Treatment of MST1-Related Diseases and Disorders

Abstract

Disclosed herein is a composition comprising an oligonucleotide that targets MST1. The oligonucleotide can comprise a small interfering RNA (siRNA) or an antisense oligonucleotide (ASO). Also provided herein is a method for treating a disease associated with MST1 mutation, comprising providing a subject with an oligonucleotide that targets MST1.

Description

[Technical Field]

[0001] cross reference This application claims the benefit of U.S. Provisional Patent Application No. 63 / 211,364, filed June 16, 2021, which is incorporated herein by reference. [Background technology]

[0002] Lung disorders are a common problem that can affect a wide range of people, and improved therapeutic agents are needed to treat these disorders. Summary of the Invention

[0003] In some embodiments, disclosed herein are compositions comprising oligonucleotides that target MST1. In some embodiments, disclosed herein are compositions comprising oligonucleotides that target MST1 and, when administered to a subject in an effective amount, increase a pulmonary function measure. In some embodiments, the pulmonary function measure includes a forced expiratory volume in 1 second (FEV1) measure, a forced expiratory volume in 1 second percent predicted (FEV1pp) measure, a forced vital capacity (FVC) measure, an FEV1 / FVC ratio measure, a forced expiratory volume, or a peak expiratory flow measure. In some embodiments, the pulmonary function measure increases by about 10% or more compared to before administration. In some embodiments, disclosed herein are compositions comprising oligonucleotides that target MST1 and, when administered to a subject in an effective amount, decrease a white blood cell measure. In some embodiments, the white blood cell measure includes a pulmonary white blood cell measure. In some embodiments, the white blood cell measure includes a circulating white blood cell measure. In some embodiments, the white blood cell measurement includes a neutrophil measurement, an eosinophil measurement, a basophil measurement, a monocyte measurement, or a lymphocyte measurement, or a combination thereof. In some embodiments, the white blood cell measurement is reduced by about 10% or more compared to before administration. Disclosed herein, in some embodiments, is a composition comprising an oligonucleotide that targets MST1 and reduces a measurement of chronic obstructive pulmonary disease (COPD) or asthma exacerbation when administered to a subject in an effective amount. In some embodiments, the measurement of COPD or asthma exacerbation is reduced by about 10% or more compared to before administration. In some embodiments, the oligonucleotide comprises a modified internucleoside linkage.In some embodiments, the modified internucleoside linkages include alkylphosphonates, phosphorothioates, methylphosphonates, phosphorodithioates, alkylphosphonothioates, phosphoramidates, carbamates, carbonates, phosphate triesters, acetamidates, or carboxymethyl esters, or combinations thereof. In some embodiments, the modified internucleoside linkages include one or more phosphorothioate linkages. In some embodiments, the oligonucleotide includes 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 includes modified nucleosides. In some embodiments, the modified nucleoside comprises a locked nucleic acid (LNA), a hexitol nucleic acid (HLA), 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-methylacetamido (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. In some embodiments, the modified nucleosides include one or more 2'-fluoro-modified nucleosides. In some embodiments, the modified nucleosides include 2'-O-alkyl-modified nucleosides. In some embodiments, the oligonucleotide includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 modified nucleosides. In some embodiments, the oligonucleotide includes 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 moiety comprises N-acetylgalactosamine (GalNAc), N-acetylglucosamine (GlcNAc), or mannose. 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, the oligonucleotide comprises a small interfering RNA (siRNA) comprising a sense strand and an antisense strand. In some embodiments, the sense strand is 12 to 30 nucleosides in length. In some embodiments, the antisense strand is 12 to 30 nucleosides in length. Disclosed herein in some embodiments is a composition comprising an oligonucleotide that inhibits expression of MST1, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, each strand independently being about 12 to 30 nucleosides in length, and at least one of the sense strand and the antisense strand comprises a nucleoside sequence comprising about 12 to 30 adjacent nucleosides of SEQ ID NO: 6185.In some embodiments, with respect to the sense strand, any one of the following is true: (i) all purines comprise 2'fluoro-modified purines and all pyrimidines comprise a mixture of 2'fluoro- and 2'methyl-modified pyrimidines; (ii) all purines comprise 2'methyl-modified purines and all pyrimidines comprise a mixture of 2'fluoro- and 2'methyl-modified pyrimidines; (iii) all purines comprise 2'fluoro-modified purines and all pyrimidines comprise 2'methyl-modified pyrimidines; (iv) all pyrimidines comprise 2'fluoro-modified pyrimidines and all purines comprise a mixture of 2'fluoro- and 2'methyl-modified purines; (v) all pyrimidines comprise 2'methyl-modified pyrimidines and all purines comprise a mixture of 2'fluoro- and 2'methyl-modified purines; or (vi) all pyrimidines comprise 2'fluoro-modified pyrimidines and all purines comprise 2'methyl-modified purines. In some embodiments, the sense strand comprises any one of modification patterns 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, 24S, or 35S.In some embodiments, with respect to the antisense strand, any one of the following is true: (i) all purines comprise 2'fluoro-modified purines and all pyrimidines comprise a mixture of 2'fluoro- and 2'methyl-modified pyrimidines; (ii) all purines comprise 2'methyl-modified purines and all pyrimidines comprise a mixture of 2'fluoro- and 2'methyl-modified pyrimidines; (iii) all purines comprise 2'methyl-modified purines and all pyrimidines comprise 2'fluoro-modified pyrimidines; (iv) all pyrimidines comprise 2'fluoro-modified pyrimidines and all purines comprise a mixture of 2'fluoro- and 2'methyl-modified purines; (v) all pyrimidines comprise 2'methyl-modified pyrimidines and all purines comprise a mixture of 2'fluoro- and 2'methyl-modified purines; or (vi) all pyrimidines comprise 2'methyl-modified pyrimidines and all purines comprise 2'fluoro-modified purines. In some embodiments, the antisense strand comprises any one of modification patterns 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 19AS, 20AS, or 21AS. In some embodiments, the sense strand comprises the nucleic acid sequence of any one of SEQ ID NOs: 1-3024 or 6358-6397, and the antisense strand comprises the nucleic acid sequence of any one of SEQ ID NOs: 3025-6048 or 6398-6417. In some embodiments, the sense strand comprises the nucleic acid sequence of any one of SEQ ID NOs: 6373, 6375, 6385, 6386, or 6387, and the antisense strand comprises the nucleic acid sequence of any one of SEQ ID NOs: 6403, 6405, 6415, 6416, or 6417. In some embodiments, the oligonucleotide comprises an antisense oligonucleotide (ASO). In some embodiments, the ASO is 12-30 nucleosides in length. Disclosed herein are compositions comprising an oligonucleotide that inhibits expression of MST1, wherein the oligonucleotide comprises an ASO of about 12-30 nucleosides in length and a nucleoside sequence complementary to about 12-30 contiguous nucleosides of SEQ ID NO: 6185.Some embodiments include a pharmaceutically acceptable carrier. Some embodiments include a method for treating a subject with a pulmonary disorder, comprising administering an effective amount of the composition to the subject. In some embodiments, the pulmonary disorder includes COPD, acute exacerbation of COPD, emphysema, chronic bronchitis, asthma, status asthmaticus, asthma-COPD overlap syndrome (ACOS), cough, lung cancer, interstitial lung disease, or pulmonary fibrosis. [Brief explanation of the drawings]

[0004] The novel features of the invention are set forth with particularity in the appended claims. For a better understanding of the features and advantages of the present invention, reference should be made to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which: [Figure 1] Western blot of MST1 protein is shown. DETAILED DESCRIPTION OF THE INVENTION

[0005] Large-scale human genetic data can improve the success rate of drug discovery and development. Genome-wide association studies (GWAS) can detect associations between genetic variants and traits in population samples. GWAS can improve our understanding of disease biology and inform appropriate treatments. GWAS can utilize genotyping and / or sequencing data and often involve evaluating 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 a variant has a significantly different frequency between cases and controls, the variant is said to be associated with disease. Relevant statistics that may be used in GWAS are the p-value as an indicator of statistical significance, the odds ratio (OR) as an indicator of effect size, or the beta coefficient (β) as an indicator of effect size. Researchers often assume an additive genetic model and calculate allelic odds ratios, which indicate that each additional copy of an allele (compared to no copies of that allele) increases (or decreases) the risk of a given disease. An additional concept in the design and interpretation of GWAS is that of linkage disequilibrium, which is the non-random association of alleles. The presence of linkage disequilibrium can obscure which variants are "causative."

[0006] Functional annotation of variants and / or wet-lab experiments can identify causal gene variants identified through GWAS, often leading to the identification of disease-causing genes. Understanding the functional effect of a causal gene variant (e.g., loss of protein function, gain of protein function, increased gene expression, or decreased gene expression) allows researchers to use the variant as a surrogate for therapeutic modulation of a target gene, providing insight into the potential therapeutic efficacy and safety of therapeutics that modulate that target.

[0007] Identifying such gene-disease associations provides insights into disease biology and can be used to identify novel therapeutic targets for the pharmaceutical industry. To translate therapeutic insights gained from human genetics, disease biology in patients must be exogenously "programmed" to recapitulate observations from human genetics. There are several therapeutic modalities that can be added when applying therapeutic targets identified through human genetics to new drugs. These may include well-established therapeutic modalities such as small molecules and monoclonal antibodies, mature modalities such as oligonucleotides, and newer 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.

[0008] 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 may also be referred to as MST1 protein. The MST1 gene may encode various transcripts or splice variants. MSP may contain 711 amino acids and have a mass of approximately 80.3 kDa. MSP may be cleaved into α and β chains. MSP may be cytoplasmic. MSP may be secreted. MSP may interact with the macrophage-stimulating protein receptor (macrophage-stimulating 1 receptor) encoded by MST1R. MST1 may be expressed in liver cells, such as hepatocytes. Secreted MSP may bind to or interact with the macrophage-stimulating protein receptor in the lung. MSP may stimulate ciliary motility in the lung. MST1 may 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 modified May 15, 2007).

[0009] Here, we have shown 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 the treatment of pulmonary disorders such as COPD, acute exacerbations of COPD, emphysema, chronic bronchitis, asthma, status asthmaticus, asthma-COPD overlap syndrome (ACOS), cough, lung cancer, interstitial lung disease, or pulmonary fibrosis.

[0010] 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 also include inhibiting or targeting MSP, and vice versa. For example, MSP can be inhibited or targeted by using the oligonucleotides described herein to inhibit or target RNA (e.g., mRNA) encoded by the MST1 gene, resulting in less MSP being produced by translation of MST1 RNA. Alternatively, MSP can be targeted or inhibited by an oligonucleotide that binds to or interacts with MST1 RNA and reduces the production of MSP from MST1 RNA. Thus, targeting MST1 can refer to binding of MST1 RNA and reducing MST1 RNA or MSP levels. The oligonucleotide may include 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 treatment.

[0011] I. Composition In some embodiments, compositions comprising oligonucleotides are disclosed herein. In some embodiments, the compositions comprise an oligonucleotide targeting MST1. In some embodiments, the compositions consist of an oligonucleotide targeting MST1. In some embodiments, the oligonucleotide reduces MST1 mRNA expression in a subject. In some embodiments, the oligonucleotide reduces MSP expression 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 methods of treating a disorder in a subject in need of treatment. Some embodiments relate to compositions comprising oligonucleotides for use in methods 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 as described herein.

[0012] 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 composition comprises 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% or more compared to before administration. In some embodiments, the MST1 mRNA level is reduced by about 2.5% or less, about 5% or less, or about 7.5% or less compared to before administration. In some embodiments, the MST1 mRNA level is reduced by about 10% or less compared to before administration. In some embodiments, the MST1 mRNA level is reduced by about 20% or less, about 30% or less, about 40% or less, about 50% or less, about 60% or less, about 70% or less, about 80% or less, or about 90% or less 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 of the foregoing two percentages.

[0013] 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 lung fluid, e.g., 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 pre-administration. In some embodiments, the MSP level is reduced by about 10% or more compared to pre-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% or more compared to before administration. In some embodiments, MSP levels are reduced by about 2.5% or less, about 5% or less, or about 7.5% or less compared to before administration. In some embodiments, MSP levels are reduced by about 10% or less compared to before administration. In some embodiments, MSP levels are reduced by about 20% or less, about 30% or less, about 40% or less, about 50% or less, about 60% or less, about 70% or less, about 80% or less, or about 90% or less 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 of the foregoing two percentages.

[0014] In some embodiments, the composition comprises an oligonucleotide that targets MST1 and, when administered to a subject in an effective amount, reduces an adverse 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), cough, lung cancer, interstitial lung disease, or pulmonary fibrosis. In some embodiments, the adverse phenotype 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 adverse phenotype is reduced by about 10% or more compared to before administration. In some embodiments, the adverse phenotype 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 adverse phenotype is reduced by about 2.5% or less, about 5% or less, or about 7.5% or less compared to before administration. In some embodiments, the adverse phenotype is reduced by about 10% or less compared to before administration. In some embodiments, the adverse phenotype is reduced by about 20% or less, about 30% or less, about 40% or less, about 50% or less, about 60% or less, about 70% or less, about 80% or less, or about 90% or less 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 either of the foregoing two percentages.

[0015] 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), cough, 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 before administration. In some embodiments, the protective phenotype is increased by about 10% or more compared to before 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 before 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 about 2.5% or less, about 5% or less, or about 7.5% or less compared to before administration. In some embodiments, the protective phenotype is increased by about 10% or less compared to before administration. In some embodiments, the protective phenotype is increased by about 20% or less, about 30% or less, about 40% or less, about 50% or less, about 60% or less, about 70% or less, about 80% or less, about 90% or less, or about 100% or less compared to before administration. In some embodiments, the protective phenotype is increased by about 200% or less, about 300% or less, about 400% or less, about 500% or less, about 600% or less, about 700% or less, about 800% or less, about 900% or less, or about 1000% or less 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 either of the foregoing two percentages.

[0016] In some embodiments, the composition comprises an oligonucleotide that targets MST1 and, when administered to a subject in an effective amount, improves (increases) a pulmonary function measure. The pulmonary function measure may include a measure of forced expiratory volume in 1 second (FEV1), forced expiratory volume in 1 second percent predicted (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 pre-administration. In some embodiments, the pulmonary function measure improves by about 10% or more compared to pre-administration. In some embodiments, pulmonary function measurements improve 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, 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 pre-administration. In some embodiments, pulmonary function measurements improve by about 2.5% or less, about 5% or less, or about 7.5% or less compared to pre-administration. In some embodiments, pulmonary function measurements improve by about 10% or less compared to pre-administration. In some embodiments, pulmonary function measures improve by about 20% or less, about 30% or less, about 40% or less, about 50% or less, about 60% or less, about 70% or less, about 80% or less, about 90% or less, or about 100% or less compared to before administration. In some embodiments, pulmonary function measures improve by about 200% or less, about 300% or less, about 400% or less, about 500% or less, about 600% or less, about 700% or less, about 800% or less, about 900% or less, or about 1000% or less 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 either of the foregoing two percentages.

[0017] White blood cell counts can be affected by lung disorders. For example, some inflammatory lung disorders, including chronic obstructive pulmonary disease (COPD) or asthma, can cause inflammation and an increase in circulating white blood cell counts, which can be treated using a composition comprising an oligonucleotide. Alternatively, the pulmonary 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 lung fluid, such as bronchoalveolar fluid. The change may be a decrease (e.g., when circulating levels of leukocytes or levels of leukocytes in the lungs are increased due to an inflammatory lung disorder). The change may 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 about 2.5% or less, about 5% or less, or about 7.5% or less compared to before administration. In some embodiments, the white blood cell measurement changes by about 10% or less compared to before administration. In some embodiments, the white blood cell count changes by about 20% or less, about 30% or less, about 40% or less, about 50% or less, about 60% or less, about 70% or less, about 80% or less, or about 90% or less compared to before administration.In some embodiments, the white blood cell measurement varies 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 of the foregoing two percentages.

[0018] 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 about 2.5% or less, about 5% or less, or about 7.5% or less compared to pre-administration. In some embodiments, COPD exacerbations are reduced by about 10% or less compared to pre-administration. In some embodiments, COPD exacerbations are reduced by about 20% or less, about 30% or less, about 40% or less, about 50% or less, about 60% or less, about 70% or less, about 80% or less, or about 90% or less compared to pre-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 either of the foregoing two percentages.

[0019] 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, the asthma 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, the asthma exacerbations are reduced by about 10% or more compared to pre-administration. In some embodiments, the 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 pre-administration. In some embodiments, the asthma exacerbations are reduced by about 2.5% or less, about 5% or less, or about 7.5% or less compared to pre-administration. In some embodiments, the asthma exacerbations are reduced by about 10% or less compared to pre-administration. In some embodiments, asthma exacerbations are reduced by about 20% or less, about 30% or less, about 40% or less, about 50% or less, about 60% or less, about 70% or less, about 80% or less, or about 90% or less 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 either of the foregoing two percentages.

[0020] 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.

[0021] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of MST1, 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 within a range defined by either of the two preceding 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 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 within the range defined by either of the aforementioned two numbers. The antisense strand can be 14-30 nucleosides in length.

