Treatment of hgfac related diseases and disorders

Abstract

Disclosed herein are compositions comprising an oligonucleotide that targets HGFAC. The oligonucleotide may include a small interfering RNA (siRNA) or an antisense oligonucleotide (ASO). Also provided herein are methods of treating cancer that include providing an oligonucleotide that targets HGFAC in a subject.

Description

TREATMENT OF HGFAC RELATED DISEASES AND DISORDERSCROSS-REFERENCE

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 582,789, filed September 14, 2023, and U.S. Provisional ApplicationNo. 63 / 585,559, filed September 26, 2023, all of which are incorporated herein by reference in their entirety.INCORPORATION BY REFERENCE OF SEQUENCE LISTING

[0002] The present application is being filed along with a Sequence Listing in electronic format. The Sequence Listing is provided as a file entitled 54462-757_601_SL, created August 23, 2024, which is 8,880,423 bytes in size. The information in the electronic format of the Sequence Listing is incorporated by reference in its entirety.BACKGROUND

[0003] Cancer is a serious threat, and improved therapeutics are needed.SUMMARY

[0004] In certain aspects, disclosed herein is a composition comprising an siRNA that targets hepatocyte growth factor activator (HGFAC), wherein the siRNA comprises a sense strand and an antisense strand, wherein the sense strand comprises a modification pattern selected from the list consisting of 54S, 55S, 20S, 43S, 16S, 108S, 61 S, and 109S; or the antisense strand comprises a modification pattern selected from the list consisting of 12AS, 14AS, 29AS, 35AS, 44AS, 45AS, 46AS, 47 AS, 48AS, 49 AS, 50AS, 5 IAS, 52AS, 53AS, 54AS, and 55AS.

[0005] In certain aspects, disclosed herein is a composition comprising an siRNA that targets hepatocyte growth factor activator (HGFAC) and when administered to a subject having cancer in an effective amount improves a clinical response related to the cancer, wherein the siRNA comprises a sense strand and an antisense strand, wherein the sense strand comprises a modification pattern selected from the list consisting of 54S, 55S, 20S, 43S, 16S, 108S, 61S, and 109S; or the antisense strand comprises a modification pattern selected from the list consisting of 12AS, 14AS, 29 AS, 35AS, 44AS, 45 AS, 46AS, 47 AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, and 55AS . In some embodiments, the improved clinical response comprises at least a 10% increase in a clinical response measurement relative to a baseline clinical response measurement obtained from the subject prior to administration of the composition. In some embodiments, the clinical response comprises progression free survival, duration of response, disease control rate, health-related quality of life, milestone survival, clinical benefit rate, pathological complete response, complete response, objective responserate, duration of clinical benefit, time to next treatment, time to treatment failure, disease-free survival, or time to cancer progression.

[0006] In certain aspects, disclosed herein is a composition comprising an siRNA that targets HGFAC and when administered to a subject in an effective amount alters an immune cell measurement in a subject, wherein the siRNA comprises a sense strand and an antisense strand, wherein the sense strand comprises a modification pattern selected from the list consisting of 54S, 55S, 20S, 43S, 16S, 62S, 61S, and 63S; or the antisense strand comprises a modification pattern selected from the list consisting of 12AS, 14AS, 29AS, 35AS, 44AS, 45AS, 46AS, 47 AS, 48AS, 49AS, 50AS, 5 IAS, 52AS, 53 AS, 54AS, and 55AS. In some embodiments, the immune cell measurement is altered by about 10% or more, as compared to prior to administration. In some embodiments, the immune cell measurement comprises a myeloid derived suppressor cell or subpopulation count, CD8+ tumor infiltrating lymphocyte count, leukocyte count, T lymphocyte count, activated T lymphocyte count, B lymphocyte count, activated B lymphocyte count, monocyte count, macrophage count, activated macrophage count, dendritic cell count, neutrophil count, eosinophil count, basophil count, or mast cell count.

[0007] In certain aspects, disclosed herein is a composition comprising an siRNA that targets HGFAC and when administered to a subject in an effective amount increases an antibody level in a subject, wherein the siRNA comprises a sense strand and an antisense strand, wherein the sense strand comprises a modification pattern selected from the list consisting of 54S, 55S, 20S, 43S, 16S, 62S, 61S, and 63S; or the antisense strand comprises a modification pattern selected from the list consisting of 12AS, 14AS, 29AS, 35AS, 44AS, 45AS, 46 AS, 47 AS, 48AS, 49AS, 50AS, 5 IAS, 52AS, 53AS, 54AS, and 55AS. In some embodiments, the antibody level is increased by about 10% or more, as compared to prior to administration. In some embodiments, the antibody level comprises an IgA level, IgG level, or IgM level.

[0008] In certain aspects, disclosed herein is a composition comprising an siRNA that targets HGFAC and when administered to a subject in an effective amount decreases a tumor marker level in a subject, wherein the siRNA comprises a sense strand and an antisense strand, wherein the sense strand comprises a modification pattern selected from the list consisting of 54S, 55S, 20S, 43S, 16S, 62S, 61S, and 63S; or the antisense strand comprises a modification pattern selected from the list consisting of 12AS, 14AS, 29AS, 35AS, 44AS, 45AS, 46AS, 47 AS, 48AS, 49 AS, 50AS, 5 IAS, 52AS, 53AS, 54AS, and 55AS. In some embodiments, the tumor marker level is decreased by about 10% or more, as compared to prior to administration. In some embodiments, the tumor marker comprises CEA, PSA, CA 125, CA 15-3, CA 19-9, CA 27.29, CA 72-4, AFP, hCG, B2M, BTA, Calcitonin, CgA, CELLSEARCH, DCP, Gastrin, HE4, LDH, NSE, NMP22, or PAP. In some embodiments, the oligonucleotide comprises a modified intemucleoside linkage. In some embodiments, the modified internucleoside linkage comprises alkylphosphonate, phosphorothioate, methylphosphonate, phosphorodithioate, alkylphosphonothioate, phosphoramidate, carbamate,carbonate, phosphate tri ester, acetamidate, or carboxymethyl ester, or a combination thereof. In some embodiments, the modified internucleoside linkage comprises one or more phosphorothioate linkages. In some embodiments, the oligonucleotide comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 modified internucleoside linkages. In some embodiments, the oligonucleotide comprises a modified nucleoside. In some embodiments, the modified nucleoside comprises a locked nucleic acid (LNA), hexitol nucleic acid (HLA), cyclohexene nucleic acid (CeNA), 2' -methoxy ethyl, 2'-O-alkyl, 2'-O-allyl, 2'-O-allyl, 2'-fluoro, or 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, 2'-deoxyfluoro nucleoside, 2'-O-N-methylacetamido (2 -0-NMA) nucleoside, a 2'-O-dimethylaminoethoxyethyl (2'-O-DMAEOE) nucleoside, 2'-O- aminopropyl (2'-O-AP) nucleoside, or2'-ara-F, or a combination thereof. In some embodiments, the modified nucleoside comprises one or more 2 ’-fluoro modified nucleosides. In some embodiments, the modified nucleoside comprises a 2’-O-alkyl modified nucleoside. In some embodiments, the oligonucleotide comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 modified nucleosides. In some embodiments, the oligonucleotide comprises a lipid attached at a 3’ or 5’ terminus of the oligonucleotide. In some embodiments, the lipid comprises cholesterol, myristoyl, palmitoyl, stearoyl, lithocholoyl, docosanoyl, docosahexaenoyl, myristyl, palmityl stearyl, or a- tocopherol, or a combination thereof. In some embodiments, the oligonucleotide comprises a sugar moiety attached at a 3’ or 5’ terminus of the oligonucleotide. In some embodiments, the sugar comprises N-acetylgalactosamine (GalNAc), N-acetylglucosamine (GlcNAc), or mannose. 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 12-30 nucleosides in length. In some embodiments, the antisense strand is 12-30 nucleosides in length.

[0009] In certain aspects, disclosed herein is a composition comprising an oligonucleotide that inhibits the expression of HGFAC, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, each strand is independently 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 SEQ ID NO: 4803, wherein the sense strand comprises a modification pattern selected from the list consisting of 54S, 55S, 20S, 43S, 16S, 62S, 61S, and 63S; or the antisense strand comprises a modification pattern selected from the list consisting of 12AS, 14AS, 29AS, 35AS, 44AS, 45AS, 46AS, 47 AS, 48AS, 49 AS, 50AS, 5 IAS, 52AS, 53AS, 54AS, and 55AS. In some embodiments, the sense strand comprises an oligonucleotide sequence of SEQ ID NO: 4599, 4597 or 4581; and the antisense strand comprises an oligonucleotide sequence of SEQ ID NO: 4654, 4652 or 4636. In some embodiments, the sense strand comprises modification pattern 20S, 43S, or 16S (SEQ ID NO: 4809, 4558 or 4519); the antisense strand comprises modification pattern 14AS, 35AS, or 49AS (SEQ ID NO: 4817, 4839 or 4846); or both (a)and (b). In some embodiments, any one of the following is true with regard to the sense strand: (a) all purines comprise fluoro modified purines and all pyrimidines comprise (i) a mixture of 2’ -O-methyl and 2’-O-methoxyethyl modified pyrimidines; or (ii) a mixture of 2’ -fluoro, 2’ -O-methyl, and 2’-O- methoxyethyl modified pyrimidines; (b) all purines comprise 2'-O-methyl modified purines and all pyrimidines comprise (i) all pyrimidines of the sense strand comprise a mixture of 2’ -fluoro and 2’-O- methoxy ethyl modified pyrimidines; or (ii) a mixture of 2’ -fluoro, 2’ -O-methyl, and 2’-O- methoxyethyl modified pyrimidines; (c) all purines comprise 2'-O-methoxyethyl modified purines and all pyrimidines comprise (i) a mixture of 2’ -fluoro and 2’ -O-methyl modified pyrimidines; or (vii) a mixture of 2’ -fluoro, 2’ -O-methyl, and 2’-O-methoxyethyl modified pyrimidines; (d) all purines comprise a mixture of 2’ -fluoro and 2'-O-methyl modified purines and all pyrimidines comprise (i) 2’- O-methoxyethyl modified pyrimidines; (ii) a mixture of 2’ -O-methyl and 2’-O-methoxyethyl modified pyrimidines; (iii) a mixture of 2’ -fluoro and 2’-O-methoxyethyl modified pyrimidines; or (iv) a mixture of 2’ -fluoro, 2’ -O-methyl, and 2’-O-methoxyethyl modified pyrimidines; (e) all purines comprise a mixture of 2’ -fluoro and 2'-O-methox ethyl modified purines and all pyrimidines of the sense strand comprise (i) 2’-O-methyl modified pyrimidines; (ii) amixture of 2’-fluoro and 2’- O-methyl modified pyrimidines; (iii) a mixture of 2’ -O-methyl and 2’-O-methoxyethyl modified pyrimidines; or (iv) a mixture of 2’ -fluoro, 2’ -O-methyl, and 2’-O-methoxyethyl modified pyrimidines; (f) all purines comprise a mixture of 2'-O-methyl and 2'-O-methoxyethyl modified purines and all pyrimidines comprise (i) 2’-fluoro modified pyrimidines; (ii) a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; (iii) amixture of 2’-fluoro and 2’-O-methoxyethyl modified pyrimidines; or (iv) a mixture of 2’ -fluoro, 2’ -O-methyl, and 2’-O-methoxyethyl modified pyrimidines; or (g) all purines comprise a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O-methoxyethyl modified purines and all pyrimidines comprise (i) 2’ -fluoro modified pyrimidines; (ii) 2’ -O-methyl modified pyrimidines; (iii) 2’-O-methoxyethyl modified pyrimidines; (iv) a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; (v) a mixture of 2’ -O-methyl and 2’-O-methoxyethyl modified pyrimidines; (vi) a mixture of 2’-fluoro and 2’-O-methoxyethyl modified pyrimidines; or (vii) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O-methoxyethyl modified pyrimidines; with the proviso that in any of the foregoing, the sense strand may include a 2’ -deoxy nucleoside. In some embodiments, any one of the following is true with regard to the antisense strand: all purines comprise 2’ -fluoro modified purines, and all pyrimidines comprise a mixture of 2’ -fluoro and 2’-O- methyl modified pyrimidines; all purines comprise 2’ -O-methyl modified purines, and all pyrimidines comprise a mixture of 2’ -fluoro and 2’ -O-methyl modified pyrimidines; all purines comprise 2’-O-methyl modified purines, and all pyrimidines comprise 2’-fluoro modified pyrimidines; all pyrimidines comprise 2’ -fluoro modified pyrimidines, and all purines comprise a mixture of 2’ -fluoro and 2’ -O-methyl modified purines; all pyrimidines comprise 2’ -O-methyl modified pyrimidines, and all purines comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines; or all pyrimidines comprise 2’ -O-methyl modified pyrimidines, and all purines comprise 2’-fluoro modified purines. In some embodiments, the oligonucleotide comprises an antisense oligonucleotide (ASO). In some embodiments, the ASO is 12-30 nucleosides in length.

[0010] In certain aspects, disclosed herein is a composition comprising an oligonucleotide that inhibits the expression of HGFAC, wherein the oligonucleotide comprises an ASO about 12-30 nucleosides in length and a nucleoside sequence complementary to about 12-30 contiguous nucleosides of SEQ ID NO: 4803.

