Examples of purines include adenine (A), inosine (I), or guanine (G), or modified versions thereof. The oligonucleotide may contain pyrimidines. Examples of pyrimidines include cytosine (C), thymine (T), or uracil (U), or modified versions thereof.

[0112] In some embodiments, the purines of the oligonucleotide comprise 2'-fluoro modified purines. In some embodiments, the purines of the oligonucleotide comprise 2'-O-methyl modified purines. In some embodiments, the purines of the oligonucleotide comprise a mixture of 2'-fluoro and 2'-O-methyl modified purines. In some embodiments, all of the purines of the oligonucleotide comprise 2'-fluoro modified purines. In some embodiments, all of the purines of the oligonucleotide comprise 2'-O-methyl modified purines. In some embodiments, all of the purines of the oligonucleotide comprise a mixture of 2'-fluoro and 2'-O-methyl modified purines.

[0113] In some embodiments, the pyrimidines of the oligonucleotide comprise 2'-fluoro modified pyrimidines. In some embodiments, the pyrimidines of the oligonucleotide comprise 2'-O-methyl modified pyrimidines. In some embodiments, the pyrimidines of the oligonucleotide comprise a mixture of 2'-fluoro and 2'-O-methyl modified pyrimidines. In some embodiments, all of the pyrimidines of the oligonucleotide comprise 2'-fluoro modified pyrimidines. In some embodiments, all of the pyrimidines of the oligonucleotide comprise 2'-O-methyl modified pyrimidines. In some embodiments, all of the pyrimidines of the oligonucleotide comprise a mixture of 2'-fluoro and 2'-O-methyl modified pyrimidines.

[0114] In some embodiments, the purines of the oligonucleotide comprise 2'-fluoro modified purines and the pyrimidines of the oligonucleotide comprise a mixture of 2'-fluoro and 2'-O-methyl modified pyrimidines. In some embodiments, the purines of the oligonucleotide comprise 2'-O-methyl modified purines and the pyrimidines of the oligonucleotide comprise a mixture of 2'-fluoro and 2'-O-methyl modified pyrimidines. In some embodiments, the purines of the oligonucleotide comprise 2'-fluoro modified purines and the pyrimidines of the oligonucleotide comprise 2'-O-methyl modified pyrimidines. In some embodiments, the purines of the oligonucleotide comprise 2'-O-methyl modified purines and the pyrimidines of the oligonucleotide comprise 2'-fluoro modified pyrimidines. In some embodiments, the pyrimidines of the oligonucleotide comprise 2'-fluoro modified pyrimidines and the purines of the oligonucleotide comprise a mixture of 2'-fluoro and 2'-O-methyl modified purines. In some embodiments, the pyrimidines of the oligonucleotide comprise 2'-O-methyl modified pyrimidines and the purines of the oligonucleotide comprise a mixture of 2'-fluoro and 2'-O-methyl modified purines. In some embodiments, the pyrimidines of the oligonucleotide comprise 2'-fluoro modified pyrimidines and the purines of the oligonucleotide comprise 2'-O-methyl modified purines. In some embodiments, the pyrimidines of the oligonucleotide comprise 2'-O-methyl modified pyrimidines and the purines of the oligonucleotide comprise 2'-fluoro modified purines.

[0115] In some embodiments, all of the purines of the oligonucleotide comprise 2'-fluoro modified purines and all of the pyrimidines of the oligonucleotide comprise a mixture of 2'-fluoro and 2'-O-methyl modified pyrimidines. In some embodiments, all of the purines of the oligonucleotide comprise 2'-O-methyl modified purines and all of the pyrimidines of the oligonucleotide comprise a mixture of 2'-fluoro and 2'-O-methyl modified pyrimidines. In some embodiments, all of the purines of the oligonucleotide comprise 2'-fluoro modified purines and all of the pyrimidines of the oligonucleotide comprise 2'-O-methyl modified pyrimidines. In some embodiments, all of the purines of the oligonucleotide comprise 2'-O-methyl modified purines and all of the pyrimidines of the oligonucleotide comprise 2'-fluoro modified pyrimidines. In some embodiments, all of the pyrimidines of the oligonucleotide comprise 2'-fluoro modified pyrimidines and all of the purines of the oligonucleotide comprise a mixture of 2'-fluoro and 2'-O-methyl modified purines. In some embodiments, all of the pyrimidines of the oligonucleotide comprise 2'-O-methyl modified pyrimidines and all of the purines of the oligonucleotide comprise a mixture of 2'-fluoro and 2'-O-methyl modified pyrimidines. In some embodiments, all of the pyrimidines of the oligonucleotide comprise 2'-fluoro modified pyrimidines and all of the purines of the oligonucleotide comprise 2'-O-methyl modified purines. In some embodiments, all of the pyrimidines of the oligonucleotide comprise 2'-O-methyl modified pyrimidines and all of the purines of the oligonucleotide comprise 2'-fluoro modified purines.

[0116] In some cases, the oligonucleotide comprises a specific modification pattern. In some embodiments, position 9, counting from the 5' end of the oligonucleotide chain, can have a 2'F modification. In some embodiments, if position 9 of the oligonucleotide chain is a pyrimidine, all purines of the oligonucleotide chain have a 2'OMe modification. In some embodiments, if position 9 is the only pyrimidine between positions 5 and 11 of the sense strand, position 9 is the only position in the oligonucleotide chain that has a 2'F modification. In some embodiments, if position 9 and the only other bases between positions 5 and 11 of the oligonucleotide chain are pyrimidines, these pyrimidines are the only two positions in the oligonucleotide chain that have a 2'F modification. In some embodiments, if position 9 and the only two other bases between positions 5 and 11 of the oligonucleotide chain are pyrimidines, and these two other pyrimidines are adjacent positions such that there are no three 2'F modifications in a row, any combination of 2'F modifications can be created, resulting in a total of three 2'F modifications. In some embodiments, if there are more than two pyrimidines between positions 5 and 11 of an oligonucleotide strand, all combinations of pyrimidines with 2'F modifications are permitted, with a total of 3-5 2'F modifications, provided that no oligonucleotide strand has three 2'F modifications in a row. Optionally, either oligonucleotide strand of the siRNA contains a modification pattern that accommodates any or all of these oligonucleotide strand rules.

[0117] In some embodiments, if position 9 of an oligonucleotide strand is a purine, all purines in the oligonucleotide strand have a 2'OMe modification. In some embodiments, if position 9 is the only purine between positions 5 and 11 of the sense strand, then position 9 is the only position in the oligonucleotide strand with a 2'F modification. In some embodiments, if position 9 and the only other bases between positions 5 and 11 of the oligonucleotide strand are purines, these purines together are the only two positions in the oligonucleotide strand with a 2'F modification. In some embodiments, if position 9 and only two other bases between positions 5 and 11 of the oligonucleotide strand are purines, and those two other purines are adjacent positions such that there are no three 2'F modifications in a row, then any combination of 2'F modifications can be made, resulting in a total of three 2'F modifications. In some embodiments, if there are more than two purines between positions 5 and 11 of the oligonucleotide strand, then all combinations of purines with 2'F modifications are possible, resulting in a total of three to five 2'F modifications, provided that the oligonucleotide strand does not have three 2'F modifications in a row. Optionally, either oligonucleotide strand of the siRNA contains a modification pattern that conforms to any or all of these oligonucleotide strand rules.

[0118] Optionally, the 9th position of oligonucleotide chain can be 2'deoxy.In these cases, 2'F and 2'OMe modification can occur in other positions of oligonucleotide chain.Optionally, any oligonucleotide chain of siRNA comprises modification pattern that conforms to the rule of oligonucleotide chain.

[0119] In some embodiments, position 9 of the sense strand comprises a 2'-fluoro-modified pyrimidine. In some embodiments, all purines of the sense strand comprise 2'-O-methyl-modified purines. In some embodiments, 1, 2, 3, 4, or 5 pyrimidines between positions 5 and 11 comprise 2'-fluoro-modified pyrimidines, provided that there are no three 2'-fluoro-modified pyrimidines in a row. In some embodiments, odd-numbered positions of the antisense strand comprise 2'-O-methyl-modified nucleotides. In some embodiments, even-numbered positions of the antisense strand comprise 2'-fluoro-modified nucleotides and unmodified deoxyribonucleotides. In some embodiments, even-numbered positions of the antisense strand comprise 2'-fluoro-modified nucleotides, 2'-O-methyl-modified nucleotides, and unmodified deoxyribonucleotides. In some embodiments, position 9 of the sense strand comprises a 2'-fluoro modified pyrimidine, all purines of the sense strand comprise 2'-O-methyl modified purines, 1, 2, 3, 4, or 5 pyrimidines between positions 5 and 11 comprise 2'-fluoro modified pyrimidines, provided that there are not three 2'-fluoro modified pyrimidines in a row, odd-numbered positions of the antisense strand comprise 2'-O-methyl modified nucleotides, and even-numbered positions of the antisense strand comprise 2'-fluoro modified nucleotides and unmodified deoxyribonucleotides.

[0120] In some embodiments, position 9 of the sense strand comprises a 2'-fluoro-modified purine. In some embodiments, all pyrimidines of the sense strand comprise 2'-O-methyl-modified purines. In some embodiments, 1, 2, 3, 4, or 5 purines between positions 5 and 11 comprise 2'-fluoro-modified purines, provided that there are no three 2'-fluoro-modified purines in a row. In some embodiments, odd-numbered positions of the antisense strand comprise 2'-O-methyl-modified nucleotides. In some embodiments, even-numbered positions of the antisense strand comprise 2'-fluoro-modified nucleotides and unmodified deoxyribonucleotides. In some embodiments, even-numbered positions of the antisense strand comprise 2'-fluoro-modified nucleotides, 2'-O-methyl-modified nucleotides, and unmodified deoxyribonucleotides. In some embodiments, position 9 of the sense strand comprises a 2'-fluoro-modified purine, all pyrimidines of the sense strand comprise 2'-O-methyl-modified pyrimidines, and 1, 2, 3, 4, or 5 purines between positions 5 and 11 comprise 2'-fluoro-modified purines, provided that there are no three 2'-fluoro-modified purines in a row; odd-numbered positions of the antisense strand comprise 2'-O-methyl-modified nucleotides; and even-numbered positions of the antisense strand comprise 2'-fluoro-modified nucleotides and unmodified deoxyribonucleotides. In some embodiments, there are no three 2'-fluoro-modified purines in a row. In some embodiments, there are no three 2'-fluoro-modified pyrimidines in a row.

[0121] In some embodiments, position 9 of the sense strand comprises an unmodified deoxyribonucleotide. In some embodiments, positions 5, 7, and 8 of the sense strand comprise 2'-fluoro-modified nucleotides. In some embodiments, all pyrimidines at positions 10-21 of the sense strand comprise 2'-O-methyl-modified pyrimidines, and all purines at positions 10-21 comprise 2'-O-methyl-modified purines or 2'-fluoro-modified purines. In some embodiments, odd-numbered positions of the antisense strand comprise 2'-O-methyl-modified nucleotides. In some embodiments, even-numbered positions of the antisense strand comprise 2'-fluoro-modified nucleotides and unmodified deoxyribonucleotides. In some embodiments, even-numbered positions of the antisense strand comprise 2'-fluoro-modified nucleotides, 2'-O-methyl-modified nucleotides, and unmodified deoxyribonucleotides. In some embodiments, position 9 of the sense strand comprises an unmodified deoxyribonucleotide, positions 5, 7, and 8 of the sense strand comprise 2'-fluoro modified nucleotides, all pyrimidines at positions 10-21 of the sense strand comprise 2'-O-methyl modified pyrimidines, and all purines at positions 10-21 comprise 2'-O-methyl modified purines or 2'-fluoro modified purines. The odd-numbered positions of the antisense strand comprise 2'-O-methyl modified nucleotides, and the even-numbered positions of the antisense strand comprise 2'-fluoro modified nucleotides and unmodified deoxyribonucleotides.

[0122] In some embodiments, position 9 of the sense strand comprises an unmodified deoxyribonucleotide. In some embodiments, positions 5, 7, and 8 of the sense strand comprise 2'-fluoro-modified nucleotides. In some embodiments, all purines at positions 10-21 of the sense strand comprise 2'-O-methyl-modified purines, and all pyrimidines at positions 10-21 comprise 2'-O-methyl-modified or 2'-fluoro-modified pyrimidines. In some embodiments, odd-numbered positions of the antisense strand comprise 2'-O-methyl-modified nucleotides. In some embodiments, even-numbered positions of the antisense strand comprise 2'-fluoro-modified nucleotides and unmodified deoxyribonucleotides. In some embodiments, even-numbered positions of the antisense strand comprise 2'-fluoro-modified nucleotides, 2'-O-methyl-modified nucleotides, and unmodified deoxyribonucleotides. In some embodiments, position 9 of the sense strand comprises an unmodified deoxyribonucleotide, positions 5, 7, and 8 of the sense strand comprise 2'-fluoro modified nucleotides, all purines at positions 10-21 of the sense strand comprise 2'-O-methyl modified purines, all pyrimidines at positions 10-21 comprise 2'-O-methyl modified pyrimidines or 2'-fluoro modified pyrimidines, odd-numbered positions of the antisense strand comprise 2'-O-methyl modified nucleotides, and even-numbered positions of the antisense strand comprise 2'-fluoro modified nucleotides and unmodified deoxyribonucleotides.

[0123] In some embodiments, the moiety comprises a negatively charged group attached to the 5'-end of the oligonucleotide. This may also be referred to as a 5'-terminal group. In some embodiments, the negatively charged group is attached to the 5'-end of the antisense strand of the siRNA disclosed herein. The 5'-terminal group may be or include 5'-terminal phosphorothioate, 5'-terminal phosphorodithioate, 5'-terminal vinylphosphonate (5'-VP), 5'-terminal methylphosphonate, 5'-terminal cyclopropylphosphonate, or 5'-deoxy-5'-C-malonyl. The 5'-terminal group may include 5'-VP. In some embodiments, the 5'-VP includes trans-vinylphosphonate or cis-vinylphosphonate. The 5'-terminal group may include an extra 5' phosphate. A combination of 5'-terminal groups may also be used.

[0124] In some embodiments, the oligonucleotide comprises a negatively charged group. The negatively charged group can aid in cell or tissue penetration. The negatively charged group can be attached to the 5' or 3' end (e.g., the 5' end) of the oligonucleotide. This is sometimes referred to as a terminal group. The terminal group can be or include phosphorothioate, phosphorodithioate, vinylphosphonate, methylphosphonate, cyclopropylphosphonate, or deoxy-C-malonyl. The terminal group can include an extra 5' phosphate, such as an extra 5' phosphate. A combination of terminal groups can also be used.

[0125] In some embodiments, the oligonucleotide comprises a phosphate mimic. In some embodiments, the phosphate mimic comprises a vinyl phosphonate. In some embodiments, the vinyl phosphonate comprises a trans-vinyl phosphonate. In some embodiments, the vinyl phosphonate comprises a cis-vinyl phosphonate. Examples of nucleotides that contain vinyl phosphonates are shown below.

[0126] [ka]

[0127] In some embodiments, vinyl phosphonates increase the stability of oligonucleotides. In some embodiments, vinyl phosphonates increase the accumulation of oligonucleotides in tissues. In some embodiments, vinyl phosphonates protect oligonucleotides from exonucleases or phosphatases. In some embodiments, vinyl phosphonates improve the binding affinity of oligonucleotides to the siRNA processing machinery.

[0128] In some embodiments, the oligonucleotide comprises one vinyl phosphonate. In some embodiments, the oligonucleotide comprises two vinyl phosphonates. In some embodiments, the oligonucleotide comprises three vinyl phosphonates. In some embodiments, the oligonucleotide comprises four vinyl phosphonates. In some embodiments, the antisense strand of the oligonucleotide comprises a vinyl phosphonate at the 5'-end. In some embodiments, the antisense strand of the oligonucleotide comprises a vinyl phosphonate at the 3'-end. In some embodiments, the sense strand of the oligonucleotide comprises a vinyl phosphonate at the 5'-end. In some embodiments, the sense strand of the oligonucleotide comprises a vinyl phosphonate at the 3'-end.

[0129] In some embodiments, the composition comprises an oligonucleotide that inhibits expression of MST1, the oligonucleotide comprising an siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises a nucleoside sequence comprising or consisting of any one of SEQ ID NOs: 6049-6086, 6125-6162, or 6186-6242, or a nucleic acid sequence thereof having one or two nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises a nucleoside sequence comprising or consisting of any one of SEQ ID NOs: 6049-6086, 6125-6162, or 6186-6242, or a nucleic acid sequence thereof having three or four nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand further comprises a 3' overhang. In some embodiments, the 3' overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range defined by any two of the foregoing numbers. In some embodiments, the 3' overhang comprises 1, 2, or more nucleosides. In some embodiments, the 3' overhang comprises 2 nucleosides. In some embodiments, the sense strand further comprises a 5' overhang. In some embodiments, the 5' overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range defined by any two of the foregoing numbers. In some embodiments, the 5' overhang comprises 1, 2, or more nucleosides. In some embodiments, the 5' overhang comprises 2 nucleosides. In some embodiments, the sense strand comprises a nucleoside sequence comprising or consisting of any one of SEQ ID NOs: 6049-6086, 6125-6162, or 6186-6242, or a nucleic acid sequence thereof having one or two nucleoside additions at the 3' end.In some embodiments, the composition comprises an oligonucleotide that inhibits expression of MST1, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises a nucleoside sequence comprising or consisting of any one of SEQ ID NOs: 6049-6086, 6125-6162, or 6186-6242. The sense strand or antisense strand may include any modification described herein. The sense strand or antisense strand may include a lipid moiety or a GalNAc moiety.