[0022] In some embodiments, a composition comprises an oligonucleotide that inhibits expression of MST1, wherein the oligonucleotide comprises an siRNA 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 strand and the antisense strand 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 strand and the antisense strand 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.

[0023] In some embodiments, a composition comprises an oligonucleotide that inhibits expression of MST1, wherein the oligonucleotide comprises an siRNA 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 strand and the antisense strand 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 strand and the antisense strand 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.

[0024] 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 sense strand and the antisense strand form a double-stranded RNA duplex.In some embodiments, the first base pair of the double-stranded RNA duplex is an AU base pair.

[0025] 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 stretch of nucleotides 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 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 stretch of nucleotides 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 two nucleosides.

[0026] 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 stretch of nucleotides 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 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 stretch of nucleotides 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 two nucleosides.

[0027] 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 a 19-mer in human MST1 mRNA.In some embodiments, the siRNA binds to a 12-mer, a 13-mer, a 14-mer, a 15-mer, a 16-mer, a 17-mer, a 18-mer, a 19-mer, a 20-mer, a 21-mer, a 22-mer, a 23-mer, a 24-mer, or a 25-mer in human MST1 mRNA.

[0028] 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 a 17-mer in non-human primate MST1 mRNA.In some embodiments, the siRNA binds to a 12-mer, a 13-mer, a 14-mer, a 15-mer, a 16-mer, a 17-mer, a 18-mer, a 19-mer, a 20-mer, a 21-mer, a 22-mer, a 23-mer, a 24-mer, or a 25-mer in non-human primate MST1 mRNA.

[0029] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of MST1, the oligonucleotide comprising 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 three 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 three 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 three 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 three mismatches in the antisense strand.

[0030] In some embodiments, a composition comprises an oligonucleotide that inhibits expression of MST1, 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 have a SNP and has a minor allele frequency (MAF) of 1% or greater (positions 2-18). In some embodiments, the MAF is about 2% or greater, about 3% or greater, about 4% or greater, about 5% or greater, about 6% or greater, about 7% or greater, about 8% or greater, about 9% or greater, about 10% or greater, about 11% or greater, about 12% or greater, about 13% or greater, about 14% or greater, about 15% or greater, about 16% or greater, about 17% or greater, about 18% or greater, about 19% or greater, or about 20% or greater.

[0031] In some embodiments, the composition comprises an oligonucleotide that inhibits the 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: 1-3024, or a nucleic acid sequence thereof with 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 with 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 stretch of nucleotides 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 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 stretch of nucleotides 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 with 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 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.

[0032] In some embodiments, the composition comprises an oligonucleotide that inhibits the 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 with 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 with 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 stretch of nucleotides 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, or a stretch of nucleotides 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 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 stretch of nucleotides 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 with 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: 3025-6048.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.

[0033] In some embodiments, the composition comprises an oligonucleotide that inhibits the 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 with 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 with 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 stretch of nucleotides 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, or a stretch of nucleotides 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 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 stretch of nucleotides 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 with one or two nucleoside additions at the 3' end. In some embodiments, a 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: 6358-6397.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.

[0034] In some embodiments, the composition comprises an oligonucleotide that inhibits the 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 with 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 with 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 stretch of nucleotides 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, or a stretch of nucleotides 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 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 stretch of nucleotides 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 with 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: 6398-6417.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.

[0035] In some embodiments, the siRNA comprises the sequence of the sense and / or antisense strand of any one of the siRNAs in 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 sequence of the sense and / or antisense strand of any one of the siRNAs in 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 sequence of the sense and / or antisense strand of any one of the siRNAs in 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 of the modifications described herein. The sense or antisense strand may comprise a lipid moiety or a GalNAc moiety.

[0036] In some embodiments, the siRNA comprises a sense strand sequence of 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 of 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 of Table 24B. The sense strand may include any of these sequences, which 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 of 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 of 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 of Table 24B. The antisense strand may comprise any of these sequences, which may include an overhang, such as a 3'UU overhang. The antisense strand may comprise any of the modifications described herein. The antisense strand may comprise a lipid moiety or a GalNAc moiety.

[0037] In some embodiments, the siRNA comprises a sense strand sequence of 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 of 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 of Table 24D. The sense strand may include any of these sequences, which 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 of 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 of 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 of Table 24D. The antisense strand may comprise any of these sequences, which may include an overhang, such as a 3'UU overhang. The antisense strand may comprise any of the modifications described herein. The antisense strand may comprise a lipid moiety or a GalNAc moiety.

[0038] In some embodiments, the siRNA comprises the sequence of the sense and / or antisense strand of an siRNA in Table 33B or Table 33C, or a nucleic acid sequence thereof with three or four nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sequence of the sense and / or antisense strand of an siRNA in Table 33B or Table 33C, 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 sense and / or antisense strand of an siRNA in Table 33B or Table 33C. In some embodiments, the siRNA is cross-reactive with non-human primate (NHP) MST1 mRNA. The sense or antisense strand may comprise any of the modifications described herein. The sense or antisense strand may comprise a lipid moiety or a GalNAc moiety.

[0039] The siRNA may include the sense and / or antisense strand base sequence of any siRNA in any table contained herein (e.g., an unmodified sequence or a base sequence with other modifications), or may include the nucleic acid sequence with one or two nucleoside substitutions, additions, or deletions, or may include the nucleic acid sequence with three or four nucleoside substitutions, additions, or deletions. In some cases, the sequence does not include an overhang (e.g., UU) included in the table.

[0040] In some embodiments, the siRNA comprises the sense and / or antisense strand sequences of siRNAs of subset A, 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 siRNAs of subset A, 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 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 of the modifications described herein. The sense or antisense strand may comprise a lipid moiety or a GalNAc moiety.

[0041] In some embodiments, the siRNA comprises the sequence of the sense and / or antisense strand of an siRNA of subset B, or a nucleic acid sequence thereof having a substitution, addition, or deletion of three or four nucleosides. In some embodiments, the siRNA comprises the sequence of the sense and / or antisense strand of an siRNA of subset B, or a nucleic acid sequence thereof having a substitution, addition, or deletion of one or two nucleosides. In some embodiments, the siRNA comprises the sequence of the sense and / or antisense strand 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 of the modifications described herein. The sense or antisense strand may comprise a lipid moiety or a GalNAc moiety.

[0042] In some embodiments, the siRNA comprises the sense and / or antisense strand sequences of siRNAs of subset C, 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 siRNAs of subset C, 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 siRNAs 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 of the modifications described herein. The sense or antisense strand may comprise a lipid moiety or a GalNAc moiety.

[0043] In some embodiments, the siRNA comprises the sequence of the sense and / or antisense strand of an siRNA of subset D, or a nucleic acid sequence thereof having a substitution, addition, or deletion of three or four nucleosides. In some embodiments, the siRNA comprises the sequence of the sense and / or antisense strand of an siRNA of subset D, or a nucleic acid sequence thereof having a substitution, addition, or deletion of one or two nucleosides. In some embodiments, the siRNA comprises the sequence of the sense and / or antisense strand of an siRNA 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 of the modifications described herein. The sense or antisense strand may comprise a lipid moiety or a GalNAc moiety.

[0044] In some embodiments, the siRNA comprises the sense and / or antisense strand sequences of siRNAs of subset E, 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 siRNAs of subset E, 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 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 of the modifications described herein. The sense or antisense strand may comprise a lipid moiety or a GalNAc moiety.

[0045] In some embodiments, the siRNA comprises the sequence of the sense and / or antisense strand of an siRNA of subset F, or a nucleic acid sequence thereof having a substitution, addition, or deletion of three or four nucleosides. In some embodiments, the siRNA comprises the sequence of the sense and / or antisense strand of an siRNA of subset F, or a nucleic acid sequence thereof having a substitution, addition, or deletion of one or two nucleosides. In some embodiments, the siRNA comprises the sequence of the sense and / or antisense strand of an siRNA 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 of the modifications described herein. The sense or antisense strand may comprise a lipid moiety or a GalNAc moiety.

[0046] In some embodiments, the siRNA comprises a sense strand having a sequence set forth in 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 of SEQ ID NOs: 6373, 6375, 6385, 6386, or 6387, at least 80% identical to any of SEQ ID NOs: 6373, 6375, 6385, 6386, or 6387, at least 85% identical to any of SEQ ID NOs: 6373, 6375, 6385, 6386, or 6387, at least 90% identical to any 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 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 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 NOs: 6373, 6375, 6385, 6386, or 6387. The sense 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') of any of the aforementioned sequences. The sense 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 sense strand may comprise a modification pattern described herein. The sense strand may comprise an overhang. The sense strand may comprise a lipid moiety. The sense strand may comprise a GalNAc moiety.

[0047] In some embodiments, the siRNA comprises an antisense strand having a sequence set forth in 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 of SEQ ID NOs: 6403, 6405, 6415, 6416, or 6417, at least 80% identical to any of SEQ ID NOs: 6403, 6405, 6415, 6416, or 6417, at least 85% identical to any of SEQ ID NOs: 6403, 6405, 6415, 6416, or 6417, at least 90% identical to any 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 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 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 NOs: 6403, 6405, 6415, 6416, or 6417. The antisense strand sequence can comprise the first 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 sequence can 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 can comprise an overhang. The antisense strand can comprise a modification pattern as described herein. The antisense strand can comprise a lipid moiety or a GalNAc moiety.

[0048] In some embodiments, the siRNA comprises a sense strand having the sequence set forth in SEQ ID NO: 6373. In some embodiments, the sense strand sequence comprises or consists of a sequence 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 one, two, three, or four 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 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. 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.

[0049] In some embodiments, the siRNA comprises a sense strand having the sequence set forth in SEQ ID NO: 6374. In some embodiments, the sense strand sequence comprises or consists of a sequence 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 one, two, three, or four 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 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: 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.

[0050] In some embodiments, the siRNA comprises a sense strand having the sequence set forth in SEQ ID NO: 6385. In some embodiments, the sense strand sequence comprises or consists of a sequence 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 one, two, three, or four 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 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: 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.

[0051] In some embodiments, the siRNA comprises a sense strand having the sequence set forth in SEQ ID NO: 6386. In some embodiments, the sense strand sequence comprises or consists of a sequence 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 one, two, three, or four 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 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: 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.

[0052] In some embodiments, the siRNA comprises a sense strand having the sequence set forth in SEQ ID NO: 6387. In some embodiments, the sense strand sequence comprises or consists of a sequence 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 one, two, three, or four 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 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: 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.

[0053] In some embodiments, the siRNA comprises an antisense strand having the sequence set forth in SEQ ID NO: 6403. In some embodiments, the antisense strand sequence comprises or consists of a sequence 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 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: 6403, 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. 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.

[0054] In some embodiments, the siRNA comprises an antisense strand having the sequence set forth in SEQ ID NO: 6405. In some embodiments, the antisense strand sequence comprises or consists of a sequence 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 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: 6405, 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: 6405. 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.

[0055] In some embodiments, the siRNA comprises an antisense strand having the sequence set forth in SEQ ID NO: 6415. In some embodiments, the antisense strand sequence comprises or consists of a sequence 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 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: 6415, 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: 6415. 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.

[0056] In some embodiments, the siRNA comprises an antisense strand having the sequence set forth in SEQ ID NO: 6416. In some embodiments, the antisense strand sequence comprises or consists of a sequence 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 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: 6416, 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: 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.

[0057] In some embodiments, the siRNA comprises an antisense strand having the sequence set forth in SEQ ID NO: 6417. In some embodiments, the antisense strand sequence comprises or consists of a sequence 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 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: 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: 6417. 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.

[0058] In some embodiments, the siRNA comprises a sense strand having the sequence set forth in SEQ ID NO: 6440. In some embodiments, the sense strand sequence comprises or consists of a sequence 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 one, two, three, or four 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 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: 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 the sequence set forth in SEQ ID NO: 6499. In some embodiments, the antisense strand sequence comprises or consists of a sequence 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 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: 6499, 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: 6499.The antisense strand may comprise a modification pattern 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.

[0059] In some embodiments, the siRNA comprises a sense strand having the sequence set forth in SEQ ID NO: 6446. In some embodiments, the sense strand sequence comprises or consists of a sequence 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 one, two, three, or four 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 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: 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 the sequence set forth in SEQ ID NO: 6505. In some embodiments, the antisense strand sequence comprises or consists of a sequence 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 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: 6505, 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: 6505.The antisense strand may comprise a modification pattern 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.

[0060] In some embodiments, the siRNA comprises a sense strand having the sequence set forth in SEQ ID NO: 6447. In some embodiments, the sense strand sequence comprises or consists of a sequence 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 one, two, three, or four 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 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: 6447. 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 the sequence set forth in SEQ ID NO: 6506. In some embodiments, the antisense strand sequence comprises or consists of a sequence 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 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: 6506, 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: 6506.The antisense strand may comprise a modification pattern 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.

[0061] In some embodiments, the siRNA comprises a sense strand having the sequence set forth in SEQ ID NO: 6448. In some embodiments, the sense strand sequence comprises or consists of a sequence 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 one, two, three, or four 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 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: 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 the sequence set forth in SEQ ID NO: 6507. In some embodiments, the antisense strand sequence comprises or consists of a sequence 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 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: 6507, 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: 6507.The antisense strand may comprise a modification pattern 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.

[0062] In some embodiments, the siRNA comprises a sense strand having the sequence set forth in SEQ ID NO: 6461. In some embodiments, the sense strand sequence comprises or consists of a sequence 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 one, two, three, or four 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 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: 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 the sequence set forth in SEQ ID NO: 6520. In some embodiments, the antisense strand sequence comprises or consists of a sequence 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 100% identical to SEQ ID NO: 6520.The antisense strand may comprise a modification pattern 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.

[0063] In some embodiments, the siRNA comprises a sense strand having the sequence set forth in SEQ ID NO: 6466. In some embodiments, the sense strand sequence comprises or consists of a sequence 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 one, two, three, or four 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 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: 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 the sequence set forth in SEQ ID NO: 6525. In some embodiments, the antisense strand sequence comprises or consists of a sequence 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 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: 6525, 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: 6525.The antisense strand may comprise a modification pattern 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.

[0064] In some embodiments, the siRNA comprises a sense strand having the sequence set forth in SEQ ID NO: 6470. In some embodiments, the sense strand sequence comprises or consists of a sequence 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 one, two, three, or four 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 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: 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 the sequence set forth in SEQ ID NO: 6529. In some embodiments, the antisense strand sequence comprises or consists of a sequence 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 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: 6529, 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: 6529.The antisense strand may comprise a modification pattern 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.

[0065] In some embodiments, the siRNA comprises a sense strand having the sequence set forth in SEQ ID NO: 6476. In some embodiments, the sense strand sequence comprises or consists of a sequence 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 one, two, three, or four 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 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: 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 the sequence set forth in SEQ ID NO: 6535. In some embodiments, the antisense strand sequence comprises or consists of a sequence 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 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: 6535, 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: 6535.The antisense strand may comprise a modification pattern 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.

[0066] 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 either of the aforementioned two numbers. In some embodiments, the ASO is 15-25 nucleosides in length. In some embodiments, the ASO is 20 nucleosides in length.

[0067] In some embodiments, a composition comprises an oligonucleotide that inhibits expression of MST1, wherein the oligonucleotide is about 12-30 nucleosides in length and comprises an ASO comprising a nucleoside sequence complementary to about 12-30 contiguous nucleosides of a full-length human MST1 mRNA sequence, such as SEQ ID NO: 6163, where (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.

[0068] In some embodiments, a composition comprises an oligonucleotide that inhibits expression of MST1, wherein the oligonucleotide is about 12-30 nucleosides in length and comprises an ASO comprising a nucleoside sequence complementary to about 12-30 contiguous nucleosides of a full-length human MST1 mRNA sequence, such as SEQ ID NO: 6185, where (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.

[0069] C. Modification Pattern In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of MST1, wherein the oligonucleotide comprises modified nucleosides and / or modified internucleoside linkages, and / or (ii) the composition comprises a pharmaceutically acceptable carrier. In some embodiments, the oligonucleotide comprises modifications including modified nucleosides and / or modified internucleoside linkages. In some embodiments, the oligonucleotide comprises modified internucleoside linkages. In some embodiments, the modified internucleoside linkages comprise alkyl phosphonates, phosphorothioates, methyl phosphonates, phosphorodithioates, alkyl phosphonothioates, phosphoramidates, carbamates, carbonates, phosphate triesters, acetamidates, or carboxymethyl esters, or combinations thereof. In some embodiments, the modified internucleoside linkages comprise one or more phosphorothioate linkages. Phosphorothioates may contain a non-bridging oxygen atom in the phosphate backbone of the oligonucleotide replaced with sulfur. The modified internucleoside linkages may be included in siRNA or ASO. Advantages of modified internucleoside linkages may include reduced toxicity or improved pharmacokinetics.