[0011] In some embodiments, the composition further comprises a pharmaceutically acceptable carrier.

[0012] In certain aspects, disclosed herein is a method of treating a subject having cancer, comprising administering an effective amount of the composition disclosed herein to the subject. In some embodiments, the method further comprises administering a checkpoint inhibitor to the subject. In some embodiments, the checkpoint inhibitor comprises a PD1 inhibitor, a PDLlinhibitor, a CTLA4 inhibitor or a combination thereof. In some embodiments, the method further comprises administering radiotherapy to the subject. In some embodiments, the cancer comprises a malignant neoplasm, a solid tumor, or a hematological cancer. In some embodiments, the cancer comprises a malignant neoplasm of a urinary tract, malignant neoplasm of an endocrine gland, malignant neoplasm of a soft tissue, malignant neoplasm of skin, malignant neoplasm of a skeletal system, malignant neoplasm of a respiratory organ, malignant neoplasm of an intrathoracic organ, malignant neoplasm of a genital organ, malignant neoplasm of a lip, malignant neoplasm of an oral cavity, malignant neoplasm of a pharynx, malignant neoplasm of an eye, malignant neoplasm of a central nervous system, malignant neoplasm of a brain, malignant neoplasm of a digestive system, malignant neoplasm of a breast, malignant neoplasm of a pancreas, or a malignant melanoma. In some embodiments, the administration improves a clinical response related to the cancer. In some embodiments, the improved clinical response comprises at least a 10% increase in a clinical response measurement relative to a baseline clinical response measurement obtained from the subject prior to administration of the composition. In some embodiments, the clinical response comprises progression free survival, duration of response, disease control rate, health-related quality of life, milestone survival, clinical benefit rate, pathological complete response, complete response, objective response rate, duration of clinical benefit, time to next treatment, time to treatment failure, disease-free survival, or time to cancer progression.

[0013] In certain aspects, disclosed herein is a method of treating cancer in a subject in need thereof, the method comprising administering the subject an effective amount of a composition that inhibits HGFAC. In certain aspects, disclosed herein is a method of treating cancer in a subject in need thereof, the method comprising administering the subject an effective amount of a composition that reduces HGFAC. In some embodiments, the composition comprises an oligonucleotide. In some embodiments, the oligonucleotide comprises an siRNA.

[0014] In certain aspects, disclosed herein is a method of treating cancer in a subject in need thereof, the method comprising administering the subject an effective amount of an siRNA that targets HGFAC. In some embodiments, the administration reduces a symptom or a clinical finding associated with the cancer by at least 10%.BRIEF DESCRIPTION OF THE DRAWINGS

[0015] FIG. 1A depicts expression of HGFAC mRNA in transfected RPE cells.

[0016] FIG. IB depicts expression of intracellular HGFAC protein expression from whole cell lysates by western blot.

[0017] FIG. 1C quantifies the fold change of HGFAC expression in difference cell variants.

[0018] FIG. ID depicts the levels of secreted HGFAC in cells transfected with wildtype or each variant.DETAILED DESCRIPTION

[0019] Large-scale human genetic data can improve the success rate of pharmaceutical discovery and development. A Genome Wide Association Study (GW AS) detects associations between genetic variants and traits in a population sample, and this improves understanding of the biology of disease and provides evidence of applicable treatments. A GWAS generally utilizes genotyping and / or sequencing data, and often involves an evaluation of millions of genetic variants that are relatively evenly distributed across the genome. The most common GWAS design is the case-control study, which involves comparing variant frequencies in cases versus controls. If a variant has a significantly different frequency in cases versus controls, that variant is considered associated with disease.Association statistics used in a GWAS include p-values, as a measure of statistical significance; odds ratios (OR), as a measure of effect size; or beta coefficients (beta), as a measure of effect size. Researchers often assume an additive genetic model and calculate an allelic odds ratio, which is the increased (or decreased) risk of disease conferred by each additional copy of an allele (compared to carrying no copies of that allele). An additional concept in design and interpretation of GWAS is that of linkage disequilibrium, which is the non-random association of alleles. The presence of linkage disequilibrium can obfuscate which variant is “causal.”

[0020] Functional annotation of variants and / or wet lab experimentation is used to identify a causal genetic variant identified via GWAS, and in many cases leads to identification of disease-causing genes. In particular, understanding the functional effect of a causal genetic variant (for example, loss of protein function, gain of protein function, increase in gene expression, or decrease in gene expression) allows that variant to be used as a proxy for therapeutic modulation of the target gene, or to gain insight into potential therapeutic efficacy and safety of a therapeutic that modulates that target.

[0021] Identification of such gene-disease associations has provided insights into disease biology and is used to identify novel therapeutic targets for the pharmaceutical industry. In order to translate thetherapeutic insights derived from human genetics, disease biology in patients is exogenously ‘programmed’ into replicating the observation from human genetics. There are several options for therapeutic modalities that may be brought to bear in translating therapeutic targets identified via human genetics into novel medicines. These include well established therapeutic modalities such as small molecules and monoclonal antibodies, maturing modalities such as oligonucleotides, and emerging modalities such as gene therapy and gene editing. The choice of therapeutic modality depends on factors such as the location of a target (for example, intracellular, extracellular, or secreted), a relevant tissue (for example, liver) and a relevant indication.

[0022] The HGFAC gene is located on chromosome 4, and encodes hepatocyte growth factor activator (HGFAC). HGFAC may include 655 amino acids or have a mass of about 70.7 kDa. HGFAC may be expressed in liver cells. HGFAC can act as a serine protease that converts hepatocyte growth factor to active form. HGFAC may be secreted, for example, into the bloodstream. HGFAC may be part of the peptidase SI protein family. An example of an HGFAC amino acid sequence, and further description of HGFAC is included at uniprot.org under accession no. Q04756 (last modified February 23, 2022).

[0023] Here it is shown that deleterious gene variants of HGFAC may result in protection from malignant neoplasms. Therefore, inhibition of HGFAC may serve as a therapeutic for treatment of a variety of cancers. Disclosed herein are compositions comprising an oligonucleotide that targets HGFAC. Where inhibition or targeting of HGFAC is disclosed, it is contemplated that some embodiments may include inhibiting or targeting a HGFAC protein or HGFAC RNA. For example, by inhibiting or targeting an RNA (e.g., mRNA) encoded by the HGFAC gene using an oligonucleotide described herein, the HGFACE protein may be inhibited or targeted as a result of there being less production of the HGFAC protein by translation of the HGFAC RNA; or a HGFAC protein may be targeted or inhibited by an oligonucleotide that binds or interacts with a HGFAC RNA and reduces production of the HGFAC protein from the HGFAC RNA. Thus, targeting HGFAC may refer to binding a HGFAC RNA and reducing HGFAC RNA or protein levels. The oligonucleotide may include a small interfering RNA (siRNA) or an antisense oligonucleotide (ASO). Also provided herein are methods of treating cancer by providing an oligonucleotide that targets HGFAC to a subject in need thereof.I. COMPOSITIONS

[0024] Disclosed herein, in some embodiments, are compositions comprising a therapeutic modality that targets or inhibits or reduces HGFAC. Non-limiting examples are listed in Table 1A. In some embodiments, a therapeutic modality, composition, or compound described herein may refer to any one of: a dsRNA agent (e.g., siRNA), antisense oligonucleotide, and a small molecule compound. In some embodiments, the composition comprises a therapeutic modality that targets HGFAC. In some embodiments, the composition consists of therapeutic modality that targets HGFAC. In someembodiments, the composition comprises an antibody or a binding fragment thereof. In some embodiments, the therapeutic modality reduces HGFAC mRNA expression in the subject. In some embodiments, the therapeutic modality reduces HGFAC protein expression in the subject. In some embodiments, a composition described herein is used in a method of treating a disorder in a subject in need thereof. Some embodiments relate to a composition for use in a method of treating a disorder such as cancer. Some embodiments relate to use of a composition, in a method of treating a disorder such as cancer.Table 1A. Therapeutic modalities

[0025] Because HGFAC is a protease, some small molecule inhibitors may be useful for inhibiting its protease activity. Some protease inhibitors may have sub-optimal IC50 values for HGFAC relative to other protein targets, or may be non-specific for HGFAC, though, so other therapeutic modalities such as antibodies or oligonucleotide therapeutics may be more useful. Nafamostat may inhibit HGFAC with an IC50 of about 150 nM for HGFAC. Nafamostat may inhibit other serine proteases with a much lower IC50 than HGFAC. In some embodiments, the small molecule is a protease inhibitor such as a serine protease inhibitor. An example of a serine protease inhibitor may include Nafamostat.

[0026] Disclosed herein, in some embodiments, are compositions comprising an oligonucleotide. In some embodiments, the composition comprises an oligonucleotide that targets HGFAC. In some embodiments, the composition consists of an oligonucleotide that targets HGFAC. In some embodiments, the oligonucleotide reduces HGFAC mRNA expression in the subject. In someembodiments, the oligonucleotide reduces HGFAC protein expression in the subject. The oligonucleotide may include a small interfering RNA (siRNA) described herein. The oligonucleotide may include an antisense oligonucleotide (ASO) described herein. In some embodiments, a composition described herein is used in a method of treating a disorder in a subject in need thereof. Some embodiments relate to a composition comprising an oligonucleotide for use in a method of treating a disorder such as cancer. Some embodiments relate to use of a composition comprising an oligonucleotide, in a method of treating a disorder such as cancer.

[0027] Some embodiments include a composition comprising an oligonucleotide that targets HGFAC and when administered to a subject in an effective amount decreases HGFAC mRNA or protein levels in a cell, fluid, or tissue. In some embodiments, the composition comprises an oligonucleotide that targets HGFAC and when administered to a subject in an effective amount decreases HGFAC mRNA levels in a cell or tissue. In some embodiments, the cell is a liver cell or hepatocyte. In some embodiments, the tissue is liver tissue. In some embodiments, the HGFAC mRNA levels are decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the HGFAC mRNA levels are decreased by about 10% or more, as compared to prior to administration. In some embodiments, the HGFAC mRNA levels are 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%, as compared to prior to administration. In some embodiments, the HGFAC mRNA levels are decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the HGFAC mRNA levels are decreased by no more than about 10%, as compared to prior to administration. In some embodiments, the HGFAC mRNA levels are decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration. In some embodiments, the HGFAC mRNA levels are decreased 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 by arange defined by any of the two aforementioned percentages.

[0028] In some embodiments, the composition comprises an oligonucleotide that targets HGFAC and when administered to a subject in an effective amount decreases HGFAC protein levels in a cell, fluid, or tissue. In some embodiments, the cell is a liver cell or hepatocyte. In some embodiments, the fluid is a serum, blood, or plasma. In some embodiments, the tissue is liver tissue. In some embodiments, the HGFAC protein levels are decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the HGFAC protein levels are decreased by about 10% or more, as compared to prior to administration. In some embodiments, the HGFAC protein levels are 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%, as compared to prior to administration. In some embodiments, the HGFAC protein levels are decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the HGFAC protein levels are decreased by no more than about 10%, as compared to prior to administration. In some embodiments, the HGFAC protein levels are decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration. In some embodiments, the HGFAC protein levels are decreased 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 by a range defined by any of the two aforementioned percentages.

[0029] In some embodiments, the composition comprises an oligonucleotide that targets HGFAC and when administered to a subject in an effective amount diminishes a cancer phenotype. The cancer may include: malignant neoplasms, solid tumors, hematological cancers, malignant neoplasms of urinary tract, malignant neoplasms of thyroid and other endocrine glands, malignant neoplasms of soft tissue, malignant neoplasms of skin, malignant neoplasms of skeletal system, malignant neoplasms of respiratory and intrathoracic organs, malignant neoplasms of male genital organs, malignant neoplasms of female genital organs, malignant neoplasms of lip, oral cavity and pharynx, malignant neoplasms of eye, brain and other parts of central nervous system, malignant neoplasms of digestive system, malignant neoplasms of breast, malignant neoplasms of pancreas, or malignant melanoma. In some embodiments, the cancer phenotype is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the cancer phenotype is decreased by about 10% or more, as compared to prior to administration. In some embodiments, the cancer phenotype 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%, as compared to prior to administration. In some embodiments, the cancer phenotype is decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the cancer phenotype is decreased by no more than about 10%, as compared to prior to administration. In some embodiments, the cancer phenotype is decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration. In some embodiments, the cancer phenotype is decreased 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 by a range defined by any of the two aforementioned percentages.