[0130] In some embodiments, the composition comprises an oligonucleotide that inhibits expression of MST1, the oligonucleotide comprising an siRNA comprising a sense strand and an antisense strand, wherein the antisense strand comprises a nucleoside sequence comprising or consisting of any one of SEQ ID NOs: 6087-6124 or 6253-6309, or a nucleic acid sequence thereof having one or two nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises a nucleoside sequence comprising or consisting of any one of SEQ ID NOs: 6087-6124 or 6253-6309, or a nucleic acid sequence thereof having three or four nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand further comprises a 3' overhang. In some embodiments, the 3' overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range defined by any two of the foregoing numbers. In some embodiments, the 3' overhang comprises one, two, or more nucleosides. In some embodiments, the 3' overhang comprises two nucleosides. In some embodiments, the antisense strand further comprises a 5' overhang. In some embodiments, the 5' overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range defined by any two of the foregoing numbers. In some embodiments, the 5' overhang comprises one, two, or more nucleosides. In some embodiments, the 5' overhang comprises two nucleosides. In some embodiments, the antisense strand comprises a nucleoside sequence comprising or consisting of any one of SEQ ID NOs: 6087-6124 or 6253-6309, or a nucleic acid sequence thereof having one or two nucleoside additions at the 3' end. In some embodiments, the composition comprises an oligonucleotide that inhibits expression of MST1, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, and the antisense strand comprises a nucleoside sequence comprising or consisting of any one of SEQ ID NOs: 6087-6124 or 6253-6309.The sense or antisense strand can include any of the modifications described herein. The sense or antisense strand can include a lipid moiety or a GalNAc moiety.

[0131] In some embodiments, the siRNA comprises a sense strand having a sequence according to any of SEQ ID NOs: 6206, 6212, 6213, 6214, 6227, 6232, 6236, or 6242. In some embodiments, the sense strand sequence is at least 75% identical to any one of SEQ ID NOs: 6206, 6212, 6213, 6214, 6227, 6232, 6236, or 6242, at least 80% identical to any one of SEQ ID NOs: 6206, 6212, 6213, 6214, 6227, 6232, 6236, or 6242, or at least 80% identical to any one of SEQ ID NOs: 6206, 6212, 6213, 6214, 6227, 6232, 6236, or 6242. In some embodiments, the sense strand sequence comprises or consists of a sequence that is at least 85% identical to any one of SEQ ID NOs: 6206, 6212, 6213, 6214, 6227, 6232, 6236, or 6242, at least 90% identical to any one of SEQ ID NOs: 6206, 6212, 6213, 6214, 6227, 6232, 6236, or 6242, or at least 95% identical to any one of SEQ ID NOs: 6206, 6212, 6213, 6214, 6227, 6232, 6236, or 6242, or a sense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of any one of SEQ ID NOs: 6206, 6212, 6213, 6214, 6227, 6232, 6236, or 6242, or a sense strand sequence thereof having one or two nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of a sequence 100% identical to 6206, 6212, 6213, 6214, 6227, 6232, 6236, or 6242. The sense strand sequence can include the first 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 nucleotides (in the 5' to 3' direction) of any of the foregoing sequences.The sense strand sequence can include the last 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 nucleotides (in the 5' to 3' direction) of any of the foregoing sequences. The sense strand can include a modification pattern described herein. The sense strand can include an overhang. The sense strand can include a lipid moiety. The sense strand can include a GalNAc moiety.

[0132] In some embodiments, the siRNA comprises an antisense strand having a sequence according to any of SEQ ID NOs: 6273, 6279, 6280, 6281, 6294, 6299, 6303, or 6309. In some embodiments, the antisense strand sequence is at least 75% identical to any one of SEQ ID NOs: 6273, 6279, 6280, 6281, 6294, 6299, 6303, or 6309, at least 80% identical to any one of SEQ ID NOs: 6273, 6279, 6280, 6281, 6294, 6299, 6303, or 6309, or at least 80% identical to any one of SEQ ID NOs: 6273, 6279, 6280, 6281, 6294, 6299 , 6273, 6279, 6280, 6281, 6294, 6299, 6303, or 6309, at least 85% identical to any one of SEQ ID NOs: 6273, 6279, 6280, 6281, 6294, 6299, 6303, or 6309, at least 90% identical to any one of SEQ ID NOs: 6273, 6279, 6280, 6281, 6294, 6299, 6303, or 6309, or at least 95% identical to any one of SEQ ID NOs: 6273, 6279, 6280, 6281, 6294, 6299, 6303, or 6309. In some embodiments, the antisense strand sequence comprises or consists of the sequence of any one of SEQ ID NOs: 6273, 6279, 6280, 6281, 6294, 6299, 6303, or 6309, or an antisense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of any one of SEQ ID NOs: 6273, 6279, 6280, 6281, 6294, 6299, 6303, or 6309, or an antisense strand sequence thereof having one or two nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of a sequence 100% identical to 6273, 6279, 6280, 6281, 6294, 6299, 6303, or 6309. The antisense strand sequence may include the first 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 nucleotides (in the 5' to 3' direction) of any of the foregoing sequences.The antisense strand sequence may comprise the last 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 nucleotides (5' to 3') of any of the aforementioned sequences. The antisense strand may comprise an overhang. The antisense strand may comprise a modification pattern described herein. The anti-antisense strand may comprise a lipid moiety or a GalNAc moiety.

[0133] In some embodiments, the siRNA comprises a sense strand having a sequence according to SEQ ID NO: 6206. In some embodiments, the sense strand sequence comprises or consists of a sequence that is at least 75% identical to SEQ ID NO: 6206, at least 80% identical to SEQ ID NO: 6206, at least 85% identical to SEQ ID NO: 6206, at least 90% identical to SEQ ID NO: 6206, or at least 95% identical to SEQ ID NO: 6206. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 6206, or a sense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 6206, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of a sequence that is 100% identical to SEQ ID NO: 6206. The sense strand may comprise a modification pattern described herein. The sense strand may comprise an overhang. The sense strand can include a lipid moiety. The sense strand can include a GalNAc moiety.

[0134] In some embodiments, the siRNA comprises a sense strand having a sequence according to SEQ ID NO: 6212. In some embodiments, the sense strand sequence comprises or consists of a sequence that is at least 75% identical to SEQ ID NO: 6212, at least 80% identical to SEQ ID NO: 6212, at least 85% identical to SEQ ID NO: 6212, at least 90% identical to SEQ ID NO: 6212, or at least 95% identical to SEQ ID NO: 6212. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 6212, or a sense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 6212, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of a sequence that is 100% identical to SEQ ID NO: 6212. The sense strand may comprise a modification pattern described herein. The sense strand may comprise an overhang. The sense strand can include a lipid moiety. The sense strand can include a GalNAc moiety.

[0135] In some embodiments, the siRNA comprises a sense strand having a sequence according to SEQ ID NO: 6213. In some embodiments, the sense strand sequence comprises or consists of a sequence that is at least 75% identical to SEQ ID NO: 6213, at least 80% identical to SEQ ID NO: 6213, at least 85% identical to SEQ ID NO: 6213, at least 90% identical to SEQ ID NO: 6213, or at least 95% identical to SEQ ID NO: 6213. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 6213, or a sense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 6213, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of a sequence that is 100% identical to SEQ ID NO: 6213. The sense strand may comprise a modification pattern described herein. The sense strand may comprise an overhang. The sense strand can include a lipid moiety. The sense strand can include a GalNAc moiety.

[0136] In some embodiments, the siRNA comprises a sense strand having a sequence according to SEQ ID NO: 6214. In some embodiments, the sense strand sequence comprises or consists of a sequence that is at least 75% identical to SEQ ID NO: 6214, at least 80% identical to SEQ ID NO: 6214, at least 85% identical to SEQ ID NO: 6214, at least 90% identical to SEQ ID NO: 6214, or at least 95% identical to SEQ ID NO: 6214. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 6214, or a sense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 6214, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of a sequence that is 100% identical to SEQ ID NO: 6214. The sense strand may comprise a modification pattern described herein. The sense strand may comprise an overhang. The sense strand can include a lipid moiety. The sense strand can include a GalNAc moiety.

[0137] In some embodiments, the siRNA comprises a sense strand having a sequence according to SEQ ID NO: 6227. In some embodiments, the sense strand sequence comprises or consists of a sequence that is at least 75% identical to SEQ ID NO: 6227, at least 80% identical to SEQ ID NO: 6227, at least 85% identical to SEQ ID NO: 6227, at least 90% identical to SEQ ID NO: 6227, or at least 95% identical to SEQ ID NO: 6227. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 6227, or a sense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 6227, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of a sequence that is 100% identical to SEQ ID NO: 6227. The sense strand may comprise a modification pattern described herein. The sense strand may comprise an overhang. The sense strand can include a lipid moiety. The sense strand can include a GalNAc moiety.

[0138] In some embodiments, the siRNA comprises a sense strand having a sequence according to SEQ ID NO: 6232. In some embodiments, the sense strand sequence comprises or consists of a sequence that is at least 75% identical to SEQ ID NO: 6232, at least 80% identical to SEQ ID NO: 6232, at least 85% identical to SEQ ID NO: 6232, at least 90% identical to SEQ ID NO: 6232, or at least 95% identical to SEQ ID NO: 6232. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 6232, or a sense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 6232, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of a sequence that is 100% identical to SEQ ID NO: 6232. The sense strand may comprise a modification pattern described herein. The sense strand may comprise an overhang. The sense strand can include a lipid moiety. The sense strand can include a GalNAc moiety.

[0139] In some embodiments, the siRNA comprises a sense strand having a sequence according to SEQ ID NO: 6236. In some embodiments, the sense strand sequence comprises or consists of a sequence that is at least 75% identical to SEQ ID NO: 6236, at least 80% identical to SEQ ID NO: 6236, at least 85% identical to SEQ ID NO: 6236, at least 90% identical to SEQ ID NO: 6236, or at least 95% identical to SEQ ID NO: 6236. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 6236, or a sense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 6236, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of a sequence that is 100% identical to SEQ ID NO: 6236. The sense strand may comprise a modification pattern described herein. The sense strand may comprise an overhang. The sense strand can include a lipid moiety. The sense strand can include a GalNAc moiety.

[0140] In some embodiments, the siRNA comprises a sense strand having a sequence according to SEQ ID NO: 6242. In some embodiments, the sense strand sequence comprises or consists of a sequence that is at least 75% identical to SEQ ID NO: 6242, at least 80% identical to SEQ ID NO: 6242, at least 85% identical to SEQ ID NO: 6242, at least 90% identical to SEQ ID NO: 6242, or at least 95% identical to SEQ ID NO: 6242. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 6242, or a sense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 6242, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of a sequence that is 100% identical to SEQ ID NO: 6242. The sense strand may comprise a modification pattern described herein. The sense strand may comprise an overhang. The sense strand can include a lipid moiety. The sense strand can include a GalNAc moiety.

[0141] In some embodiments, the siRNA comprises an antisense strand having a sequence according to SEQ ID NO: 6273. In some embodiments, the antisense strand sequence comprises or consists of a sequence that is at least 75% identical to SEQ ID NO: 6273, at least 80% identical to SEQ ID NO: 6273, at least 85% identical to SEQ ID NO: 6273, at least 90% identical to SEQ ID NO: 6273, or at least 95% identical to SEQ ID NO: 6273. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 6273, or its antisense strand sequence having one, two, three, or four nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 6273, or its antisense strand sequence having one or two nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of a sequence that is 100% identical to SEQ ID NO: 6273. The antisense strand may contain a modification pattern described herein. The antisense strand may comprise an overhang. The antisense strand may comprise a lipid moiety. The antisense strand may comprise a GalNAc moiety.

[0142] In some embodiments, the siRNA comprises an antisense strand having a sequence according to SEQ ID NO: 6279. In some embodiments, the antisense strand sequence comprises or consists of a sequence that is at least 75% identical to SEQ ID NO: 6279, at least 80% identical to SEQ ID NO: 6279, at least 85% identical to SEQ ID NO: 6279, at least 90% identical to SEQ ID NO: 6279, or at least 95% identical to SEQ ID NO: 6279. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 6279 or its antisense strand sequence having one, two, three, or four nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 6279 or its antisense strand sequence having one or two nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of a sequence that is 100% identical to SEQ ID NO: 6279. The antisense strand may contain a modification pattern described herein. The antisense strand may comprise an overhang. The antisense strand may comprise a lipid moiety. The antisense strand may comprise a GalNAc moiety.

[0143] In some embodiments, the siRNA comprises an antisense strand having a sequence according to SEQ ID NO: 6280. In some embodiments, the antisense strand sequence comprises or consists of a sequence that is at least 75% identical to SEQ ID NO: 6280, at least 80% identical to SEQ ID NO: 6280, at least 85% identical to SEQ ID NO: 6280, at least 90% identical to SEQ ID NO: 6280, or at least 95% identical to SEQ ID NO: 6280. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 6280, or its antisense strand sequence having one, two, three, or four nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 6280, or its antisense strand sequence having one or two nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of a sequence that is 100% identical to SEQ ID NO: 6280. The antisense strand may contain a modification pattern described herein. The antisense strand may comprise an overhang. The antisense strand may comprise a lipid moiety. The antisense strand may comprise a GalNAc moiety.

[0144] In some embodiments, the siRNA comprises an antisense strand having a sequence according to SEQ ID NO: 6281. In some embodiments, the antisense strand sequence comprises or consists of a sequence that is at least 75% identical to SEQ ID NO: 6281, at least 80% identical to SEQ ID NO: 6281, at least 85% identical to SEQ ID NO: 6281, at least 90% identical to SEQ ID NO: 6281, or at least 95% identical to SEQ ID NO: 6281. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 6281, or its antisense strand sequence having one, two, three, or four nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 6281, or its antisense strand sequence having one or two nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of a sequence that is 100% identical to SEQ ID NO: 6281. The antisense strand may contain a modification pattern described herein. The antisense strand may comprise an overhang. The antisense strand may comprise a lipid moiety. The antisense strand may comprise a GalNAc moiety.

[0145] In some embodiments, the siRNA comprises an antisense strand having a sequence according to SEQ ID NO: 6294. In some embodiments, the antisense strand sequence comprises or consists of a sequence that is at least 75% identical to SEQ ID NO: 6294, at least 80% identical to SEQ ID NO: 6294, at least 85% identical to SEQ ID NO: 6294, at least 90% identical to SEQ ID NO: 6294, or at least 95% identical to SEQ ID NO: 6294. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 6294, or its antisense strand sequence having one, two, three, or four nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 6294, or its antisense strand sequence having one or two nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of a sequence that is 100% identical to SEQ ID NO: 6294. The antisense strand may contain a modification pattern described herein. The antisense strand may comprise an overhang. The antisense strand may comprise a lipid moiety. The antisense strand may comprise a GalNAc moiety.

[0146] In some embodiments, the siRNA comprises an antisense strand having a sequence according to SEQ ID NO: 6299. In some embodiments, the antisense strand sequence comprises or consists of a sequence that is at least 75% identical to SEQ ID NO: 6299, at least 80% identical to SEQ ID NO: 6299, at least 85% identical to SEQ ID NO: 6299, at least 90% identical to SEQ ID NO: 6299, or at least 95% identical to SEQ ID NO: 6299. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 6299, or its antisense strand sequence having one, two, three, or four nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 6299, or its antisense strand sequence having one or two nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of a sequence that is 100% identical to SEQ ID NO: 6299. The antisense strand may contain a modification pattern described herein. The antisense strand may comprise an overhang. The antisense strand may comprise a lipid moiety. The antisense strand may comprise a GalNAc moiety.

[0147] In some embodiments, the siRNA comprises an antisense strand having a sequence according to SEQ ID NO: 6303. In some embodiments, the antisense strand sequence comprises or consists of a sequence that is at least 75% identical to SEQ ID NO: 6303, at least 80% identical to SEQ ID NO: 6303, at least 85% identical to SEQ ID NO: 6303, at least 90% identical to SEQ ID NO: 6303, or at least 95% identical to SEQ ID NO: 6303. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 6303, or its antisense strand sequence having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 6303, or its antisense strand sequence having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of a sequence that is 100% identical to SEQ ID NO: 6303. The antisense strand may contain a modification pattern described herein. The antisense strand may comprise an overhang. The antisense strand may comprise a lipid moiety. The antisense strand may comprise a GalNAc moiety.

[0148] In some embodiments, the siRNA comprises an antisense strand having a sequence according to SEQ ID NO: 6309. In some embodiments, the antisense strand sequence comprises or consists of a sequence that is at least 75% identical to SEQ ID NO: 6309, at least 80% identical to SEQ ID NO: 6309, at least 85% identical to SEQ ID NO: 6309, at least 90% identical to SEQ ID NO: 6309, or at least 95% identical to SEQ ID NO: 6309. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 6309, or its antisense strand sequence having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 6309, or its antisense strand sequence having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of a sequence that is 100% identical to SEQ ID NO: 6309. The antisense strand may contain a modification pattern described herein. The antisense strand may comprise an overhang. The antisense strand may comprise a lipid moiety. The antisense strand may comprise a GalNAc moiety.

[0149] 1.Hydrophobic part In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of MST1, wherein the oligonucleotide comprises a hydrophobic moiety. The hydrophobic moiety can be attached at the 3' or 5' end of the oligonucleotide. The hydrophobic moiety can comprise a lipid such as a fatty acid. The hydrophobic moiety can comprise a hydrocarbon. The hydrocarbon can be linear. The hydrocarbon can be nonlinear. The hydrophobic moiety can comprise a lipid moiety or a cholesterol moiety, or a combination thereof.

[0150] In some embodiments, the composition comprises an oligonucleotide that inhibits expression of MST1, wherein the oligonucleotide comprises a lipid attached at the 3' or 5' end of the oligonucleotide. In some embodiments, the lipid comprises cholesterol, myristoyl, palmitoyl, stearoyl, lithocholic acid, docosanoyl, docosahexaenoyl, myristyl, palmityl, stearyl, or α-tocopherol, or a combination thereof.