[0070] In some embodiments, a 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 series 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, 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, 20 or more modified internucleoside linkages, 21 or more modified internucleoside linkages, 22 or more modified internucleoside linkages, 23 or more modified internucleoside linkages, 24 or more modified internucleoside linkages, 25 or more modified internucleoside linkages, 26 or more modified internucleoside linkages, 27 or more modified internucleoside linkages, 28 or more modified internucleoside linkages, 29 or more modified internucleoside linkages, 30 or more modified internucleoside linkages, 31 or more modified internucleoside linkages, 32 or more modified internucleoside linkages, 33 or more modified internucleoside linkages, 34 or more modified internucleoside linkages, 35 or more modified internucleoside linkages, or more 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.

[0071] In some embodiments, a 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 (HLA), a cyclohexene nucleic acid (CeNA), a 2'-methoxyethyl, a 2'-O-alkyl, 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 an HLA. 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'-fluoro group. In some embodiments, the modified nucleoside comprises a 2'-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'-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 a 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. Advantages of modified nucleosides may include reduced toxicity or improved pharmacokinetics.

[0072] 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 of nucleosides 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.

[0073] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of MST1, wherein the oligonucleotide comprises a moiety attached to the 3' or 5' end of the oligonucleotide. Examples of the moiety 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, and the moiety is attached to the 5' end of the sense strand. In some embodiments, the oligonucleotide is an siRNA having a sense strand, and the moiety is attached to the 3' end of the sense strand. In some embodiments, the oligonucleotide is an siRNA having an antisense strand, and the moiety is attached to the 5' end of the antisense strand. In some embodiments, the oligonucleotide is an siRNA having an antisense strand, and the moiety is attached to the 3' end of the antisense strand. In some embodiments, the oligonucleotide is an ASO, and the moiety is attached to the 5' end of the ASO. In some embodiments, the oligonucleotide is an ASO, and the moiety is attached to the 3' end of the ASO.

[0074] In some embodiments, the oligonucleotide is delivered to a cell or tissue by binding 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 cell-extracellular matrix (ECM) adhesion. In some embodiments, the moiety comprises an epithelial-specific integrin. Integrin αvβ6 (αvβ6) may be an example of an epithelial-specific integrin αvβ6, which 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 injured lung epithelium.

[0075] In some embodiments, the oligonucleotide is conjugated 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 to facilitate targeting or delivery of an oligonucleotide bound to a specific cell type or tissue (e.g., a cell expressing integrin αvβ3 or αvβ6). In some embodiments, multiple integrin targeting ligands are conjugated to the oligonucleotide. In some embodiments, the oligonucleotide-integrin targeting ligand conjugate is selectively internalized by lung epithelial cells, either by receptor-mediated endocytosis or other means.

[0076] An example of a targeting group useful for delivering an oligonucleotide comprising an integrin-targeting ligand may be based on a peptide or peptidomimetic containing the arginine-glycine-aspartic acid (RGD) peptide. In some embodiments, a 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 to the 3' or 5' end of the oligonucleotide. The RGD peptide may be linear. The RGD peptide may be cyclic. The RGD peptide may 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-Azido) (SEQ ID NO: 6184), RGD derived from aminobenzoic acid, or a combination thereof. In some embodiments, the RGD peptide comprises multiple such RGD peptides. For example, the RGD peptide may comprise two, three, or four RGD peptides. Some embodiments comprise an arginine-glycine-glutamic acid peptide.

[0077] The oligonucleotide may contain purines. Examples of purines include adenine (A) 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.

[0078] In some embodiments, the purines of the oligonucleotide comprise 2' fluoro-modified purines. In some embodiments, the purines of the oligonucleotide comprise 2' methyl-modified purines. In some embodiments, the purines of the oligonucleotide comprise a mixture of 2' fluoro- and 2' methyl-modified purines. In some embodiments, all the purines of the oligonucleotide comprise 2' fluoro-modified purines. In some embodiments, all the purines of the oligonucleotide comprise 2' methyl-modified purines. In some embodiments, all the purines of the oligonucleotide comprise a mixture of 2' fluoro- and 2' methyl-modified purines.

[0079] In some embodiments, the pyrimidines of the oligonucleotide comprise 2'fluoro-modified pyrimidines. In some embodiments, the pyrimidines of the oligonucleotide comprise 2'methyl-modified pyrimidines. In some embodiments, the pyrimidines of the oligonucleotide comprise a mixture of 2'fluoro- and 2'methyl-modified pyrimidines. In some embodiments, all pyrimidines of the oligonucleotide comprise 2'fluoro-modified pyrimidines. In some embodiments, all pyrimidines of the oligonucleotide comprise 2'methyl-modified pyrimidines. In some embodiments, all pyrimidines of the oligonucleotide comprise a mixture of 2'fluoro- and 2'methyl-modified pyrimidines.

[0080] 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'methyl-modified pyrimidines. In some embodiments, the purines of the oligonucleotide comprise 2'methyl-modified purines and the pyrimidines of the oligonucleotide comprise a mixture of 2'fluoro- and 2'methyl-modified pyrimidines. In some embodiments, the purines of the oligonucleotide comprise 2'fluoro-modified purines and the pyrimidines of the oligonucleotide comprise 2'methyl-modified pyrimidines. In some embodiments, the purines of the oligonucleotide comprise 2'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'methyl-modified purines. In some embodiments, the pyrimidines of the oligonucleotide comprise 2'methyl-modified pyrimidines and the purines of the oligonucleotide comprise a mixture of 2'fluoro- and 2'methyl-modified purines. In some embodiments, the pyrimidines of the oligonucleotide comprise 2'fluoro-modified pyrimidines and the purines of the oligonucleotide comprise 2'methyl-modified purines. In some embodiments, the pyrimidines of the oligonucleotide comprise 2' methyl-modified pyrimidines and the purines of the oligonucleotide comprise 2' fluoro-modified purines.

[0081] In some embodiments, all purines of the oligonucleotide comprise 2'-fluoro modified purines and all pyrimidines of the oligonucleotide comprise a mixture of 2'-fluoro and 2'-methyl modified pyrimidines. In some embodiments, all purines of the oligonucleotide comprise 2'-methyl modified purines and all pyrimidines of the oligonucleotide comprise a mixture of 2'-fluoro and 2'-methyl modified pyrimidines. In some embodiments, all purines of the oligonucleotide comprise 2'-fluoro modified purines and all pyrimidines of the oligonucleotide comprise 2'-methyl modified pyrimidines. In some embodiments, all purines of the oligonucleotide comprise 2'-methyl modified purines and all pyrimidines of the oligonucleotide comprise 2'-fluoro modified pyrimidines. In some embodiments, all pyrimidines of the oligonucleotide comprise 2'-fluoro modified pyrimidines and all purines of the oligonucleotide comprise a mixture of 2'-fluoro and 2'-methyl modified purines. In some embodiments, all pyrimidines of the oligonucleotide comprise 2'-methyl modified pyrimidines and all purines of the oligonucleotide comprise a mixture of 2'-fluoro and 2'-methyl modified purines. In some embodiments, all pyrimidines of the oligonucleotide comprise 2'-fluoro ... 2'-methyl modified purines. In some embodiments, the pyrimidines of the oligonucleotide comprise 2' methyl modified pyrimidines and all purines of the oligonucleotide comprise 2' fluoro modified purines.

[0082] 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 in 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 of the oligonucleotide chain and one other base between positions 5 and 11 are pyrimidines, both of these pyrimidines are the only two positions in the oligonucleotide chain that have a 2'F modification. In some embodiments, if position 9 of the oligonucleotide chain and two other bases between positions 5 and 11 are pyrimidines, and these two other pyrimidines are adjacent positions, so that there are no three 2'F modifications in a row, any combination of 2'F modifications can be made to give 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 possible, with a total of 3-5 2'F modifications, provided that no oligonucleotide strand has three 2'F modifications in a row. In some cases, either oligonucleotide strand of the siRNA contains a modification pattern that conforms to any or all of these strands of the oligonucleotide rules.

[0083] 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 one other base between positions 5 and 11 of an oligonucleotide strand are the only purines, then both of these purines are the only two positions in the oligonucleotide strand with a 2'F modification. In some embodiments, if position 9 and two other bases between positions 5 and 11 of an oligonucleotide strand are the only purines, and these two other purines are adjacent, such that there are no three 2'F modifications in a row, then any combination of 2'F modifications that results in a total of three 2'F modifications can be made. In some embodiments, if there are more than two purines between positions 5 and 11 of an oligonucleotide strand, then all combinations of purines with 2'F modifications that result in a total of three to five 2'F modifications are possible, provided that there are no three 2'F modifications in a row in the oligonucleotide strand. In some cases, either oligonucleotide strand of the siRNA contains a modification pattern that conforms to any or all of these strands of the oligonucleotide rules.

[0084] In some cases, the 9th position of the oligonucleotide chain can be 2'deoxy.In these cases, 2'F and 2'OMe modifications can occur at other positions of the oligonucleotide chain.In some cases, any oligonucleotide chain of siRNA comprises the modification pattern that conforms to these chains of oligonucleotide rules.

[0085] In some embodiments, position 9 of the sense strand contains a 2'-fluoro-modified pyrimidine. In some embodiments, all purines in the sense strand contain 2'-O-methyl-modified purines. In some embodiments, 1, 2, 3, 4, or 5 pyrimidines between positions 5 and 11 contain 2'-fluoro-modified pyrimidines, provided that there are not three 2'-fluoro-modified pyrimidines in a row. In some embodiments, odd-numbered positions of the antisense strand contain 2'-O-methyl-modified nucleotides. In some embodiments, even-numbered positions of the antisense strand contain 2'-fluoro-modified nucleotides and unmodified deoxyribonucleotides. In some embodiments, even-numbered positions of the antisense strand contain 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.

[0086] In some embodiments, position 9 of the sense strand contains a 2'-fluoro-modified purine. In some embodiments, all pyrimidines of the sense strand contain 2'-O-methyl-modified purines. In some embodiments, 1, 2, 3, 4, or 5 purines between positions 5 and 11 contain 2'-fluoro-modified purines, provided that there are not three 2'-fluoro-modified purines in a row. In some embodiments, odd-numbered positions of the antisense strand contain 2'-O-methyl-modified nucleotides. In some embodiments, even-numbered positions of the antisense strand contain 2'-fluoro-modified nucleotides and unmodified deoxyribonucleotides. In some embodiments, even-numbered positions of the antisense strand contain 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.

[0087] 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 of the sense strand 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, 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.

[0088] 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 pyrimidines 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 and 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.

[0089] In some embodiments, the moiety comprises a negatively charged group attached to the 5' end of the oligonucleotide. This may 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-vinyl phosphate or cis-vinyl phosphate. The 5'-terminal group may include an extra 5' phosphate. A combination of 5'-terminal groups may be used.

[0090] 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 can be 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, for example, an extra 5' phosphate. A combination of terminal groups can also be used.

[0091] 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 trans-vinyl phosphate. In some embodiments, the vinyl phosphonate comprises cis-vinyl phosphate. Examples of nucleotides containing vinyl phosphonates are shown below.

[0092] [ka]

[0093] 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 siRNA processing machinery.

[0094] 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.

[0095] 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 stretch of nucleotides 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 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 stretch of nucleotides 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 two 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 with one or two nucleoside additions at the 3' end.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, 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 comprise any of the modifications described herein. The sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety.

[0096] 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 stretch of nucleotides 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 stretch of nucleotides 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 with one or two additional nucleosides at the 3' end.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, wherein the antisense strand comprises a nucleoside sequence comprising or consisting of any one of SEQ ID NOs: 6087-6124 or 6253-6309. The sense strand or antisense strand may comprise any of the modifications described herein. The sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety.

[0097] In some embodiments, the siRNA comprises a sense strand having a sequence set forth in 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. , 6236, or 6242, 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. 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 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 SEQ ID NOs: 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 (5' to 3') of any of the foregoing sequences.The sense 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 sense strand may comprise a modification pattern as described herein. The sense strand may comprise an overhang. The sense strand may comprise a lipid moiety. The sense strand may comprise a GalNAc moiety.

[0098] In some embodiments, the siRNA comprises an antisense strand having a sequence set forth in any of SEQ ID NOs: 6273, 6279, 6280, 6281, 6294, 6299, 6303, or 6309. In some embodiments, the sense 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 any one of SEQ ID NOs: 6273, 6279, 6280, 6281, 6294, 6299, 6303, or 6309, 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 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 SEQ ID NOs: 6273, 6279, 6280, 6281, 6294, 6299, 6303, or 6309. 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') of any of the foregoing sequences.The antisense strand sequence can 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 above sequences.The antisense strand can comprise an overhang.The antisense strand can comprise the modification pattern described herein.The antisense strand can comprise a lipid moiety or a GalNAc moiety.

[0099] In some embodiments, the siRNA comprises a sense strand having the sequence set forth in SEQ ID NO: 6206. In some embodiments, the sense strand sequence comprises or consists of a sequence 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 one, two, three, or four 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 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: 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.

[0100] In some embodiments, the siRNA comprises a sense strand having the sequence set forth in SEQ ID NO: 6212. In some embodiments, the sense strand sequence comprises or consists of a sequence 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 one, two, three, or four 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 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: 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.

[0101] In some embodiments, the siRNA comprises a sense strand having the sequence set forth in SEQ ID NO: 6213. In some embodiments, the sense strand sequence comprises or consists of a sequence 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 one, two, three, or four 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 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: 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.

[0102] In some embodiments, the siRNA comprises a sense strand having the sequence set forth in SEQ ID NO: 6214. In some embodiments, the sense strand sequence comprises or consists of a sequence 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 one, two, three, or four 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 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: 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.

[0103] In some embodiments, the siRNA comprises a sense strand having the sequence set forth in SEQ ID NO: 6227. In some embodiments, the sense strand sequence comprises or consists of a sequence 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 one, two, three, or four 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 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: 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.

[0104] In some embodiments, the siRNA comprises a sense strand having the sequence set forth in SEQ ID NO: 6232. In some embodiments, the sense strand sequence comprises or consists of a sequence 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 one, two, three, or four 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 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: 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.

[0105] In some embodiments, the siRNA comprises a sense strand having the sequence set forth in SEQ ID NO: 6236. In some embodiments, the sense strand sequence comprises or consists of a sequence 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 one, two, three, or four 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 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: 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.

[0106] In some embodiments, the siRNA comprises a sense strand having the sequence set forth in SEQ ID NO: 6242. In some embodiments, the sense strand sequence comprises or consists of a sequence 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 one, two, three, or four 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 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: 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.

[0107] In some embodiments, the siRNA comprises an antisense strand having the sequence set forth in SEQ ID NO: 6273. In some embodiments, the antisense strand sequence comprises or consists of a sequence 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 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: 6273, 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: 6273. 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.

[0108] In some embodiments, the siRNA comprises an antisense strand having the sequence set forth in SEQ ID NO: 6279. In some embodiments, the antisense strand sequence comprises or consists of a sequence 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 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: 6279, 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: 6279. 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.

[0109] In some embodiments, the siRNA comprises an antisense strand having the sequence set forth in SEQ ID NO: 6280. In some embodiments, the antisense strand sequence comprises or consists of a sequence 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 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: 6280, 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: 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.

[0110] In some embodiments, the siRNA comprises an antisense strand having the sequence set forth in SEQ ID NO: 6281. In some embodiments, the antisense strand sequence comprises or consists of a sequence 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 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: 6281, 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: 6281. 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.

[0111] In some embodiments, the siRNA comprises an antisense strand having the sequence set forth in SEQ ID NO: 6294. In some embodiments, the antisense strand sequence comprises or consists of a sequence 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 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: 6294, 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: 6294. 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.

[0112] In some embodiments, the siRNA comprises an antisense strand having the sequence set forth in SEQ ID NO: 6299. In some embodiments, the antisense strand sequence comprises or consists of a sequence 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 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: 6299, 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: 6299. 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.

[0113] In some embodiments, the siRNA comprises an antisense strand having the sequence set forth in SEQ ID NO: 6303. In some embodiments, the antisense strand sequence comprises or consists of a sequence 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 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: 6303, 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: 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.

[0114] In some embodiments, the siRNA comprises an antisense strand having the sequence set forth in SEQ ID NO: 6309. In some embodiments, the antisense strand sequence comprises or consists of a sequence 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 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: 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 SEQ ID NO: 6309. 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.

[0115] 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 to 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.

[0116] In some embodiments, the composition comprises an oligonucleotide that inhibits expression of MST1, wherein the oligonucleotide comprises a lipid attached to 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.

[0117] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of MST1, wherein the oligonucleotide comprises a hydrophobic ligand or hydrophobic moiety. In some embodiments, the hydrophobic ligand or hydrophobic moiety comprises cholesterol. In some embodiments, the hydrophobic ligand or hydrophobic moiety comprises a cholesterol derivative. In some embodiments, the hydrophobic ligand or hydrophobic moiety is attached at the 3' end of the oligonucleotide. In some embodiments, the hydrophobic ligand or hydrophobic moiety is attached at the 5' end of the oligonucleotide. In some embodiments, the composition comprises a sense strand, wherein the hydrophobic ligand or hydrophobic 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 hydrophobic 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 hydrophobic moiety attached at the 3' end or 5' end of the oligonucleotide.