[0030] In some embodiments, the composition comprises an oligonucleotide that targets HGFAC and when administered to a subject in an effective amount enhances a protective phenotype against a cancer in the subject. An example of a protective phenotype may include an anti-cancer immuneresponse. The cancer may include: malignant neoplasms, solid tumors, hematological cancers, malignant neoplasms of urinary tract, malignant neoplasms of thyroid and other endocrine glands, malignant neoplasms of soft tissue, malignant neoplasms of skin, malignant neoplasms of skeletal system, malignant neoplasms of respiratory and intrathoracic organs, malignant neoplasms of male genital organs, malignant neoplasms of female genital organs, malignant neoplasms of lip, oral cavity and pharynx, malignant neoplasms of eye, brain and other parts of central nervous system, malignant neoplasms of digestive system, malignant neoplasms of breast, malignant neoplasms of pancreas, or malignant melanoma. In some embodiments, the protective phenotype is increased by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the protective phenotype is increased by about 10% or more, as compared to prior to 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, as compared to prior to 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, as compared to prior to administration. In some embodiments, the protective phenotype is increased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration In some embodiments, the protective phenotype is increased by no more than about 10%, as compared to prior to administration. In some embodiments, the protective phenotype is increased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100%, as compared to prior to administration. In some embodiments, the protective phenotype is increased by no more than about 200%, no more than about 300%, no more than about 400%, no more than about 500%, no more than about 600%, no more than about 700%, no more than about 800%, no more than about 900%, or no more than about 1000%, as compared to prior to 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 by arange defined by any of the two aforementioned percentages.

[0031] In some embodiments, the composition comprises an oligonucleotide that targets HGFAC and when administered to a subject in an effective amount increases or improves a clinical response in the subject. The clinical response may include: immune specific related response criteria (irRC) such as set forth in iRECIST, progression free survival (PFS), duration of response (DOR), disease control rate (DCR), health-related quality of life, milestone survival, clinical benefit rate, pathological complete response, complete response, objective response rate, duration of clinical benefit, time to next treatment, time to treatment failure, disease-free survival, or time to progression. In someembodiments, the clinical response is increased by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the clinical response is increased by about 10% or more, as compared to prior to administration. In some embodiments, the clinical response 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, as compared to prior to administration. In some embodiments, the clinical response 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, as compared to prior to administration. In some embodiments, the clinical response is increased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the clinical response is increased by no more than about 10%, as compared to prior to administration. In some embodiments, the clinical response is increased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100%, as compared to prior to administration. In some embodiments, the clinical response is increased by no more than about 200%, no more than about 300%, no more than about 400%, no more than about 500%, no more than about 600%, no more than about 700%, no more than about 800%, no more than about 900%, or no more than about 1000%, as compared to prior to administration. In some embodiments, the clinical response 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 by a range defined by any of the two aforementioned percentages.

[0032] In some embodiments, the composition comprises an oligonucleotide that targets HGFAC and when administered to a subject in an effective amount improves a cell count measurement in the subject. The cell count measurement may be an immune cell count measurement. The cell count measurement may be indicative of an anti-cancer immune response. The cell count measurement may include a cancer cell count measurement. The improvement may comprise a change. In some embodiments, the change is an increase, in some embodiments, the change is a decrease (e.g., a cancer cell count). The cell count measurement may include: myeloid derived suppressor cell (MDSC) counts and subpopulations, CD8+ tumor infiltrating lymphocytes (TILs), leukocyte counts, T lymphocyte counts, T lymphocyte activation states, B lymphocyte counts, B lymphocyte activation states, monocyte counts, macrophage counts, macrophage activation states, dendritic cell counts, neutrophil counts, eosinophil counts, basophil counts, or mast cell counts. In some embodiments, cell count measurement is improved by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the cell count measurement is improved by about 10% or more, as compared to prior to administration. In some embodiments, the cell countmeasurement is improved 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%, as compared to prior to administration. In some embodiments, the cell count measurement is improved by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the cell count measurement is improved by no more than about 10%, as compared to prior to administration. In some embodiments, the cell count measurement is improved by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration. In some embodiments, the cell count measurement is improved 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 by a range defined by any of the two aforementioned. In some embodiments where the improvement is an increase, the change is by more than 100%.

[0033] In some embodiments, the composition comprises an oligonucleotide that targets HGFAC and when administered to a subject in an effective amount improves antibody levels in the subject. The antibody levels may be indicative of an anti-cancer immune response. The improvement may comprise a change. In some embodiments, the change is an increase, in some embodiments, the change is a decrease. The antibody levels may include: IgA levels, IgG levels, or IgM levels. In some embodiments, the antibody levels are improved by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the antibody levels are improved by about 10% or more, as compared to prior to administration. In some embodiments, the antibody levels are improved 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%, as compared to prior to administration. In some embodiments, the antibody levels are improved by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the antibody levels are improved by no more than about 10%, as compared to prior to administration. In some embodiments, the antibody levels are improved by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration. In some embodiments, the antibody levels are improved 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 by arange defined by any of the two aforementioned percentages. In some embodiments where the improvement is an increase, the change is by more than 100%.

[0034] In some embodiments, the composition comprises an oligonucleotide that targets HGFAC and when administered to a subject in an effective amount improves tumor marker levels in the subject. The improvement may comprise a change. In some embodiments, the change is an increase, in someembodiments, the change is a decrease. The tumor marker levels may include levels of tumor markers such as CEA, PSA, CA 125, CA 15-3, CA 19-9, CA 27.29, CA 72-4, AFP, hCG, B2M, BTA, Calcitonin, CgA, CELLSEARCH, DCP, Gastrin, HE4, LDH, NSE, NMP22, or PAP. In some embodiments, the tumor marker levels are improved by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration In some embodiments, the tumor marker levels are improved by about 10% or more, as compared to prior to administration. In some embodiments, the tumor marker levels are improved 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%, as compared to prior to administration. In some embodiments, the tumor marker levels are improved by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the tumor marker levels are improved by no more than about 10%, as compared to prior to administration. In some embodiments, the tumor marker levels are improved by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration. In some embodiments, the tumor marker levels are improved 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 by a range defined by any of the two aforementioned percentages. In some embodiments where the improvement is an increase, the change is by more than 100%.A. siRNAs

[0035] In some embodiments, the composition comprises an oligonucleotide that targets HGFAC, wherein the oligonucleotide comprises a small interfering RNA (siRNA). In some embodiments, the composition comprises an oligonucleotide that targets HGFAC, wherein the oligonucleotide comprises a small interfering RNA (siRNA) comprising a sense strand and an antisense strand.

[0036] In some embodiments, the composition comprises an oligonucleotide that reduces or inhibits the expression of HGFAC, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand 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 a range defined by any of the two aforementioned numbers. The sense strand may be 14-30 nucleosides in length. In some embodiments, the composition comprises an antisense strand is 12-30 nucleosides in length. In some embodiments, the composition comprises an antisense strand that is 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleosides in length, or arange defined by any of the two aforementioned numbers. The antisense strand may be 14-30 nucleosides in length.

[0037] In some embodiments, the composition comprises an oligonucleotide that inhibits or reduces the expression of HGFAC, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, each strand is independently about 12-30 nucleosides in length, and atleast one of the sense strand and the antisense strand comprises a nucleoside sequence comprising about 12-30 contiguous nucleosides of a full-length human HGFAC mRNA sequence such as SEQ ID NO: 4803. In some embodiments, at least one of the sense strand and the antisense strand comprise 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: 4803.

[0038] In some embodiments, the composition comprises an oligonucleotide that reduces or inhibits the expression of HGFAC. In some embodiments, the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand comprising an oligonucleotide sequences as disclosed in Tables A-H. In some embodiments, the sense strand and the antisense strand each comprises a strand that is independently about 19-21 nucleosides in length, and at least one of the sense strand and the antisense strand comprises a nucleoside sequence comprising about 15 contiguous nucleosides of oligonucleotide sequences as disclosed in Tables A-H. In some embodiments, the composition comprises an oligonucleotide that inhibits or reduces the expression of HGFAC, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein 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.

[0039] In some embodiments, the sense strand further comprises a 3’ overhang. In some embodiments, the 3’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 3’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 3’ overhang comprises 2 nucleosides. In some embodiments, the sense strand further comprises a 5’ overhang. In some embodiments, the 5’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 5’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 5’ overhang comprises 2 nucleosides.

[0040] In some embodiments, the antisense strand further comprises a 3’ overhang. In some embodiments, the 3’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 3’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 3’ overhang comprises 2 nucleosides. In some embodiments, the antisense strand further comprises a 5’ overhang. In some embodiments, the 5’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 5’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 5’ overhang comprises 2 nucleosides.

[0041] In some embodiments, the composition comprises an oligonucleotide that inhibits or reduces the expression of HGFAC, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the siRNA binds with a 19mer in a human HGFAC mRNA. Insome embodiments, the siRNA binds with a 12mer, a 13mer, a 14mer, a 15mer, a 16mer, a 17mer, a 18mer, a 19mer, a 20mer, a 21mer, a 22mer, a 23mer, a 24mer, or a 25mer in a human HGFAC mRNA.

[0042] In some embodiments, the composition comprises an oligonucleotide that inhibits or reduces the expression of HGFAC, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the siRNA binds with a 17mer in a non-human primate HGFAC mRNA. In some embodiments, the siRNA binds with a 12mer, a 13mer, a 14mer, a 15mer, a 16mer, a 17mer, a 18mer, a 19mer, a 20mer, a 21mer, a 22mer, a 23mer, a 24mer, or a 25mer in a non-human primate HGFAC mRNA.

[0043] In some embodiments, the composition comprises an oligonucleotide that inhibits or reduces the expression of HGFAC, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the siRNA binds with a human HGFAC mRNA and less than or equal to 20 human off-targets, with no more than 2 mismatches in the antisense strand. In some embodiments, the siRNA binds with a human HGFAC mRNA and less than or equal to 10 human off- targets, with no more than 2 mismatches in the antisense strand. In some embodiments, the siRNA binds with a human HGFAC mRNA and less than or equal to 30 human off-targets, with no more than2 mismatches in the antisense strand. In some embodiments, the siRNA binds with a human HGFAC mRNA and less than or equal to 40 human off-targets, with no more than 2 mismatches in the antisense strand. In some embodiments, the siRNA binds with a human HGFAC mRNA and less than or equal to 50 human off-targets, with no more than 2 mismatches in the antisense strand. In some embodiments, the siRNA binds with a human HGFAC mRNA and less than or equal to 10 human off- targets, with no more than 3 mismatches in the antisense strand. In some embodiments, the siRNA binds with a human HGFAC mRNA and less than or equal to 20 human off-targets, with no more than3 mismatches in the antisense strand. In some embodiments, the siRNA binds with a human HGFAC mRNA and less than or equal to 30 human off-targets, with no more than 3 mismatches in the antisense strand. In some embodiments, the siRNA binds with a human HGFAC mRNA and less than or equal to 40 human off-targets, with no more than 3 mismatches in the antisense strand. In some embodiments, the siRNA binds with a human HGFAC mRNA and less than or equal to 50 human off- targets, with no more than 3 mismatches in the antisense strand.

[0044] In some embodiments, the composition comprises an oligonucleotide that inhibits or reduces the expression of HGFAC, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, siRNA binds with a human HGFAC mRNA target site that does not harbor an SNP, with a minor allele frequency (MAF) greater or equal to 1% (pos. 2-18). In some embodiments, the MAF is greater or equal to about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, or about 20%.

[0045] In some embodiments, the composition comprises an oligonucleotide that inhibits or reduces the expression of HGFAC, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1-2051, 4562-4616, 4757-4779, or 4856, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1-2051, 4562-4616, 4757-4779, or 4856, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand further comprises a 3’ overhang. In some embodiments, the 3’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 3’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 3’ overhang comprises 2 nucleosides. In some embodiments, the sense strand further comprises a 5’ overhang. In some embodiments, the 5’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 5’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 5’ overhang comprises 2 nucleosides. In some embodiments, the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1-2051, 4562-4616, 4757-4779, or 4856, or a nucleic acid sequence thereof having 1 or 2 nucleoside additions at the 3’ end. In some embodiments, the composition comprises an oligonucleotide that inhibits or reduces the expression of HGFAC, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1-2051, 4562-4616, 4757-4779 or 4856.

[0046] In any of SEQ ID NOs: 1-2051, 4562-4616, 4757-4779, or 4856, thymine (T) may be replaced with Uracil (U). Any of the aforementioned siRNAs may include a sense strand or antisense strand where the 5’ nucleoside has been modified to an A. Any one of the aforementioned siRNAs may include a sense strand or antisense strand sequence wherein the 5’ nucleoside has been modified to a U or T. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 1-2051, 4562-4616, 4757-4779, or 4856 is modified to an A, T, C, U, or G. In some embodiments, position 6 (from the 5’ end) of any one of SEQ ID NOs: 1-2051, 4562-4616, 4757-4779, or 4856 is modified to an A, T, C, U, or G. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 1-2051, 4562-4616, 4757-4779, or 4856 is modified to an A, T, C, U, or G. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs 1-2051, 4562-4616, 4757-4779, or 4856 is modified to an A. In some embodiments, position 6 (from the 5’ end) of any one of SEQ ID NOs: 1- 2051, 4562-4616, 4757-4779, or 4856 is modified to an A. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs SEQ ID NOs: 1-2051, 4562-4616, 4757-4779, or 4856 is modified to an A. In some embodiments, position 1 and position 6, position 1 and position 19,position 6 and position 19, or position 1, position 6, and position 19 of any one of SEQ ID NOs 1- 2051, 4562-4616, 4757-4779, or 4856 is modified to an A. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs 1-2051, 4562-4616, 4757-4779, or 4856 is modified to an T or U. In some embodiments, position 6 (from the 5’ end) of any one of SEQ ID NOs: 1-2051, 4562-4616, 4757-4779, or 4856 is modified to a T or U. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs 1-2051, 4562-4616, 4757-4779, or 4856 is modified to a T or U. In some embodiments, position 1 and position 6, position 1 and position 19, position 6 and position 19, or position 1, position 6, and position 19 of any one of SEQ ID NOs 1-2051, 4562-4616, 4757-4779, or 4856 is modified to a T or U. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 1-2051, 4562-4616, 4757-4779, or 4856 is modified to an G. In some embodiments, position 6 (from the 5’ end) of any one of SEQ ID NOs: 1-2051, 4562-4616, 4757-4779, or 4856 is modified to an G. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs 1-2051, 4562-4616, 4757-4779, or 4856 is modified to an G. In some embodiments, position 1 and position 6, position 1 and position 19, position 6 and position 19, or position 1, position 6, and position 19 of any one of SEQ ID NOs 1-2051, 4562-4616, 4757-4779, or 4856 is modified to an G. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 1-2051, 4562-4616, or 4757- 4779 is modified to an C. In some embodiments, position 6 (from the 5’ end) of any one of SEQ ID NOs: 1-2051, 4562-4616, 4757-4779, or 4856 is modified to an C. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs 1-2051, 4562-4616, 4757-4779, or 4856 is modified to an C. In some embodiments, position 1 and position 6, position 1 and position 19, position 6 and position 19, or position 1, position 6, and position 19 of any one of SEQ ID NOs 1-2051, 4562-4616, 4757-4779, or 4856 is modified to an C.