[0151] In some embodiments, the composition comprises an oligonucleotide that inhibits expression of MST1, wherein the oligonucleotide comprises a hydrophobic ligand or moiety. In some embodiments, the hydrophobic ligand or moiety comprises cholesterol. In some embodiments, the hydrophobic ligand or moiety comprises a cholesterol derivative. In some embodiments, the hydrophobic ligand or moiety is attached at the 3' end of the oligonucleotide. In some embodiments, the hydrophobic ligand or moiety is attached at the 5' end of the oligonucleotide. In some embodiments, the composition comprises a sense strand, wherein the hydrophobic ligand or moiety is attached to the sense strand (e.g., attached to the 5' end of the sense strand or attached to the 3' end of the sense strand). In some embodiments, the composition comprises an antisense strand, wherein the hydrophobic ligand or moiety is attached to the antisense strand (e.g., attached to the 5' end of the antisense strand or attached to the 3' end of the antisense strand). In some embodiments, the composition comprises a hydrophobic ligand or moiety attached at the 3' or 5' end of the oligonucleotide.

[0152] In some embodiments, the hydrophobic moiety is attached to the oligonucleotide (e.g., the sense strand and / or the antisense strand of an siRNA). In some embodiments, the hydrophobic moiety is attached at the 3' end of the oligonucleotide. In some embodiments, the hydrophobic moiety is attached at the 5' end of the oligonucleotide. In some embodiments, the hydrophobic moiety comprises cholesterol. In some embodiments, the hydrophobic moiety comprises cyclohexanyl.

[0153] In some embodiments, the composition comprises an oligonucleotide that inhibits MST1 expression, wherein the oligonucleotide comprises a lipid attached at the 3' or 5' end of the oligonucleotide. In some embodiments, the lipid is attached at the 3' end of the oligonucleotide. In some embodiments, the lipid is attached at the 5' end of the oligonucleotide. In some embodiments, the lipid comprises cholesterol, myristoyl, palmitoyl, stearoyl, lithocholoyl, docosanoyl, docosahexaenoyl, myristyl, palmityl, stearyl, or α-tocopherol, or a combination thereof. In some embodiments, the lipid comprises stearyl, lithocholoyl, docosanyl, docosahexaenyl, or myristyl. In some embodiments, the lipid comprises cholesterol. In some embodiments, the lipid comprises a sterol, such as cholesterol. In some embodiments, the lipid comprises stearyl, t-butylphenol, n-butylphenol, octylphenol, dodecylphenol, phenyl n-dodecyl, octadecylbenzamide, hexadecylbenzamide, or octadecylcyclohexyl. In some embodiments, the lipid comprises phenyl para C12.

[0154] In some embodiments, the oligonucleotide has the structure:

[0155] [ka] In some embodiments, the oligonucleotide has the structure:

[0156] [ka] In some embodiments, the oligonucleotide has the structure:

[0157] [ka] In some embodiments, the oligonucleotide has the structure:

[0158] [ka] The oligonucleotides may include any of the structures shown, including the entire structure, or may include a lipid moiety. In some embodiments, n is 1-3. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, R is an alkyl group. In some embodiments, the alkyl group contains 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbons. In some embodiments, the alkyl group contains 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 carbons, or a range defined by any two of the foregoing numbers. In some embodiments, the alkyl group contains 4-18 carbons. In some embodiments, the lipid moiety comprises an alcohol or ether.

[0159] In some embodiments, the lipid comprises a fatty acid. In some embodiments, the lipid comprises a lipid shown in Table 1. The example lipid moieties in Table 1 are shown attached at the 5' end of the oligonucleotide, and the 5' terminal phosphate of the oligonucleotide is shown with the lipid moiety. In some embodiments, the lipid moieties in Table 1 can be attached at a different attachment point than that shown. For example, the attachment point of any of the lipid moieties in the table can be at the 3' end of the oligonucleotide. In some embodiments, lipids are used to target oligonucleotides to non-hepatic cells or tissues.

[0160] [Table 1-1]

[0161] [Table 1-2]

[0162] In some embodiments, the lipid or lipid moiety contains 16-18 carbons. In some embodiments, the lipid contains 16 carbons. In some embodiments, the lipid contains 17 carbons. In some embodiments, the lipid contains 18 carbons. In some embodiments, the lipid moiety contains 16 carbons. In some embodiments, the lipid moiety contains 17 carbons. In some embodiments, the lipid moiety contains 18 carbons.

[0163] The hydrophobic portion may include a linker containing a carbocycle. The carbocycle may be six-membered. Some examples of carbocycles include phenyl or cyclohexyl. The linker may include phenyl. The linker may include cyclohexyl. The lipid is attached to the carbocycle and then attached to the phosphate (e.g., the 5' or 3' phosphate) of the oligonucleotide. In some embodiments, the lipid or hydrocarbon and the sense end are connected to the phenyl or cyclohexyl linker in a 1,4, 1,3, or 1,2 substitution pattern (e.g., para, meta, or ortho phenyl configuration). In some embodiments, the lipid or hydrocarbon and the sense end are connected to the phenyl or cyclohexyl linker in a 1,4 substitution pattern (e.g., paraphenyl configuration). The lipid may be attached to the carbocycle in a 1,4 substitution pattern relative to the oligonucleotide. The lipid may be attached to the carbocycle in a 1,3 substitution pattern relative to the oligonucleotide. The lipid may be attached to the carbocycle in a 1,2 substitution pattern relative to the oligonucleotide. The lipid may be attached to the carbocycle in an ortho configuration relative to the oligonucleotide. The lipid may be attached to the carbocycle in the para configuration relative to the oligonucleotide. The lipid may be attached to the carbocycle in the meta configuration relative to the oligonucleotide.

[0164] The lipid portion has the following structure:

[0165] [ka] In some embodiments, the lipid moiety may comprise or consist of the structure:

[0166] [ka] In some embodiments, the lipid moiety comprises or consists of the structure:

[0167] [ka] In some embodiments, the lipid moiety comprises the structure:

[0168] [ka] In some embodiments, n comprises or consists of: In some embodiments, the dotted line indicates a covalent connection. The covalent connection can be between the ends of the sense or antisense strand. For example, the connection can be to the 5' end of the sense strand. In some embodiments, n is 0 to 3. In some embodiments, n is 1 to 3. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, R is an alkyl group. In some embodiments, the alkyl group contains 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbons. In some embodiments, the alkyl group contains 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 carbons, or a range defined by any two of the foregoing numbers. In some embodiments, R comprises or consists of an alkyl group containing 4 to 18 carbons. In some embodiments, R is not octane. In some embodiments, R is a carbon containing 4 to 7 or 9 to 18 carbons. In some embodiments, the lipid moiety is not a phenyloctyl group.

[0169] In some embodiments, the 5' hydrophobic portion has the structure:

[0170] [ka] where the dotted line indicates a covalent attachment of the 5'-end of the sense strand to the terminus, n is 1-3, and R is an alkyl group containing 4-18 carbons. In some embodiments, R is not octane. In some embodiments, the alkyl group contains 4-7 or 9-18 carbons. In some embodiments, the alkyl group contains 14 carbons. In some embodiments, the alkyl group contains 15 carbons. In some embodiments, the alkyl group contains 16 carbons. In some embodiments, the alkyl group contains 17 carbons. In some embodiments, the alkyl group contains 18 carbons. In some embodiments, the 5' hydrophobic portion comprises a hydrophobic moiety of Table 1. In some embodiments, the 5' hydrophobic portion comprises phenyl para-C12. In some embodiments, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14. In some embodiments, n is 0-3. In some embodiments, n is 1-3. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, the hydrophobic moiety comprises an alcohol or an ether. In some embodiments, R is an unsaturated alkyl group. In some embodiments, the unsaturated alkyl group may be monounsaturated. In some embodiments, the unsaturated alkyl group may be unsaturated at the omega-3, omega-4, omega-5, omega-6, omega-7, omega-8, omega-9 position, or a combination thereof. In some embodiments, the 5' hydrophobic moiety is not a phenyloctyl group.

[0171] The hydrophobic portion may include a linker comprising a carbocycle. The carbocycle may be six-membered. Some examples of carbocycles include phenyl or cyclohexyl. The linker may include phenyl. The linker may include cyclohexyl. The lipid is attached to the carbocycle and then attached to the phosphate (e.g., the 5' or 3' phosphate) of the oligonucleotide. In some embodiments, the lipid or hydrocarbon and the sense end are connected to the phenyl or cyclohexyl linker in a 1,4, 1,3, or 1,2 substitution pattern (e.g., para, meta, or ortho phenyl configuration). In some embodiments, the lipid or hydrocarbon and the sense end are connected to the phenyl or cyclohexyl linker in a 1,4 substitution pattern (e.g., paraphenyl configuration). The lipid may be attached to the carbocycle in the ortho configuration relative to the oligonucleotide. The lipid may be attached to the carbocycle in the para configuration relative to the oligonucleotide. The lipid may be attached to the carbocycle in the meta configuration relative to the oligonucleotide. The lipid may be attached to the carbocycle in the 1,4 configuration relative to the oligonucleotide. The lipid may be attached to the carbocycle in a 1,3 configuration relative to the oligonucleotide. The lipid may be attached to the carbocycle in a 1,2 configuration relative to the oligonucleotide.

[0172] The lipid may be attached at the 5' end of the oligonucleotide. The 5' end may have one phosphate linking the lipid moiety to the 5' carbon of the sugar of the oligonucleotide. The 5' end may have two phosphates linking the lipid moiety to the 5' carbon of the sugar of the oligonucleotide. The 5' end may have three phosphates linking the lipid moiety to the 5' carbon of the sugar of the oligonucleotide. The 5' end may have one phosphate attached to the 5' carbon of the sugar of the oligonucleotide, one phosphate attached to the lipid moiety. The 5' end may have two phosphates attached to the 5' carbon of the sugar of the oligonucleotide, one of the two phosphates attached to the lipid moiety. The 5' end may have three phosphates attached to the 5' carbon of the sugar of the oligonucleotide, one of the three phosphates attached to the lipid moiety. The sugar may comprise a ribose. The sugar may comprise a deoxyribose. The sugar may be modified, such as a 2'-modified sugar (e.g., 2'-O-methyl or 2'-fluororibose). The 5'-terminal phosphate may contain modifications such as sulfur instead of oxygen. The two 5'-terminal phosphates may contain modifications such as sulfur instead of oxygen. The three 5'-terminal phosphates may contain modifications such as sulfur instead of oxygen.

[0173] In some embodiments, the oligonucleotide comprises one lipid moiety. In some embodiments, the oligonucleotide comprises two lipid moieties. In some embodiments, the oligonucleotide comprises three lipid moieties. In some embodiments, the oligonucleotide comprises four lipid moieties.

[0174] Some embodiments relate to a method for producing an oligonucleotide containing a hydrophobic conjugate. The strategy for producing a hydrophobic conjugate can include the use of a phosphoramidite reagent based on a six-membered ring alcohol such as phenol or cyclohexanol. The phosphoramidite can react with a nucleotide to connect the nucleotide to a hydrophobic moiety, thereby producing a hydrophobic conjugate. Some examples of phosphoramidite reagents that can be used to produce a hydrophobic conjugate are provided as follows:

[0175] [ka] In some embodiments, n is 1 to 3. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, R is an alkyl group. In some embodiments, the alkyl group contains 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbons. In some embodiments, the alkyl group contains 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 carbons, or a range defined by any two of the foregoing numbers. In some embodiments, R comprises or consists of an alkyl group containing 4 to 18 carbons. Any one of the phosphoramidite reagents can react with the 5' end of an oligonucleotide to produce an oligonucleotide containing a hydrophobic moiety. In some embodiments, the phosphoramidite reagent reacts with the 5' end of the sense strand of an siRNA. Then, the sense strand can be hybridized with the antisense strand to form a duplex.Hybridization can be carried out by incubating the sense and antisense strands in a solution at a given temperature.The temperature can be gradually lowered.The temperature can include or comprise the temperature that includes the annealing temperature for the sense and antisense strands.The temperature can include or comprise a temperature that is lower than the annealing temperature for the sense and antisense strands.The temperature can also be lower than the melting temperature of the sense and antisense strands.

[0176] The lipid may be attached to the oligonucleotide by a linker, which may comprise polyethylene glycol (e.g., tetraethylene glycol).

[0177] The modifications described herein can be useful for delivery to cells or tissues, e.g., extrahepatic delivery or targeting of oligonucleotide compositions. The modifications described herein can be useful for targeting of oligonucleotide compositions to cells or tissues.

[0178] 2.Sugar part In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of MST1, wherein the oligonucleotide comprises a sugar moiety. The sugar moiety may comprise an N-acetylgalactose moiety (e.g., an N-acetylgalactosamine (GalNAc) moiety), an N-acetylglucose moiety (e.g., an N-acetylglucosamine (GlcNAc) moiety), a fucose moiety, or a mannose moiety. The sugar moiety may comprise one, two, three, or more sugar molecules. The sugar moiety may be attached at the 3' or 5' end of the oligonucleotide. The sugar moiety may comprise an N-acetylgalactose moiety. The sugar moiety may comprise an N-acetylgalactosamine (GalNAc) moiety. The sugar moiety may comprise an N-acetylglucose moiety. The sugar moiety may comprise an N-acetylglucosamine (GlcNAc) moiety. The sugar moiety may comprise a fucose moiety. The sugar moiety may comprise a mannose moiety. N-acetylglucose, GlcNAc, fucose, or mannose can be useful for targeting macrophages by targeting or binding to mannose receptors such as CD206. The sugar moiety can be useful for binding to or targeting asialoglycoprotein receptors, such as the asialoglycoprotein receptor on hepatocytes. The GalNAc moiety can bind to the asialoglycoprotein receptor. The GalNAc moiety can target hepatocytes.

[0179] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of MST1, wherein the oligonucleotide comprises an N-acetylgalactosamine (GalNAc) moiety. GalNAc can be useful for hepatocyte targeting. The GalNAc moiety can comprise a bivalent or trivalent branched linker. The oligo can be linked to one, two, or three GalNAc molecules via a bivalent or trivalent branched linker. The GalNAc can comprise one, two, three, or more GalNAc molecules. The GalNAc moiety can be linked at the 3' or 5' end of the oligonucleotide.

[0180] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of MST1, wherein the oligonucleotide comprises an N-acetylgalactosamine (GalNAc) ligand for hepatocyte targeting. In some embodiments, the composition comprises GalNAc. In some embodiments, the composition comprises a GalNAc derivative. In some embodiments, the GalNAc ligand is attached at the 3' end of the oligonucleotide. In some embodiments, the GalNAc ligand is attached at the 5' end of the oligonucleotide. In some embodiments, the composition comprises a sense strand, wherein the GalNAc ligand is attached to the sense strand (e.g., attached to the 5' end of the sense strand or attached to the 3' end of the sense strand). In some embodiments, the composition comprises an antisense strand, wherein the GalNAc ligand is attached to the antisense strand (e.g., attached to the 5' end of the antisense strand or attached to the 3' end of the antisense strand). In some embodiments, the composition comprises a GalNAc ligand attached to the 3' or 5' end of the oligonucleotide.

[0181] In some embodiments herein, a composition is disclosed comprising an oligonucleotide that inhibits the expression of MST1, wherein the oligonucleotide comprises a GalNAc moiety. The GalNAc moiety may be comprised in any of the formulas, structures, or GalNAc moieties shown below. ...

[0182] [ka] or a salt thereof, wherein J is an oligonucleotide; w is independently selected from the range of 1 to 20; v is independently selected from the range of 1 to 20; n is selected from the values ​​1 to 20, m is selected from the values ​​1 to 20, z is selected from the values ​​1 to 3, When z is 3, Y is C; If z is 2, Y is CR 6 and When z is 1, Y is C(R 6 )2, Q is Independently halogen, -CN, -NO2, -OR 7 , -SR 7 , -N(R 7 )2, C(O)R 7 , -C(O)N(R 7 )2, -N(R 7 )C(O)R 7 , -N(R 7 )C(O)N(R 7 )2, -OC(O)N(R 7 )2, -N(R 7 )C(O)OR 7 , -C(O)OR 7 , -OC(O)R 7 , -S(O)R 7 , and C 1-6 C optionally substituted with one or more groups selected from alkyl 3-10 selected from carbocyclic rings, C 1-6 the alkyl is substituted with one or more substituents independently selected from halogen, —CN, —OH, —SH, —NO, and —NH; R 1 teeth, -O-, -S-, -N(R 7 )-, -C(O)-, -C(O)N(R 7 )-, -N(R 7 )C(O)-, -N(R 7 )C(O)N(R 7 )-, -OC(O)N(R 7 )-, -N(R 7 )C(O)O-, -C(O)O-, -OC(O)-, -S(O)-, -S(O)2-, -OS(O)2-, -OP(O)(OR7)O-, -SP(O)(OR 7 )O-, -OP(S)(OR 7 )O-, -OP(O)(SR 7 )O-, -OP(O)(OR 7 )S-, -OP(O)(O -)O-, -SP(O)(O - )O-, -OP(S)(O - )O-, -OP(O)(S - )O-, -OP(O)(O - )S-, -OP(O)(OR 7 )NR 7 -, -OP(O)(N(R 7 )2)NR 7 -, -OP(OR 7 )O-, -OP(N(R 7 )2)O-, -OP(OR 7 )N(R 7 )-, and -OPN(R 7 )2NR 7 -, and R 2 are each independently Independently halogen, -OR 7 , -SR 7 , -N(R 7 )2, -C(O)R 7 , -C(O)N(R 7 )2, -N(R 7 )C(O)R 7 , -N(R 7 )C(O)N(R 7 )2, -OC(O)N(R 7 )2, -N(R 7 )C(O)OR 7 , -C(O)OR 7 , -OC(O)R 7 , and -S(O)R 7 C optionally substituted with one or more substituents selected from 1-6 alkyl, R 3 and R 4 are each independently -OR 7 , -SR 7 , -N(R 7 )2, -C(O)R 7 , -C(O)N(R 7 )2, -N(R 7 )C(O)R 7 , -N(R 7 )C(O)N(R 7 )2, -OC(O)N(R7 )2, -N(R 7 )C(O)OR 7 , -C(O)OR 7 , -OC(O)R 7 , and -S(O)R 7 is selected from R 5 are each independently -OC(O)R 7 , -OC(O)N(R 7 )2, -N(R 7 )C(O)R 7 , -N(R 7 )C(O)N(R 7 )2, -N(R 7 )C(O)OR 7 , -C(O)R 7 , -C(O)OR 7 , and -C(O)N(R 7 )2 is selected, R 6 are each independently hydrogen, Halogen, -CN, -NO2, -OR 7 , -SR 7 , -N(R 7 )2, -C(O)R 7 , -C(O)N(R 7 )2, -N(R 7 )C(O)R 7 , -N(R 7 )C(O)N(R 7 )2, -OC(O)N(R 7 )2, -N(R 7 )C(O)OR 7 , -C(O)OR 7 , -OC(O)R 7 , and -S(O)R 7 , and Independently halogen, -CN, -NO2, -OR 7 , -SR 7 , -N(R 7 )2, C(O)R 7 , -C(O)N(R 7 )2, -N(R 7 )C(O)R 7 , -N(R 7 )C(O)N(R 7)2, -OC(O)N(R 7 )2, -N(R 7 )C(O)OR 7 , -C(O)OR 7 , -OC(O)R 7 , and -S(O)R 7 C optionally substituted with one or more substituents selected from 1-6 alkyl, R 7 are each independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl (each independently halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 alkyl)2, -NH(C 1-6 alkyl), C 3-10 optionally substituted with one or more substituents selected from carbocycles, and 3- to 10-membered heterocycles, and C 3-10 Carbocycles and 3- to 10-membered heterocycles (each independently containing halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 alkyl)2, -NH(C 1-6 alkyl), C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic rings, 3- to 10-membered heterocyclic rings, and C 1-6 Optionally substituted with one or more substituents selected from haloalkyl), or a salt thereof, is described.