[0118] In some embodiments, the hydrophobic moiety is attached to the oligonucleotide (e.g., the sense strand and / or 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.

[0119] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of MST1, wherein the oligonucleotide comprises a lipid attached to 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, lithocholyl, docosanoyl, docosahexaenoyl, myristyl, palmityl, stearyl, or α-tocopherol, or a combination thereof. In some embodiments, the lipid comprises stearyl, lithocholyl, docosanyl, docosahexaenoyl, 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.

[0120] In some embodiments, the oligonucleotide comprises aspects of any of the following structures:

[0121] [ka] In some embodiments, the oligonucleotide comprises aspects of any of the following structures:

[0122] [ka] In some embodiments, the oligonucleotide comprises aspects of any of the following structures:

[0123] [ka] In some embodiments, the oligonucleotide comprises any of the following structural variations. The oligonucleotide may comprise the entire structure or a lipid portion of any of the structures shown. 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 preceding numbers of carbons. In some embodiments, the alkyl group contains 4-18 carbons. In some embodiments, the lipid moiety comprises an alcohol or ether.

[0124] In some embodiments, the lipid comprises a fatty acid. In some embodiments, the lipid comprises a lipid depicted in Table 1. The exemplary lipid moieties in Table 1 are shown attached to 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 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.

[0125] [Table 1-1]

[0126] [Table 1-2]

[0127] 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.

[0128] 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 may be attached to the carbocycle, which may then be attached to the phosphate (e.g., the 5' or 3' phosphate) of the oligonucleotide. In some embodiments, the lipid or hydrocarbon and the end of the sense strand are connected to a 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 end of the sense strand are connected to a phenyl or cyclohexyl linker in a 1,4 substitution pattern (e.g., para-phenyl 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 orientation relative to the oligonucleotide. The lipid may be attached to the carbocycle in a para orientation relative to the oligonucleotide. The lipid may be attached to the carbocycle in a meta orientation relative to the oligonucleotide.

[0129] The lipid portion has the following structure:

[0130] [ka] In some embodiments, the lipid moiety may comprise or consist of the structure:

[0131] [ka] In some embodiments, the lipid moiety comprises or consists of the structure:

[0132] [ka] In some embodiments, the lipid moiety comprises or consists of the structure:

[0133] [ka] or consists of the structure above. In some embodiments, the dotted line represents a covalent bond. The covalent bond can be between the ends of the sense strand or the antisense strand. For example, the bond 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 of carbons. In some embodiments, R comprises or consists of an alkyl group containing 4 to 18 carbons.

[0134] The lipid moiety can be attached to the 5' end of the oligonucleotide. The 5' end can have one phosphate attaching the lipid moiety to the 5' carbon of the sugar of the oligonucleotide. The 5' end can have two phosphates attaching the lipid moiety to the 5' carbon of the sugar of the oligonucleotide. The 5' end can have three phosphates attaching the lipid moiety to the 5' carbon of the sugar of the oligonucleotide. The 5' end can have one phosphate attached to the 5' carbon of the sugar of the oligonucleotide, where one phosphate is attached to the lipid moiety. The 5' end can have two phosphates attached to the 5' carbon of the sugar of the oligonucleotide, where one of the two phosphates is attached to the lipid moiety. The 5' end can have three phosphates attached to the 5' carbon of the sugar of the oligonucleotide, where one of the three phosphates is attached to the lipid moiety. The sugar can include ribose. The sugar can include deoxyribose. The sugar can 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 5' terminal two phosphates may contain modifications such as sulfur instead of oxygen, and the 5' terminal three phosphates may contain modifications such as sulfur instead of oxygen.

[0135] 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.

[0136] Some embodiments relate to a method for producing oligonucleotides that contain hydrophobic conjugates.The strategy for producing hydrophobic conjugates can include the use of phosphoramidite reagents based on 6-membered alcohols such as phenol or cyclohexanol.The phosphoramidite can be reacted with nucleotide to connect the nucleotide to hydrophobic moiety, thereby producing hydrophobic conjugates.Some examples of phosphoramidite reagents that can be used to produce hydrophobic conjugates are provided as follows:

[0137] [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 preceding numbers of carbons. In some embodiments, R comprises or consists of an alkyl group containing 4 to 18 carbons. Any one of the phosphoramidite reagents can be reacted with the 5' end of an oligonucleotide to generate an oligonucleotide containing a hydrophobic moiety. In some embodiments, the phosphoramidite reagent is reacted with the 5' end of the sense strand of the siRNA. Then, sense strand can be hybridized with antisense strand to form double strand.Hybridization can be carried out by incubating sense strand and antisense strand in solution at a predetermined temperature.The temperature can be gradually lowered.The temperature can include or include the temperature that includes the annealing temperature of sense strand and antisense strand.The temperature can include or include the temperature that is lower than the annealing temperature of sense strand and antisense strand.The temperature can be lower than the melting temperature of sense strand and antisense strand.

[0138] The lipid may be attached to the oligonucleotide by a linker, which may comprise polyethylene glycol (e.g., tetraethylene glycol).

[0139] The modifications described herein can be useful for delivery to cells or tissues, for example, extrahepatic delivery or targeting of oligonucleotide compositions. The modifications described herein can be useful for targeting oligonucleotide compositions to cells or tissues.

[0140] 2.Sugar part In some embodiments, a 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 to 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 when they target or bind 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.

[0141] 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 moiety can comprise one, two, three, or more GalNAc molecules. The GalNAc moiety can be linked to the 3' or 5' end of the oligonucleotide.

[0142] 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 to the 3' end of the oligonucleotide. In some embodiments, the GalNAc ligand is attached to 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.

[0143] In some embodiments, disclosed herein is a composition 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. ...

[0144] [ka] or a salt thereof, J is an oligonucleotide, each w is independently selected from any value between 1 and 20; each v is independently selected from any value between 1 and 20; n is selected from any value between 1 and 20, m is selected from any value between 1 and 20, z is selected from any value between 1 and 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 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 substituents independently selected from alkyl 3-10 Carbocyclic rings (where C 1-6 alkyl is optionally 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 )2-NR 7 -, and R 2 are 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 independently selected from 1-6 independently selected from alkyl, R 3 and R 4 are respectively -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)OR7 , -OC(O)R 7 , and -S(O)R 7 are independently selected from R 5 are -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 are independently selected from R 6 are respectively, 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 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)OR7 , -OC(O)R 7 , and -S(O)R 7 C optionally substituted with one or more substituents independently selected from 1-6 alkyl, R 7 are respectively, hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl (each of which is 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 independently selected from carbocycle, and 3- to 10-membered heterocycle; and C 3-10 Carbocycles and 3- to 10-membered heterocycles (each of which is selected from the group consisting of 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 1-6haloalkyl). In some embodiments, each w is independently selected from any value from 1 to 10. In some embodiments, each w is independently selected from any value from 1 to 5. In some embodiments, each w is 1. In some embodiments, each v is independently selected from any value from 1 to 10. In some embodiments, each v is independently selected from any value from 1 to 5. In some embodiments, each v is 1. In some embodiments, n is selected from any value from 1 to 10. In some embodiments, n is selected from any value from 1 to 5. In some embodiments, n is 2. In some embodiments, m is selected from any value from 1 to 10. In some embodiments, m is selected from any value from 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 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 independently selected from 5-6 In some embodiments, Q is a C 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 carbocycle. In some embodiments, Q is selected from phenyl and cyclohexyl, each of which is 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 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-. In some embodiments, R 1 is -OP(O)(OR 7 )O- and -OP(OR 7 )O-. In some embodiments, R 2 is halogen, -OR 7 , -OC(O)R 7 , -SR 7 , -N(R 7 )2, C(O)R 7 , and -S(O)R 7 C substituted with one or more substituents independently selected from 1-3 In some embodiments, R 2 -OR 7 , -OC(O)R 7 , -SR 7 , and -N(R 7 C substituted with one or more substituents independently selected from 1-3 In some embodiments, R 2 -OR 7 and -OC(O)R 7 C substituted with one or more substituents independently 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 7 In some embodiments, R 3 -OR 7 - and -OC(O)R 7In 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 respectively, hydrogen, and halogens, -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 independently selected from a carbocycle or a 3- to 10-membered heterocycle 1-6 In some embodiments, R 7are halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, and -OC, respectively. 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 independently selected from alkyl 1-6 In some embodiments, R 7 each 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 and Y is C; Q is phenyl or cyclohexyl, each of which is selected from the group consisting of halogen, -CN, -OH, -SH, -NO2, -NH2, and C 1-3 optionally substituted with one or more substituents independently selected from alkyl; 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-; R 2 is a C1 alkyl substituted with -OH or -OC(O)CH3, R 3 is -OH or -OC(O)CH3, R 4 is -OH or -OC(O)CH3, and R 5 is —NH(O)CH. In some embodiments, the compound is

[0145] [ka]

[0146]

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[0147]

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[0148]

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[0149]

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[0150]

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[0151]

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[0152]

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[0153] Some embodiments include the following, where J is an oligonucleotide:

[0154] [ka] J may include one or more additional phosphates or one or more phosphorothioates attached to the oligonucleotide. J may include one or more additional phosphates attached to the oligonucleotide. J may include one or more phosphorothioates attached to the oligonucleotide.

[0155] Some embodiments include the following, where J is an oligonucleotide:

[0156] [ka] J may include one or more additional phosphates or one or more phosphorothioates attached to the oligonucleotide. J may include one or more additional phosphates attached to the oligonucleotide. J may include one or more phosphorothioates attached to the oligonucleotide.

[0157] Some embodiments include the following, where J is an oligonucleotide:

[0158] [ka] J may comprise one or more phosphates or phosphorothioates attached to the oligonucleotide. J may comprise one or more phosphates attached to the oligonucleotide. J may comprise a phosphate attached to the oligonucleotide. J may comprise one or more phosphorothioates attached to the oligonucleotide. J may comprise a phosphorothioate attached to the oligonucleotide.

[0159] Some embodiments include the following, where J is an oligonucleotide:

[0160] [ka] 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 include one or more phosphates or phosphorothioates bound to the oligonucleotide. J can include one or more phosphates bound to the oligonucleotide. J can include a phosphate bound to the oligonucleotide. J can include one or more phosphorothioates bound to the oligonucleotide. J can include a phosphorothioate bound to the oligonucleotide.

[0161] Some embodiments include the following, where the phosphate or "5'" indicates the connection to the oligonucleotide:

[0162] [ka]

[0163] Some embodiments include the following, where the phosphate or "5'" indicates the connection to the oligonucleotide:

[0164] [ka]

[0165] Some embodiments include the following, where J is an oligonucleotide:

[0166] [ka] J may comprise one or more phosphates or phosphorothioates bound to the oligonucleotide. J may comprise one or more phosphates bound to the oligonucleotide. J may comprise a phosphate bound to the oligonucleotide. J may comprise one or more phosphorothioates bound to the oligonucleotide. J may comprise a phosphorothioate bound to the oligonucleotide.

[0167] Some embodiments include the following, where J is an oligonucleotide:

[0168] [ka] The structure in this compound bound 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 bound to the oligonucleotide. J can include one or more phosphates bound to the oligonucleotide. J can include a phosphate bound to the oligonucleotide. J can include one or more phosphorothioates bound to the oligonucleotide. J can include a phosphorothioate bound to the oligonucleotide.

[0169] 3. siRNA modification patterns In some embodiments, a 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 the modification pattern 1S:5' NfsnsNfnNfnNfNfNfnNfnNfnNfnNfnNfnNfsnsn-3' (SEQ ID NO: 6164), 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' nsnsnnNfnNfNfNfnnnnnnnnnnsnsn-3' (SEQ ID NO: 6165), 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 following modification pattern 3S:5' nsnsnnNfnNfnNfnnnnnnnnnnsnsn-3' (SEQ ID NO: 6166), 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' In some embodiments, the sense strand comprises the following modification pattern 5S:5'-nsnsnnNfnNfNfNfNfNfNfnNfnNfnNfnNfnNfsnsnN-moiety-3' (SEQ ID NO: 6167), 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 following modification pattern 5S:5'-nsnsnnNfnNfNfNfnnnnnnnnnnsnsnN-moiety-3' (SEQ ID NO: 6168), 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 moiety in modification pattern 4S or 5S comprises an integrin targeting ligand. In some embodiments, the 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' (SEQ ID NO: 6169), 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' nsnsnnNfNfNfNfNfNfnnnnnnnnnnsnsn-3' (SEQ ID NO: 6170), 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' (SEQ ID NO: 6171), 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' (SEQ ID NO: 6172), 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' (SEQ ID NO: 6320), 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' (SEQ ID NO: 6321), 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' (SEQ ID NO: 6322), 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'-snnnnNfNfNfNfNfnnnnnnnnsnsn-3' (SEQ ID NO: 6323), 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' (SEQ ID NO: 6324), 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' (SEQ ID NO: 6325), 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' (SEQ ID NO: 6326), 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' (SEQ ID NO: 6327), 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' (SEQ ID NO: 6328), 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' (SEQ ID NO: 6329), 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' (SEQ ID NO: 6330), 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' (SEQ ID NO: 6331), 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' (SEQ ID NO: 6332), 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'-snnnnNfNfNfNfnnnnnnnnnnsnsn-3' (SEQ ID NO: 6333), 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'-snnnnnNfNfnNfNfnnnnnnnnnsnsn-3' (SEQ ID NO: 6334), 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' (SEQ ID NO: 6335), 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' (SEQ ID NO: 6336), 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' (SEQ ID NO: 6337), 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' (SEQ ID NO: 6338), 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' (SEQ ID NO: 6339), 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' (SEQ ID NO: 6340), 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' (SEQ ID NO: 6341), 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 modification pattern 32S:5'-snnnnNfnnNfNfnnnnnnnnnnsnsn-3' (SEQ ID NO: 6342), 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 modification pattern 33S:5'-snnnnNfndNnNfnNfnnnnnnnnsnsn-3' (SEQ ID NO: 6343), 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 modification pattern 34. In some embodiments, the sense strand comprises the modification pattern 35S:5'-snnnnnnnnNfdNNfnnnnnnnnsnsn-3' (SEQ ID NO: 6344), 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' (SEQ ID NO: 6319), where "Nf" is a 2' fluoro-modified nucleoside, "n" is a 2' O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage.

[0170] In some embodiments, a 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 the modification pattern 1AS:5' nsNfsnNfnNfnNfnNfnnnNfnNfnsnsn-3' (SEQ ID NO: 6173), 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 2AS:5' nsNfsnnnNfnNfNfNfnnnnNfnNfnnnsnsn-3' (SEQ ID NO: 6174), 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' (SEQ ID NO: 6175), 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' (SEQ ID NO: 6176), 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' (SEQ ID NO: 6177), 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' (SEQ ID NO: 6178), 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' (SEQ ID NO: 6179), 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' (SEQ ID NO: 6180), 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' (SEQ ID NO: 6345), 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' (SEQ ID NO: 6346), 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' (SEQ ID NO: 6347), 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' (SEQ ID NO: 6348), 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' (SEQ ID NO: 6349), 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'-nsNfsnnNfnNfnnNfnNfnNfnNfnNfnNfnsnsn-3' (SEQ ID NO: 6350), 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' (SEQ ID NO: 6351), 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' (SEQ ID NO: 6352), 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' (SEQ ID NO: 6353), 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'-nsNfsnnnNfnNfnNfnNfnNfnNfnNfnNfnsnsn-3' (SEQ ID NO: 6354), 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'-nsNfsnNfnNfnNfnnnNfnNfnNfnNfnsnsn-3' (SEQ ID NO: 6355), 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' (SEQ ID NO: 6356), 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' (sequence number 6357), where "Nf" is a 2' fluoro-modified nucleoside, "n" is a 2' O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage.

[0171] In some embodiments, a 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, or 21AS. 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, or 21AS. 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, or 21AS. 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, or 21AS. 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, or 21AS. 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, or 21AS.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, or 21AS. 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, or 21AS. 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, or 21AS. 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, or 21AS. 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, or 21AS. 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, or 21AS.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, or 21AS. 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, or 21AS. 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, or 21AS. 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, or 21AS. 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, or 21AS. 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, or 21AS.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, or 21AS. 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, or 21AS. 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, or 21AS. 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, or 21AS. 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, or 21AS. 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, or 21AS.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, or 21AS. 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, or 21AS. 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, or 21AS. 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, or 21AS. 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, or 21AS. 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, or 21AS.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, or 21AS. 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, or 21AS. 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, or 21AS. 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, or 21AS. 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, or 21AS.