[0047] In some embodiments, the composition comprises an oligonucleotide that inhibits or reduces the expression of HGFAC, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1 -2051, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1-2051, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand further comprises a 3’ overhang. In some embodiments, the 3’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 3’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 3’ overhang comprises 2 nucleosides. In some embodiments, the sense strand further comprises a 5’ overhang. In some embodiments, the 5’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 5’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 5’ overhang comprises 2nucleosides. In some embodiments, the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1-2051, or a nucleic acid sequence thereof having 1 or 2 nucleoside additions at the 3’ end. In some embodiments, the composition comprises an oligonucleotide that inhibits or reduces the expression of HGFAC, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1-2051. In some embodiments, the composition comprises an oligonucleotide that inhibits or reduces the expression of HGFAC, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 4562-4616, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 4562-4616, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand further comprises a 3’ overhang. In some embodiments, the 3’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 3’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 3’ overhang comprises 2 nucleosides. In some embodiments, the sense strand further comprises a 5’ overhang. In some embodiments, the 5’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 5’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 5’ overhang comprises 2 nucleosides. In some embodiments, the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 4562-4616, or a nucleic acid sequence thereof having 1 or 2 nucleoside additions at the 3’ end. In some embodiments, the composition comprises an oligonucleotide that inhibits or reduces the expression of HGFAC, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 4562-4616.

[0048] In some embodiments, the composition comprises an oligonucleotide that inhibits or reduces the expression of HGFAC, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 4757-4779, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 4757-4779, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand further comprises a 3’ overhang. In some embodiments, the 3’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range ofnucleotides defined by any two of the aforementioned numbers. In some embodiments, the 3’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 3’ overhang comprises 2 nucleosides. In some embodiments, the sense strand further comprises a 5’ overhang. In some embodiments, the 5’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 5’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 5’ overhang comprises 2 nucleosides. In some embodiments, the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 4757 -4779, or a nucleic acid sequence thereof having 1 or 2 nucleoside additions at the 3’ end. In some embodiments, the composition comprises an oligonucleotide that inhibits or reduces the expression of HGFAC, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 4757-4779.

[0049] In some embodiments, the composition comprises an oligonucleotide that inhibits or reduces the expression of HGFAC, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of SEQ ID NO: 4856, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of SEQ ID NO: 4856, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand further comprises a 3’ overhang. In some embodiments, the 3’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 3’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 3’ overhang comprises 2 nucleosides. In some embodiments, the sense strand further comprises a 5’ overhang. In some embodiments, the 5’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 5’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 5’ overhang comprises 2 nucleosides. In some embodiments, the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of SEQ ID NO: 4856, or a nucleic acid sequence thereof having 1 or 2 nucleoside additions at the 3’ end. In some embodiments, the composition comprises an oligonucleotide that inhibits or reduces the expression of HGFAC, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of SEQ ID NO: 4856.

[0050] In some embodiments, the composition comprises an oligonucleotide that inhibits or reduces the expression of HGFAC, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises a nucleoside sequence comprisingor consisting of the sequence of any one of SEQ ID NOs: 1791, 4581, 4582, 4597, 4599, 4613, 4615, or 4776, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1791, 4581, 4582, 4597, 4599, 4613, 4615, or 4776, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand further comprises a 3’ overhang. In some embodiments, the 3’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 3’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 3’ overhang comprises 2 nucleosides. In some embodiments, the sense strand further comprises a 5’ overhang. In some embodiments, the 5’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 5’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 5’ overhang comprises 2 nucleosides. In some embodiments, the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1791, 4581, 4582, 4597, 4599, 4613, 4615, or 4776, or a nucleic acid sequence thereof having 1 or 2 nucleoside additions at the 3’ end. In some embodiments, the composition comprises an oligonucleotide that inhibits or reduces the expression of HGFAC, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1791, 4581, 4582, 4597, 4599, 4613, 4615, or 4776.

[0051] In some embodiments, the composition comprises an oligonucleotide that inhibits or reduces the expression of HGFAC, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the antisense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 2052-4102, 4617-4671, 4780- 4802, or 4857, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 2052-4102, 4617-4671, 4780- 4802, or 4857, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand further comprises a 3’ overhang. In some embodiments, the 3’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 3’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 3’ overhang comprises 2 nucleosides. In some embodiments, the antisense strand further comprises a 5’ overhang. In some embodiments, the 5’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 5’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 5’ overhang comprises 2 nucleosides. In some embodiments, the antisense strand comprises a nucleoside sequence comprisingor consisting of the sequence of any one of SEQ ID NOs: 2052-4102, 4617-4671, 4780-4802, or 4857, or a nucleic acid sequence thereof having 1 or 2 nucleoside additions at the 3’ end. In some embodiments, the composition comprises an oligonucleotide that inhibits or reduces the expression of HGFAC, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the antisense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 2052-4102, 4617-4671, 4780-4802, or 4857.

[0052] In any of SEQ ID NOs: 1-2051, 4562-4616, 4757-4779, or 4856, thymine (T) may be replaced with Uracil (U). Any of the aforementioned siRNAs may include a sense strand or antisense strand where the 5’ nucleoside has been modified to an A. Any one of the aforementioned siRNAs may include a sense strand or antisense strand sequence wherein the 5’ nucleoside has been modified to a U or T. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 1-2051, 4562-4616, 4757-4779, or 4856 is modified to an A, T, C, U, or G. In some embodiments, position 6 (from the 5’ end) of any one of SEQ ID NOs: 1-2051, 4562-4616, 4757-4779, or 4856 is modified to an A, T, C, U, or G. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 1-2051, 4562-4616, 4757-4779, or 4856 is modified to an A, T, C, U, or G. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs 1-2051, 4562-4616, 4757-4779, or 4856 is modified to an A. In some embodiments, position 6 (from the 5’ end) of any one of SEQ ID NOs: 1- 2051, 4562-4616, 4757-4779, or 4856 is modified to an A. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs SEQ ID NOs: 1-2051, 4562-4616, 4757-4779, or 4856 is modified to an A. In some embodiments, position 1 and position 6, position 1 and position 19, position 6 and position 19, or position 1, position 6, and position 19 of any one of SEQ ID NOs 1- 2051, 4562-4616, or 4757-4779 is modified to an A. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs 1-2051, 4562-4616, 4757-4779, or 4856 is modified to an T or U. In some embodiments, position 6 (from the 5’ end) of any one of SEQ ID NOs: 2052-4102, 4617-4671, 4780-4802, or 4857 is modified to a T or U. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs 1-2051, 4562-4616, or 4757-4779 is modified to a T or U. In some embodiments, position 1 and position 6, position 1 and position 19, position 6 and position 19, or position 1, position 6, and position 19 of any one of SEQ ID NOs 1-2051, 4562-4616, 4757-4779, or 4856 is modified to a T or U. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 21-2051, 4562-4616, 4757-4779, or 4856 is modified to an G. In some embodiments, position 6 (from the 5’ end) of any one of SEQ ID NOs: 1-2051, 4562-4616, 4757-4779, or 4856 is modified to an G. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs 1- 2051, 4562-4616, 4757-4779, or 4856 is modified to an G. In some embodiments, position 1 and position 6, position 1 and position 19, position 6 and position 19, or position 1, position 6, and position 19 of any one of SEQ ID NOs 1-2051, 4562-4616, 4757-4779, or 4856 is modified to an G. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 1-2051, 4562-4616, 4757-4779, or 4856 is modified to an C. In some embodiments, position 6 (from the 5’ end) of anyone of SEQ ID NOs: 1-2051, 4562-4616, 4757-4779, or 4856 is modified to an C. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs 2052-4102, 4617-4671, 4780- 4802, or 4857 is modified to an C. In some embodiments, position 1 and position 6, position 1 and position 19, position 6 and position 19, or position 1, position 6, and position 19 of any one of 2052- 4102, 4617-4671, 4780-4802, or 4857 is modified to an C.

[0053] In some embodiments, the composition comprises an oligonucleotide that inhibits or reduces the expression of HGFAC, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the antisense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 2052-4102, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 2052-4102, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand further comprises a 3’ overhang. In some embodiments, the 3’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 3’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 3’ overhang comprises 2 nucleosides. In some embodiments, the antisense strand further comprises a 5’ overhang. In some embodiments, the 5’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 5’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 5’ overhang comprises 2 nucleosides. In some embodiments, the antisense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 2052-4102, or a nucleic acid sequence thereof having 1 or 2 nucleoside additions at the 3’ end. In some embodiments, the composition comprises an oligonucleotide that inhibits or reduces the expression of HGFAC, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the antisense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 2052-4102.

[0054] In some embodiments, the composition comprises an oligonucleotide that inhibits or reduces the expression of HGFAC, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the antisense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 4617-4671, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 4617-4671, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand further comprises a 3’ overhang. In some embodiments, the 3’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementionednumbers. In some embodiments, the 3’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 3’ overhang comprises 2 nucleosides. In some embodiments, the antisense strand further comprises a 5’ overhang. In some embodiments, the 5’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 5’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 5’ overhang comprises 2 nucleosides. In some embodiments, the antisense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 4617 -4671, or a nucleic acid sequence thereof having 1 or 2 nucleoside additions at the 3’ end. In some embodiments, the composition comprises an oligonucleotide that inhibits or reduces the expression of HGFAC, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the antisense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 4617-4671.

[0055] In some embodiments, the composition comprises an oligonucleotide that inhibits or reduces the expression of HGFAC, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the antisense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 4780-4802, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 4780-4802, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand further comprises a 3’ overhang. In some embodiments, the 3’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 3’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 3’ overhang comprises 2 nucleosides. In some embodiments, the antisense strand further comprises a 5’ overhang. In some embodiments, the 5’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 5’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 5’ overhang comprises 2 nucleosides. In some embodiments, the antisense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 4780-4802, or a nucleic acid sequence thereof having 1 or 2 nucleoside additions at the 3’ end. In some embodiments, the composition comprises an oligonucleotide that inhibits or reduces the expression of HGFAC, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the antisense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 4780-4802.

[0056] In some embodiments, the composition comprises an oligonucleotide that inhibits or reduces the expression of HGFAC, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the antisense strand comprises a nucleoside sequencecomprising or consisting of the sequence of SEQ ID NO: 4857, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises a nucleoside sequence comprising or consisting of the sequence of SEQ ID NO: 4857, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand further comprises a 3’ overhang. In some embodiments, the 3’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 3’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 3’ overhang comprises 2 nucleosides. In some embodiments, the antisense strand further comprises a 5’ overhang. In some embodiments, the 5’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 5’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 5’ overhang comprises 2 nucleosides. In some embodiments, the antisense strand comprises a nucleoside sequence comprising or consisting of the sequence of SEQ ID NO: 4857, or a nucleic acid sequence thereof having 1 or 2 nucleoside additions at the 3’ end. In some embodiments, the composition comprises an oligonucleotide that inhibits or reduces the expression of HGFAC, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the antisense strand comprises a nucleoside sequence comprising or consisting of the sequence of SEQ ID NO: 4857.

[0057] In some embodiments, the composition comprises an oligonucleotide that inhibits or reduces the expression of HGFAC, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the antisense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 3842, 4636, 4637, 4652, 4654, 4668, 4670, or 4799, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 3842, 4636, 4637, 4652, 4654, 4668, 4670, or 4799, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand further comprises a 3’ overhang. In some embodiments, the 3’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 3’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 3’ overhang comprises 2 nucleosides. In some embodiments, the antisense strand further comprises a 5’ overhang. In some embodiments, the 5’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 5’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 5’ overhang comprises 2 nucleosides. In some embodiments, the antisense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 3842, 4636, 4637, 4652, 4654, 4668, 4670, or 4799, or a nucleic acid sequence thereof having 1 or 2 nucleoside additions at the 3’end. In some embodiments, the composition comprises an oligonucleotide that inhibits or reduces the expression of HGFAC, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the antisense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 3842, 4636, 4637, 4652, 4654, 4668, 4670, or 4799.