[0183] In some embodiments, each w is independently selected from a value of 1 to 10. In some embodiments, each w is independently selected from a value of 1 to 5. In some embodiments, each w is 1. In some embodiments, each v is independently selected from a value of 1 to 10. In some embodiments, each v is independently selected from a value of 1 to 5. In some embodiments, each v is 1. In some embodiments, n is selected from a value of 1 to 10. In some embodiments, n is selected from a value of 1 to 5. In some embodiments, n is 2. In some embodiments, m is selected from a value of 1 to 10. In some embodiments, m is selected from a value of 1 to 5. In some embodiments, m is selected from 1 and 2. In some embodiments, z is 3 and Y is C. In some embodiments, Q is independently selected from halogen, —CN, —NO2, —OR 7 , -SR 7 , -N(R 7 )2, -C(O)R 7 , -C(O)N(R 7 )2, -N(R 7 )C(O)R 7 , -N(R 7 )C(O)N(R 7 )2, -OC(O)N(R 7 )2, -N(R 7 )C(O)OR 7 , -C(O)OR 7 , -OC(O)R 7 , and -S(O)R 7 C optionally substituted with one or more substituents selected from 5-6 In some embodiments, Q is selected from carbocycles, optionally substituted with one or more substituents independently selected from halogen, —CN, —OH, —SH, —NO, and —NH. 5-6In some embodiments, Q is selected from carbocycles. In some embodiments, Q is selected from phenyl and cyclohexyl, each optionally substituted with one or more substituents independently selected from halogen, —CN, —OH, —SH, —NO2, and —NH2. In some embodiments, Q is selected from phenyl. In some embodiments, Q is selected from cyclohexyl. In some embodiments, R 1 is -OP(O)(OR 7 )O-, -SP(O)(OR 7 )O-, -OP(S)(OR 7 )O-, -OP(O)(SR 7 )O-, -OP(O)(OR 7 )S-, -OP(O)(O - )O-, -SP(O)(O - )O-, -OP(S)(O - )O-, -OP(O)(S - )O-, -OP(O)(O - )S-, -OP(O)(OR 7 )NR 7 -, -OP(O)(N(R 7 )2)NR 7 -, -OP(OR 7 )O-, -OP(N(R 7 )2)O-, -OP(OR 7 )N(R 7 )-, and -OPN(R 7 )2-NR 7 In some embodiments, R 1 is -OP(O)(OR 7 )O-, -SP(O)(OR 7 )O-, -OP(S)(OR 7 )O-, -OP(O)(SR 7 )O-, -OP(O)(OR 7 )S-, -OP(O)(O - )O-, -SP(O)(O - )O-, -OP(S)(O - )O-, -OP(O)(S - )O-, -OP(O)(O - )S-, and -OP(OR 7 )O-. In some embodiments, R 1is -OP(O)(OR 7 )O-, -OP(S)(OR 7 )O-, -OP(O)(O - )O-, -OP(S)(O - )O-, -OP(O)(S - )O-, and -OP(OR 7 )O-. In some embodiments, R 1 is -OP(O)(OR 7 )O- and -OP(OR 7 )O. In some embodiments, R 2 are independently halogen, -OR 7 , -OC(O)R 7 , -SR 7 , -N(R 7 )2, -C(O)R 7 , and -S(O)R 7 C optionally substituted with one or more substituents selected from 1-3 In some embodiments, R 2 independently -OR 7 , -OC(O)R 7 , -SR 7 , and -N(R 7 C optionally substituted with one or more substituents selected from 1-3 In some embodiments, R 2 independently -OR 7 and -OC(O)R 7 C optionally substituted with one or more substituents selected from 1-3 In some embodiments, R 3 is halogen, -OR 7 , -SR 7 , -N(R 7 )2, -C(O)R 7 , -OC(O)R 7 , and -S(O)R 7 In some embodiments, R 3 -OR 7 , -SR 7 , -OC(O)R 7 , and -N(R 7In some embodiments, R 3 -OR 7 - and -OC(O)R 7 In some embodiments, R 4 is halogen, -OR 7 , -SR 7 , -N(R 7 )2, -C(O)R 7 , -OC(O)R 7 , and -S(O)R 7 In some embodiments, R 4 -OR 7 , -SR 7 , -OC(O)R 7 , and -N(R 7 In some embodiments, R 4 -OR 7 - and -OC(O)R 7 In some embodiments, R 5 is -OC(O)R 7 , -OC(O)N(R 7 )2, -N(R 7 )C(O)R 7 , -N(R 7 )C(O)N(R 7 )2, and -N(R 7 )C(O)OR 7 In some embodiments, R 5 is -OC(O)R 7 and -N(R 7 )C(O)R 7 In some embodiments, R 7 are each independently hydrogen, and are each independently halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 alkyl)2, -NH(C 1-6 alkyl), C 3-10 C optionally substituted with one or more substituents selected from a carbocycle or a 3- to 10-membered heterocycle 1-6 In some embodiments, R 7are each independently halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 alkyl)2, and -NH(C 1-6 C optionally substituted with one or more substituents selected from 1-6 In some embodiments, R 7 are each independently a C optionally substituted with one or more substituents independently selected from halogen, —CN, —OH, and —SH. 1-6 In some embodiments, w is 1, v is 1, n is 2, m is 1 or 2, z is 3, Y is C, and Q is phenyl or cyclohexyl, each of which is independently selected from halogen, —CN, —OH, —SH, —NO, —NH, and C. 1-3 optionally substituted with one or more substituents selected from alkyl, R 1 is -OP(O)(OR 7 )O-, -OP(S)(OR 7 )O-, -OP(O)(O - )O-, -OP(S)(O - )O-, -OP(O)(S - )O-, and -OP(OR 7 )O-, and R 2 is a C1 alkyl substituted with -OH or -OC(O)CH3, and R 3 is -OH or -OC(O)CH3, and R 4 is -OH or -OC(O)CH3, and R 5 is —NH(O)CH. In some embodiments, the compound is

[0184] [ka]

[0185] [ka]

[0186] [ka]

[0187] [ka]

[0188] [ka]

[0189] [ka]

[0190] [ka] In some embodiments, the oligonucleotide (J) is attached at the 5' or 3' end of the oligonucleotide. In some embodiments, the oligonucleotide comprises DNA. In some embodiments, the oligonucleotide comprises RNA. In some embodiments, the oligonucleotide comprises one or more modified internucleoside linkages. In some embodiments, the one or more modified internucleoside linkages comprise alkyl phosphonate, phosphorothioate, methyl phosphonate, phosphorodithioate, alkyl phosphonothioate, phosphoramidate, carbamate, carbonate, phosphate triester, acetamidate, or carboxymethyl ester, or a combination thereof. In some embodiments, the oligonucleotide comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 modified internucleoside linkages. In some embodiments, the compound binds to an asialoglycoprotein receptor. In some embodiments, the compound targets hepatocytes.

[0191] Some embodiments include:

[0192] [ka] wherein J is an oligonucleotide. J may include one or more additional phosphates or one or more phosphorothioates linked to the oligonucleotide. J may include one or more additional phosphates linked to the oligonucleotide. J may include one or more phosphorothioates linked to the oligonucleotide.

[0193] Some embodiments include:

[0194] [ka] wherein J is an oligonucleotide. J may include one or more additional phosphates or one or more phosphorothioates linked to the oligonucleotide. J may include one or more additional phosphates linked to the oligonucleotide. J may include one or more phosphorothioates linked to the oligonucleotide.

[0195] Some embodiments include:

[0196] [ka] wherein J is an oligonucleotide. J may comprise one or more phosphates or phosphorothioates linked to the oligonucleotide. J may comprise one or more phosphates linked to the oligonucleotide. J may comprise a phosphate linked to the oligonucleotide. J may comprise one or more phosphorothioates linked to the oligonucleotide. J may comprise a phosphorothioate linked to the oligonucleotide.

[0197] Some embodiments include:

[0198] [ka] wherein J is an oligonucleotide. The structure in this compound bound to an oligonucleotide (J) is an example of a GalNAc moiety. J can include one or more phosphates or phosphorothioates linked to the oligonucleotide. J can include one or more phosphates linked to the oligonucleotide. J can include a phosphate linked to the oligonucleotide. J can include one or more phosphorothioates linked to the oligonucleotide. J can include a phosphorothioate linked to the oligonucleotide.

[0199] Some embodiments include:

[0200] [ka] wherein J is an oligonucleotide. J may include one or more additional phosphates or one or more phosphorothioates linked to the oligonucleotide. J may include one or more additional phosphates linked to the oligonucleotide. J may include one or more phosphorothioates linked to the oligonucleotide.

[0201] Some embodiments include:

[0202] [ka] wherein J is an oligonucleotide. J may include one or more additional phosphates or one or more phosphorothioates linked to the oligonucleotide. J may include one or more additional phosphates linked to the oligonucleotide. J may include one or more phosphorothioates linked to the oligonucleotide.

[0203] Some embodiments include:

[0204] [ka] wherein J is an oligonucleotide. J may comprise one or more phosphates or phosphorothioates linked to the oligonucleotide. J may comprise one or more phosphates linked to the oligonucleotide. J may comprise a phosphate linked to the oligonucleotide. J may comprise one or more phosphorothioates linked to the oligonucleotide. J may comprise a phosphorothioate linked to the oligonucleotide.

[0205] Some embodiments include:

[0206] [ka] wherein J is an oligonucleotide. The structure in this compound bound to the oligonucleotide (J) is sometimes referred to as "ETL17" and is an example of a GalNAc moiety. J can comprise one or more phosphates or phosphorothioates linked to the oligonucleotide. J can comprise one or more phosphates linked to the oligonucleotide. J can comprise a phosphate linked to the oligonucleotide. J can comprise one or more phosphorothioates linked to the oligonucleotide. J can comprise a phosphorothioate linked to the oligonucleotide.

[0207] Some embodiments include:

[0208] [ka] where the phosphate or "5'" indicates the connection to the oligonucleotide.

[0209] Some embodiments include:

[0210] [ka] where the phosphate or "5'" indicates the connection to the oligonucleotide.

[0211] Some embodiments include:

[0212] [ka] wherein J is an oligonucleotide and may include one or more phosphates or phosphorothioates linked to the oligonucleotide. J may include one or more phosphates linked to the oligonucleotide. J may include phosphates linked to the oligonucleotide. J may include one or more phosphorothioates linked to the oligonucleotide. J may include phosphorothioates linked to the oligonucleotide.

[0213] Some embodiments include:

[0214] [ka] wherein J is an oligonucleotide. The structure in this compound that binds to the oligonucleotide (J) is sometimes referred to as "ETL1" and is an example of a GalNAc moiety. J can include one or more phosphates or phosphorothioates linked to the oligonucleotide. J can include one or more phosphates linked to the oligonucleotide. J can include a phosphate linked to the oligonucleotide. J can include one or more phosphorothioates linked to the oligonucleotide. J can include a phosphorothioate linked to the oligonucleotide.

[0215] In some embodiments herein, a composition is disclosed comprising an oligonucleotide that inhibits expression of a target gene, wherein the oligonucleotide comprises a GalNAc moiety. The GalNAc moiety may be comprised in any of the formulas, structures, or GalNAc moieties shown below. ... comprising a GalNAc moiety of formula (III), (IV), or (V):

[0216] [ka]

[0217] [ka] or a salt thereof, wherein J is an oligonucleotide; w is independently selected from a value of 0 to 20; v is independently selected from a value of 0 to 20; n is selected from the values ​​0 to 20, m is selected from the values ​​0 to 20, p is selected from the values ​​0 to 1, w is selected from the values ​​0 to 20, t is selected from the values ​​0 to 1, x is selected from the values ​​0 to 1, r is selected from a value between 0 and 20, u is selected from the values ​​0 to 20, Q independently represents halogen, -CN, -NO2, -OR 7 , -SR 7 , -N(R 7 )2, C(O)R 7 , -C(O)N(R 7 )2, -N(R 7 )C(O)R 7 , -N(R 7 )C(O)N(R 7 )2, -OC(O)N(R7 )2, -N(R 7 )C(O)OR 7 , -C(O)OR 7 , -OC(O)R 7 , -S(O)R 7 , and C 1-6 C optionally substituted with one or more groups selected from alkyl 3-20 a carbocyclic, heterocyclic, or acyclic linker, 1-6 the alkyl is substituted with one or more substituents independently selected from halogen, —CN, —OH, —SH, —NO, and —NH; R 1 -O-, -S-, -N(R 7 )-, -C(O)-, -C(O)N(R 7 )-, -N(R 7 )C(O)-, -N(R 7 )C(O)N(R 7 )-, -OC(O)N(R 7 )-, -N(R 7 )C(O)O-, C(O)O-, -OC(O)-, -S(O)-, -S(O)2-, -OS(O)2-, -OP(O)(OR 7 )O-, -SP(O)(OR 7 )O-, -OP(S)(OR 7 )O-, -OP(O)(SR 7 )O-, -OP(O)(OR 7 )S-, -OP(O)(O - )O-, -SP(O)(O - )O-, -OP(S)(O - )O-, -OP(O)(S - )O-, -OP(O)(O - )S-, -OP(O)(OR 7 )NR 7 -, -OP(O)(N(R 7 )2)NR 7 -, -OP(OR 7 )O-, -OP(N(R 7 )2)O-, -OP(OR 7 )N(R 7 )-, and -OPN(R 7 )2NR 7-, and R 7 are each independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl (each independently halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 alkyl)2, -NH(C 1-6 alkyl), C 3-10 optionally substituted with one or more substituents selected from carbocycle, and 3- to 10-membered heterocycle, and C 3-10 Carbocycles and 3- to 10-membered heterocycles (each independently containing halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 alkyl)2, -NH(C 1-6 alkyl), C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic rings, 3- to 10-membered heterocyclic rings, and C 1-6 Optionally substituted with one or more substituents selected from haloalkyl), or a salt thereof, is described.

[0218] As used herein, the following structures are used:

[0219] [ka] wherein J is an oligonucleotide.

[0220] The structure in this compound that is linked to the oligonucleotide (J) is sometimes referred to as "L96" and is an example of a GalNAc moiety. J, in some cases, comprises one or more phosphates or phosphorothioates linked to the oligonucleotide. J, in some cases, comprises one or more phosphates linked to the oligonucleotide. J, in some cases, comprises a phosphate linked to the oligonucleotide. J, in some cases, comprises one or more phosphorothioates linked to the oligonucleotide. J, in some cases, comprises a phosphorothioate linked to the oligonucleotide.

[0221] As used herein, the following structures are used:

[0222] [ka] wherein J is an oligonucleotide.

[0223] The structure in this compound bound to the oligonucleotide (J) is sometimes referred to as "NAG37" and is an example of a GalNAc moiety. J, in some cases, comprises one or more phosphates or phosphorothioates linked to the oligonucleotide. J, in some cases, comprises one or more phosphates linked to the oligonucleotide. J, in some cases, comprises one or more phosphates linked to the oligonucleotide. J, in some cases, comprises one or more phosphorothioates linked to the oligonucleotide. J, in some cases, comprises phosphorothioates linked to the oligonucleotide.

[0224] As used herein, the following structures are used:

[0225] [ka] wherein J is an oligonucleotide.

[0226] The structure in this compound linked to the oligonucleotide (J) is, in some instances, referred to as "GluGalNAc" and is an example of a GalNAc moiety. J, in some instances, comprises one or more phosphates or phosphorothioates linked to the oligonucleotide. J, in some instances, comprises one or more phosphates linked to the oligonucleotide. J, in some instances, comprises one or more phosphates linked to the oligonucleotide. J, in some instances, comprises one or more phosphorothioates linked to the oligonucleotide. J, in some instances, comprises phosphorothioates linked to the oligonucleotide.

[0227] As used herein, the following structures are used:

[0228] [ka] wherein J and K are independently H, a GalNAc moiety, or an oligonucleotide.