[0172] In some embodiments, the sense strand comprises 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, or 35S, and the antisense strand comprises pattern 1AS. In some embodiments, the sense strand comprises 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, or 35S, and the antisense strand comprises pattern 2AS. In some embodiments, the sense strand comprises 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, or 35S, and the antisense strand comprises pattern 3AS. In some embodiments, the sense strand comprises 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, or 35S, and the antisense strand comprises pattern 4AS. In some embodiments, the sense strand comprises 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, or 35S, and the antisense strand comprises pattern 5AS.In some embodiments, the sense strand comprises 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, or 35S, and the antisense strand comprises pattern 6AS. In some embodiments, the sense strand comprises 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, or 35S, and the antisense strand comprises pattern 7AS. In some embodiments, the sense strand comprises 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, or 35S, and the antisense strand comprises pattern 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, or 35S, and the antisense strand comprises the pattern 9AS. In some embodiments, the sense strand comprises 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, or 35S, and the antisense strand comprises pattern 10AS.In some embodiments, the sense strand comprises 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, or 35S, and the antisense strand comprises pattern 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, or 35S, and the antisense strand comprises the pattern 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, or 35S, and the antisense strand comprises the pattern 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, or 35S, and the antisense strand comprises the pattern 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, or 35S, and the antisense strand comprises the pattern 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, or 35S, and the antisense strand comprises the pattern 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, or 35S, and the antisense strand comprises the pattern 17AS. In some embodiments, the sense strand comprises 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, or 35S, and the antisense strand comprises pattern 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, or 35S, and the antisense strand comprises the pattern 19AS. In some embodiments, the sense strand comprises 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, or 35S, and the antisense strand comprises pattern 20AS.In some embodiments, the sense strand comprises 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, or 35S, and the antisense strand comprises pattern 21AS.

[0173] 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, or 21AS. 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, or 35S. In some embodiments, the sense strand or the antisense strand comprises the modification pattern ASO1.

[0174] 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'-methyl modified purines. In some embodiments, the purines in the sense strand comprise a mixture of 2'-fluoro and 2'-methyl modified purines. In some embodiments, all purines in the sense strand comprise 2'-fluoro modified purines. In some embodiments, all purines in the sense strand comprise 2'-methyl modified purines. In some embodiments, all purines in the sense strand comprise a mixture of 2'-fluoro and 2'-methyl modified purines.

[0175] 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'-methyl-modified pyrimidines. In some embodiments, the pyrimidines of the sense strand comprise a mixture of 2'-fluoro and 2'-methyl-modified pyrimidines. In some embodiments, all pyrimidines of the sense strand comprise 2'-fluoro-modified pyrimidines. In some embodiments, all pyrimidines of the sense strand comprise 2'-methyl-modified pyrimidines. In some embodiments, all pyrimidines of the sense strand comprise a mixture of 2'-fluoro and 2'-methyl-modified pyrimidines.

[0176] 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'-methyl-modified pyrimidines. In some embodiments, the purines of the sense strand comprise 2'-methyl-modified purines, and the pyrimidines of the sense strand comprise a mixture of 2'-fluoro and 2'-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'-methyl-modified pyrimidines. In some embodiments, the purines of the sense strand comprise 2'-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'-methyl-modified purines. In some embodiments, the pyrimidines of the sense strand comprise 2'-methyl-modified pyrimidines, and the purines of the sense strand comprise a mixture of 2'-fluoro and 2'-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' methyl-modified purines. In some embodiments, the pyrimidines of the sense strand comprise 2' methyl-modified pyrimidines and the purines of the sense strand comprise 2' fluoro-modified purines.

[0177] 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'-methyl modified pyrimidines. In some embodiments, all purines in the sense strand comprise 2'-methyl modified purines, and all pyrimidines in the sense strand comprise a mixture of 2'-fluoro and 2'-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'-methyl modified pyrimidines. In some embodiments, all purines in the sense strand comprise 2'-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'-methyl modified purines. In some embodiments, all pyrimidines in the sense strand comprise 2'-methyl modified pyrimidines, and all purines in the sense strand comprise a mixture of 2'-fluoro and 2'-methyl modified purines. In some embodiments, all pyrimidines in the sense strand comprise 2' fluoro-modified pyrimidines and all purines in the sense strand comprise 2' methyl-modified purines, In some embodiments, all pyrimidines in the sense strand comprise 2' methyl-modified pyrimidines and all purines in the sense strand comprise 2' fluoro-modified purines.

[0178] In some embodiments, the purines in the antisense strand comprise 2'-fluoro modified purines. In some embodiments, the purines in the antisense strand comprise 2'-methyl modified purines. In some embodiments, the purines in the antisense strand comprise a mixture of 2'-fluoro and 2'-methyl modified purines. In some embodiments, all purines in the antisense strand comprise 2'-fluoro modified purines. In some embodiments, all purines in the antisense strand comprise 2'-methyl modified purines. In some embodiments, all purines in the antisense strand comprise a mixture of 2'-fluoro and 2'-methyl modified purines.

[0179] 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'-methyl-modified pyrimidines. In some embodiments, the pyrimidines of the antisense strand comprise a mixture of 2'-fluoro and 2'-methyl-modified pyrimidines. In some embodiments, all pyrimidines of the antisense strand comprise 2'-fluoro-modified pyrimidines. In some embodiments, all pyrimidines of the antisense strand comprise 2'-methyl-modified pyrimidines. In some embodiments, all pyrimidines of the antisense strand comprise a mixture of 2'-fluoro and 2'-methyl-modified pyrimidines.

[0180] 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'-methyl-modified pyrimidines. In some embodiments, the purines of the antisense strand comprise 2'-methyl-modified purines, and the pyrimidines of the antisense strand comprise a mixture of 2'-fluoro and 2'-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'-methyl-modified pyrimidines. In some embodiments, the purines of the antisense strand comprise 2'-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'-methyl-modified purines. In some embodiments, the pyrimidines of the antisense strand comprise 2'-methyl-modified pyrimidines, and the purines of the antisense strand comprise a mixture of 2'-fluoro and 2'-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' methyl-modified purines. In some embodiments, the pyrimidines of the antisense strand comprise 2' methyl-modified pyrimidines and the purines of the antisense strand comprise 2' fluoro-modified purines.

[0181] 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'-methyl modified pyrimidines. In some embodiments, all purines in the antisense strand comprise 2'-methyl-modified purines, and all pyrimidines in the antisense strand comprise a mixture of 2'-fluoro and 2'-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'-methyl modified pyrimidines. In some embodiments, all purines in the antisense strand comprise 2'-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'-methyl modified purines. In some embodiments, all pyrimidines in the antisense strand comprise 2'-methyl-modified pyrimidines, and all purines in the antisense strand comprise a mixture of 2'-fluoro and 2'-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' methyl-modified purines. In some embodiments, all pyrimidines in the antisense strand comprise 2' methyl-modified pyrimidines and all purines in the antisense strand comprise 2' fluoro-modified purines.

[0182] In some embodiments, disclosed herein is a composition comprising an oligonucleotide that targets MST1 and reduces the expression of MST1 when administered to a subject in an effective amount, wherein the oligonucleotide comprises 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 a substitution, addition, or deletion of one or two nucleosides of an oligonucleotide sequence with at least one internucleoside linkage modified and at least one nucleoside modified, and the antisense strand comprises an antisense strand sequence described herein with at least one internucleoside linkage modified and at least one nucleoside modified, or an oligonucleotide sequence comprising a substitution, addition, or deletion of one or two nucleosides of an oligonucleotide sequence with at least one internucleoside linkage modified and at least one nucleoside modified. Some embodiments relate to a method comprising administering the composition to a subject.

[0183] In some embodiments, the siRNA comprises the sequence of the sense and / or antisense strand of an siRNA in Table 9, or a nucleic acid sequence thereof having three or four nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sequence of the sense and / or antisense strand of an siRNA in Table 9, or a nucleic acid sequence thereof having one or two nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sequence of the sense and / or antisense strand of an siRNA in Table 9. The siRNA may contain the same internucleoside linkage modifications or nucleoside modifications as those in Table 9. The siRNA may contain any different nucleoside linkage modifications or nucleoside modifications that are different from those in Table 9. The siRNA may contain some unmodified internucleoside linkages or nucleosides.

[0184] In some embodiments, the siRNA comprises the sequence of the sense and / or antisense strand of an siRNA in Table 10, or a nucleic acid sequence thereof having three or four nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sequence of the sense and / or antisense strand of an siRNA in Table 10, or a nucleic acid sequence thereof having one or two nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sequence of the sense and / or antisense strand of an siRNA in Table 10. The siRNA may contain the same internucleoside linkage modifications or nucleoside modifications as those in Table 10. The siRNA may contain any different nucleoside linkage modifications or nucleoside modifications that are different from those in Table 10. The siRNA may contain some unmodified internucleoside linkages or nucleosides.

[0185] In some embodiments, the siRNA comprises the sequence of the sense and / or antisense strand of an siRNA in Table 24A, or a nucleic acid sequence thereof with three or four nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sequence of the sense and / or antisense strand of an siRNA in Table 24A, 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 sense and / or antisense strand of an siRNA in Table 24A. The siRNA may contain the same internucleoside linkage modifications or nucleoside modifications as those in Table 24A. The siRNA may contain any different nucleoside linkage modifications or nucleoside modifications that are different from those in Table 24A. The siRNA may contain some unmodified internucleoside linkages or nucleosides.

[0186] In some embodiments, the siRNA comprises the sequence of the sense and / or antisense strand of an siRNA in Table 24C, or a nucleic acid sequence thereof with three or four nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sequence of the sense and / or antisense strand of an siRNA in Table 24C, 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 sense and / or antisense strand of an siRNA in Table 24C. The siRNA may contain the same internucleoside linkage or nucleoside modifications as those in Table 24C. The siRNA may contain any different nucleoside linkage or nucleoside modifications that are different from those in Table 24C. The siRNA may contain some unmodified internucleoside linkages or nucleosides.

[0187] In some embodiments, the siRNA comprises the sequence of the sense and / or antisense strand of an siRNA in Table 30, or a nucleic acid sequence thereof with three or four nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sequence of the sense and / or antisense strand of an siRNA in Table 30, 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 sense and / or antisense strand of an siRNA in Table 30. The siRNA may contain the same internucleoside linkage modifications or nucleoside modifications as those in Table 30. The siRNA may contain any different nucleoside linkage modifications or nucleoside modifications that are different from those in Table 30. The siRNA may contain some unmodified internucleoside linkages or nucleosides.

[0188] The siRNA may comprise the sequence of the sense and / or antisense strand of any of the siRNAs in the tables contained herein, including modifications, or may comprise nucleic acid sequences thereof with one or two nucleoside substitutions, additions, or deletions, or may comprise nucleic acid sequences thereof with three or four nucleoside substitutions, additions, or deletions.

[0189] In some embodiments, the siRNA comprises a sense strand having the sequence set forth in SEQ ID NO: 6208. In some embodiments, the sense strand sequence comprises or consists of a sequence at least 75% identical to SEQ ID NO: 6208, at least 80% identical to SEQ ID NO: 6208, at least 85% identical to SEQ ID NO: 6208, at least 90% identical to SEQ ID NO: 6208, or at least 95% identical to SEQ ID NO: 6208. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 6208, or a sense strand sequence thereof having one, two, three, or four nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 6208, 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 SEQ ID NO: 6208. 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 the sequence set forth in SEQ ID NO: 6267. In some embodiments, the antisense strand sequence comprises or consists of a sequence at least 75% identical to SEQ ID NO: 6267, at least 80% identical to SEQ ID NO: 6267, at least 85% identical to SEQ ID NO: 6267, at least 90% identical to SEQ ID NO: 6267, or at least 95% identical to SEQ ID NO: 6267. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 6267, 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: 6267, 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: 6267. The antisense strand may include a moiety such as a GalNAc moiety or a lipid moiety.

[0190] In some embodiments, the siRNA comprises a sense strand having the sequence set forth in SEQ ID NO: 6214. In some embodiments, the sense strand sequence comprises or consists of a sequence 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 one, two, three, or four 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 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: 6214. 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 the sequence set forth in SEQ ID NO: 6273. In some embodiments, the antisense strand sequence comprises or consists of a sequence 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 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: 6273, 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: 6273. The antisense strand may include a moiety such as a GalNAc moiety or a lipid moiety.

[0191] In some embodiments, the siRNA comprises a sense strand having the sequence set forth in SEQ ID NO: 6215. In some embodiments, the sense strand sequence comprises or consists of a sequence at least 75% identical to SEQ ID NO: 6215, at least 80% identical to SEQ ID NO: 6215, at least 85% identical to SEQ ID NO: 6215, at least 90% identical to SEQ ID NO: 6215, or at least 95% identical to SEQ ID NO: 6215. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 6215, or a sense strand sequence thereof having one, two, three, or four nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 6215, 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 SEQ ID NO: 6215. 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 the sequence set forth in SEQ ID NO: 6274. In some embodiments, the antisense strand sequence comprises or consists of a sequence at least 75% identical to SEQ ID NO: 6274, at least 80% identical to SEQ ID NO: 6274, at least 85% identical to SEQ ID NO: 6274, at least 90% identical to SEQ ID NO: 6274, or at least 95% identical to SEQ ID NO: 6274. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 6274, 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: 6274, 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: 6274. The antisense strand may include a moiety such as a GalNAc moiety or a lipid moiety.

[0192] In some embodiments, the siRNA comprises a sense strand having the sequence set forth in SEQ ID NO: 6216. In some embodiments, the sense strand sequence comprises or consists of a sequence at least 75% identical to SEQ ID NO: 6216, at least 80% identical to SEQ ID NO: 6216, at least 85% identical to SEQ ID NO: 6216, at least 90% identical to SEQ ID NO: 6216, or at least 95% identical to SEQ ID NO: 6216. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 6216, or a sense strand sequence thereof having one, two, three, or four nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 6216, 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 SEQ ID NO: 6216. 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 the sequence set forth in SEQ ID NO: 6275. In some embodiments, the antisense strand sequence comprises or consists of a sequence at least 75% identical to SEQ ID NO: 6275, at least 80% identical to SEQ ID NO: 6275, at least 85% identical to SEQ ID NO: 6275, at least 90% identical to SEQ ID NO: 6275, or at least 95% identical to SEQ ID NO: 6275. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 6275, 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: 6275, 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: 6275. The antisense strand may include a moiety such as a GalNAc moiety or a lipid moiety.

[0193] In some embodiments, the siRNA comprises a sense strand having the sequence set forth in SEQ ID NO: 6229. In some embodiments, the sense strand sequence comprises or consists of a sequence at least 75% identical to SEQ ID NO: 6229, at least 80% identical to SEQ ID NO: 6229, at least 85% identical to SEQ ID NO: 6229, at least 90% identical to SEQ ID NO: 6229, or at least 95% identical to SEQ ID NO: 6229. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 6229, or a sense strand sequence thereof having one, two, three, or four nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 6229, 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 SEQ ID NO: 6229. 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 the sequence set forth in SEQ ID NO: 6288. In some embodiments, the antisense strand sequence comprises or consists of a sequence at least 75% identical to SEQ ID NO: 6288, at least 80% identical to SEQ ID NO: 6288, at least 85% identical to SEQ ID NO: 6288, at least 90% identical to SEQ ID NO: 6288, or at least 95% identical to SEQ ID NO: 6288. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 6288, 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: 6288, 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: 6288. The antisense strand may include a moiety such as a GalNAc moiety or a lipid moiety.

[0194] In some embodiments, the siRNA comprises a sense strand having the sequence set forth in SEQ ID NO: 6234. In some embodiments, the sense strand sequence comprises or consists of a sequence at least 75% identical to SEQ ID NO: 6234, at least 80% identical to SEQ ID NO: 6234, at least 85% identical to SEQ ID NO: 6234, at least 90% identical to SEQ ID NO: 6234, or at least 95% identical to SEQ ID NO: 6234. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 6234, or a sense strand sequence thereof having one, two, three, or four nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 6234, 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 SEQ ID NO: 6234. 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 the sequence set forth in SEQ ID NO: 6293. In some embodiments, the antisense strand sequence comprises or consists of a sequence at least 75% identical to SEQ ID NO: 6293, at least 80% identical to SEQ ID NO: 6293, at least 85% identical to SEQ ID NO: 6293, at least 90% identical to SEQ ID NO: 6293, or at least 95% identical to SEQ ID NO: 6293. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 6293, 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: 6293, 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: 6293. The antisense strand may include a moiety such as a GalNAc moiety or a lipid moiety.

[0195] In some embodiments, the siRNA comprises a sense strand having the sequence set forth in SEQ ID NO: 6238. In some embodiments, the sense strand sequence comprises or consists of a sequence at least 75% identical to SEQ ID NO: 6238, at least 80% identical to SEQ ID NO: 6238, at least 85% identical to SEQ ID NO: 6238, at least 90% identical to SEQ ID NO: 6238, or at least 95% identical to SEQ ID NO: 6238. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 6238, or a sense strand sequence thereof having one, two, three, or four nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 6238, 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 SEQ ID NO: 6238. 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 the sequence set forth in SEQ ID NO: 6297. In some embodiments, the antisense strand sequence comprises or consists of a sequence at least 75% identical to SEQ ID NO: 6297, at least 80% identical to SEQ ID NO: 6297, at least 85% identical to SEQ ID NO: 6297, at least 90% identical to SEQ ID NO: 6297, or at least 95% identical to SEQ ID NO: 6297. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 6297, 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: 6297, 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: 6297. The antisense strand may include a moiety such as a GalNAc moiety or a lipid moiety.