[0058] In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in any one of Tables A-E, G, H, 5, 14, 24, 27, 31, 35, 39, 43, 45, 46 or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in any one of Tables A-E, G, H, 5, 14, 24, 27, 31, 35, 39, 43, 45, 46 or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in any one of Tables A-E, G, H, 5, 14, 24, 27, 31, 35, 39, 43, 45, 46. In some embodiments, the siRNA is cross-reactive with a non-human primate (NHP) HGFAC mRNA. The siRNA may include one or more internucleoside linkages and / or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand that lacks a 3’ A of a sense strand sequence in any one of Tables A-E, G, H, 5, 14, 24, 27, 31, 35, 39, 43, 45, 46. Any of the aforementioned siRNAs may include a sense strand that lacks a 5’ U of an antisense strand sequence in any one of Tables A- E, G, H, 5, 14, 24, 27, 31, 35, 39, 43, 45, 46

[0059] In some embodiments, the sense and / or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and / or antisense strand sequence in Tables A-E, G, H, 5, 14, 24, 27, 31, 35, 39, 43, 45 and 46. In some embodiments, the composition comprises an oligonucleotide that inhibits or reduces the expression of HGFAC, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand comprise a oligonucleotide sequences as disclosed in Tables A-E, G, H, 5, 14, 24, 27, 31, 35, 39, 43, 45 and 46, each strand is independently about 19-21 nucleosides in length, and at least one of the sense strand and the antisense strand comprises a nucleoside sequence comprising at least about 15 contiguous nucleosides of oligonucleotide sequences as disclosed in Tables A-E, G, H, 5, 14, 24, 27, 31, 35, 39, 43, 45 and 46.

[0060] In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of subset A, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of subset A, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of subset A. In some embodiments, the siRNA is cross-reactive with a non-human primate (NHP) HGFAC mRNA. ThesiRNA may include one or more intemucleoside linkages and / or one or more nucleoside modifications.

[0061] In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of subset B, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of subset B, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of subset B. In some embodiments, the siRNA is cross-reactive with a non-human primate (NHP) HGFAC mRNA. The siRNA may include one or more intemucleoside linkages and / or one or more nucleoside modifications.

[0062] In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of subset C, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of subset C, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of subset C. In some embodiments, the siRNA is cross-reactive with a non-human primate (NHP) HGFAC mRNA. The siRNA may include one or more intemucleoside linkages and / or one or more nucleoside modifications.

[0063] In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of subset D, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of subset D, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of subset D. In some embodiments, the siRNA is cross-reactive with a non-human primate (NHP) HGFAC mRNA. The siRNA may include one or more intemucleoside linkages and / or one or more nucleoside modifications.

[0064] In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of subset E, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of subset E, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of subset E. In some embodiments, the siRNA is cross-reactive with a non-human primate (NHP) HGFAC mRNA. ThesiRNA may include one or more intemucleoside linkages and / or one or more nucleoside modifications.

[0065] In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of subset G, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of subset G, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of subset G. In some embodiments, the siRNA is cross-reactive with a non-human primate (NHP) HGFAC mRNA. The siRNA may include one or more intemucleoside linkages and / or one or more nucleoside modifications.

[0066] In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of subset H, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of subset H, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of subset H. In some embodiments, the siRNA is cross-reactive with a non-human primate (NHP) HGFAC mRNA. The siRNA may include one or more intemucleoside linkages and / or one or more nucleoside modifications.

[0067] In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of Table 5, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of Table 5, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of Table 5. In some embodiments, the siRNA is cross-reactive with a non-human primate (NHP) HGFAC mRNA. The siRNA may include one or more intemucleoside linkages and / or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand that lacks a 3’ A of a sense strand sequence in Table 5. Any of the aforementioned siRNAs may include a sense strand that lacks a 5’ U of an antisense strand sequence in Table 5. In some embodiments, the sense and / or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and / or antisense strand sequence in Table 5. In some embodiments, the composition comprises an oligonucleotide that inhibits or reduces the expression of HGFAC, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand comprise a oligonucleotide sequences as disclosed in Table 5, each strand is independently about 19-21 nucleosides in length, andat least one of the sense strand and the antisense strand comprises a nucleoside sequence comprising at least about 15 contiguous nucleosides of oligonucleotide sequences as disclosed in Tables 5.

[0068] In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of Table 14, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of Table 14, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of Table 14. In some embodiments, the siRNA is cross-reactive with a non-human primate (NHP) HGFAC mRNA. The siRNA may include one or more intemucleoside linkages and / or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand that lacks a 3’ A of a sense strand sequence in Table 14. Any of the aforementioned siRNAs may include a sense strand that lacks a 5’ U of an antisense strand sequence in Table 14. In some embodiments, the sense and / or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and / or antisense strand sequence in Table 14. In some embodiments, the composition comprises an oligonucleotide that inhibits or reduces the expression of HGFAC, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand comprise a oligonucleotide sequences as disclosed in Tables 14, each strand is independently about 19-21 nucleosides in length, and at least one of the sense strand and the antisense strand comprises a nucleoside sequence comprising at least about 15 contiguous nucleosides of oligonucleotide sequences as disclosed in Tables 14. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of Table 24, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of Table 24, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of Table 24. In some embodiments, the siRNA is cross-reactive with a non-human primate (NHP) HGFAC mRNA. The siRNA may include one or more intemucleoside linkages and / or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand that lacks a 3’ A of a sense strand sequence in Table 24. Any of the aforementioned siRNAs may include a sense strand that lacks a 5’ U of an antisense strand sequence in Table 24. In some embodiments, the sense and / or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and / or antisense strand sequence in Table 24. In some embodiments, the composition comprises an oligonucleotide that inhibits or reduces the expression of HGFAC, wherein the oligonucleotidecomprises an siRNA comprising a sense strand and an antisense strand comprise a oligonucleotide sequences as disclosed in Tables 24, each strand is independently about 19-21 nucleosides in length, and at least one of the sense strand and the antisense strand comprises a nucleoside sequence comprising at least about 15 contiguous nucleosides of oligonucleotide sequences as disclosed in Tables 24.

[0069] In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of Table 27, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of Table 27, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of Table 27. In some embodiments, the siRNA is cross-reactive with a non-human primate (NHP) HGFAC mRNA. The siRNA may include one or more intemucleoside linkages and / or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand that lacks a 3’ A of a sense strand sequence in Table 27. Any of the aforementioned siRNAs may include a sense strand that lacks a 5’ U of an antisense strand sequence in Table 27. In some embodiments, the sense and / or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and / or antisense strand sequence in Table 27. In some embodiments, the composition comprises an oligonucleotide that inhibits or reduces the expression of HGFAC, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand comprise a oligonucleotide sequences as disclosed in Tables 27, each strand is independently about 19-21 nucleosides in length, and at least one of the sense strand and the antisense strand comprises a nucleoside sequence comprising at least about 15 contiguous nucleosides of oligonucleotide sequences as disclosed in Tables 27.

[0070] In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of Table 31, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of Table 31, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of Table 31. In some embodiments, the siRNA is cross-reactive with a non-human primate (NHP) HGFAC mRNA. The siRNA may include one or more intemucleoside linkages and / or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand that lacks a 3’ A of a sense strand sequence in Table 31. Any of the aforementioned siRNAs may include a sense strand that lacks a 5’ U of an antisense strand sequence in Table 31. In some embodiments, the sense and / or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and / or antisense strand sequence in Table 31. In some embodiments, the composition comprises an oligonucleotide that inhibits or reduces the expression of HGFAC, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand comprise a oligonucleotide sequences as disclosed in Tables 31, each strand is independently about 19-21 nucleosides in length, and at least one of the sense strand and the antisense strand comprises a nucleoside sequence comprising at least about 15 contiguous nucleosides of oligonucleotide sequences as disclosed in Tables 31.

[0071] In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of Table 35, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of Table 35, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of Table 35. In some embodiments, the siRNA is cross-reactive with a non-human primate (NHP) HGFAC mRNA. The siRNA may include one or more intemucleoside linkages and / or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand that lacks a 3’ A of a sense strand sequence in Table 35. Any of the aforementioned siRNAs may include a sense strand that lacks a 5’ U of an antisense strand sequence in Table 35. In some embodiments, the sense and / or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and / or antisense strand sequence in Table 35. In some embodiments, the composition comprises an oligonucleotide that inhibits or reduces the expression of HGFAC, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand comprise a oligonucleotide sequences as disclosed in Tables 35, each strand is independently about 19-21 nucleosides in length, and at least one of the sense strand and the antisense strand comprises a nucleoside sequence comprising at least about 15 contiguous nucleosides of oligonucleotide sequences as disclosed in Tables 35.

[0072] In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of Table 39, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of Table 39, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of Table 39. In some embodiments, the siRNA is cross-reactive with a non-human primate (NHP) HGFAC mRNA. The siRNA may include one or more intemucleoside linkages and / or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand that lacks a 3’ A of asense strand sequence in Table 39. Any of the aforementioned siRNAs may include a sense strand that lacks a 5’ U of an antisense strand sequence in Table 39. In some embodiments, the sense and / or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and / or antisense strand sequence in Table 39. In some embodiments, the composition comprises an oligonucleotide that inhibits or reduces the expression of HGFAC, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand comprise a oligonucleotide sequences as disclosed in Tables 39, each strand is independently about 19-21 nucleosides in length, and at least one of the sense strand and the antisense strand comprises a nucleoside sequence comprising at least about 15 contiguous nucleosides of oligonucleotide sequences as disclosed in Tables 39.

[0073] In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of Table 43, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of Table 43, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of Table 43. In some embodiments, the siRNA is cross-reactive with a non-human primate (NHP) HGFAC mRNA. The siRNA may include one or more internucleoside linkages and / or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand that lacks a 3’ A of a sense strand sequence in Table 43. Any of the aforementioned siRNAs may include a sense strand that lacks a 5’ U of an antisense strand sequence in Table 43. In some embodiments, the sense and / or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and / or antisense strand sequence in Table 43. In some embodiments, the composition comprises an oligonucleotide that inhibits or reduces the expression of HGFAC, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand comprise a oligonucleotide sequences as disclosed in Tables 43, each strand is independently about 19-21 nucleosides in length, and at least one of the sense strand and the antisense strand comprises a nucleoside sequence comprising at least about 15 contiguous nucleosides of oligonucleotide sequences as disclosed in Tables 43. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of Table 45, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of Table 45, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of Table 45. In some embodiments, the siRNA is cross-reactive with a non-human primate (NHP) HGFAC mRNA. ThesiRNA may include one or more intemucleoside linkages and / or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand that lacks a 3’ A of a sense strand sequence in Table 45. Any of the aforementioned siRNAs may include a sense strand that lacks a 5’ U of an antisense strand sequence in Table 45. In some embodiments, the sense and / or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and / or antisense strand sequence in Table 45. In some embodiments, the composition comprises an oligonucleotide that inhibits or reduces the expression of HGFAC, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand comprise a oligonucleotide sequences as disclosed in Tables 45, each strand is independently about 19-21 nucleosides in length, and at least one of the sense strand and the antisense strand comprises a nucleoside sequence comprising at least about 15 contiguous nucleosides of oligonucleotide sequences as disclosed in Tables 45.

[0074] In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of Table 46, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of Table 46, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of Table 46. In some embodiments, the siRNA is cross-reactive with a non-human primate (NHP) HGFAC mRNA. The siRNA may include one or more intemucleoside linkages and / or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand that lacks a 3’ A of a sense strand sequence in Table 46. Any of the aforementioned siRNAs may include a sense strand that lacks a 5’ U of an antisense strand sequence in Table 46. In some embodiments, the sense and / or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and / or antisense strand sequence in Table 46. In some embodiments, the composition comprises an oligonucleotide that inhibits or reduces the expression of HGFAC, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand comprise a oligonucleotide sequences as disclosed in Tables 46, each strand is independently about 19-21 nucleosides in length, and at least one of the sense strand and the antisense strand comprises a nucleoside sequence comprising at least about 15 contiguous nucleosides of oligonucleotide sequences as disclosed in Tables 46.B. ASOs

[0075] In some embodiments, the composition comprises an oligonucleotide that inhibits or reduces the expression of HGFAC, wherein the oligonucleotide comprises an antisense oligonucleotide (ASO). In some embodiments, the ASO is 12-30 nucleosides in length. In some embodiments, theASO is 14-30 nucleosides in length. In some embodiments, the ASO is at least about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleosides in length, or a range defined by any of the two aforementioned numbers. In some embodiments, the ASO is 15-25 nucleosides in length. In some embodiments, the ASO is 20 nucleosides in length.