[0229] In some cases, the structures in these compounds are attached to an oligonucleotide (J or K) and are referred to as "ademA GalNAc, ademG GalNAc, ademC GalNAc, or ademU GalNAc" depending on the base used in the nucleotide. In some cases, 2 to 4 GalNAc moieties are attached to the oligonucleotide. In some cases, the location of the GalNAc moiety is at the 3' or 5' end of the oligonucleotide chain (J or K = H) or internally (J and K are oligonucleotides). In some cases, J and K may contain one or more phosphates or phosphorothioates linked to the oligonucleotide. In some cases, J and K contain one or more phosphates linked to the oligonucleotide. In some cases, J and K contain phosphates linked to the oligonucleotide. In some cases, J and K contain one or more phosphorothioates linked to the oligonucleotide. In some cases, J and K contain phosphorothioates linked to the oligonucleotide.

[0230] As used herein, the following structures are used:

[0231] [ka]

[0232] [ka]

[0233] [ka]

[0234] [ka] wherein R is an oligonucleotide.

[0235] The structure in this compound bound to the oligonucleotide (R) is sometimes referred to as H1, H2, H3, H4, H5, H6, H7, or H9, and is an example of a GalNAc moiety. In some cases, R comprises one or more phosphates or phosphorothioates linked to the oligonucleotide. In some cases, R comprises one or more phosphates linked to the oligonucleotide. In some cases, R comprises phosphates linked to the oligonucleotide. In some cases, R comprises one or more phosphorothioates linked to the oligonucleotide. In some cases, R comprises phosphorothioates linked to the oligonucleotide.

[0236] As used herein, the following structures are used:

[0237] [ka] A sugar moiety comprising the formula: is provided, where J is an oligonucleotide. The structure in this compound bound to an oligonucleotide (J) is sometimes referred to as "K2GalNAc" and is an example of a GalNAc moiety. J, in some instances, comprises one or more phosphates or phosphorothioates linked to the oligonucleotide. J, in some instances, comprises one or more phosphates linked to the oligonucleotide. J, in some instances, comprises a phosphate linked to the oligonucleotide. J, in some instances, comprises one or more phosphorothioates linked to the oligonucleotide. J, in some instances, comprises a phosphorothioate linked to the oligonucleotide.

[0238] As used herein, the following structures are used:

[0239] [ka] A sugar moiety comprising the formula: is provided, wherein J is an oligonucleotide and X is S or O. The structure in this compound bound to the oligonucleotide (J) is, in some instances, referred to as "ST23" and is an example of a GalNAc moiety. J, in some instances, comprises one or more phosphates or phosphorothioates linked to the oligonucleotide. J, in some instances, comprises one or more phosphates linked to the oligonucleotide. J, in some instances, comprises a phosphate linked to the oligonucleotide. J, in some instances, comprises one or more phosphorothioates linked to the oligonucleotide. J, in some instances, comprises a phosphorothioate linked to the oligonucleotide.

[0240] As used herein, the following structures are used:

[0241] [ka] A sugar moiety comprising the formula: is provided, where J is an oligonucleotide. The structure in this compound bound to the oligonucleotide (J) is, in some instances, referred to as "GalNAc23" and is an example of a GalNAc moiety. J, in some instances, comprises one or more phosphates or phosphorothioates linked to the oligonucleotide. J, in some instances, comprises one or more phosphates linked to the oligonucleotide. J, in some instances, comprises a phosphate linked to the oligonucleotide. J, in some instances, comprises one or more phosphorothioates linked to the oligonucleotide. J, in some instances, comprises a phosphorothioate linked to the oligonucleotide.

[0242] As used herein, the following structures are used:

[0243] [ka] wherein J or K comprises an oligonucleotide.

[0244] The structures in these compounds are sometimes linked to an oligonucleotide (J or K) and are referred to as "PyrGalNAc," "PipGalNAc," and "TEG-GalNAc," which are examples of GalNAc moieties. In some cases, 2 to 4 GalNAc moieties are linked to the oligonucleotide. The GalNAc moieties can be located at the 3' or 5' end of the oligonucleotide chain (J or K = H) or internally (J and K are oligonucleotides). In some cases, J and K contain one or more phosphates or phosphorothioates linked to the oligonucleotide. In some cases, J and K contain one or more phosphates linked to the oligonucleotide. In some cases, J and K contain phosphates linked to the oligonucleotide. In some cases, J and K contain one or more phosphorothioates linked to the oligonucleotide. In some cases, J and K contain phosphorothioates linked to the oligonucleotide.

[0245] As used herein, the following structures are used:

[0246] [ka] wherein J is an oligonucleotide.

[0247] The structure in this compound bound to the oligonucleotide (J) is sometimes referred to as "THA" and is an example of a GalNAc moiety. J, in some cases, comprises one or more phosphates or phosphorothioates linked to the oligonucleotide. J, in some cases, comprises one or more phosphates linked to the oligonucleotide. J, in some cases, comprises one or more phosphates linked to the oligonucleotide. J, in some cases, comprises one or more phosphorothioates linked to the oligonucleotide. J, in some cases, comprises phosphorothioates linked to the oligonucleotide.

[0248] As used herein, the following structures are used:

[0249] [ka] wherein Nu is an oligonucleotide.

[0250] The structure in this compound bound to the oligonucleotide (Nu) is sometimes referred to as "L-9" and is an example of a GalNAc moiety. Nu, in some cases, comprises one or more phosphates or phosphorothioates linked to the oligonucleotide. Nu, in some cases, comprises one or more phosphates linked to the oligonucleotide. Nu, in some cases, comprises phosphates linked to the oligonucleotide. Nu, in some cases, comprises one or more phosphorothioates linked to the oligonucleotide. Nu, in some cases, comprises phosphorothioates linked to the oligonucleotide.

[0251] As used herein, the following structures are used:

[0252] [ka] wherein J is an oligonucleotide.

[0253] The structure in this compound linked to the oligonucleotide (J) is sometimes referred to as "Sirius GalNAc" and is an example of a GalNAc moiety. J, in some cases, comprises one or more phosphates or phosphorothioates linked to the oligonucleotide. J, in some cases, comprises one or more phosphates linked to the oligonucleotide. J, in some cases, comprises one or more phosphates linked to the oligonucleotide. J, in some cases, comprises one or more phosphorothioates linked to the oligonucleotide. J, in some cases, comprises phosphorothioates linked to the oligonucleotide.

[0254] 3. siRNA modification patterns In some embodiments, the composition comprises an oligonucleotide that inhibits expression of MST1, the oligonucleotide comprising an siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises the modification pattern 1S:5'-NfsnsNfnNfnNfNfNfnNfnNfnNfnNfnNfnNfsnsn-3, where "Nf" is a 2'-fluoro-modified nucleoside, "n" is a 2'-O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the sense strand comprises the modification pattern 2S:5'-nsnsnnNfnNfNfNfNfnnnnnnnnnnsnsn-3', where "Nf" is a 2'-fluoro-modified nucleoside, "n" is a 2'-O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the sense strand comprises the modification pattern 3S:5'-nsnsnnNfnNfnNfnnnnnnnnnnsnsn-3', where "Nf" is a 2'-fluoro-modified nucleoside, "n" is a 2'-O-methyl modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the sense strand comprises the modification pattern 4S:5'-NfsnsNfnNfnNfNfNfNfNfnNfnNfnNfnNfnNfsnsnN-moiety-3', where "Nf" is a 2'-fluoro-modified nucleoside, "n" is a 2'-O-methyl modified nucleoside, "s" is a phosphorothioate linkage, and N comprises one or more nucleosides. In some embodiments, the sense strand comprises the modification pattern 5S:5'-nsnsnnNfnNfNfNfnnnnnnnnnnsnsnN-moiety-3', where "Nf" is a 2'-fluoro-modified nucleoside, "n" is a 2'-O-methyl-modified nucleoside, "s" is a phosphorothioate linkage, and N comprises one or more nucleosides. In some embodiments, a moiety in modification pattern 4S or 5S comprises an integrin-targeting ligand. In some embodiments, a moiety in modification pattern 4S or 5S is a sugar moiety. In some embodiments, the sense strand comprises the modification pattern 6S:5'-NfsnsNfnNfnNfnNfnNfnNfnNfnNfnNfnNfsnsn-3', where "Nf" is a 2'-fluoro-modified nucleoside, "n" is a 2'-O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage.In some embodiments, the sense strand comprises the modification pattern 7S:5'-nsnsnnNfNfNfNfNfnnnnnnnnnnsnsn-3', where "Nf" is a 2'-fluoro-modified nucleoside, "n" is a 2'-O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the sense strand comprises the modification pattern 8S:5'-nsnsnnnNfNfNfNfnnnnnnnnnnsnsn-3', where "Nf" is a 2'-fluoro-modified nucleoside, "n" is a 2'-O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the sense strand comprises the modification pattern 9S:5'-nsnsnnnnNfNfNfNfnnnnnnnnnsnsn-3', where "Nf" is a 2'-fluoro-modified nucleoside, "n" is a 2'-O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the sense strand comprises the modification pattern 10S:5'-snnnnNfnnnNfNfnnnnnnnnnsnsn-3', where "Nf" is a 2'-fluoro-modified nucleoside, "n" is a 2'-O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the sense strand comprises the modification pattern 11S:5'-sNfnNfnNfnNfndNnNfnnnNfnNfnnsnsn-3', where "Nf" is a 2'-fluoro-modified nucleoside, "n" is a 2'-O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the sense strand comprises the modification pattern 12S:5'-sNfnNfnNfnNfndNnnnNfnNfnnnnsnsn-3', where "Nf" is a 2'-fluoro-modified nucleoside, "n" is a 2'-O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the sense strand comprises the modification pattern 13S:5'-snnnnNfNfNfNfnNfnnnnnnnnsnsn-3', where "Nf" is a 2'-fluoro-modified nucleoside, "n" is a 2'-O-methyl modified nucleoside, and "s" is a phosphorothioate linkage.In some embodiments, the sense strand comprises the modification pattern 14S:5'-snnnnnNfNfNfNfnnnnnnnnnnsnsn-3', where "Nf" is a 2'-fluoro-modified nucleoside, "n" is a 2'-O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the sense strand comprises the modification pattern 15S:5'-snnnnNfnNfnNfnnnnnnnnnnsnsn-3', where "Nf" is a 2'-fluoro-modified nucleoside, "n" is a 2'-O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the sense strand comprises the modification pattern 16S:5'-nsnsnnNfNfnNfNfnnnnnnnnnnsnsn-3', where "Nf" is a 2'-fluoro-modified nucleoside, "n" is a 2'-O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the sense strand comprises the modification pattern 17S:5'-NfsnsNfnNfnNfndNnNfnnnNfnNfnnsnsn-3', where "Nf" is a 2'-fluoro-modified nucleoside, "n" is a 2'-O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the sense strand comprises the modification pattern 18S:5'-nsnsnnnnNfNfNfNfNfnnnnnnnnsnsn-3', where "Nf" is a 2'-fluoro-modified nucleoside, "n" is a 2'-O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the sense strand comprises the modification pattern 19S:5'-nsnsnnnNfNfNfNfNfnnnnnnnnnsnsn-3', where "Nf" is a 2'-fluoro-modified nucleoside, "n" is a 2'-O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the sense strand comprises the modification pattern 20S:5'-snnnnnNfnNfNfnnnnnnnnnnsnsn-3', where "Nf" is a 2'-fluoro-modified nucleoside, "n" is a 2'-O-methyl modified nucleoside, and "s" is a phosphorothioate linkage.In some embodiments, the sense strand comprises the modification pattern 21S:5'-snnnnnnNfNfNfNfNfnnnnnnnnsnsn-3', where "Nf" is a 2'-fluoro-modified nucleoside, "n" is a 2'-O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the sense strand comprises the modification pattern 22S:5'-snnnnNfNfnnNfnnnnnnnnnnsnsn-3', where "Nf" is a 2'-fluoro-modified nucleoside, "n" is a 2'-O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the sense strand comprises the modification pattern 23S:5'-snnnnNfNfnNfNfnnnnnnnnnnsnsn-3', where "Nf" is a 2'-fluoro-modified nucleoside, "n" is a 2'-O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the sense strand comprises the modification pattern 24S:5'-snnnnnNfNfNfNfnnnnnnnnnsnsn-3', where "Nf" is a 2'-fluoro-modified nucleoside, "n" is a 2'-O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the sense strand comprises the modification pattern 25S:5'-snnnnnnNfnNfnNfnnnnnnnnsnsn-3', where "Nf" is a 2'-fluoro-modified nucleoside, "n" is a 2'-O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the sense strand comprises the modification pattern 26S:5'-snnnnnNfnnNfnNfnnnnnnnnsnsn-3', where "Nf" is a 2'-fluoro-modified nucleoside, "n" is a 2'-O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the sense strand comprises the modification pattern 27S:5'-snnnnNfnnNfNfNfNfnnnnnnnnsnsn-3', where "Nf" is a 2'-fluoro-modified nucleoside, "n" is a 2'-O-methyl modified nucleoside, and "s" is a phosphorothioate linkage.In some embodiments, the sense strand comprises the modification pattern 28S:5'-snnnnnNfNfNfNfNfnnnnnnnnnsnsn-3', where "Nf" is a 2'-fluoro-modified nucleoside, "n" is a 2'-O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the sense strand comprises the modification pattern 29S:5'-snnnnnNfnnNfNfnnnnnnnnnsnsn-3', where "Nf" is a 2'-fluoro-modified nucleoside, "n" is a 2'-O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the sense strand comprises the modification pattern 30S:5'-snnnnnnNfnNfNfnnnnnnnnnsnsn-3', where "Nf" is a 2'-fluoro-modified nucleoside, "n" is a 2'-O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the sense strand comprises the modification pattern 31S:5'-snnnnNfNfnnNfNfnnnnnnnnnsnsn-3', where "Nf" is a 2'-fluoro-modified nucleoside, "n" is a 2'-O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the sense strand comprises the modification pattern 32S:5'-snnnnNfnnNfNfnnnnnnnnnnsnsn-3', where "Nf" is a 2'-fluoro-modified nucleoside, "n" is a 2'-O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the sense strand comprises the modification pattern 33S:5'-snnnnNfndNnNfnNfnnnnnnnnsnsn-3', where "Nf" is a 2'-fluoro-modified nucleoside, "n" is a 2'-O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the sense strand comprises the modification pattern 34S:5'-snnnnnnnnNfdNNfnnnnnnnnsnsn-3', where "Nf" is a 2'-fluoro-modified nucleoside, "n" is a 2'-O-methyl modified nucleoside, and "s" is a phosphorothioate linkage.In some embodiments, the sense strand comprises the modification pattern 35S:5'-snnnnNfnnnNfnNfnnnnnnnnsnsn-3', where "Nf" is a 2'-fluoro-modified nucleoside, "n" is a 2'-O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the sense strand comprises the modification pattern 36S:5'-snnnnnnNfNfnNfnnnnnnnnsnsn-3', where "Nf" is a 2'-fluoro-modified nucleoside, "n" is a 2'-O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the sense strand comprises the modification pattern 37S:5'-snnnnnnNfdNNfnNfnnnnnnnnsnsn-3', where "Nf" is a 2'-fluoro-modified nucleoside, "n" is a 2'-O-methyl modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the sense strand comprises the modification pattern 38S:5'-snnnnnnndNNfNfnNfnnn. '-snnnnNfnNfnNfnnnnnnnnsnsn-3', where "Nf" is a 2'-fluoro-modified nucleoside, "n" is a 2'-O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the sense strand comprises the modification pattern 39S:5'-snnnnNfnNfnNfnNfnnnnnnnnsnsn-3', where "Nf" is a 2'-fluoro-modified nucleoside, "n" is a 2'-O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the sense strand comprises the modification pattern 40S:5'-snnnnNfnnNfNfnNfnnnnnnnnsnsn-3', where "Nf" is a 2'-fluoro-modified nucleoside, "n" is a 2'-O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage.