[0196] In some embodiments, the siRNA comprises a sense strand having the sequence set forth in SEQ ID NO: 6244. In some embodiments, the sense strand sequence comprises or consists of a sequence at least 75% identical to SEQ ID NO: 6244, at least 80% identical to SEQ ID NO: 6244, at least 85% identical to SEQ ID NO: 6244, at least 90% identical to SEQ ID NO: 6244, or at least 95% identical to SEQ ID NO: 6244. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 6244, or a sense strand sequence thereof having one, two, three, or four nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 6244, 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 SEQ ID NO: 6244. 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 the sequence set forth in SEQ ID NO: 6303. In some embodiments, the antisense strand sequence comprises or consists of a sequence 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 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: 6303, 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: 6303. The antisense strand may include a moiety such as a GalNAc moiety or a lipid moiety.

[0197] 4. ASO modification pattern 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 comprises the modification pattern ASO1:5' nsnsnsnsnsdNsdNsdNsdNsdNsdNsdNsdNsdNsdNsdNsnsnsnsnsn-3' (SEQ ID NO: 6181), where "dN" is any deoxynucleotide, "n" is a 2'O-methyl or 2'O-methoxyethyl modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the ASO 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, 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 12AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, or 21AS.

[0198] D. Formulation In some embodiments, the composition is a pharmaceutical composition. In some embodiments, the composition is sterile. In some embodiments, the composition further comprises a pharmaceutically acceptable carrier.

[0199] In some embodiments, the pharmaceutically acceptable carrier comprises water. In some embodiments, the pharmaceutically acceptable carrier comprises a buffer solution. In some embodiments, the pharmaceutically acceptable diluent is saline. In some embodiments, the pharmaceutically acceptable carrier comprises water, a buffer solution, or saline. In some embodiments, the composition comprises a liposome. In some embodiments, the pharmaceutically acceptable carrier comprises a liposome, a lipid, a nanoparticle, a protein, a protein-antibody conjugate, a peptide, cellulose, a nanogel, or a combination thereof. In some embodiments, the oligonucleotide is combined with a lipid, a nanoparticle, a polymer, a liposome, a micelle, or another delivery system.

[0200] In some embodiments, the composition is formulated for delivery to the lungs of a subject. In some embodiments, the composition is formulated for inhalation. In some embodiments, the composition is formulated for aerosolization. In some embodiments, the composition is formulated for administration by a nebulizer.

[0201] II. Methods and Uses In some embodiments, disclosed herein are methods of administering the compositions described herein to a subject. Some embodiments relate to uses of the compositions described herein, such as administering the compositions to a subject.

[0202] Some embodiments relate to methods of treating a disorder in a subject in need of treatment. Some embodiments relate to the use of a composition described herein in the treatment method. Some embodiments include administering a composition described herein to a subject with the disorder. In some embodiments, the administration treats the disorder in the subject. In some embodiments, the composition treats the disorder in the subject.

[0203] In some embodiments, treatment includes preventing, inhibiting, or ameliorating a disorder in a subject. Some embodiments relate to the use of a composition described herein in a method for preventing, inhibiting, or ameliorating a disorder. Some embodiments relate to a method for preventing, inhibiting, or ameliorating a disorder in a subject. Some embodiments include administering a composition described herein to a subject with a disorder. In some embodiments, the administration prevents, inhibits, or ameliorates the disorder in the subject. In some embodiments, the composition prevents, inhibits, or ameliorates the disorder in the subject.

[0204] Some embodiments relate to methods of preventing a disorder in a subject. Some embodiments relate to the use of a composition described herein in a method of preventing a disorder. Some embodiments comprise administering a composition described herein to a subject having the disorder. In some embodiments, the administration prevents the disorder in the subject. In some embodiments, the composition prevents the disorder in the subject.

[0205] Some embodiments relate to methods of inhibiting a disorder in a subject. Some embodiments relate to the use of a composition described herein in a method of inhibiting a disorder. Some embodiments comprise administering a composition described herein to a subject having the disorder. In some embodiments, the administration inhibits the disorder in the subject. In some embodiments, the composition inhibits the disorder in the subject.

[0206] Some embodiments relate to methods of reversing a disorder in a subject. Some embodiments relate to the use of a composition described herein in methods of reversing a disorder. Some embodiments comprise administering a composition described herein to a subject with a disorder. In some embodiments, the administration reverses the disorder in the subject. In some embodiments, the composition reverses the disorder in the subject.

[0207] In some embodiments, administration is systemic. In some embodiments, administration is intravenous. In some embodiments, administration is by injection. In some embodiments, administration is to the lungs of a subject. In some embodiments, administration is by inhalation. In some embodiments, administration is by use of a nebulizer.

[0208] A. Disability Some embodiments of the methods described herein include treating a disorder in a subject in need thereof. In some embodiments, the disorder is a pulmonary disorder. Non-limiting examples of pulmonary disorders may include chronic obstructive pulmonary disease (COPD), acute exacerbation of COPD, emphysema, chronic bronchitis, asthma, status asthmaticus, asthma-COPD overlap syndrome (ACOS), cough, lung cancer, interstitial lung disease, or pulmonary fibrosis. The pulmonary disorder may include an obstructive airway disorder such as COPD or asthma. In some embodiments, the pulmonary disorder includes COPD. In some embodiments, the pulmonary disorder includes an acute exacerbation of COPD. In some embodiments, the pulmonary disorder includes emphysema. In some embodiments, the pulmonary disorder includes chronic bronchitis. In some embodiments, the pulmonary disorder includes asthma. In some embodiments, the pulmonary disorder includes status asthmaticus. In some embodiments, the pulmonary disorder includes ACOS. In some embodiments, the pulmonary disorder includes cough. In some embodiments, the pulmonary disorder includes lung cancer. In some embodiments, the pulmonary disorder includes interstitial lung disease. In some embodiments, the pulmonary disorder includes pulmonary fibrosis. Lung damage can result from smoking or smoke inhalation.

[0209] B. Subject Some embodiments of the methods described herein involve treating a subject. Non-limiting examples of subjects include vertebrates, animals, mammals, dogs, cats, cows, rodents, mice, rats, primates, monkeys, and humans. In some embodiments, the subject is a vertebrate. In some embodiments, the subject is an animal. In some embodiments, the subject is a mammal. In some embodiments, the subject is a dog. In some embodiments, the subject is a cat. In some embodiments, the subject is a cow. In some embodiments, the subject is a mouse. In some embodiments, the subject is a rat. In some embodiments, the subject is a primate. In some embodiments, the subject is a monkey. In some embodiments, the subject is an animal, mammal, dog, cat, cow, rodent, mouse, rat, primate, or monkey. In some embodiments, the subject is a human. In some embodiments, the subject is a male. In some embodiments, the subject is a female. In some embodiments, the subject is an adult (e.g., at least 18 years old).

[0210] C. Baseline Measurements Some embodiments of the method described herein include obtaining baseline measurements from subject.For example, in some embodiments, baseline measurements are obtained from subject before treating subject.Non-limiting examples of baseline measurements include baseline lung function measurements, baseline white blood cell measurements, baseline chronic obstructive pulmonary disease (COPD) exacerbation measurements, baseline asthma exacerbation measurements, baseline MSP measurements, or baseline MST1 mRNA measurements.

[0211] In some embodiments, the baseline measurements are obtained directly from the subject. In some embodiments, the baseline measurements are obtained by observation, for example, by observation of the subject or tissue of the subject. In some embodiments, the baseline measurements are obtained non-invasively using an imaging device.

[0212] In some embodiments, the baseline measurement is obtained on a sample from the subject. In some embodiments, the baseline measurement is obtained on one or more histological tissue sections. In some embodiments, the baseline measurement is obtained by performing an assay, such as an immunoassay, a colorimetric assay, or a fluorescent assay, on a sample obtained from the subject. In some embodiments, the baseline measurement is obtained by an immunoassay, a colorimetric assay, a fluorescent assay, or a chromatographic (e.g., HPLC) assay. In some embodiments, the baseline measurement is obtained by PCR.

[0213] In some embodiments, the baseline measurement is a baseline pulmonary function measurement. In some embodiments, the baseline measurement is a baseline spirometry measurement. The baseline spirometry measurement may be obtained using a spirometer. The spirometer may generate a respiratory curve, including a volume-time curve or a flow-volume loop. In some embodiments, the baseline spirometry measurement is obtained by having the subject breathe into a spirometer sensor. Examples of baseline spirometry measurements may include a baseline forced expiratory volume in 1 second (FEV1) measurement, a baseline forced expiratory volume in 1 second percent predicted (FEV1pp) measurement, a baseline forced vital capacity (FVC) measurement, a baseline FEV1 / FVC ratio, a baseline forced expiratory volume, or a baseline peak expiratory flow measurement. In some embodiments, the baseline measurement includes a baseline forced expiratory volume in 1 second (FEV1) measurement. In some embodiments, the baseline measurement comprises a baseline ratio of predicted forced expiratory volume in one second (FEV1pp) measurement. In some embodiments, the baseline measurement comprises a baseline forced vital capacity (FVC) measurement. In some embodiments, the baseline measurement comprises a baseline FEV1 / FVC ratio. The baseline FEV1 / FVC ratio may optionally be less than 70% or less than 80%. In some embodiments, the baseline measurement comprises a baseline forced expiratory volume. In some embodiments, the baseline measurement comprises a baseline peak expiratory flow measurement.

[0214] In some embodiments, the baseline measurements include baseline white blood cell measurements. In some embodiments, the baseline white blood cell measurements include baseline circulating white blood cell measurements. In some embodiments, the baseline white blood cell measurements include baseline lung tissue white blood cell measurements. In some embodiments, the baseline white blood cell measurements include baseline lung fluid (e.g., bronchoalveolar fluid) white blood cell measurements. In some embodiments, the baseline white blood cell measurements include baseline white blood cell counts. In some embodiments, the baseline white blood cell measurements include baseline white blood cell concentrations. In some embodiments, the baseline white blood cell measurements include baseline white blood cell percentages. Percentages may also be related to other cells. Examples of white blood cells that may be included in the baseline white blood cell measurements include neutrophils, eosinophils, basophils, monocytes, or lymphocytes. The white blood cells may include neutrophils. The white blood cells may include eosinophils. The white blood cells may include basophils. The white blood cells may include monocytes. The white blood cells may include lymphocytes. In some embodiments, the baseline white blood cell count is obtained by an assay such as an immunoassay, a colorimetric assay, or a fluorescent assay. In some embodiments, the baseline white blood cell count is elevated compared to a control white blood cell count. For example, a subject suffering from an inflammatory lung disorder who has not been treated with a composition described herein may have a high white blood cell count in the subject's blood or lungs. In some embodiments, the baseline white blood cell count is determined in lung tissue or lung fluid, such as bronchoalveolar fluid, and may include baseline measurements of neutrophils and macrophages.

[0215] In some embodiments, the baseline measurement value includes a baseline chronic obstructive pulmonary disease (COPD) exacerbation measurement value. A COPD exacerbation may include a COPD relapse, such as an acute increase in the severity of respiratory symptoms, such as dyspnea. The baseline COPD exacerbation measurement value may include the baseline number of COPD relapses, and may be included in a given time frame, such as relapses per day, week, month, or year. The baseline COPD exacerbation measurement value may include the baseline frequency of COPD exacerbations. The baseline COPD exacerbation measurement value may include a baseline measurement of worsening respiratory symptoms, such as increased dyspnea, cough, sputum volume, or sputum purulence. The baseline COPD exacerbation measurement value may include a baseline measurement of events, such as when a subject's condition changes sufficiently to require a change in treatment. The baseline COPD exacerbation measurement value may include a baseline peak flow test, a baseline respiratory nitric oxide test, or a baseline blood oxygen level test.

[0216] In some embodiments, the baseline measurements include baseline asthma exacerbation measurements. An asthma exacerbation may include an asthma attack, e.g., a narrowing of the bronchi causing difficulty breathing. A baseline asthma exacerbation measurement may include a baseline number of asthma attacks, and may include a given time frame, such as recurrence by day, week, month, or year. A baseline asthma exacerbation measurement may include a baseline frequency of asthma exacerbations. A baseline asthma exacerbation measurement may include a baseline bronchial measurement, such as a measurement of bronchial diameter, bronchial circumference, or bronchial area. A baseline asthma exacerbation measurement may include a baseline amount of bronchial narrowing, such as a constriction rate. A baseline asthma exacerbation measurement may include a baseline wheezing measurement, a baseline cough measurement, a baseline chest tightness measurement, a baseline shortness of breath measurement, a baseline agitation measurement, a baseline hyperventilation measurement, a baseline heart rate measurement, a baseline pulmonary function measurement, or a baseline measurement of speech or difficulty breathing. The baseline asthma exacerbation measurements may include a baseline peak flow test, a baseline respiratory nitric oxide measurement, or a baseline blood oxygen level test.

[0217] In some embodiments, the baseline measurement is a baseline MSP measurement. In some embodiments, the baseline MSP measurement comprises a baseline MSP level. In some embodiments, the baseline MSP level is expressed as the mass or percentage of MSP per sample weight. In some embodiments, the baseline MSP level is expressed as the mass or percentage of MSP per sample volume. In some embodiments, the baseline MSP level is expressed as the mass or percentage of MSP per total protein in the sample. In some embodiments, the baseline MSP measurement is a baseline circulating MSP measurement. In some embodiments, the baseline MSP measurement is obtained by an assay such as an immunoassay, a colorimetric assay, or a fluorescent assay.

[0218] In some embodiments, the baseline measurement is a baseline MST1 mRNA measurement. In some embodiments, the baseline MST1 mRNA measurement is a baseline MST1 mRNA level. In some embodiments, the baseline MST1 mRNA level is expressed as the amount or percentage of MST1 mRNA per sample weight. In some embodiments, the baseline MST1 mRNA level is expressed as the amount or percentage of MST1 mRNA per sample volume. In some embodiments, the baseline MST1 mRNA level is expressed as the amount or percentage of MST1 mRNA per total mRNA in the sample. In some embodiments, the baseline MST1 mRNA level is expressed as the amount or percentage of MST1 mRNA per total nucleic acid in the sample. In some embodiments, the baseline MST1 mRNA level is expressed relative to another mRNA level, such as the mRNA level of a housekeeping gene in the sample. In some embodiments, the baseline MST1 mRNA measurement is obtained by an assay such as a polymerase chain reaction (PCR) assay. In some embodiments, the PCR comprises quantitative PCR (qPCR). In some embodiments, the PCR comprises reverse transcription of MST1 mRNA.

[0219] Some embodiments of the methods described herein include obtaining a sample from a subject. In some embodiments, a baseline measurement is obtained from a sample obtained from the subject. In some embodiments, the sample is obtained from the subject prior to administration or treatment of the subject with a composition described herein. In some embodiments, the baseline measurement is obtained in a sample obtained from the subject prior to administration of the composition to the subject.

[0220] In some embodiments, the sample comprises a fluid. In some embodiments, the sample is a fluid sample. For example, a baseline MSP measurement may be obtained in a fluid sample obtained from a patient. In some embodiments, a baseline MST1 mRNA measurement is obtained in a fluid sample. In some embodiments, the sample is a blood, plasma, or serum sample. In some embodiments, a baseline MST1 mRNA measurement is obtained in a fluid sample. In some embodiments, the sample comprises blood. In some embodiments, the sample is a blood sample. In some embodiments, the sample is a whole blood sample. In some embodiments, the blood is fractionated or centrifuged. In some embodiments, the sample comprises plasma. In some embodiments, the sample is a plasma sample. The blood sample may be a plasma sample. In some embodiments, the sample comprises serum. In some embodiments, the sample is a serum sample. The blood sample may be a serum sample. In some embodiments, the fluid sample comprises a lung fluid sample. In some embodiments, the lung fluid sample comprises alveolar fluid. In some embodiments, the lung fluid sample comprises bronchial fluid. In some embodiments, the lung fluid sample comprises bronchoalveolar fluid. Lung fluid may be obtained by a lavage method, such as bronchoalveolar lavage. The lavage method may involve the use of a bronchoscope.

[0221] In some embodiments, the sample comprises tissue. In some embodiments, the sample is a tissue sample. In some embodiments, the tissue comprises liver, lung, or vascular tissue. For example, the baseline MST1 mRNA measurement or baseline MSP measurement may be obtained in a lung or liver sample obtained from a patient. In some embodiments, the tissue comprises liver tissue. The liver may comprise hepatocytes. In some embodiments, the tissue comprises lung tissue. The lung may comprise lung epithelial cells, type I pneumocytes, type II pneumocytes, macrophages, alveolar macrophages, goblet cells, club cells, or fibroblasts. In some embodiments, the tissue comprises vascular tissue. The vascular tissue may comprise vascular endothelial cells. For example, lung tissue may comprise vascular endothelial cells.