[0076] In some embodiments, the composition comprises an oligonucleotide that inhibits or reduces the expression of HGFAC, wherein the oligonucleotide comprises an ASO about 12-30 nucleosides in length and comprising a nucleoside sequence complementary to about 12-30 contiguous nucleosides of a full-length human HGFAC mRNA sequence such as SEQ ID NO: 4803; wherein (i) the oligonucleotide comprises a modification comprising a modified nucleoside and / or a modified internucleoside linkage, and / or (ii) the composition comprises a pharmaceutically acceptable carrier. In some embodiments, the ASO comprise 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: 4803.C. Modifications

[0077] In some embodiments, the composition comprises an oligonucleotide that inhibits or reduces the expression of HGFAC, wherein the oligonucleotide comprises a modification comprising a modified nucleoside and / or a modified internucleoside linkage, and / or (ii) the composition comprises a pharmaceutically acceptable carrier. In some embodiments, the oligonucleotide comprises a modification comprising a modified nucleoside and / or a modified internucleoside linkage. In some embodiments, the oligonucleotide comprises a modified intemucleoside linkage. In some embodiments, the modified internucleoside linkage comprises alkylphosphonate, phosphorothioate, methylphosphonate, phosphorodithioate, alkylphosphonothioate, phosphoramidate, carbamate, carbonate, phosphate tri ester, acetamidate, or carboxymethyl ester, or a combination thereof. In some embodiments, the modified internucleoside linkage comprises one or more phosphorothioate linkages. A phosphorothioate may include a nonbridging oxygen atom in a phosphate backbone of the oligonucleotide that is replaced by sulfur. Modified internucleoside linkages may be included in siRNAs or ASOs. Benefits of the modified intemucleoside linkage may include decreased toxicity or improved pharmacokinetics.

[0078] In some embodiments, the oligonucleotide comprises a duplex consisting of 21 -36 nucleotide single strands with base pairing between 17-25 of the base pairs. In some embodiments, the duplex comprises blunt-ends at the 5 ’or 3’ ends of each strand. One strand (antisense strand) is complementary to a target mRNA. Each end of the antisense strand has one to five phosphorothioate bonds. The 5’ end has an optional phosphate mimic such as a vinyl phosphonate. In some embodiments, the oligonucleotide is used to knock down a target mRNA or a target protein. In some embodiments, the sense strand has the same sequence as the target mRNA. In some embodiments, there are 1-5 phosphorothi oates at the 5’ and 3’ ends.

[0079] In some embodiments, the composition comprises an oligonucleotide that inhibits or reduces the expression of HGFAC, wherein the oligonucleotide comprises a modified internucleoside linkage, wherein the oligonucleotide comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 modified internucleoside linkages, or a range of modified internucleoside linkages defined by any two of the aforementioned numbers. In some embodiments, the oligonucleotide comprises no more than 18 modified intemucleoside linkages. In some embodiments, the oligonucleotide comprises no more than 20 modified intemucleoside linkages. In some embodiments, the oligonucleotide comprises 2 or more modified intemucleoside linkages, 3 or more modified intemucleoside linkages, 4 or more modified intemucleoside linkages, 5 or more modified intemucleoside linkages, 6 or more modified intemucleoside linkages, 7 or more modified intemucleoside linkages, 8 or more modified intemucleoside linkages, 9 or more modified intemucleoside linkages, 10 or more modified intemucleoside linkages, 11 or more modified intemucleoside linkages, 12 or more modified intemucleoside linkages, 13 or more modified intemucleoside linkages, 14 or more modified intemucleoside linkages, 15 or more modified intemucleoside linkages, 16 or more modified intemucleoside linkages, 17 or more modified intemucleoside linkages, 18 or more modified intemucleoside linkages, 19 or more modified intemucleoside linkages, or 20 or more modified intemucleoside linkages.

[0080] In some embodiments, the composition comprises an oligonucleotide that inhibits or reduces the expression of HGFAC, wherein the oligonucleotide comprises the modified nucleoside. In some embodiments, the modified nucleoside comprises a locked nucleic acid (LNA), hexitol nucleic acid (HLA), cyclohexene nucleic acid (CeNA), 2'-methoxyethyl, 2'-0-alkyl, 2'-O-allyl, 2'-fluoro, or 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 HLA. In some embodiments, the modified nucleoside comprises CeNA. In some embodiments, the modified nucleoside comprises a 2'- methoxy ethyl group. In some embodiments, the modified nucleoside comprises a 2'-0-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, 2'- deoxy fluoro nucleoside, 2'-O-N-methylacetamido (2-O-NMA) nucleoside, a 2'-O- dimethylaminoethoxyethyl (2-O-DMAEOE) nucleoside, 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 2'-ara-F. In some embodiments, the modifiednucleoside comprises one or more 2’ -fluoro modified nucleosides. In some embodiments, the modified nucleoside comprises a 2’-0-alkyl modified nucleoside. In some embodiments, the modified nucleoside comprises a 2’-O-methyl inosine nucleoside. In some embodiments, the modified nucleoside comprises an unlocked nucleic acid. Benefits of the modified nucleoside may include decreased toxicity or improved pharmacokinetics.

[0081] In some embodiments, the modified nucleoside comprises an unlocked nucleic acid. An unlocked nucleic acid may comprise the following structure:wherein the base can be any pyrimidine or purine.

[0082] In some embodiments, the oligonucleotide comprises a modified nucleoside. In some embodiments, the modified nucleoside comprises a locked nucleic acid and an abasic site:are independently an H or a 3’ or 5’ linkage to a nucleotide via a phosphodiester or phosphorothioate bond.

[0083] In some embodiments, the oligonucleotide comprises a phosphate mimic. In some embodiments, the phosphate mimic comprises methylphosphonate. An example of a nucleotide that comprises a methylphosphonate is shown below:methylphosphonate 2’-O-methyl Uridine).

[0084] In some embodiments, the oligonucleotide comprises a duplex consisting of 21 -36 nucleotide single strands with base pairing between 17-25 of the base pairs. In some embodiments, the duplex comprises blunt-ends at the 5 ’or 3’ ends of each strand. One strand (antisense strand) is complementary to a target mRNA. Each end of the antisense strand has one to five phosphorothioate bonds. The 5’ end has an optional phosphate mimic such as a vinyl phosphonate. In some embodiments, the oligonucleotide is used to knock down a target mRNA or a target protein. In some embodiments, the sense strand has the same sequence as the target mRNA. In some embodiments, there are 1-5 phosphorothi oates at the 5’ and 3’ ends.

[0085] 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 aforementioned numbers. In some embodiments, the oligonucleotide comprises no more than 19 modified nucleosides. In some embodiments, the oligonucleotide comprises no more than 21 modified nucleosides. In some embodiments, the oligonucleotide comprises 2 or more modified nucleosides, 3 or more modified nucleosides, 4 or more modified nucleosides, 5 or more modified nucleosides, 6 or more modified nucleosides, 7 or more modified nucleosides, 8 or more modified nucleosides, 9 or more modified nucleosides, 10 or more modified nucleosides, 11 or more modified nucleosides, 12 or more modified nucleosides, 13 or more modified nucleosides, 14 or more modified nucleosides, 15 or more modified nucleosides, 16 or more modified nucleosides, 17 or more modified nucleosides, 18 or more modified nucleosides, 19 or more modified nucleosides, 20 or more modified nucleosides, or 21 or more modified nucleosides.

[0086] In some embodiments, the composition comprises an oligonucleotide that inhibits or reduces the expression of HGFAC, wherein the oligonucleotide comprises a moiety attached at a 3’ or 5’ terminus of the oligonucleotide. Examples of moieties include a hydrophobic moiety or 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 a 5’ end of the sense strand. In some embodiments, the oligonucleotide is an siRNA having a sense strand, and the moiety is attached to a 3’ end of the sense strand. In some embodiments, the oligonucleotide is an siRNA having an antisense strand, and the moiety is attached to a 5’ end of the antisense strand. In some embodiments, the oligonucleotide is an siRNA having an antisense strand, and the moiety is attached to a 3’ end of the antisense strand. In some embodiments, the oligonucleotide is an ASO, and the moiety is attached to a 5’ end of the ASO. In some embodiments, the oligonucleotide is an ASO, and the moiety is attached to a 3’ end of the ASO.

[0087] In some embodiments, the sense strand comprises at least three modified nucleosides, wherein the three modifications comprise a 2’ -fluoro modified nucleoside, a 2’-O-methyl modified nucleoside, and 2’-O-methoxyethyl. In some embodiments, the sense strand comprises at least two modified nucleosides, wherein the two modifications comprise a 2’ -fluoro modified nucleoside, a 2’ - O-methyl modified nucleoside, and 2’ -O-methoxy ethyl. In some embodiments, each nucleoside of thesense strand comprises a modified nucleoside, wherein the modified nucleosides are selected from the group consisting of a 2’ -fluoro modified nucleoside, a 2’-O-ethyl modified nucleoside, and 2’-O- methoxy ethyl. In some embodiments, the sense strand comprises at least a 2’ -fluoro modified nucleoside, a 2’-O-methyl modified nucleoside, and 2’-O-methoxyethyl.

[0088] In some embodiments, the antisense strand is combination of 2’-fluoro and 2’-O-methyl modifications. In some embodiments, each nucleoside of the antisense strand comprises a modified nucleoside, wherein the modified nucleosides are selected from the group consisting of a 2’ -fluoro modified nucleoside and a2’-O-methyl modified nucleoside. In some embodiments, the sense strand comprises at least a 2’ -fluoro modified nucleoside and a 2’-O-methyl modified nucleoside.

[0089] The oligonucleotide may include purines. Examples of purines include adenine (A), inosine (I), guanine (G), or modified versions thereof. The oligonucleotide may include pyrimidines. Examples of pyrimidines include cytosine (C), thymine (T), or uracil (U), or modified versions thereof.

[0090] In some embodiments, the sense strand comprises purines and pyrimidines. In some embodiments, all purine nucleosides comprise 2’ -fluoro, and all pyrimidine nucleosides are modified with a mixture of 2’-O-methyl and 2’-O-methoxyethyl. In some embodiments, all purine nucleosides comprise 2’ -O-methyl, and all pyrimidine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methoxyethyl. In some embodiments, all purine nucleosides comprise 2’-O-methoxyethyl, and all pyrimidine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methyl. In some embodiments, all pyrimidine nucleosides comprise 2’ -fluoro, and all purine nucleosides are modified with a mixture of 2’-O-methyl and 2’-O-methoxyethyl. In some embodiments, all pyrimidine nucleosides comprise 2’ -O-methyl, and all purine nucleosides are modified with a mixture of 2’- fluoro and 2’-O-methoxyethyl. In some embodiments, all pyrimidine nucleosides comprise 2’-O- methoxy ethyl, and all purine nucleosides are modified with a mixture of 2’ -fluoro and 2’ -O-methyl. In some embodiments, the sense strand may include a 2’ -deoxy nucleoside.

[0091] In some embodiments, at least one nucleotide at position 4 or 5 of the sense strand comprises a 2’-O-methoxyethyl modified nucleoside. In some embodiments, at least one nucleotide of the sense strand from position 6 to 9 comprise a 2’-fluoro-modified nucleoside. In some embodiments, at least two nucleotides of the sense strand at position 6 to 9 comprise a 2’-fluoro-modified nucleoside. In some embodiments, at least three nucleotides of the sense strand at positions 6 to 9 comprise a 2’- fluoro-modified nucleoside. In some embodiments, each nucleotide from positions 6 to 9 of the sense strand comprise a 2’-fluoro-modified nucleoside. In some embodiments, at least one nucleotide at position 16 to 20 of the sense strand comprises a 2’-O-methyl modified nucleoside. In some embodiments, at least two nucleotides at position 16 to 20 of the sense strand comprise a 2’ -O-methyl modified nucleoside. In some embodiments, at least three nucleotides at position 16 to 20 of the sense strand comprise a 2’-O-methyl modified nucleoside. In some embodiments, at least four nucleotides at position 16 to 20 of the sense strand comprise a 2’ -O-methyl modified nucleoside. In someembodiments, all nucleotides at position 16 to 20 of the sense strand comprise a 2’-O-methyl modified nucleoside.

[0092] In some embodiments, any of the following is true with regards to the antisense strand: all purine nucleosides comprise 2’ -fluoro, and all pyrimidine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methyl; all purine nucleosides comprise 2’-O-methyl, and all pyrimidine nucleosides are modified with a mixture of 2’ -fluoro and 2’-O-methyl; all purine nucleosides comprise 2’-O-methyl, and all pyrimidine nucleosides comprise 2’ -fluoro; all pyrimidine nucleosides comprise 2’-fluoro, and all purine nucleosides are modified with a mixture of 2’-fluoro and 2’-O- methyl; all pyrimidine nucleosides comprise 2’-O-methyl, and all purine nucleosides are modified with a mixture of 2’ -fluoro and 2’ -O-methyl; or all pyrimidine nucleosides comprise 2’ -O-methyl, and all purine nucleosides comprise 2’-fluoro. In some embodiments, all purine nucleosides comprise 2’- fluoro, and all pyrimidine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methyl. In some embodiments, all purine nucleosides comprise 2’ -O-methyl, and all pyrimidine nucleosides are modified with a mixture of 2’ -fluoro and 2’ -O-methyl; all purine nucleosides comprise 2’ -O-methyl, and all pyrimidine nucleosides comprise 2’ -fluoro. In some embodiments, all pyrimidine nucleosides comprise 2’-fluoro, and all purine nucleosides are modified with a mixture of 2’-fluoro and 2’-O- methyl; all pyrimidine nucleosides comprise 2’ -O-methyl, and all purine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methyl. In some embodiments, all pyrimidine nucleosides comprise 2’ -O-methyl, and all purine nucleosides comprise 2’ -fluoro.