[0255] In some embodiments, the composition comprises an oligonucleotide that inhibits expression of MST1, the oligonucleotide comprising an siRNA comprising a sense strand and an antisense strand, wherein the antisense strand comprises a modification pattern 1AS:5'-nsNfsnNfnNfnNfnNfnnnNfnNfnsnsn-3', where "Nf" is a 2'-fluoro-modified nucleoside, "n" is a 2'-O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the antisense strand comprises a modification pattern 2AS:5'-nsNfsnnnNfnNfNfNfnnnnNfnNfnnnsnsn-3', where "Nf" is a 2'-fluoro-modified nucleoside, "n" is a 2'-O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the antisense strand comprises the modification pattern 3AS:5'-nsNfsnnnNfnnnnnnnNfnNfnnnsnsn-3', where "Nf" is a 2'-fluoro-modified nucleoside, "n" is a 2'-O-methyl modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the antisense strand comprises the modification pattern 4AS:5'-nsNfsnNfnNfnnnnnnnNfnNfnnnsnsn-3', where "Nf" is a 2'-fluoro-modified nucleoside, "n" is a 2'-O-methyl modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the antisense strand comprises the modification pattern 5AS:5'-nsNfsnnnnnnnnnnnNfnNfnnnsnsn-3', where "Nf" is a 2'-fluoro-modified nucleoside, "n" is a 2'-O-methyl modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the antisense strand comprises the modification pattern 6AS:5'-nsNfsnnnNfnnNfnnnnNfnNfnnnsnsn-3', where "Nf" is a 2'-fluoro-modified nucleoside, "n" is a 2'-O-methyl modified nucleoside, and "s" is a phosphorothioate linkage.In some embodiments, the antisense strand comprises the modification pattern 7AS:5'-nsNfsnNfnNfnNfnNfnNfnNfnNfnNfnsnsn-3', where "Nf" is a 2'-fluoro-modified nucleoside, "n" is a 2'-O-methyl modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the antisense strand comprises the modification pattern 8AS:5'-nsNfsnnnnnnnnnnnNfnnnnnsnsn-3', where "Nf" is a 2'-fluoro-modified nucleoside, "n" is a 2'-O-methyl modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the antisense strand comprises the modification pattern 9AS:5'-nsNfsnNfnnnNfnnnNfnNfnNfnNfnsnsn-3', where "Nf" is a 2'-fluoro-modified nucleoside, "n" is a 2'-O-methyl modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the antisense strand comprises the modification pattern 10AS:5'-nsNfsnNfnNfnnnNfnNfnNfnNfnNfnsnsn-3', where "Nf" is a 2'-fluoro-modified nucleoside, "n" is a 2'-O-methyl modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the antisense strand comprises the modification pattern 11AS:5'-nsNfsnNfnNfnnnnnNfnNfnNfnNfnsnsn-3', where "Nf" is a 2'-fluoro-modified nucleoside, "n" is a 2'-O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the antisense strand comprises the modification pattern 12AS:5'-nsNfsnNfnnNfNfnNfnNfnNfnNfnNfnsnsn-3', where "Nf" is a 2'-fluoro-modified nucleoside, "n" is a 2'-O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the antisense strand comprises the modification pattern 13AS: 5'-nsNfsnNfnnnNfnNfnNfnNfnNfnNfnsnsn-3', where "Nf" is a 2'-fluoro-modified nucleoside, "n" is a 2'-O-methyl modified nucleoside, and "s" is a phosphorothioate linkage.In some embodiments, the antisense strand comprises the modification pattern 14AS:5'-nsNfsnnNfnNfnnNfnNfnNfnNfnNfnsnsn-3', where "Nf" is a 2'-fluoro-modified nucleoside, "n" is a 2'-O-methyl modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the antisense strand comprises the modification pattern 15AS:5'-nsNfsnnnnNfnnNfnNfnNfnNfnNfnsnsn-3', where "Nf" is a 2'-fluoro-modified nucleoside, "n" is a 2'-O-methyl modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the antisense strand comprises the modification pattern 16AS:5'-nsNfsnnnNfnnnNfnNfnNfnNfnNfnsnsn-3', where "Nf" is a 2'-fluoro-modified nucleoside, "n" is a 2'-O-methyl modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the antisense strand comprises the modification pattern 17AS:5'-nsNfsnNfnnNfnnNfnNfnNfnNfnNfnsnsn-3', where "Nf" is a 2'-fluoro-modified nucleoside, "n" is a 2'-O-methyl modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the antisense strand comprises the modification pattern 18AS:5'-nsNfsnnnNfnNfnNfnNfnNfnNfnNfnsnsn-3', where "Nf" is a 2'-fluoro-modified nucleoside, "n" is a 2'-O-methyl modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the antisense strand comprises the modification pattern 19AS:5'-nsNfsnNfnNfnNfnNfnnnNfnNfnNfnsnsn-3', where "Nf" is a 2'-fluoro-modified nucleoside, "n" is a 2'-O-methyl modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the antisense strand comprises the modification pattern 20AS: 5'-nsNfsnnnNfnNfnnnNfnNfnNfnNfnsnsn-3', where "Nf" is a 2'-fluoro-modified nucleoside, "n" is a 2'-O-methyl modified nucleoside, and "s" is a phosphorothioate linkage.In some embodiments, the antisense strand comprises the modification pattern 21AS:5'-nsNfsnnNfnnnnNfnNfnNfnNfnNfnsnsn-3', where "Nf" is a 2'-fluoro-modified nucleoside, "n" is a 2'-O-methyl modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the antisense strand comprises the modification pattern 22AS:5'-nsNfsnnnnNfnnnnNfnNfnNfnNfnsnsn-3', where "Nf" is a 2'-fluoro-modified nucleoside, "n" is a 2'-O-methyl modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the antisense strand comprises the modification pattern 23AS:5'-nsNfsnnnnNfnnNfnnnNfnNfnNfnsnsn-3', where "Nf" is a 2'-fluoro-modified nucleoside, "n" is a 2'-O-methyl modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the antisense strand comprises the modification pattern 24AS:5'-nsNfsnNfnnNfnNfnnNfnNfnNfnNfnsnsn-3', where "Nf" is a 2'-fluoro-modified nucleoside, "n" is a 2'-O-methyl modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the antisense strand comprises the modification pattern 24AS:5'-nsNfsnNfnnNfnNfnnNfnNfnNfnNfnsnsn-s' (SEQ ID NO: 6671), where "Nf" is a 2'-fluoro-modified nucleoside, "n" is a 2'-O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the antisense strand comprises the modification pattern 25AS:5'-nsNfsnnnNfnNfnNfnNfnNfnNfnNfnnnsnsn-s' (SEQ ID NO: 6720), where "Nf" is a 2'-fluoro-modified nucleoside, "n" is a 2'-O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage.In some embodiments, the antisense strand comprises modification pattern 26AS:5'-nsNfsnnnNfnNfnNfnnnnNfnNfnsnsn-s' (SEQ ID NO: 6721), where "Nf" is a 2'-fluoro-modified nucleoside, "n" is a 2'-O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the antisense strand comprises modification pattern 27AS:5'-nsNfsnnnNfnNfnnnnnNfnNfnsnsn-s' (SEQ ID NO: 6722), where "Nf" is a 2'-fluoro-modified nucleoside, "n" is a 2'-O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the antisense strand comprises the modification pattern 28AS:5'-nsNfsnnnNfnNfnnnnnNfnNfnnnsnsn-s' (SEQ ID NO: 6723), where "Nf" is a 2'-fluoro-modified nucleoside, "n" is a 2'-O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the antisense strand comprises the modification pattern 29AS:5'-nsNfsnnNfnNfnnNfnnNfnnNfnNfnsnsn-s' (SEQ ID NO: 6724), where "Nf" is a 2'-fluoro-modified nucleoside, "n" is a 2'-O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the antisense strand comprises the modification pattern 30AS: 5'-nsNfsnnNfnNfnnNfnnnNfnNfnnnsnsn-s' (SEQ ID NO: 6725), where "Nf" is a 2'-fluoro-modified nucleoside, "n" is a 2'-O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage.

[0256] In some embodiments, the antisense strand comprises the modification pattern 31AS: 5'-nsNfsnnNfnNfnnnnNfnNfnNfnNfnsnsn-s' (SEQ ID NO: 6726), where "Nf" is a 2'-fluoro-modified nucleoside, "n" is a 2'-O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage.

[0257] In some embodiments, the composition comprises an oligonucleotide that inhibits expression of MST1, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises pattern 1S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, or 31AS. In some embodiments, the sense strand comprises pattern 2S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, or 31AS. In some embodiments, the sense strand comprises pattern 3S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, or 31AS. In some embodiments, the sense strand comprises pattern 4S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, or 31AS.In some embodiments, the sense strand comprises pattern 5S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, or 31AS. In some embodiments, the sense strand comprises pattern 6S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, or 31AS. In some embodiments, the sense strand comprises pattern 7S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, or 31AS. In some embodiments, the sense strand comprises pattern 8S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, or 31AS. In some embodiments, the sense strand comprises pattern 9S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, or 31AS.In some embodiments, the sense strand comprises pattern 10S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, or 31AS. In some embodiments, the sense strand comprises pattern 11S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, or 31AS. In some embodiments, the sense strand comprises pattern 12S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, or 31AS. In some embodiments, the sense strand comprises pattern 13S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, or 31AS. In some embodiments, the sense strand comprises pattern 14S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, or 31AS.In some embodiments, the sense strand comprises pattern 15S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, or 31AS. In some embodiments, the sense strand comprises pattern 16S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, or 31AS. In some embodiments, the sense strand comprises pattern 17S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, or 31AS. In some embodiments, the sense strand comprises pattern 18S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, or 31AS. In some embodiments, the sense strand comprises pattern 19S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, or 31AS.In some embodiments, the sense strand comprises pattern 20S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, or 31AS. In some embodiments, the sense strand comprises pattern 21S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, or 31AS. In some embodiments, the sense strand comprises pattern 22S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, or 31AS. In some embodiments, the sense strand comprises pattern 23S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, or 31AS. In some embodiments, the sense strand comprises pattern 24S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, or 31AS.In some embodiments, the sense strand comprises pattern 25S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, or 31AS. In some embodiments, the sense strand comprises pattern 26S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, or 31AS. In some embodiments, the sense strand comprises pattern 27S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS. , 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, or 31AS. In some embodiments, the sense strand comprises pattern 28S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, or 31AS. In some embodiments, the sense strand comprises pattern 29S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, or 31AS. In some embodiments, the sense strand comprises pattern 30S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, or 31AS. In some embodiments, the sense strand comprises pattern 31S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, or 31AS.In some embodiments, the sense strand comprises pattern 32S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, or 31AS. In some embodiments, the sense strand comprises pattern 33S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, or 31AS. In some embodiments, the sense strand comprises pattern 34S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, or 31AS. In some embodiments, the sense strand comprises pattern 35S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, or 31AS. In some embodiments, the sense strand comprises pattern 36S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, or 31AS.In some embodiments, the sense strand comprises pattern 37S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, or 31AS. In some embodiments, the sense strand comprises pattern 38S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, or 31AS. In some embodiments, the sense strand comprises pattern 39S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, or 31AS. In some embodiments, the sense strand comprises pattern 40S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, or 31AS.

[0258] In some embodiments, the sense strand comprises the pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, or 40S, and the antisense strand comprises 1AS. In some embodiments, the sense strand comprises the pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, or 40S, and the antisense strand comprises 2AS. In some embodiments, the sense strand comprises the pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, or 40S, and the antisense strand comprises 3AS. In some embodiments, the sense strand comprises the pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, or 40S, and the antisense strand comprises 4AS. In some embodiments, the sense strand comprises the pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, or 40S, and the antisense strand comprises 5AS.In some embodiments, the sense strand comprises the pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, or 40S, and the antisense strand comprises 6AS. In some embodiments, the sense strand comprises the pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, or 40S, and the antisense strand comprises 7AS. In some embodiments, the sense strand comprises the pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, or 40S, and the antisense strand comprises 8AS. In some embodiments, the sense strand comprises the pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, or 40S, and the antisense strand comprises 9AS. In some embodiments, the sense strand comprises the pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, or 40S, and the antisense strand comprises 10AS.In some embodiments, the sense strand comprises the pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, or 40S, and the antisense strand comprises 11AS. In some embodiments, the sense strand comprises the pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, or 40S, and the antisense strand comprises 12AS. In some embodiments, the sense strand comprises the pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, or 40S, and the antisense strand comprises 13AS. In some embodiments, the sense strand comprises the pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, or 40S, and the antisense strand comprises 14AS. In some embodiments, the sense strand comprises the pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, or 40S, and the antisense strand comprises 15AS.In some embodiments, the sense strand comprises the pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, or 40S, and the antisense strand comprises 16AS. In some embodiments, the sense strand comprises the pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, or 40S, and the antisense strand comprises 17AS. In some embodiments, the sense strand comprises the pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, or 40S, and the antisense strand comprises 18AS. In some embodiments, the sense strand comprises the pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, or 40S, and the antisense strand comprises 19AS. In some embodiments, the sense strand comprises the pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, or 40S, and the antisense strand comprises 20AS.In some embodiments, the sense strand comprises the pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, or 40S, and the antisense strand comprises 21AS. In some embodiments, the sense strand comprises the pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, or 40S, and the antisense strand comprises 22AS. In some embodiments, the sense strand comprises the pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, or 40S, and the antisense strand comprises 23AS. In some embodiments, the sense strand comprises the pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, or 40S, and the antisense strand comprises 24AS. In some embodiments, the sense strand comprises the pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, or 40S, and the antisense strand comprises 25AS.In some embodiments, the sense strand comprises the pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, or 40S, and the antisense strand comprises 26AS. In some embodiments, the sense strand comprises the pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19. S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, or 40S, and the antisense strand comprises 27AS. In some embodiments, the sense strand comprises the pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, or 40S, and the antisense strand comprises 28AS. In some embodiments, the sense strand comprises the pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, or 40S, and the antisense strand comprises 29AS. In some embodiments, the sense strand comprises the pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, or 40S, and the antisense strand comprises 30AS. In some embodiments, the sense strand comprises the pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, or 40S, and the antisense strand comprises 31AS.

[0259] In some embodiments, the sense strand comprises modification pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, or 31AS. In some embodiments, the antisense strand comprises modification pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, or 40S. In some embodiments, the sense strand or the antisense strand comprises modification pattern ASO1.

[0260] In some embodiments, the purines in the sense strand comprise 2'-fluoro modified purines. In some embodiments, the purines in the sense strand comprise 2'-O-methyl modified purines. In some embodiments, the purines in the sense strand comprise a mixture of 2'-fluoro and 2'-O-methyl modified purines. In some embodiments, all of the purines in the sense strand comprise 2'-fluoro modified purines. In some embodiments, all of the purines in the sense strand comprise 2'-O-methyl modified purines. In some embodiments, all of the purines in the sense strand comprise a mixture of 2'-fluoro and 2'-O-methyl modified purines.

[0261] In some embodiments, the pyrimidines of the sense strand comprise 2'-fluoro modified pyrimidines. In some embodiments, the pyrimidines of the sense strand comprise 2'-O-methyl modified pyrimidines. In some embodiments, the pyrimidines of the sense strand comprise a mixture of 2'-fluoro and 2'-O-methyl modified pyrimidines. In some embodiments, all of the pyrimidines of the sense strand comprise 2'-fluoro modified pyrimidines. In some embodiments, all of the pyrimidines of the sense strand comprise 2'-O-methyl modified pyrimidines. In some embodiments, all of the pyrimidines of the sense strand comprise a mixture of 2'-fluoro and 2'-O-methyl modified pyrimidines.

[0262] In some embodiments, the purines of the sense strand comprise 2'-fluoro modified purines, and the pyrimidines of the sense strand comprise a mixture of 2'-fluoro and 2'-O-methyl modified pyrimidines. In some embodiments, the purines of the sense strand comprise 2'-O-methyl modified purines, and the pyrimidines of the sense strand comprise a mixture of 2'-fluoro and 2'-O-methyl modified pyrimidines. In some embodiments, the purines of the sense strand comprise 2'-fluoro modified purines, and the pyrimidines of the sense strand comprise 2'-O-methyl modified pyrimidines. In some embodiments, the purines of the sense strand comprise 2'-O-methyl modified purines, and the pyrimidines of the sense strand comprise 2'-fluoro modified pyrimidines. In some embodiments, the pyrimidines of the sense strand comprise 2'-fluoro modified pyrimidines, and the purines of the sense strand comprise a mixture of 2'-fluoro and 2'-O-methyl modified purines. In some embodiments, the pyrimidines of the sense strand comprise 2'-O-methyl modified pyrimidines, and the purines of the sense strand comprise a mixture of 2'-fluoro and 2'-O-methyl modified purines. In some embodiments, the pyrimidines of the sense strand comprise 2'-fluoro modified pyrimidines, and the purines of the sense strand comprise 2'-O-methyl modified purines. In some embodiments, the pyrimidines of the sense strand comprise 2'-O-methyl modified pyrimidines, and the purines of the sense strand comprise 2'-fluoro modified purines.

[0263] In some embodiments, all purines in the sense strand comprise 2'-fluoro modified purines, and all pyrimidines in the sense strand comprise a mixture of 2'-fluoro and 2'-O-methyl modified pyrimidines. In some embodiments, all purines in the sense strand comprise 2'-O-methyl modified purines, and all pyrimidines in the sense strand comprise a mixture of 2'-fluoro and 2'-O-methyl modified pyrimidines. In some embodiments, all purines in the sense strand comprise 2'-fluoro modified purines, and all pyrimidines in the sense strand comprise 2'-O-methyl modified pyrimidines. In some embodiments, all purines in the sense strand comprise 2'-O-methyl modified purines, and all pyrimidines in the sense strand comprise 2'-fluoro modified pyrimidines. In some embodiments, all pyrimidines in the sense strand comprise 2'-fluoro modified pyrimidines, and all purines in the sense strand comprise a mixture of 2'-fluoro and 2'-O-methyl modified purines. In some embodiments, all of the pyrimidines in the sense strand comprise 2'-O-methyl modified pyrimidines, and all of the purines in the sense strand comprise a mixture of 2'-fluoro and 2'-O-methyl modified purines. In some embodiments, all of the pyrimidines in the sense strand comprise 2'-fluoro modified pyrimidines, and all of the purines in the sense strand comprise 2'-O-methyl modified purines. In some embodiments, all of the pyrimidines in the sense strand comprise 2'-O-methyl modified pyrimidines, and all of the purines in the sense strand comprise 2'-fluoro modified purines.

[0264] In some embodiments, the purines in the antisense strand comprise 2'-fluoro modified purines. In some embodiments, all of the purines in the antisense strand comprise 2'-O-methyl modified purines. In some embodiments, the purines in the antisense strand comprise a mixture of 2'-fluoro and 2'-O-methyl modified purines. In some embodiments, all of the purines in the antisense strand comprise 2'-fluoro modified purines. In some embodiments, all of the purines in the antisense strand comprise 2'-O-methyl modified purines. In some embodiments, all of the purines in the antisense strand comprise a mixture of 2'-fluoro and 2'-O-methyl modified purines.

[0265] In some embodiments, the pyrimidines of the antisense strand comprise 2'-fluoro modified pyrimidines. In some embodiments, the pyrimidines of the antisense strand comprise 2'-O-methyl modified pyrimidines. In some embodiments, the pyrimidines of the antisense strand comprise a mixture of 2'-fluoro and 2'-O-methyl modified pyrimidines. In some embodiments, all of the pyrimidines of the antisense strand comprise 2'-fluoro modified pyrimidines. In some embodiments, all of the pyrimidines of the antisense strand comprise 2'-O-methyl modified pyrimidines. In some embodiments, all of the pyrimidines of the antisense strand comprise a mixture of 2'-fluoro and 2'-O-methyl modified pyrimidines.