[0222] In some embodiments, the sample comprises cells. In some embodiments, the sample comprises cells. In some embodiments, the cells are liver cells. In some embodiments, the liver cells are hepatocytes. In some embodiments, the cells are lung cells. In some embodiments, the lung cells are lung epithelial cells. In some embodiments, the lung cells are type I pneumocytes. In some embodiments, the lung cells are type II pneumocytes. In some embodiments, the lung cells are macrophages. In some embodiments, the lung cells are alveolar macrophages. In some embodiments, the lung cells are goblet cells. In some embodiments, the lung cells are club cells. In some embodiments, the lung cells are fibroblasts. In some embodiments, the cells are vasculature cells. In some embodiments, the vasculature cells are endothelial cells.

[0223] D.Effects In some embodiments, the composition or administration of the composition affects a measurement such as a lung function measurement, a white blood cell measurement, a chronic obstructive pulmonary disease (COPD) exacerbation measurement, an asthma exacerbation measurement, an MSP measurement (e.g., circulating or tissue MSP levels), or an MST1 mRNA measurement compared to a baseline measurement.

[0224] Some embodiments of the methods described herein include obtaining a measurement from a subject. For example, the measurement may be obtained from the subject after treating the subject. In some embodiments, the measurement is obtained in a second sample (such as a fluid or tissue sample described herein) obtained from the subject after administering the composition to the subject. In some embodiments, the measurement indicates that the disorder has been treated.

[0225] In some embodiments, the measurements are obtained directly from the subject. In some embodiments, the measurements are obtained non-invasively using an imaging device. In some embodiments, the measurements are obtained in a second sample from the subject. In some embodiments, the measurements are obtained in one or more histological tissue sections. In some embodiments, the measurements are obtained by performing an assay on the second sample obtained from the subject. In some embodiments, the measurements are obtained by an assay such as an assay described herein. In some embodiments, the assay is an immunoassay, a colorimetric assay, a fluorescent assay, a chromatographic (e.g., HPLC) assay, or a PCR assay. In some embodiments, the measurements are obtained by an assay such as an immunoassay, a colorimetric assay, a fluorescent assay, or a chromatographic (e.g., HPLC) assay. In some embodiments, the measurements are obtained by PCR. In some embodiments, the measurements are obtained by histological examination. In some embodiments, the measurements are obtained by observation. In some embodiments, additional measurements are made in a third sample, a fourth sample, a fifth sample, etc.

[0226] In some embodiments, measurements are obtained within 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 12 hours, 18 hours, or 24 hours after administration of the composition. In some embodiments, measurements are obtained within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days after administration of the composition. In some embodiments, measurements are obtained within 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 6 months, 1 year, 2 years, 3 years, 4 years, or 5 years after administration of the composition. In some embodiments, measurements are obtained 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 12 hours, 18 hours, or 24 hours after administration of the composition. In some embodiments, measurements are obtained 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days after administration of the composition. In some embodiments, measurements are obtained 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 6 months, 1 year, 2 years, 3 years, 4 years, or 5 years after administration of the composition.

[0227] In some embodiments, the composition reduces the measurement compared to a baseline measurement. For example, an adverse phenotype of a lung disorder may be reduced by administration of the composition. In some embodiments, the reduction is measured in a second sample obtained from the subject after administering the composition to the subject. In some embodiments, the reduction is measured directly in the subject after administering the composition to the subject. In some embodiments, the measurement is reduced by about 2.5% or more, about 5% or more, or about 7.5% or more compared to the baseline measurement. In some embodiments, the measurement is reduced by about 10% or more compared to the baseline measurement. In some embodiments, the measurement 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, or about 90% or more compared to the baseline measurement. In some embodiments, the measurement is reduced by about 2.5% or less, about 5% or less, or about 7.5% or less compared to the baseline measurement. In some embodiments, the measurement is reduced by about 10% or less compared to the baseline measurement. In some embodiments, the measurement is decreased by about 20% or less, about 30% or less, about 40% or less, about 50% or less, about 60% or less, about 70% or less, about 80% or less, about 90% or less, or about 100% or less compared to the baseline measurement, hi some embodiments, the measurement is decreased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or a range defined by either of the two aforementioned percentages.

[0228] In some embodiments, the composition increases the measurement compared to a baseline measurement. For example, a protective lung phenotype may be increased upon administration of the composition. In some embodiments, the increase is measured in a second sample obtained from the subject after administering the composition to the subject. In some embodiments, the increase is measured directly in the subject after administering the composition to the subject. In some embodiments, the measurement increases by about 2.5% or more, about 5% or more, or about 7.5% or more compared to the baseline measurement. In some embodiments, the measurement increases by about 10% or more compared to the baseline measurement. In some embodiments, the measurement increases 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, or about 90% or more compared to the baseline measurement. In some embodiments, the measurement increases by about 100% or more, about 250% or more, about 500% or more, about 750% or more, or about 1000% or more compared to the baseline measurement. In some embodiments, the measurement increases by about 2.5% or less, about 5% or less, or about 7.5% or less compared to the baseline measurement. In some embodiments, the measurement increases by about 10% or less compared to the baseline measurement. In some embodiments, the measurement increases by about 20% or less, about 30% or less, about 40% or less, about 50% or less, about 60% or less, about 70% or less, about 80% or less, about 90% or less, or about 100% or less compared to the baseline measurement. In some embodiments, the measurement increases by about 100% or less, about 250% or less, about 500% or less, about 750% or less, or about 1000% or less compared to the baseline measurement. In some embodiments, the measurement increases by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 250%, 500%, 750%, or 1000%, or a range defined by either of two of the foregoing percentages.

[0229] In some embodiments, the measurement is a pulmonary function measurement. In some embodiments, the measurement is a spirometry measurement. The spirometry measurement may be obtained using a spirometer. The spirometer may generate a respiratory curve, including a volume-time curve or a flow-volume loop. In some embodiments, the spirometry measurement is obtained by having the subject breathe into a spirometer sensor. Examples of spirometry measurements may include a forced expiratory volume in 1 second (FEV1) measurement, a forced expiratory volume in 1 second percent predicted (FEV1pp) measurement, a forced vital capacity (FVC) measurement, an FEV1 / FVC ratio, a forced expiratory volume, or a peak expiratory flow measurement. In some embodiments, the measurement includes a forced expiratory volume in 1 second (FEV1). In some embodiments, the measurement includes a percent predicted forced expiratory volume in 1 second (FEV1pp). In some embodiments, the measurement includes a forced vital capacity (FVC) measurement. In some embodiments, the measurement comprises the FEV1 / FVC ratio. The FEV1 / FVC ratio may optionally be less than 70% or less than 80%. In some embodiments, the measurement comprises forced expiratory volume. In some embodiments, the measurement comprises a peak expiratory flow measurement.

[0230] In some embodiments, the composition increases a pulmonary function measure compared to a baseline pulmonary function measure. In some embodiments, the increase is measured directly in the subject after administering the composition to the subject. In some embodiments, the pulmonary function measure increases by about 2.5% or more, about 5% or more, or about 7.5% or more compared to the baseline pulmonary function measure. In some embodiments, the pulmonary function measure increases by about 10% or more compared to the baseline pulmonary function measure. In some embodiments, the pulmonary function measure increases 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, or about 90% or more compared to the baseline pulmonary function measure. In some embodiments, the pulmonary function measure increases by about 100% or more, about 250% or more, about 500% or more, about 750% or more, or about 1000% or more compared to the baseline pulmonary function measure. In some embodiments, the pulmonary function measure increases by about 2.5% or less, about 5% or less, or about 7.5% or less compared to the baseline pulmonary function measure. In some embodiments, the pulmonary function measure increases by about 10% or less compared to the baseline pulmonary function measure. In some embodiments, the pulmonary function measure increases by about 20% or less, about 30% or less, about 40% or less, about 50% or less, about 60% or less, about 70% or less, about 80% or less, about 90% or less, or about 100% or less compared to the baseline pulmonary function measure. In some embodiments, the pulmonary function measure increases by about 100% or less, about 250% or less, about 500% or less, about 750% or less, or about 1000% or less compared to the baseline pulmonary function measure. In some embodiments, the pulmonary function measurement increases by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 250%, 500%, 750%, or 1000%, or a range defined by either of two of the foregoing percentages.

[0231] In some embodiments, the measurements include white blood cell measurements. In some embodiments, the white blood cell measurements include circulating white blood cell measurements. In some embodiments, the white blood cell measurements include lung tissue white blood cell measurements. In some embodiments, the white blood cell measurements include lung fluid (e.g., bronchoalveolar fluid) white blood cell measurements. In some embodiments, the white blood cell measurements include white blood cell counts. In some embodiments, the white blood cell measurements include white blood cell concentrations. In some embodiments, the white blood cell measurements include white blood cell percentages. Percentages may also be relative to other cells. Examples of white blood cells that may be included in white blood cell measurements include neutrophils, eosinophils, basophils, monocytes, or lymphocytes. The white blood cells may include neutrophils. The white blood cells may include eosinophils. The white blood cells may include basophils. The white blood cells may include monocytes. The white blood cells may include lymphocytes. In some embodiments, the white blood cell measurements are obtained by an assay such as an immunoassay, a colorimetric assay, or a fluorescent assay. In some embodiments, the white blood cell count is normal compared to a control white blood cell count. For example, a subject suffering from an inflammatory lung disorder who has not been treated with a composition described herein may have had an elevated white blood cell count that is now low or normal. In some embodiments, the white blood cell count is determined in lung tissue or lung fluid, e.g., bronchoalveolar fluid, and may include measurements of neutrophils and macrophages.

[0232] In some embodiments, the composition reduces white blood cell measurements compared to a baseline white blood cell measurement. In some embodiments, the reduction is measured in a second sample obtained from the subject after administering the composition to the subject. In some embodiments, the white blood cell measurement is reduced by about 2.5% or more, about 5% or more, or about 7.5% or more compared to the baseline white blood cell measurement. In some embodiments, the white blood cell measurement is reduced by about 10% or more compared to the baseline white blood cell measurement. In some embodiments, the white blood cell measurement 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, or about 80% or more compared to the baseline white blood cell measurement. In some embodiments, the white blood cell measurement is reduced by about 2.5% or less, about 5% or less, or about 7.5% or less compared to the baseline white blood cell measurement. In some embodiments, the white blood cell measurement is reduced by about 10% or less compared to the baseline white blood cell measurement. In some embodiments, the white blood cell measurement is decreased by about 20% or less, about 30% or less, about 40% or less, about 50% or less, about 60% or less, about 70% or less, or about 80% or less compared to the baseline white blood cell measurement. In some embodiments, the white blood cell measurement is decreased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or a range defined by any two of the aforementioned percentages. In some embodiments, the white blood cell measurement is decreased by any of the aforementioned percentages or percentage ranges compared to the baseline white blood cell measurement.

[0233] In some embodiments, the measurement values ​​include chronic obstructive pulmonary disease (COPD) exacerbation measurement values. COPD exacerbation may include COPD relapses, such as an acute increase in the severity of respiratory symptoms, such as dyspnea. COPD exacerbation measurement values ​​may include the number of COPD relapses, and may be included in a given time frame, such as relapses per day, week, month, or year. COPD exacerbation measurement values ​​may include the frequency of COPD exacerbations. COPD exacerbation measurement values ​​may include measurements of worsening respiratory symptoms, such as increased dyspnea, cough, sputum volume, or sputum purulence. COPD exacerbation measurement values ​​may include measurements of events, such as when a subject's condition changes sufficiently to require a change in treatment. COPD exacerbation measurement values ​​may include peak flow tests, respiratory nitric oxide measurements, or blood oxygen level tests.

[0234] In some embodiments, the composition reduces a COPD exacerbation measurement compared to a baseline COPD exacerbation measurement. In some embodiments, the reduction is measured in a second sample obtained from the subject after administering the composition to the subject. In some embodiments, the reduction is measured directly in the subject after administering the composition to the subject. In some embodiments, the COPD exacerbation measurement is reduced by about 2.5% or more, about 5% or more, or about 7.5% or more compared to the baseline COPD exacerbation measurement. In some embodiments, the COPD exacerbation measurement is reduced by about 10% or more compared to the baseline COPD exacerbation measurement. In some embodiments, the COPD exacerbation measurement 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, or about 90% or more compared to the baseline COPD exacerbation measurement. In some embodiments, the COPD exacerbation measurement is reduced by about 2.5% or less, about 5% or less, or about 7.5% or less compared to the baseline COPD exacerbation measurement. In some embodiments, the COPD exacerbation measurement is reduced by about 10% or less compared to the baseline COPD exacerbation measurement. In some embodiments, the COPD exacerbation measurement is reduced by about 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% or less compared to the baseline COPD exacerbation measurement. In some embodiments, the COPD exacerbation measurement is reduced by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or a range defined by either of the two aforementioned percentages.

[0235] In some embodiments, the measurements include asthma exacerbation measurements. An asthma exacerbation may include an asthma attack, e.g., a narrowing of the bronchi causing difficulty breathing. An asthma exacerbation measurement may include the number of asthma attacks and may be included in a given time frame, such as recurrence by day, week, month, or year. An asthma exacerbation measurement may include a bronchial measurement, such as a measurement of bronchial diameter, bronchial circumference, or bronchial area. An asthma exacerbation measurement may include an amount of bronchial narrowing, such as a constriction rate. An asthma exacerbation measurement may include a wheezing measurement, a cough measurement, a chest tightness measurement, a shortness of breath measurement, an agitation measurement, a hyperventilation measurement, a heart rate measurement, a pulmonary function measurement, or a measurement of speaking or difficulty breathing. An asthma exacerbation measurement may include a peak flow test, a respiratory nitric oxide measurement, or a blood oxygen level test.

[0236] In some embodiments, the composition reduces an asthma exacerbation measurement compared to a baseline asthma exacerbation measurement. In some embodiments, the reduction is measured in a second sample obtained from the subject after administering the composition to the subject. In some embodiments, the reduction is measured directly in the subject after administering the composition to the subject. In some embodiments, the asthma exacerbation measurement is reduced by about 2.5% or more, about 5% or more, or about 7.5% or more compared to the baseline asthma exacerbation measurement. In some embodiments, the asthma exacerbation measurement is reduced by about 10% or more compared to the baseline asthma exacerbation measurement. In some embodiments, the asthma exacerbation measurement 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, or about 90% or more compared to the baseline asthma exacerbation measurement. In some embodiments, the asthma exacerbation measurement is reduced by about 2.5% or less, about 5% or less, or about 7.5% or less compared to the baseline asthma exacerbation measurement. In some embodiments, the asthma exacerbation measurement is reduced by about 10% or less compared to the baseline asthma exacerbation measurement. In some embodiments, the asthma exacerbation measurement is reduced by about 20% or less, about 30% or less, about 40% or less, about 50% or less, about 60% or less, about 70% or less, about 80% or less, about 90% or less, or about 100% or less compared to the baseline asthma exacerbation measurement. In some embodiments, the asthma exacerbation measurement is reduced by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or a range defined by either of the two aforementioned percentages.

[0237] In some embodiments, the measurement is an MSP measurement. In some embodiments, the MSP measurement comprises an MSP level. In some embodiments, the MSP level is expressed as the mass or percentage of MSP per sample weight. In some embodiments, the MSP level is expressed as the mass or percentage of MSP per sample volume. In some embodiments, the MSP level is expressed as the mass or percentage of MSP per total protein in the sample. In some embodiments, the MSP measurement is a circulating MSP measurement. In some embodiments, the MSP measurement is obtained by an assay such as an immunoassay, a colorimetric assay, or a fluorescent assay.

[0238] In some embodiments, the composition reduces MSP measurements compared to baseline MSP measurements. In some embodiments, the composition reduces circulating MSP levels compared to baseline MSP measurements. In some embodiments, the composition reduces tissue MSP levels compared to baseline MSP measurements. In some embodiments, the reduced MSP levels are measured in a second sample obtained from the subject after administering the composition to the subject. In some embodiments, the second sample is a blood, serum, plasma, liver, or lung sample. In some embodiments, the MSP measurements are reduced by about 2.5% or more, about 5% or more, or about 7.5% or more compared to baseline MSP measurements. In some embodiments, the MSP measurements are reduced by about 10% or more compared to baseline MSP measurements. In some embodiments, the MSP measurements 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 baseline MSP measurements. In some embodiments, the MSP measurement is decreased by about 2.5% or less, about 5% or less, or about 7.5% or less compared to the baseline MSP measurement. In some embodiments, the MSP measurement is decreased by about 10% or less compared to the baseline MSP measurement. In some embodiments, the MSP measurement is decreased by about 20% or less, about 30% or less, about 40% or less, about 50% or less, about 60% or less, about 70% or less, about 80% or less, about 90% or less, or about 100% or less compared to the baseline MSP measurement. In some embodiments, the MSP measurement is decreased by 2.5%, 5%, 7.5%, 19%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or a range defined by either of the two aforementioned percentages.

[0239] In some embodiments, the measurement is an MST1 mRNA measurement. In some embodiments, the MST1 mRNA measurement comprises an MST1 mRNA level. In some embodiments, the MST1 mRNA level is expressed as the amount or percentage of MST1 mRNA per sample weight. In some embodiments, the MST1 mRNA level is expressed as the amount or percentage of MST1 mRNA per sample volume. In some embodiments, the MST1 mRNA level is expressed as the amount or percentage of MST1 mRNA per total mRNA in the sample. In some embodiments, the MST1 mRNA level is expressed as the amount or percentage of MST1 mRNA per total nucleic acid in the sample. In some embodiments, the MST1 mRNA level is expressed relative to another mRNA level, such as the mRNA level of a housekeeping gene in the sample. In some embodiments, the MST1 mRNA measurement is obtained by an assay such as a PCR assay. In some embodiments, the PCR comprises qPCR. In some embodiments, the PCR comprises reverse transcription of MST1 mRNA.