[0093] In some embodiments, the composition comprises an oligonucleotide that inhibits or reduces the expression of HGFAC, wherein the oligonucleotide comprises a hydrophobic moiety. The hydrophobic moiety may be attached at a 3’ or 5’ terminus of the oligonucleotide. The hydrophobic moiety may include a lipid such as a fatty acid. The hydrophobic moiety may include a hydrocarbon. The hydrocarbon may be linear. The hydrocarbon may be non-linear. The hydrophobic moiety may include a lipid moiety or a cholesterol moiety, or a combination thereof.

[0094] In some embodiments, the composition comprises an oligonucleotide that inhibits or reduces the expression of HGFAC, wherein the oligonucleotide comprises a lipid attached at a 3’ or 5’ terminus of the oligonucleotide. In some embodiments, the lipid comprises cholesterol, myristoyl, palmitoyl, stearoyl, lithocholoyl, docosanoyl, docosahexaenoyl, myristyl, palmityl stearyl, or a- tocopherol, or a combination thereof.

[0095] In some embodiments, the composition comprises an oligonucleotide that inhibits or reduces the expression of HGFAC, wherein the oligonucleotide comprises a sugar moiety. The sugar moiety may include an N-acetyl galactose moiety (e.g., an N-acetylgalactosamine (GalNAc) moiety), an N- acetyl glucose moiety (e.g., an N-acetylglucosamine (GlcNAc) moiety), a fucose moiety, or a mannose moiety. The sugar moiety may include 1, 2, 3, or more sugar molecules. The sugar moiety may be attached at a 3’ or 5’ terminus of the oligonucleotide. The sugar moiety may include an N- acetyl galactose moiety. The sugar moiety may include an N-acetylgalactosamine (GalNAc) moiety.The sugar moiety may include an N-acetyl glucose moiety. The sugar moiety may include N- acetylglucosamine (GlcNAc) moiety. The sugar moiety may include a fucose moiety. The sugar moiety may include a mannose moiety. N-acetyl glucose, GlcNAc, fucose, or mannose may be useful for targeting macrophages since they may target or bind a mannose receptor such as CD206.

[0096] In some embodiments, the composition comprises an oligonucleotide that inhibits or reduces the expression of HGFAC, wherein the oligonucleotide comprises an N-acetylgalactosamine (GalNAc) moiety. GalNAc may be useful for hepatocyte targeting. The GalNAc moiety may include a bivalent or trivalent branched linker. The oligo may be attached to 1, 2 or 3 GalNAcs through a bivalent or trivalent branched linker. The GalNAc moiety may include 1, 2, 3, or more GalNAc molecules. The GalNAc moiety may be attached at a 3’ or 5’ terminus of the oligonucleotide.

[0097] In some embodiments, purines of the oligonucleotide comprise 2’ -fluoro modified purines. In some embodiments, purines of the oligonucleotide comprise 2’-O-methyl modified purines. In some embodiments, purines of the oligonucleotide comprise a mixture of 2’ -fluoro and 2’-O-methyl modified purines. In some embodiments, all purines of the oligonucleotide comprise 2 ’-fluoro modified purines. In some embodiments, all purines of the oligonucleotide comprise 2’-O-methyl modified purines. In some embodiments, all purines of the oligonucleotide comprise a mixture of 2’- fluoro and 2’-O-methyl modified purines. In some embodiments, 2’-O-methyl includes 2’-O-methyl.

[0098] In some embodiments, pyrimidines of the oligonucleotide comprise 2’ -fluoro modified pyrimidines. In some embodiments, pyrimidines of the oligonucleotide comprise 2’-O-methyl modified pyrimidines. In some embodiments, pyrimidines of the oligonucleotide comprise a mixture of 2’ -fluoro and 2’-O-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’-O-methyl modified pyrimidines. In some embodiments, all pyrimidines of the oligonucleotide comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines.

[0099] In some embodiments, purines of the oligonucleotide comprise 2 ’-fluoro modified purines, and pyrimidines of the oligonucleotide comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines. In some embodiments, purines of the oligonucleotide comprise 2’-O-methyl modified purines, and pyrimidines of the oligonucleotide comprise a mixture of 2’ -fluoro and 2’-O-methyl modified pyrimidines. In some embodiments, purines of the oligonucleotide comprise 2’ -fluoro modified purines, and pyrimidines of the oligonucleotide comprise 2’-O-methyl modified pyrimidines. In some embodiments, purines of the oligonucleotide comprise 2’-O-methyl modified purines, and pyrimidines of the oligonucleotide comprise 2’ -fluoro modified pyrimidines. In some embodiments, pyrimidines of the oligonucleotide comprise 2’-fluoro modified pyrimidines, and purines of the oligonucleotide comprise amixture of 2’-fluoro and 2’-O-methyl modified purines. In some embodiments, pyrimidines of the oligonucleotide comprise 2’-O-methyl modified pyrimidines, and purines of the oligonucleotide comprise a mixture of 2’ -fluoro and 2’ -O-methyl modified purines.In some embodiments, pyrimidines of the oligonucleotide comprise 2’ -fluoro modified pyrimidines, and purines of the oligonucleotide comprise 2’-O-methyl modified purines. In some embodiments, pyrimidines of the oligonucleotide comprise 2’-O-methyl modified pyrimidines, and purines of the oligonucleotide comprise 2’ -fluoro modified purines.[OOlOOJIn 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’-O-methyl modified pyrimidines. In some embodiments, all purines of the oligonucleotide comprise 2’-O-methyl modified purines, and all pyrimidines of the oligonucleotide comprise a mixture of 2’ -fluoro and 2’-O-methyl modified pyrimidines. In some embodiments, all purines of the oligonucleotide comprise 2’ -fluoro modified purines, and all pyrimidines of the oligonucleotide comprise 2’-O-methyl modified pyrimidines. In some embodiments, all purines of the oligonucleotide comprise 2’-O-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’-O-methyl modified purines. In some embodiments, all pyrimidines of the oligonucleotide comprise 2’-O-methyl modified pyrimidines, and all purines of the oligonucleotide comprise a mixture of 2’ -fluoro and 2’-O-methyl modified purines. In some embodiments, all pyrimidines of the oligonucleotide comprise 2’ -fluoro modified pyrimidines, and all purines of the oligonucleotide comprise 2’-O-methyl modified purines. In some embodiments, all pyrimidines of the oligonucleotide comprise 2’-O-methyl modified pyrimidines, and all purines of the oligonucleotide comprise 2’ -fluoro modified purines.

[0101] In some cases, the oligonucleotide comprises a particular modification pattern. In some embodiments, position 9 counting from the 5’ end of the of a strand of the oligonucleotide may have a 2’F modification. In some embodiments, when position 9 of a strand of the oligonucleotide is a pyrimidine, then all purines in a strand of the oligonucleotide have a 2’OMe modification. In some embodiments, when position 9 is the only pyrimidine between positions 5 and 11 of the sense stand, then position 9 is the only position with a 2’F modification in a strand of the oligonucleotide. In some embodiments, when position 9 and only one other base between positions 5 and 11 of a strand of the oligonucleotide are pyrimidines, then both of these pyrimidines are the only two positions with a 2’F modification in a strand of the oligonucleotide. In some embodiments, when position 9 and only two other bases between positions 5 and 11 of a strand of the oligonucleotide are pyrimidines, and those two other pyrimidines are in adjacent positions so that there would be not three 2’F modifications in a row, then any combination of 2’F modifications can be made that give three 2’F modifications in total. In some embodiments, when there are more than 2 pyrimidines between positions 5 and 11 of a strand of the oligonucleotide, then all combinations of pyrimidines having the 2’F modification are allowed that have three to five 2’F modifications in total, provided that a strand of the oligonucleotide does not have three 2’F modifications in a row. In some cases, a strand of the oligonucleotide of anyof the siRNAs comprises a modification patern which conforms to any or all of these a strand of the oligonucleotide rules.

[0102] In some embodiments, when position 9 of a strand of the oligonucleotide is a purine, then all purines in a strand of the oligonucleotide have a 2’0Me modification. In some embodiments, when position 9 is the only purine between positions 5 and 11 of the sense stand, then position 9 is the only position with a 2’F modification in a strand of the oligonucleotide. In some embodiments, when position 9 and only one other base between positions 5 and 11 of a strand of the oligonucleotide are purines, then both of these purines are the only two positions with a 2’F modification in a strand of the oligonucleotide. In some embodiments, when position 9 and only two other bases between positions 5 and 11 of a strand of the oligonucleotide are purines, and those two other purines are in adjacent positions so that there would be not three 2’ F modifications in a row, then any combination of 2’F modifications can be made that give three 2’F modifications in total. In some embodiments, when there are more than 2 purines between positions 5 and 11 of a strand of the oligonucleotide, then all combinations of purines having the 2’F modification are allowed that have three to five 2’F modifications in total, provided that a strand of the oligonucleotide does not have three 2’F modifications in a row. In some cases, a strand of the oligonucleotide of any of the siRNAs comprises a modification pattern which conforms to any or all of these a strand of the oligonucleotide rules.

[0103] In some cases, position 9 of a strand of the oligonucleotide can be a 2’deoxy. In these cases, 2’F and 2’0Me modifications may occur at the other positions of a strand of the oligonucleotide. In some cases, a strand of the oligonucleotide of any of the siRNAs comprises a modification pattern which conforms to these a strand of the oligonucleotide rules.

[0104] In some embodiments, position nine of the sense strand comprises a 2’-fluoro-modified pyrimidine. In some embodiments, all purines of the sense strand comprise 2’-O-methyl modified purines. In some embodiments, 1, 2, 3, 4, or 5 pyrimidines between positions 5 and 11 comprise a 2’- fluoro-modified pyrimidine, provided there are not three 2’ -fluoro- modified pyrimidines in a row. In some embodiments, the odd-numbered positions of the antisense strand comprise 2’-O-methyl modified nucleotides. In some embodiments, the even-numbered positions of the antisense strand comprise 2’-fluoro-modified nucleotides and unmodified deoxyribonucleotide. In some embodiments, the even-numbered positions of the antisense strand comprise 2’-fluoro-modified nucleotides, 2’-O- methyl modified nucleotides and unmodified deoxyribonucleotide. In some embodiments, position nine of the sense strand comprises a 2’-fluoro-modified pyrimidine; all purines of the sense strand comprises 2’-O-methyl modified purines; 1, 2, 3, 4, or 5 pyrimidines between positions 5 and 11 comprise a 2’-fluoro-modified pyrimidine, provided there are not three 2’-fluoro-modified pyrimidines in a row; the odd-numbered positions of the antisense strand comprise 2’ -O-methyl modified nucleotides; and the even-numbered positions of the antisense strand comprise 2’-fluoro- modified nucleotides and unmodified deoxyribonucleotides.

[0105] In some embodiments, position nine of the sense strand comprises a 2’-fluoro-modified purine. In some embodiments, all pyrimidines of the sense strand comprise 2’-O-methyl modified purines. In some embodiments, 1, 2, 3, 4, or 5 purines between positions 5 and 11 comprise a 2’- fluoro-modified purine, provided there are not three 2’-fluoro-modified purine in a row. In some embodiments, the odd-numbered positions of the antisense strand comprise 2’ -O-methyl modified nucleotides. In some embodiments, the even-numbered positions of the antisense strand comprise 2’- fluoro-modified nucleotides and unmodified deoxyribonucleotide. In some embodiments, the even- numbered positions of the antisense strand comprise 2’-fluoro-modified nucleotides, 2’ -O-methyl modified nucleotides and unmodified deoxyribonucleotide. In some embodiments, position nine of the sense strand comprises a 2’-fluoro-modified purine; all pyrimidine of the sense strand comprises 2’- O-methyl modified pyrimidines; 1, 2, 3, 4, or 5 purines between positions 5 and 11 comprise a 2’- fluoro-modified purines, provided there are not three 2’-fluoro-modified purines in a row; the odd- numbered positions of the antisense strand comprise 2’ -O-methyl modified nucleotides; and the even- numbered positions of the antisense strand comprise 2’-fluoro-modified nucleotides and unmodified deoxyribonucleotides. In some embodiments, there are not three 2’-fluoro-modified purines in a row. In some embodiments, there are not three 2’-fluoro-modified pyrimidines in a row.

[0106] In some embodiments, position nine of the sense strand comprises an unmodified deoxyribonucleotide. In some embodiments, positions 5, 7, and 8 of the sense strand comprise 2’ - fluoro-modifed nucleotides. In some embodiments, all pyrimidines in positions 10 to 21 of the sense strand comprise 2’ -O-methyl modified pyrimidines and all purines in positions 10 to 21 of the comprise 2’ -O-methyl modified purines or 2’-fluoro-modified purines. In some embodiments, the odd-numbered positions of the antisense strand comprise 2’ -O-methyl modified nucleotides. In some embodiments, the even-numbered positions of the antisense strand comprise 2’ -fluoro-modified nucleotides and unmodified deoxyribonucleotides. In some embodiments, the even-numbered positions of the antisense strand comprise 2’ -fluoro-modified nucleotides, 2’ -O-methyl modified nucleotides and unmodified deoxyribonucleotides. In some embodiments, position nine of the sense strand comprises an unmodified deoxyribonucleotide; positions 5, 7, and 8 of the sense strand comprise 2’-fluoro-modifed nucleotides; all pyrimidines in positions 10 to 21 of the sense strand comprise 2’-O-methyl modified pyrimidines and all purines in positions 10 to 21 of the comprise 2’ - O-methyl modified purines or 2 ’-fluoro-modified purines; the odd-numbered positions of the antisense strand comprise 2’ -O-methyl modified nucleotides; and the even-numbered positions of the antisense strand comprise 2’ -fluoro-modified nucleotides and unmodified deoxyribonucleotides.