[0266] In some embodiments, the purines of the antisense strand comprise 2'-fluoro modified purines, and the pyrimidines of the antisense strand comprise a mixture of 2'-fluoro and 2'-O-methyl modified pyrimidines. In some embodiments, the purines of the antisense strand comprise 2'-O-methyl modified purines, and the pyrimidines of the antisense strand comprise a mixture of 2'-fluoro and 2'-O-methyl modified pyrimidines. In some embodiments, the purines of the antisense strand comprise 2'-fluoro modified purines, and the pyrimidines of the antisense strand comprise 2'-O-methyl modified pyrimidines. In some embodiments, the purines of the antisense strand comprise 2'-O-methyl modified purines, and the pyrimidines of the antisense strand comprise 2'-fluoro modified pyrimidines. In some embodiments, the pyrimidines of the antisense strand comprise 2'-fluoro modified pyrimidines, and the purines of the antisense strand comprise a mixture of 2'-fluoro and 2'-O-methyl modified purines. In some embodiments, the pyrimidines of the antisense strand comprise 2'-O-methyl modified pyrimidines, and the purines of the antisense strand comprise a mixture of 2'-fluoro and 2'-O-methyl modified purines. In some embodiments, the pyrimidines of the antisense strand comprise 2'-fluoro modified pyrimidines, and the purines of the antisense strand comprise 2'-O-methyl modified purines. In some embodiments, the pyrimidines of the antisense strand comprise 2'-O-methyl modified pyrimidines, and the purines of the antisense strand comprise 2'-fluoro modified purines.

[0267] In some embodiments, all purines in the antisense strand comprise 2'-fluoro modified purines, and all pyrimidines in the antisense strand comprise a mixture of 2'-fluoro and 2'-O-methyl modified pyrimidines. In some embodiments, all purines in the antisense strand comprise 2'-O-methyl modified purines, and all pyrimidines in the antisense strand comprise a mixture of 2'-fluoro and 2'-O-methyl modified pyrimidines. In some embodiments, all purines in the antisense strand comprise 2'-fluoro modified purines, and all pyrimidines in the antisense strand comprise 2'-O-methyl modified pyrimidines. In some embodiments, all purines in the antisense strand comprise 2'-O-methyl modified purines, and all pyrimidines in the antisense strand comprise 2'-fluoro modified pyrimidines. In some embodiments, all pyrimidines in the antisense strand comprise 2'-fluoro modified pyrimidines, and all purines in the antisense strand comprise a mixture of 2'-fluoro and 2'-O-methyl modified purines. In some embodiments, all pyrimidines in the antisense strand comprise 2'-O-methyl modified pyrimidines, and all purines in the antisense strand comprise a mixture of 2'-fluoro and 2'-O-methyl modified purines. In some embodiments, all pyrimidines in the antisense strand comprise 2'-fluoro modified pyrimidines, and all purines in the antisense strand comprise 2'-O-methyl modified purines. In some embodiments, all pyrimidines in the antisense strand comprise 2'-O-methyl modified pyrimidines, and all purines in the antisense strand comprise 2'-fluoro modified purines.

[0268] In some embodiments herein, modified oligonucleotides are disclosed.Modified oligonucleotides can be siRNAs that contain ribose ring modifications and phosphate linkages.Modifications can be in specific patterns that maximize cell delivery, stability, and efficiency.siRNAs can also contain vinyl phosphonates and hydrophobic groups.These modifications can aid in delivery to cells or tissues within a subject.Modified oligonucleotides can be used in methods such as treatment methods or methods for reducing gene expression.

[0269] In some embodiments, the oligonucleotide comprises a 21-nucleotide single-stranded duplex that forms base pairs with 19 base pairs between them. In some embodiments, the duplex comprises two single-stranded nucleotide overhangs at the 3' end of each strand. The single strand (antisense strand) is complementary to MST1 mRNA. Each end of the antisense strand has one to two phosphorothioate linkages. The 5' end has an optional phosphonate mimic, such as vinyl phosphonate. In some embodiments, the oligonucleotide is used to knock down MST1 mRNA or a target protein. In some embodiments, the sense strand has the same sequence as MST1 mRNA. In some embodiments, one to two phosphorothioates are present at the 3' end. In some embodiments, one or no phosphorothioates are present at the 5' end. In some embodiments, a 12-25 carbon hydrophobic conjugate is attached at the 5' end via a phosphodiester bond.

[0270] In some cases, the sense strand of any of the siRNAs comprises an siRNA with a specific modification pattern. In some embodiments, the 9th position, counting from the 5' end of the sense strand, can have a 2'F modification. In some embodiments, if the 9th position of the sense strand is a pyrimidine, all the purines of the sense strand have a 2'OMe modification. In some embodiments, if the 9th position is the only pyrimidine between the 5th and 11th positions of the sense strand, then the 9th position is the only position with a 2'F modification in the sense strand. In some embodiments, if the 9th position and the only other base between the 5th and 11th positions of the sense strand are pyrimidines, then these pyrimidines are the only two positions with a 2'F modification in the sense strand. In some embodiments, if the 9th position and the only two other bases between the 5th and 11th positions of the sense strand are pyrimidines, and these two other pyrimidines are adjacent positions such that there are no three 2'F modifications in a row, then any combination of 2'F modifications can be made, resulting in a total of three 2'F modifications. In some embodiments, if there are more than two pyrimidines between positions 5 and 11 of the sense strand, all combinations of pyrimidines with 2'F modifications are allowed, with a total of 3-5 2'F modifications, provided the sense strand does not have three 2'F modifications in a row. Optionally, the sense strand of one of the siRNAs contains a modification pattern that accommodates any or all of these sense strand rules.

[0271] In some embodiments, if position 9 of the sense strand is a purine, all purines in the sense strand have a 2'OMe modification. In some embodiments, if position 9 is the only purine between positions 5 and 11 of the sense strand, then position 9 is the only position with a 2'F modification in the sense strand. In some embodiments, if position 9 and the only other bases between positions 5 and 11 of the sense strand are purines, these purines together are the only two positions with a 2'F modification in the sense strand. In some embodiments, if position 9 and only two other bases between positions 5 and 11 of the sense strand are purines, and those two other purines are adjacent positions such that there are no three 2'F modifications in a row, then any combination of 2'F modifications can be made, resulting in a total of three 2'F modifications. In some embodiments, if there are more than two purines between positions 5 and 11 of the sense strand, then all combinations of purines with 2'F modifications are possible, resulting in a total of three to five 2'F modifications, provided the sense strand does not have three 2'F modifications in a row. Optionally, the sense strand of either siRNA contains a modification pattern that conforms to any or all of these sense strand rules.

[0272] Optionally, position 9 of the sense strand can be 2'deoxy. In these cases, 2'F and 2'OMe modifications can occur at other positions of the sense strand. Optionally, any sense strand of siRNA comprises a modification pattern that conforms to the rules of the sense strand.

[0273] In some embodiments, the sense strand comprises or consists of RNA or modified RNA nucleotides. In some embodiments, the sense strand comprises deoxynucleosides. The deoxynucleosides can include DNA nucleosides. In some embodiments, the deoxynucleosides can comprise or consist of 2' deoxynucleosides. The deoxynucleosides can be at positions (5' to 3', with the 5' position being 1) in the sense strand. The positions in the sense strand can be or include positions 2, 4, 6, 8, 9, 10, 12, 14, 16, or 18, or a combination of these positions. The positions in the sense strand can be or include positions 2, 4, 6, 8, 10, 12, 14, 16, or 18, or a combination of these positions. Positions within the sense strand can be or include positions 2, 6, 9, 10, 14, or 18, or combinations of these positions. Positions within the sense strand can be or include positions 2, 6, 10, 14, or 18, or combinations of these positions. Positions within the sense strand can be or include positions 4, 8, 9, 12, or 16, or combinations of these positions. Positions within the sense strand can be or include positions 4, 8, 12, or 16, or combinations of these positions. Positions within the sense strand can include position 9. Positions within the sense strand can be position 9. The sense strand can include 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 deoxynucleosides. In some embodiments, the sense strand may contain one deoxynucleoside. The sense strand may contain 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 deoxynucleosides, or a range defined by any two of the aforementioned numbers of deoxynucleosides. The sense strand may contain deoxynucleosides at all positions. The sense strand may contain deoxynucleosides at some positions. The sense strand may contain deoxynucleosides at every other position. The sense strand may contain one deoxynucleoside. The sense strand may contain at least one deoxynucleoside.The sense strand may comprise at least two deoxynucleosides. The sense strand may comprise at least three deoxynucleosides. The sense strand may comprise at least four deoxynucleosides. The sense strand may comprise at least five deoxynucleosides. The sense strand may comprise at least six deoxynucleosides. The sense strand may comprise at least seven deoxynucleosides. The sense strand may comprise at least eight deoxynucleosides. The sense strand may comprise at least nine deoxynucleosides. The sense strand may comprise at least ten deoxynucleosides. The sense strand may comprise at most two deoxynucleosides. The sense strand may comprise at most three deoxynucleosides. The sense strand may comprise at most four deoxynucleosides. The sense strand may comprise at most five deoxynucleosides. The sense strand can include at most 6 deoxynucleosides. The sense strand can include at most 7 deoxynucleosides. The sense strand can include at most 8 deoxynucleosides. The sense strand can include at most 9 deoxynucleosides. The sense strand can include at most 10 deoxynucleosides.

[0274] In some embodiments, the antisense strand comprises or consists of RNA or modified RNA nucleotides. In some embodiments, the antisense strand comprises deoxynucleosides. The deoxynucleosides can comprise DNA nucleosides. In some embodiments, the deoxynucleosides comprise or consist of 2' deoxynucleosides. The antisense strand can comprise 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 deoxynucleosides, or a range defined by any two of the aforementioned numbers of deoxynucleosides.

[0275] In some embodiments where deoxynucleosides are included in the sense strand (e.g., the 9th nucleotide counting from the 5' end), the nucleosides at positions 1-8 comprise a mixture of 2'-fluoro and 2'-O-methyl modified nucleosides. In some embodiments where deoxynucleosides are included in the sense strand, the purines at positions 1-8 comprise a mixture of 2'-fluoro and 2'-O-methyl modified nucleosides. In some embodiments where deoxynucleosides are included in the sense strand, the pyrimidines at positions 1-8 comprise a mixture of 2'-fluoro and 2'-O-methyl modified nucleosides. In some embodiments where deoxynucleosides are included in the sense strand, all nucleosides at positions 1-8 comprise 2'-O-methyl modified nucleosides. In some embodiments where deoxynucleosides are included in the sense strand, all purines at positions 1-8 comprise 2'-O-methyl modified nucleosides. In some embodiments where deoxynucleosides are included in the sense strand, the pyrimidines at positions 1-8 all comprise 2'-O-methyl modified nucleosides. In some embodiments where deoxynucleosides are included in the sense strand, the purines at positions 1-8 all comprise a mixture of 2'-fluoro and 2'-O-methyl modified nucleosides and the pyrimidines at positions 1-8 all comprise 2'-O-methyl modified nucleosides. In some embodiments where deoxynucleosides are included in the sense strand, the pyrimidines at positions 1-8 all comprise a mixture of 2'-fluoro and 2'-O-methyl modified nucleosides and the purines at positions 1-8 all comprise 2'-O-methyl modified nucleosides.

[0276] Some embodiments disclosed herein include a composition comprising an oligonucleotide that targets MST1 and reduces the expression of MST1 when administered to a cell, the oligonucleotide comprising a small interfering RNA (siRNA) comprising a sense strand and an antisense strand, wherein the sense strand comprises a sense strand sequence described herein with at least one internucleoside linkage modified and at least one nucleoside modified, or a sense strand sequence comprising one or two nucleoside substitutions, additions, or deletions of an oligonucleotide sequence with at least one internucleoside linkage modified and at least one nucleoside modified, and the antisense strand comprises an oligonucleotide sequence with at least one internucleoside linkage modified and at least one nucleoside modified, or a sense strand sequence comprising one or two nucleoside substitutions, additions, or deletions of an antisense strand sequence with at least one internucleoside linkage modified and at least one nucleoside modified, as described herein. Some embodiments relate to a method comprising administering the composition to a subject.

[0277] In some embodiments, the siRNA comprises a sense strand, an antisense strand, and a lipid moiety attached to the end of the sense strand or the antisense strand, wherein the lipid moiety comprises a phenyl or cyclohexanyl linker, and the linker is attached to the lipid and the end of the sense strand or the antisense strand. In some embodiments, with respect to the sense strand, (a) all purines comprise fluoro-modified purines and all pyrimidines comprise (i) a mixture of 2'-O-methyl and 2'-O-methoxyethyl modified pyrimidines, or (ii) a mixture of 2'-fluoro, 2'-O-methyl and 2'-O-methoxyethyl modified pyrimidines; (b) all purines comprise 2'-O-methyl modified purines and all pyrimidines comprise (i) a mixture of 2'-fluoro and 2'-O-methoxyethyl modified pyrimidines, or (ii) a mixture of 2'-fluoro, 2'-O-methyl and 2'-O-methoxyethyl modified pyrimidines; (c) all purines comprise 2'-O-methoxyethyl modified purines and all pyrimidines comprise (i) a mixture of 2'-fluoro and 2'-O-methyl modified pyrimidines, or (ii) a mixture of 2'-fluoro, 2'-O-methyl and 2'-O-methoxyethyl modified pyrimidines; (d) all purines comprise 2'-fluoro and 2'-O-methyl modified pyrimidines. (ii) a mixture of 2'-O-methyl and 2'-O-methoxyethyl modified pyrimidines; (iii) a mixture of 2'-fluoro and 2'-O-methoxyethyl modified pyrimidines; or (iv) a mixture of 2'-fluoro, 2'-O-methyl, and 2'-O-methoxyethyl modified pyrimidines; (e) all purines are 2'-fluoro and 2'-O-methoxyethyl modified purines; wherein all of the pyrimidines in the sense strand comprise (i) 2'-O-methyl modified pyrimidines, (ii) a mixture of 2'-fluoro and 2'-O-methyl modified pyrimidines, (iii) a mixture of 2'-O-methyl and 2'-O-methoxyethyl modified pyrimidines, or (iv) a mixture of 2'-fluoro, 2'-O-methyl and 2'-O-methoxyethyl modified pyrimidines; and (f) all of the purines comprise a mixture of 2'-O-methyl and 2'-O-methoxyethyl modified purines.all of the pyrimidines comprise (i) 2'-fluoro modified pyrimidines, (ii) a mixture of 2'-fluoro and 2'-O-methyl modified pyrimidines, (iii) a mixture of 2'-fluoro and 2'-O-methoxyethyl modified pyrimidines, or (iv) a mixture of 2'-fluoro, 2'-O-methyl and 2'-O-methoxyethyl modified pyrimidines, or (g) all of the purines comprise a mixture of 2'-fluoro, 2'-O-methyl and 2'-O-methoxyethyl modified purines and all of the pyrimidines are (i) 2'-fluoro modified (ii) 2'-O-methyl modified pyrimidines, (iii) 2'-O-methoxyethyl modified pyrimidines, (iv) a mixture of 2'-fluoro and 2'-O-methyl modified pyrimidines, (v) a mixture of 2'-O-methyl and 2'-O-methoxyethyl modified pyrimidines, (vi) a mixture of 2'-fluoro and 2'-O-methoxyethyl modified pyrimidines, or (vii) a mixture of 2'-fluoro, 2'-O-methyl and 2'-O-methoxyethyl modified pyrimidines. In some embodiments, with respect to the antisense strand, any one of the following is true: all purines comprise 2'-fluoro modified purines and all pyrimidines comprise a mixture of 2'-fluoro and 2'-O-methyl modified pyrimidines; all purines comprise 2'-O-methyl modified purines and all pyrimidines comprise a mixture of 2'-fluoro and 2'-O-methyl modified pyrimidines; all purines comprise 2'-O-methyl modified purines and all pyrimidines comprise 2'-fluoro modified pyrimidines; all pyrimidines comprise 2'-fluoro modified pyrimidines and all purines comprise a mixture of 2'-fluoro and 2'-O-methyl modified purines; all pyrimidines comprise 2'-O-methyl modified pyrimidines and all purines comprise a mixture of 2'-fluoro and 2'-O-methyl modified purines; or all pyrimidines comprise 2'-O-methyl modified pyrimidines and all purines comprise 2'-fluoro modified purines. In some embodiments, the siRNA comprises a sense strand and an antisense strand, wherein the antisense strand comprises a 5' end comprising a vinyl phosphonate and two phosphorothioate linkages and a 3' end comprising two phosphorothioate linkages, and the sense strand comprises(a) all purines comprise fluoro-modified purines and all pyrimidines comprise (i) a mixture of 2'-O-methyl and 2'-O-methoxyethyl modified pyrimidines, or (ii) a mixture of 2'-fluoro, 2'-O-methyl and 2'-O-methoxyethyl modified pyrimidines; (b) all purines comprise 2'-O-methyl modified purines and all pyrimidines comprise (vi) a mixture of 2'-fluoro and 2'-O-methoxyethyl modified pyrimidines, or (ii) a mixture of 2'-fluoro, 2'-O-methyl and 2'-O-methoxyethyl modified pyrimidines. (c) all purines are 2'-O-methoxyethyl modified purines and all pyrimidines are (i) a mixture of 2'-fluoro and 2'-O-methyl modified pyrimidines or (vii) a mixture of 2'-fluoro, 2'-O-methyl and 2'-O-methoxyethyl modified pyrimidines; (d) all purines are 2'-fluoro and 2'-O-methyl modified purines and all pyrimidines are (i) a mixture of 2'-O-methoxyethyl modified pyrimidines, (ii) a mixture of 2'-O-methyl and 2'-O-methoxyethyl modified pyrimidines; (i (ii) a mixture of 2'-fluoro and 2'-O-methoxyethyl modified pyrimidines, or (iv) a mixture of 2'-fluoro, 2'-O-methyl and 2'-O-methoxyethyl modified pyrimidines; (e) all purines comprise a mixture of 2'-fluoro and 2'-O-methoxyethyl modified purines and all pyrimidines in the sense strand are (i) 2'-O-methyl modified pyrimidines, (ii) a mixture of 2'-fluoro and 2'-O-methyl modified pyrimidines, (iii) a mixture of 2'-O-methyl and 2'-O-methoxyethyl modified pyrimidines; or (i (v) comprising a mixture of 2'-fluoro, 2'-O-methyl, and 2'-O-methoxyethyl modified pyrimidines; (f) comprising all purines comprising a mixture of 2'-O-methyl and 2'-O-methoxyethyl modified purines and all pyrimidines comprising (i) 2'-fluoro modified pyrimidines, (ii) a mixture of 2'-fluoro and 2'-O-methyl modified pyrimidines, (iii) a mixture of 2'-fluoro and 2'-O-methoxyethyl modified pyrimidines, or (iv) a mixture of 2'-fluoro, 2'-O-methyl, and 2'-O-methoxyethyl modified pyrimidines;or (g) all of the purines comprise a mixture of 2'-fluoro, 2'-O-methyl, and 2'-O-methoxyethyl modified purines and all of the pyrimidines comprise (i) 2'-fluoro modified pyrimidines, (ii) 2'-O-methyl modified pyrimidines, (iii) 2'-O-methoxyethyl modified pyrimidines, (iv) a mixture of 2'-fluoro and 2'-O-methyl modified pyrimidines, (v) a mixture of 2'-O-methyl and 2'-O-methoxyethyl modified pyrimidines, (vi) a mixture of 2'-fluoro and 2'-O-methoxyethyl modified pyrimidines, or (vii) a mixture of 2'-fluoro, 2'-O-methyl, and 2'-O-methoxyethyl modified pyrimidines. With respect to the antisense strand, any one of the following is true: all purines comprise 2'-fluoro modified purines and all pyrimidines comprise a mixture of 2'-fluoro and 2'-O-methyl modified pyrimidines; all purines comprise 2'-O-methyl modified purines and all pyrimidines comprise a mixture of 2'-fluoro and 2'-O-methyl modified pyrimidines; all purines comprise 2'-O-methyl modified purines and all pyrimidines comprise 2'-fluoro modified pyrimidines; all pyrimidines comprise 2'-fluoro modified pyrimidines and all purines comprise a mixture of 2'-fluoro and 2'-O-methyl modified purines; all pyrimidines comprise 2'-O-methyl modified pyrimidines and all purines comprise a mixture of 2'-fluoro and 2'-O-methyl modified purines; or all pyrimidines comprise 2'-O-methyl modified pyrimidines and all purines comprise 2'-fluoro modified purines.