[0240] In some embodiments, the composition reduces the MST1 mRNA measurement compared to a baseline MST1 mRNA measurement. In some embodiments, the MST1 mRNA measurement is obtained in a second sample obtained from the subject after administering the composition to the subject. In some embodiments, the composition reduces the MST1 mRNA level relative to the baseline MST1 mRNA level. In some embodiments, the reduced MST1 mRNA level is measured in a second sample obtained from the subject after administering the composition to the subject. In some embodiments, the second sample is a lung sample. In some embodiments, the second sample is a liver sample. In some embodiments, the MST1 mRNA measurement is reduced by about 2.5% or more, about 5% or more, or about 7.5% or more compared to the baseline MST1 mRNA measurement. In some embodiments, the MST1 mRNA measurement is reduced by about 10% or more compared to the baseline MST1 mRNA measurement. In some embodiments, the MST1 mRNA measurement is decreased 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 a baseline MST1 mRNA measurement. In some embodiments, the MST1 mRNA measurement is decreased by about 2.5% or less, about 5% or less, or about 7.5% or less compared to a baseline MST1 mRNA measurement. In some embodiments, the MST1 mRNA measurement is decreased by about 10% or less compared to a baseline MST1 mRNA measurement. In some embodiments, the MST1 mRNA measurement is decreased by about 20% or less, about 30% or less, about 40% or less, about 50% or less, about 60% or less, about 70% or less, about 80% or less, about 90% or less, or about 100% or less compared to a baseline MST1 mRNA measurement. In some embodiments, the MST1 mRNA measurement is reduced by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or by a range defined by either of two of the foregoing percentages.

[0241] III. Definition Unless otherwise defined, all terminology, notations, and other technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs. In some instances, terms having commonly understood meanings are defined herein for clarity and / or ready reference, and the inclusion of such definitions herein should not necessarily be construed as indicating a substantial difference from that commonly understood in the art.

[0242] Throughout this application, various embodiments may be presented in a range format. It should be understood that the description in range format is for convenience and brevity only and should not be construed as an inflexible limitation on the scope of the present disclosure. Accordingly, the description of a range should be considered to have specifically disclosed all possible subranges and individual numerical values ​​within that range. For example, the description of a range such as 1 to 6 should be considered to have specifically disclosed subranges such as 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 6, and 3 to 6, as well as individual numerical values ​​within the range, such as 1, 2, 3, 4, 5, and 6. This applies regardless of the broadness of the range.

[0243] As used in this specification and claims, "a," "an," and "the" include plural references unless the content clearly dictates otherwise. For example, the term "sample" includes multiple samples, including mixtures thereof.

[0244] "Determining," "measuring," "evaluating," "assessing," "assaying," and "analyzing" are often used interchangeably herein to refer to forms of measurement. The terms include determining whether an element is present (e.g., detecting). Such terms can include quantitative, qualitative, or quantitative and qualitative determinations. Assessing can be relative or absolute. "Detecting the presence of" can include determining the amount of something present, in addition to determining whether something is present or absent, depending on the context.

[0245] The terms "subject" and "patient" may be used interchangeably. A "subject" may be a biological entity that contains expressed genetic material. The biological entity may be, for example, a plant, an animal, or a microorganism, including bacteria, viruses, fungi, and protozoa. The subject may be a mammal. The mammal may be a human. The subject may be diagnosed with or suspected of being at high risk for a disease. In some cases, the subject is not necessarily diagnosed with or suspected of being at high risk for a disease.

[0246] As used herein, a number followed by the term "about" refers to a number that is plus or minus 10% of that number. A range followed by the term "about" refers to a range of minus 10% of the minimum value and plus 10% of the maximum value.

[0247] As used herein, the terms "treatment" or "treating" are used in reference to a pharmaceutical or other intervention regimen to obtain a beneficial or desired result in a recipient. Beneficial or desired results include, but are not limited to, a therapeutic benefit and / or a prophylactic benefit. A therapeutic benefit may also refer to the eradication or amelioration of the condition or underlying disease being treated. Similarly, a therapeutic benefit may be achieved by the eradication or amelioration of one or more physiological symptoms associated with an underlying disease, such that an improvement in the subject is observed, even though the subject may still be affected by the underlying disease. A prophylactic benefit includes delaying, preventing, or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof. With regard to a prophylactic benefit, a subject at risk of developing a particular disease or reporting one or more physiological symptoms of a disease can receive treatment even if a diagnosis of the disease has not been made.

[0248] Some embodiments refer to nucleic acid sequence information. In some embodiments, it is contemplated that thymine (T) may be replaced with uracil (U), or vice versa. For example, some sequences in the sequence listing may list T, but in some embodiments, these may be replaced with U. In some oligonucleotides having a nucleic acid sequence containing uracil, uracil may be replaced with thymine. Similarly, in some oligonucleotides having a nucleic acid sequence containing thymine, thymine may be replaced with uracil. In some embodiments, oligonucleotides such as siRNAs comprise or consist of RNA. In some embodiments, oligonucleotides may comprise or consist of DNA. For example, ASOs may comprise DNA.

[0249] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0250] VI. Working Examples Example 1: Variants in MST1 show protective association against obstructive pulmonary disease and related traits.

[0251] Variants in MST1 were evaluated for association with lung disease and related lung and leukocyte traits in approximately 382,000 individuals using genotype data from the UK Biobank cohort. The variants evaluated included: (1) rs142690032, a low-frequency (AAF = 0.02) MST1 gain-of-stop variant (Arg651Ter; R651Ter) that prematurely terminates the MST1 protein at amino acid 651; (2) rs3197999, a common (AAF = 0.29) MST1 missense variant (Arg703Cys; R703C) experimentally characterized as an MST1 hypomorphic variant and also an MST1↓pQTL; and (3) rs3020779, a common (AAF = 0.82) MST1 synonymous variant (Pro153Pro; P153P) that is an MST1 sQTL for liver and lung and a lung↓eQTL for MST1R, the receptor for MST1R, encoding MSP. All three variants were considered hypomorphic or loss-of-function variants, resulting in reduced abundance or activity of the MST1 gene product.

[0252] The analysis used logistic or linear regression models with age, sex, and the first 10 principal components of genetic ancestry as covariates. The analysis resulted in the identification of associations of individual MST1 variants (Tables 2A, 2B, 2C, and 2D). For example, there were protective associations with multiple lung disease-related traits. The variants evaluated were associated with protection from COPD and asthma and a lower risk of inhaled beta-agonist prescriptions (Tables 2A and 2B). Furthermore, the variants evaluated were associated with increased lung function (FEV1 and FVC) and decreased circulating neutrophil counts (Tables 2C and 2D).

[0253] [Table 2A]

[0254] [Table 2B]

[0255] [Table 2C]

[0256] [Table 2D]

[0257] These results demonstrate that loss of MST1 function protects against COPD and asthma, improves lung function, and reduces circulating neutrophils, a key pro-inflammatory cell type in obstructive airway diseases. These results further demonstrate that therapeutic inhibition of MST1 can confer similar disease-protective effects.

[0258] Protective mutations in MST1 result in loss of MST1 protein Pre-mRNA expression constructs encoding wild-type and R651Ter (Arg651Ter; rs142690032) proteins were generated. The pre-mRNA of the MST1 protein-coding transcript (ENST00000449682), containing exons, introns, and 5' and 3' UTRs, was cloned into the pcDNA3.1(+) vector driven by the CMV promoter. An empty vector was used as a control. For the R651Ter expression construct, the A allele replaced the G allele at DNA position chr3:49684379 (human genome build 38). This generated a premature R651Ter stop codon.

[0259] Huh7 cell transfection was optimized. Huh7 cells were seeded into T75 flasks in complete growth medium and grown for 48 hours, after which the medium was replaced. Cells were then transfected with 15 μg of plasmid DNA and 45 μl of TransIT-2020. Cells were incubated for 48 hours and then harvested.

[0260] Cell lysates from transfected cells were assayed to assess intracellular MST1 protein by Western blot (Figure 1). In Huh7 cells transfected with an empty vector, MST1 was undetectable by Western blot. In cells transfected with the wild-type construct, MST1 was detected by Western blot as a band of approximately 80 kDa. In cells transfected with the R651Ter construct, MST1 was substantially reduced by Western blot compared to the wild-type, suggesting that the premature stop codon results in loss of MST1 via nonsense-mediated decay or degradation at the protein level.

[0261] These data provide experimental validation that MST1 gene variants, resulting in loss of MST1 protein abundance or function, are associated with protection from COPD and asthma, improved lung function, and reduced circulating neutrophils. Therefore, therapeutic inhibition or modulation of MST1 may be an effective genetically informed treatment for these diseases and conditions.

[0262] Example 2: Bioinformatics selection of sequences to identify therapeutic siRNAs to downregulate MST1 mRNA expression A screening set was defined based on bioinformatic analysis. Therapeutic siRNAs were designed to target human MST1 and the MST1 sequences of at least one toxicologically relevant species, in this case, the non-human primate (NHP) rhesus and cynomolgus macaques. The driving force behind the design of the screening set was the predicted specificity of the siRNAs for the relevant species' transcriptomes and cross-reactivity between species. Predicted specificities in human, rhesus, cynomolgus, mouse, and rat were determined for the sense (S) and antisense (AS) strands. These were assigned a "specificity score," which took into account the number and position of mismatches, as well as the possibility of unintended downregulation of any other transcripts due to full or partial complementarity of the siRNA strand (up to four mismatches within positions 2–18). In this way, off-targets for the antisense and sense strands of each siRNA were identified. In addition, the number of potential off-targets was used as an additional specificity factor in the specificity score. If identified, siRNAs with high specificity and a low number of predicted off-targets offer the advantage of increased targeting specificity.

[0263] In addition to selecting siRNA sequences with high sequence specificity for MST1 mRNA, we analyzed the siRNA sequences within their seed regions for similarity to the seed regions of known miRNAs. siRNAs can function like miRNAs through base pairing with complementary sequences within the 3'-UTR of mRNA molecules. Complementarity typically encompasses the 5'-bases 2-7 of the miRNA (seed region). To avoid siRNAs that act through functional miRNA binding sites, we avoided siRNA strands containing natural miRNA seed regions. Seed ...

Claims

**Claim 1**: A composition comprising an oligonucleotide that targets MST1 and, when administered to a subject in an effective amount, (a) a pulmonary function measurement (b) a white blood cell measurement (c) a measurement of the symptoms or exacerbation of chronic obstructive pulmonary disease (COPD), or (d) a measurement of the symptoms or exacerbation of asthma and improves the same. **Claim 2** The composition according to claim 1, wherein the pulmonary function measurement includes a forced expiratory volume in one second (FEV1) measurement, a ratio of FEV1 to predicted FEV1 (FEV1pp) measurement, a forced vital capacity (FVC) measurement, an FEV1 / FVC ratio measurement, a forced expiratory volume, or a peak expiratory flow measurement. **Claim 3**: The composition according to claim 1, wherein the white blood cell measurement includes a neutrophil measurement, an eosinophil measurement, a basophil measurement, a monocyte measurement, or a lymphocyte measurement, a macrophage measurement, a neutrophil-lymphocyte ratio measurement, or a combination thereof. **Claim 4**: The composition according to claim 1, wherein the oligonucleotide includes a modified internucleoside linkage. **Claim 5**: The composition according to claim 1, wherein the oligonucleotide includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 modified internucleoside linkages. **Claim 6**: The composition according to claim 1, wherein the oligonucleotide includes a modified nucleoside. **Claim 7**: The composition according to claim 1, wherein the oligonucleotide includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 modified nucleosides. **Claim 8**: The composition according to claim 1, wherein the oligonucleotide includes a lipid, a sugar moiety, or an integrin-targeting ligand attached to the 3'-end or 5'-end of the oligonucleotide. **Claim 9**: (a) The lipid includes cholesterol, myristoyl, palmitoyl, stearoyl, lithocholoyl, docosanyl, docosahexaenoyl, myristyl, palmityl stearyl, or α-tocopherol, or a combination thereof; (b) The sugar includes N-acetylgalactosamine (GalNAc), N-acetylglucosamine (GlcNAc), or mannose, or (c) The integrin includes integrin α-v-β-6, or an arginine-glycine-aspartic acid (RGD) peptide, the composition according to claim 8. **Claim 10**: The oligonucleotide includes small interfering RNA (siRNA) including a sense strand and an antisense strand, and each strand is independently 12 to 30 nucleosides in length, the composition according to claim 1. **Claim 11**: (a) The sense strand includes a modification pattern 30S: 5'-snnnnnnnNfnNfNfnnnnnnnnsnsn-3'; (b) The antisense strand includes a modification pattern 15AS: 5'-nsNfsnnnnNfnNfnNfnNfnNfnNfnnsnsn-3', or (c) Both (a) and (b), where n is each of 2'-O-methyl (2'-OMe) A, G, C, and U, Nf is each of 2'-fluoro (2'-F) A, G, C, and U, and s is a phosphorothioate bond, the composition according to claim 10. **Claim 12**: A composition including an oligonucleotide that inhibits the expression of MST1, where the oligonucleotide is (a) siRNA including a sense strand and an antisense strand, and each strand is independently about 12 to 30 nucleosides in length, and at least one of the sense strand and the antisense strand includes a nucleoside sequence including 12 to 30 adjacent nucleosides of SEQ ID NO: 6185, siRNA, or (b) An antisense oligonucleotide (ASO) having a length of 12 to 30 nucleosides, and a nucleoside sequence complementary to 12 to 30 adjacent nucleosides of SEQ ID NO: 6185 A composition comprising the same.

13. Regarding the sense strand, the following: All purines contain 2'-fluoro-modified purines, and all pyrimidines contain a mixture of 2'-fluoro- and 2'-O-methyl-modified pyrimidines, All purines contain 2'-O-methyl-modified purines, and all pyrimidines contain a mixture of 2'-fluoro- and 2'-O-methyl-modified pyrimidines, All purines contain 2'-fluoro-modified purines, and all pyrimidines contain 2'-O-methyl-modified pyrimidines, All pyrimidines contain 2'-fluoro-modified pyrimidines, and all purines contain a mixture of 2'-fluoro- and 2'-O-methyl-modified purines, All pyrimidines contain 2'-O-methyl-modified pyrimidines, and all purines contain a mixture of 2'-fluoro- and 2'-O-methyl-modified purines, or All pyrimidines contain 2'-fluoro-modified pyrimidines, and all purines contain 2'-O-methyl-modified purines, Any one of the above applies, or Regarding the antisense strand, the following: All purines contain 2'-fluoro-modified purines, and all pyrimidines contain a mixture of 2'-fluoro- and 2'-O-methyl-modified pyrimidines, All purines contain 2'-O-methyl-modified purines, and all pyrimidines contain a mixture of 2'-fluoro- and 2'-O-methyl-modified pyrimidines, All purines contain 2'-O-methyl-modified purines, and all pyrimidines contain 2'-fluoro-modified pyrimidines, All pyrimidines include 2'-fluoro modified pyrimidines, and all purines include a mixture of 2'-fluoro and 2'-O-methyl modified purines. All pyrimidines include 2'-O-methyl modified pyrimidines, and all purines include a mixture of 2'-fluoro and 2'-O-methyl modified purines, or All pyrimidines include 2'-O-methyl modified pyrimidines, and all purines include 2'-fluoro modified purines. The composition according to claim 12, wherein any one of the above applies.

14. The composition according to claim 12, wherein the sense strand includes the oligonucleotide sequence of SEQ ID NO: 2999 or 6385, and the antisense strand includes the oligonucleotide sequence of SEQ ID NO: 6023 or 6415.

15. The composition according to any one of claims 1 to 14, further comprising a pharmaceutically acceptable carrier.

16. A composition comprising an oligonucleotide that regulates the expression of MST1 for use in a method of treating a subject having a lung disorder, the method comprising administering an effective amount of the composition to the subject, and the oligonucleotide is (a) siRNA comprising a sense strand and an antisense strand, each strand independently being 12 to 30 nucleosides in length, and at least one of the sense strand and the antisense strand comprising a nucleoside sequence comprising 12 to 30 adjacent nucleosides of SEQ ID NO: 6185, or (b) an antisense oligonucleotide (ASO) 12 to 30 nucleosides in length, and a nucleoside sequence complementary to the 12 to 30 adjacent nucleosides of SEQ ID NO: 6185. The composition comprising the above.

17. The composition according to claim 16, wherein the lung disorder includes COPD, acute exacerbation of COPD, emphysema, chronic bronchitis, asthma, status asthmaticus, asthma-COPD overlap syndrome (ACOS), cough, dyspnea, lung cancer, interstitial lung disease, or pulmonary fibrosis.