[0278] In some embodiments, with respect to the sense strand, (a) all purines comprise fluoro-modified purines and all pyrimidines comprise (i) a mixture of 2'-O-methyl and 2'-O-methoxyethyl modified pyrimidines, or (ii) a mixture of 2'-fluoro, 2'-O-methyl and 2'-O-methoxyethyl modified pyrimidines; (b) all purines comprise 2'-O-methyl modified purines and all pyrimidines comprise (i) a mixture of 2'-fluoro and 2'-O-methoxyethyl modified pyrimidines, or (ii) a mixture of 2'-fluoro and 2'-O- (c) all purines are 2'-O-methoxyethyl modified purines and all pyrimidines are (i) a mixture of 2'-fluoro and 2'-O-methyl modified pyrimidines or (ii) a mixture of 2'-fluoro, 2'-O-methyl, and 2'-O-methoxyethyl modified pyrimidines; (d) all purines are 2'-fluoro and 2'-O-methyl modified purines and all pyrimidines are (i) 2'-O-methoxyethyl modified pyrimidines, (ii) (iii) a mixture of 2'-O-methyl and 2'-O-methoxyethyl modified pyrimidines, or (iv) a mixture of 2'-fluoro, 2'-O-methyl and 2'-O-methoxyethyl modified pyrimidines; (e) all purines comprise a mixture of 2'-fluoro and 2'-O-methoxyethyl modified purines and all pyrimidines in the sense strand are (i) 2'-O-methyl modified pyrimidines, (ii) a mixture of 2'-fluoro and 2'-O-methyl modified pyrimidines; (iii) a mixture of 2'-O-methyl and 2'-O-methoxyethyl modified pyrimidines, or (iv) a mixture of 2'-fluoro, 2'-O-methyl and 2'-O-methoxyethyl modified pyrimidines; (f) a mixture of all purines with 2'-O-methyl and 2'-O-methoxyethyl modified purines and all pyrimidines with (i) 2'-fluoro modified pyrimidines, (ii) a mixture of 2'-fluoro and 2'-O-methyl modified pyrimidines, or (iii) a mixture of 2'-fluoro and 2'-O-methoxyethyl modified pyrimidines;or (iv) a mixture of ...

Claims

1. A composition comprising an siRNA targeting MST1, wherein the siRNA comprises a sense strand and an antisense strand, and the siRNA comprises a sense strand comprising any one of SEQ ID NOs: 6600-6631 or 6696-6707, or an antisense strand comprising any one of SEQ ID NOs: 6632-6683 or 6708-6719.

2. 2. The siRNA of claim 1, wherein the sense sequence comprises SEQ ID NO: 6616, 6446, 6602, 6448, 6476, 6603, 6611, 6612, or 6707, and the antisense sequence comprises SEQ ID NO: 6648, 6505, 6635, 6507, 6535, 6634, 6643, 6644, or 6719.

3. 3. The siRNA of claim 1 or 2, wherein the sense sequence comprises a sequence selected from the group consisting of 6552, 6214, 6539, 6216, 6244, 6538, 6547, 6548, and 6683.

4. The siRNA of any one of claims 1 to 3, wherein the antisense sequence comprises a sequence selected from the group consisting of 6584, 6273, 6571, 6275, 6303, 6570, 6579, 6580, and 6695.

5. The composition of any one of claims 1 to 4, wherein the oligonucleotide comprises a modified internucleoside linkage.

6. 6. The composition of claim 5, wherein the modified internucleoside linkage comprises an alkyl phosphonate, phosphorothioate, methyl phosphonate, phosphorodithioate, alkyl phosphonothioate, phosphoramidate, carbamate, carbonate, phosphate triester, acetamidate, or carboxymethyl ester, or a combination thereof.

7. The composition of claim 6 , wherein the modified internucleoside linkages comprise one or more phosphorothioate linkages.

8. 8. The composition of any one of claims 1 to 7, wherein the oligonucleotide comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 modified internucleoside linkages.

9. The composition of any one of claims 1 to 8, wherein the oligonucleotide comprises a modified nucleoside.

10. 10. The composition of claim 9, wherein the modified nucleoside comprises a locked nucleic acid (LNA), a hexitol nucleic acid (HNA), a cyclohexene nucleic acid (CeNA), a 2'-methoxyethyl, a 2'-O-alkyl, a 2'-O-allyl, a 2'-O-allyl, a 2'-fluoro, or a 2'-deoxy, or a combination thereof.

11. The composition of claim 10 , wherein the modified nucleoside comprises an LNA.

12. 11. The composition of claim 10, wherein the modified nucleoside comprises a 2',4' constrained ethyl nucleic acid.

13. 11. The composition of claim 10, wherein the modified nucleoside comprises a 2'-O-methyl nucleoside, a 2'-deoxyfluoro nucleoside, a 2'-O-N-methylacetamide (2'-O-NMA) nucleoside, a 2'-O-dimethylaminoethoxyethyl (2'-O-DMAEOE) nucleoside, a 2'-O-aminopropyl (2'-O-AP) nucleoside, or a 2'-ara-F, or a combination thereof.

14. 11. The composition of claim 10, wherein the modified nucleosides comprise one or more 2'-fluoro modified nucleosides.

15. 11. The composition of claim 10, wherein the modified nucleoside comprises a 2'-O-alkyl modified nucleoside.

16. 16. The composition of any one of claims 1 to 15, wherein the oligonucleotide comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 modified nucleosides.

17. The composition of any one of claims 1 to 16, wherein the oligonucleotide comprises a lipid attached at the 3' or 5' end of the oligonucleotide.

18. 18. The composition of claim 17, wherein the lipid comprises cholesterol, myristoyl, palmitoyl, stearoyl, lithocoloyl, docosanoyl, docosahexaenoyl, myristyl, palmitylstearyl, or alpha-tocopherol, or a combination thereof.

19. The composition of any one of claims 1 to 18, wherein the oligonucleotide comprises a sugar moiety attached at the 3' or 5' end of the oligonucleotide.

20. 20. The composition of claim 19, wherein the sugar comprises N-acetylgalactosamine (GalNAc), N-acetylglucosamine (GlcNAc), or mannose.

21. The sugar moiety 【Chemistry 1】 20. The composition of claim 19, comprising: wherein J comprises said oligonucleotide; and J comprises an optional phosphate or phosphorothioate linked to said oligonucleotide.

22. The composition of any one of claims 1 to 21, wherein the oligonucleotide comprises an integrin-targeting ligand attached at the 3' or 5' end of the oligonucleotide.

23. 23. The composition of claim 22, wherein the integrin comprises integrin alpha-v-beta-6.

24. 24. The composition of claim 23, wherein the integrin targeting ligand comprises an arginine-glycine-aspartic acid (RGD) peptide.

25. With respect to the sense strand, all purines comprise 2'-fluoro modified purines and all pyrimidines comprise a mixture of 2'-fluoro and 2'-methyl modified pyrimidines; all purines comprise 2'-methyl modified purines and all pyrimidines comprise a mixture of 2'-fluoro and 2'-methyl modified pyrimidines; all purines comprise 2'-fluoro modified purines and all pyrimidines comprise 2'-methyl modified pyrimidines; all pyrimidines comprise 2'-fluoro modified pyrimidines and all purines comprise a mixture of 2'-fluoro and 2'-methyl modified purines; all pyrimidines comprise 2'-methyl modified pyrimidines and all purines comprise a mixture of 2'-fluoro and 2'-methyl modified purines; or All pyrimidines contain 2'-fluoro modified pyrimidines and all purines contain 2'-methyl modified purines The composition according to any one of claims 1 to 24, wherein any one of the following applies:

26. With respect to the sense strand, (a) all of the purines comprise fluoro-modified purines and all of the pyrimidines comprise (i) a mixture of 2'-O-methyl and 2'-O-methoxyethyl modified pyrimidines, or (ii) a mixture of 2'-fluoro, 2'-O-methyl and 2'-O-methoxyethyl modified pyrimidines; (b) all purines include 2'-O-methyl modified purines and all pyrimidines in the sense strand include (i) a mixture of 2'-fluoro and 2'-O-methoxyethyl modified pyrimidines, or (ii) a mixture of 2'-fluoro, 2'-O-methyl, and 2'-O-methoxyethyl modified pyrimidines; (c) all of the purines comprise 2'-O-methoxyethyl modified purines and all of the pyrimidines comprise (i) a mixture of 2'-fluoro and 2'-O-methyl modified pyrimidines, or (ii) a mixture of 2'-fluoro, 2'-O-methyl, and 2'-O-methoxyethyl modified pyrimidines; (d) all of the purines comprise a mixture of 2'-fluoro and 2'-O-methyl modified purines and all of the pyrimidines comprise (i) 2'-O-methoxyethyl modified pyrimidines, (ii) a mixture of 2'-O-methyl and 2'-O-methoxyethyl modified pyrimidines, (iii) a mixture of 2'-fluoro and 2'-O-methoxyethyl modified pyrimidines, or (iv) a mixture of 2'-fluoro, 2'-O-methyl and 2'-O-methoxyethyl modified pyrimidines; (e) all of the purines comprise a mixture of 2'-fluoro and 2'-O-methoxyethyl modified purines, and all of the pyrimidines in the sense strand comprise (i) 2'-O-methyl modified pyrimidines, (ii) a mixture of 2'-fluoro and 2'-O-methyl modified pyrimidines, (iii) a mixture of 2'-O-methyl and 2'-O-methoxyethyl modified pyrimidines, or (iv) a mixture of 2'-fluoro, 2'-O-methyl and 2'-O-methoxyethyl modified pyrimidines; (f) all of the purines comprise a mixture of 2'-O-methyl and 2'-O-methoxyethyl modified purines and all of the pyrimidines comprise (i) 2'-fluoro modified pyrimidines, (ii) a mixture of 2'-fluoro and 2'-O-methyl modified pyrimidines, (iii) a mixture of 2'-fluoro and 2'-O-methoxyethyl modified pyrimidines, or (iv) a mixture of 2'-fluoro, 2'-O-methyl, and 2'-O-methoxyethyl modified pyrimidines; or (g) all of the purines comprise a mixture of 2'-fluoro, 2'-O-methyl, and 2'-O-methoxyethyl modified purines, and all of the pyrimidines comprise (i) 2'-fluoro modified pyrimidines, (ii) 2'-O-methyl modified pyrimidines, (iii) 2'-O-methoxyethyl modified pyrimidines, (iv) a mixture of 2'-fluoro and 2'-O-methyl modified pyrimidines, (v) a mixture of 2'-O-methyl and 2'-O-methoxyethyl modified pyrimidines, (vi) a mixture of 2'-fluoro and 2'-O-methoxyethyl modified pyrimidines, or (vii) a mixture of 2'-fluoro, 2'-O-methyl, and 2'-O-methoxyethyl modified pyrimidines.

25. The composition of claim 1, wherein any one of the following applies, provided that in any of the foregoing, the sense strand may comprise a 2'-deoxynucleoside.

27. Regarding the antisense strand, all purines comprise 2'-fluoro modified purines and all pyrimidines comprise a mixture of 2'-fluoro and 2'-methyl modified pyrimidines; all purines comprise 2'-methyl modified purines and all pyrimidines comprise a mixture of 2'-fluoro and 2'-methyl modified pyrimidines; all purines comprise 2'-methyl modified purines and all pyrimidines comprise 2'-fluoro modified pyrimidines; all pyrimidines comprise 2'-fluoro modified pyrimidines and all purines comprise a mixture of 2'-fluoro and 2'-methyl modified purines; all pyrimidines comprise 2'-methyl modified pyrimidines and all purines comprise a mixture of 2'-fluoro and 2'-methyl modified purines; or All pyrimidines contain 2'-methyl modified pyrimidines and all purines contain 2'-fluoro modified purines The composition according to any one of claims 1 to 26, wherein any one of the following applies:

28. A composition comprising an siRNA targeting MST1, wherein the siRNA comprises a sense strand and an antisense strand, and the sense strand comprises a modification pattern selected from the group consisting of 36S, 37S, 38S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, and 48S, or the antisense strand comprises a modification pattern selected from the group consisting of 2AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, and 37AS.

29. 29. The composition of claim 28, comprising a sense strand comprising any one of SEQ ID NOs: 1-3024, 6317, 6358-6387, 6418-6476, 6600-6631, or 6696-6707, or an antisense strand comprising any one of SEQ ID NOs: 3025-6048, 6318, 6388-6417, 6477-6535, 6632-6683, or 6708-6719.

30. A composition comprising an siRNA targeting MST1, wherein the siRNA comprises a sense strand and an antisense strand, and the siRNA comprises a sense strand comprising any one of SEQ ID NOs: 6672-6683 or 6526-6567, or an antisense strand comprising any one of SEQ ID NOs: 6568-6599 or 6684-6695.

31. 31. The siRNA of claim 30, wherein the sense sequence comprises SEQ ID NO: 6616, 6446, 6602, 6448, 6476, 6603, 6611, 6612, or 6707, and the antisense sequence comprises SEQ ID NO: 6648, 6505, 6635, 6507, 6535, 6634, 6643, 6644, or 6719.

32. 32. The siRNA of claim 30 or 31, wherein the sense sequence comprises a sequence selected from the group consisting of 6552, 6214, 6539, 6216, 6244, 6538, 6547, 6548, and 6683.

33. The siRNA of any one of claims 30 to 32, wherein the antisense sequence comprises a sequence selected from the group consisting of 6584, 6273, 6571, 6275, 6303, 6570, 6579, 6580, and 6695.

34. A composition comprising the oligonucleotide of any one of claims 1 to 33, which composition increases a pulmonary function measure when administered to a subject in an effective amount.

35. 35. The composition of claim 34, wherein the pulmonary function measure comprises a forced expiratory volume in one second (FEV1) measure, a predicted forced expiratory volume fraction in one second (FEV1pp) measure, a forced vital capacity (FVC) measure, an FEV1 / FVC ratio measure, a forced expiratory volume, or a peak expiratory flow measure.

36. 36. The composition of claim 34 or 35, wherein the pulmonary function measurement is increased by about 10% or more compared to before administration.

37. A composition comprising the oligonucleotide of any one of claims 1 to 33, which composition reduces white blood cell counts when administered to a subject in an effective amount.

38. 38. The composition of claim 37, wherein the white blood cell measurement comprises a lung white blood cell measurement.

39. 38. The composition of claim 37, wherein the white blood cell measurement comprises a circulating white blood cell measurement.

40. 38. The composition of claim 37, wherein the white blood cell measurements include a neutrophil measurement, an eosinophil measurement, a basophil measurement, a monocyte measurement, a macrophage measurement, a lymphocyte measurement, or a neutrophil-lymphocyte ratio measurement, or a combination thereof.

41. The composition of any one of claims 37 to 40, wherein the white blood cell measurement value is reduced by about 10% or more compared to before administration.

42. 34. A composition comprising the oligonucleotide of any one of claims 1 to 33, which, when administered to a subject in an effective amount, reduces a measure of chronic obstructive pulmonary disease (COPD) or asthma exacerbations or symptoms.

43. 43. The composition of claim 42, wherein the COPD or asthma exacerbation or symptom measure is reduced by about 10% or more compared to before administration.

44. The composition of any one of claims 1 to 43, further comprising a pharmaceutically acceptable carrier.

45. 45. The composition of claim 44, which, when administered to a subject, does not affect any safety or toxicity measurements in the subject.

46. 46. ​​A method of treating a subject suffering from a pulmonary disorder, comprising administering to said subject an effective amount of a composition according to any one of claims 1 to 45.

47. 47. The method of claim 46, wherein the pulmonary disorder comprises COPD, acute exacerbation of COPD, emphysema, chronic bronchitis, asthma, status asthmaticus, asthma and COPD overlap syndrome (ACOS), bronchiectasis, cough, dyspnea, mucus hypersecretion, lung cancer, interstitial lung disease, or pulmonary fibrosis.

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