[0107] In some embodiments, position nine of the sense strand comprises an unmodified deoxyribonucleotide. In some embodiments, positions 5, 7, and 8 of the sense strand comprise 2’- fluoro-modifed nucleotides. In some embodiments, all purines in positions 10 to 21 of the sense strand comprise 2’-O-methyl modified purines and all pyrimidines in positions 10 to 21 of the comprise 2’ - O-methyl modified pyrimidines or 2 ’-fluoro-modified pyrimidines. In some embodiments, the odd-numbered positions of the antisense strand comprise 2’-O-methyl modified nucleotides. In some embodiments, the even-numbered positions of the antisense strand comprise 2’-fluoro-modified nucleotides and unmodified deoxyribonucleotides. In some embodiments, the even-numbered positions of the antisense strand comprise 2’-fluoro-modified nucleotides, 2’-O-methyl modified nucleotides and unmodified deoxyribonucleotides. In some embodiments, position nine of the sense strand comprises an unmodified deoxyribonucleotide; positions 5, 7, and 8 of the sense strand comprise 2’-fluoro-modifed nucleotides; all purines in positions 10 to 21 of the sense strand comprise 2’-O-methyl modified purines and all pyrimidines in positions 10 to 21 of the comprise 2’ -O-methyl modified pyrimidines or 2’-fluoro-modified pyrimidines; the odd-numbered positions of the antisense strand comprise 2’ -O-methyl modified nucleotides; and the even-numbered positions of the antisense strand comprise 2’-fluoro-modified nucleotides and unmodified deoxyribonucleotide.

[0108] In some embodiments, the moiety includes a negatively charged group attached at a 5’ end of the oligonucleotide. This may be referred to as a 5 ’ -end group. In some embodiments, the negatively charged group is attached at a 5’ end of an antisense strand of an siRNA disclosed herein. The 5’ -end group may be or include a 5 ’-end phosphorothioate, 5 ’-end phosphorodithioate, 5 ’-end vinylphosphonate (5 ’-VP), 5 ’-end methylphosphonate, 5 ’-end cyclopropyl phosphonate, or a 5’- deoxy-5’-C-malonyl. The 5’-end group may comprise 5’-VP. In some embodiments, the 5’-VP comprises a trans- vinylphosphonate or cis- vinylphosphonate. The 5 ’-end group may include an extra 5’ phosphate. A combination of 5 ’-end groups may be used.

[0109] In some embodiments, the oligonucleotide includes a negatively charged group. The negatively charged group may aid in cell or tissue penetration. The negatively charged group may be attached at a 5’ or 3’ end (e.g., a 5’ end) of the oligonucleotide. This may be referred to as an end group. The end group may be or include a phosphorothioate, phosphorodithioate, vinylphosphonate, methylphosphonate, cyclopropyl phosphonate, or a deoxy-C-malonyl. The end group may include an extra 5’ phosphate such as an extra 5’ phosphate. A combination of end groups may be used. [OOllOJIn some embodiments, the oligonucleotide includes a phosphate mimic. In some embodiments, the phosphate mimic comprises vinyl phosphonate. In some embodiments, the vinyl phosphonate comprises a trans- vinylphosphonate. In some embodiments, the vinyl phosphonate comprises a cis- vinylphosphonate. An example of a nucleotide that includes a vinyl phosphonate is shown below.5’ vinylphosphonate 2’-0 Methyl Uridine[OOlllJIn some embodiments, the vinyl phosphonate increases the stability of the oligonucleotide. In some embodiments, the vinyl phosphonate increases the accumulation of the oligonucleotide in tissues. In some embodiments, the vinyl phosphonate protects the oligonucleotide from an exonuclease or a phosphatase. In some embodiments, the vinyl phosphonate improves the binding affinity of the oligonucleotide with the siRNA processing machinery.

[0112] In some embodiments, the oligonucleotide includes 1 vinyl phosphonate. In some embodiments, the oligonucleotide includes 2 vinyl phosphonates. In some embodiments, the oligonucleotide includes 3 vinyl phosphonates. In some embodiments, the oligonucleotide includes 4 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.1. Hydrophobic moieties

[0113] In some embodiments, the composition comprises an oligonucleotide that inhibits or reduces the expression of HGFAC, wherein the oligonucleotide comprises a hydrophobic moiety. The hydrophobic moiety may be attached at a 3’ or 5’ terminus of the oligonucleotide. The hydrophobic moiety may include a lipid such as a fatty acid. The hydrophobic moiety may include a hydrocarbon. The hydrocarbon may be linear. The hydrocarbon may be non-linear. The hydrophobic moiety may include a lipid moiety or a cholesterol moiety, or a combination thereof.

[0114] In some embodiments, the composition comprises an oligonucleotide that inhibits or reduces the expression of HGFAC, wherein the oligonucleotide comprises a lipid attached at a 3’ or 5’ terminus of the oligonucleotide. In some embodiments, the lipid comprises cholesterol, myristoyl, palmitoyl, stearoyl, lithocholoyl, docosanoyl, docosahexaenoyl, myristyl, palmityl, stearyl, or a- tocopherol, or a combination thereof.

[0115] In some embodiments, the composition comprises an oligonucleotide that inhibits or reduces the expression of HGFAC, wherein the oligonucleotide comprises a hydrophobic ligand or moiety. Insome embodiments, the hydrophobic ligand or moiety comprises cholesterol. In some embodiments, the hydrophobic ligand or moiety comprises a cholesterol derivative. In some embodiments, the hydrophobic ligand or moiety is attached at a 3’ terminus of the oligonucleotide. In some embodiments, the hydrophobic ligand or moiety s attached at a 5’ terminus of the oligonucleotide. In some embodiments, the composition comprises a sense strand, and the hydrophobic ligand or moiety is attached to the sense strand (e.g., attached to a 5’ end of the sense strand, or attached to a 3’ end of the sense strand). In some embodiments, the composition comprises an antisense strand, and the hydrophobic ligand or moiety is attached to the antisense strand (e.g., attached to a 5’ end of the antisense strand, or attached to a 3’ end of the antisense strand). In some embodiments, the composition comprises a hydrophobic ligand or moiety attached at a 3’ or 5’ terminus of the oligonucleotide.

[0116] In some embodiments, a hydrophobic moiety is attached to the oligonucleotide (e.g., a sense strand and / or an antisense strand of a siRNA). In some embodiments, a hydrophobic moiety is attached at a 3’ terminus of the oligonucleotide. In some embodiments, a hydrophobic moiety is attached at a 5’ terminus of the oligonucleotide. In some embodiments, the hydrophobic moiety comprises cholesterol. In some embodiments, the hydrophobic moiety includes a cyclohexanyl.

[0117] In some embodiments, the composition comprises an oligonucleotide that inhibits or reduces the expression of HGFAC, wherein the oligonucleotide comprises a lipid attached at a 3’ or 5’ terminus of the oligonucleotide. In some embodiments, a lipid is attached at a 3’ terminus of the oligonucleotide. In some embodiments, a lipid is attached at a 5’ terminus of the oligonucleotide. In some embodiments, the lipid comprises cholesterol, myristoyl, palmitoyl, stearoyl, lithocholoyl, docosanoyl, docosahexaenoyl, myristyl, palmityl, stearyl, or a-tocopherol, or a combination thereof. In some embodiments, the lipid comprises stearyl, lithocholyl, docosanyl, docosahexaenyl, or myristyl. In some embodiments, the lipid comprises cholesterol. In some embodiments, the lipid includes 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.

[0118] In some embodiments, the oligonucleotide comprises any aspect of the following structure:. In some embodiments, the oligonucleotide comprises anyaspect of the following structure:. In some embodiments, the oligonucleotide comprises any aspect of the following structure:. In some embodiments, the oligonucleotide comprises any aspect of the following structure.The aspect included in the oligonucleotide may include the entire structure, or may include the lipid moiety, 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 aforementioned numbers of carbons. In some embodiments, the alkyl group contains 4-18 carbons. In some embodiments, the lipid moiety comprises an alcohol or ether.

[0119] In some embodiments, the lipid includes a fatty acid. In some embodiments, the lipid comprises a lipid depicted in Table IB. The example lipid moieties in Table IB are shown attached at a 5’ end of an oligonucleotide, in which the 5’ terminal phosphate of the oligonucleotide is shown with the lipid moiety. In some embodiments, a lipid moiety in Table IB may be attached at a different point of attachment than shown. For example, the point of attachment of any of the lipid moieties in the table may be at a 3’ oligonucleotide end. In some embodiments, the lipid is used for targeting the oligonucleotide to a non-hepatic cell or tissue.Table IB. Hydrophobic moiety examples

[0120] In some embodiments, the lipid or lipid moiety includes 16 to 18 carbons. In some embodiments, the lipid includes 16 carbons. In some embodiments, the lipid includes 17 carbons. In some embodiments, the lipid includes 18 carbons. In some embodiments, the lipid moiety includes 16 carbons. In some embodiments, the lipid moiety includes 17 carbons. In some embodiments, the lipid moiety includes 18 carbons.

[0121] The hydrophobic moiety may include a linker that comprises a carbocycle. The carbocycle may be six-membered. Some examples of a carbocycle include phenyl or cyclohexyl. The linker may include a phenyl. The linker may include a cyclohexyl. The lipid may be attached to the carbocycle, which may in turn be attached at a phosphate (e. g. , 5 ’ or 3 ’ phosphate) of the oligonucleotide. In some embodiments, the lipid or hydrocarbon, and the end of the sense are connected to the phenyl or cyclohexyl linker in the 1,4; 1,3; or 1,2 substitution pattern (e.g., the para, meta, or ortho phenyl configuration). In some embodiments, the lipid or hydrocarbon, and the end of the sense are connected to the phenyl or cyclohexyl linker in the 1,4- substitution pattern (e.g., the para phenyl configuration). The lipid may be attached to the carbocycle in the 1,4- substitution pattern relative to the oligonucleotide. The lipid may be attached to the carbocycle in the 1,3 -substitution pattern relative to the oligonucleotide. The lipid may be attached to the carbocycle in the 1,2-substitution pattern relative to the oligonucleotide. The lipid may be attached to the carbocycle in the ortho orientation relative to the oligonucleotide. The lipid may be attached to the carbocycle in the para orientation relative to the oligonucleotide. The lipid may be attached to the carbocycle in the meta orientation relative to the oligonucleotide.

[0122] The lipid moiety may comprise or consist of the following structuresome embodiments, the lipid moiety comprises or consists of the following structure.. In some embodiments, the lipid moiety comprises the following structure:consist of the following structure:In some embodiments, the dotted line indicates a covalent connection. The covalent connection may between an end of the sense or antisense strand. For example, the connection may be to the 5’ end of the sense strand. In some embodiments, n is 0-3. In some embodiments, n is 1-3. 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, Ris 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 aforementioned numbers of carbons. In some embodiments, R comprises or consists of an alkyl group containing 4-18 carbons.

[0123] The lipid moiety may be attached at a 5’ end of the oligonucleotide. The 5’ end may have one phosphate linking the lipid moiety to a 5’ carbon of a sugar of the oligonucleotide. The 5’ end may have two phosphates linking the lipid moiety to a 5’ carbon of a sugar of the oligonucleotide. The 5’ end may have three phosphates linking the lipid moiety to a 5’ carbon of a sugar of the oligonucleotide. The 5’ end may have one phosphate connected to the 5’ carbon of a sugar of theoligonucleotide, where the one phosphate is connected to the lipid moiety. The 5’ end may have two phosphates connected to the 5’ carbon of a sugar of the oligonucleotide, where the one of the two phosphates is connected to the lipid moiety. The 5’ end may have three phosphates connected to the 5’ carbon of a sugar of the oligonucleotide, where the one of the three phosphates is connected to the lipid moiety. The sugar may include a ribose. The sugar may include a deoxyribose. The sugar may be modified a such as a 2’ -modified sugar (e. g., a 2’ -O-methyl or 2’ -fluoro ribose). A phosphate of the 5’ end may include a modification such as a sulfur in place of an oxygen. Two phosphates of the 5’ end may include a modification such as a sulfur in place of an oxygen. Three phosphates of the 5’ end may include a modification such as a sulfur in place of an oxygen.

[0124] In some embodiments, the oligonucleotide includes 1 lipid moiety. In some embodiments, the oligonucleotide includes 2 lipid moieties. In some embodiments, the oligonucleotide includes 3 lipid moieties. In some embodiments, the oligonucleotide includes 4 lipid moieties.

[0125] Some embodiments relate to a method of making an oligonucleotide comprising a hydrophobic conjugate. A strategy for making hydrophobic conjugates may include use of a phosphorami dite reagent based upon a 6-membered ring alcohol such as a phenol or cyclohexanol. The phosphoramidite may be reacted to a nucleotide to connect the nucleotide to the hydrophobic moiety, and thereby produce the hydrophobic conjugate. Some examples of phosphoramidite reagents that may be used to produce a hydrophobic conjugate are provided as follows:or. 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, Ris 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 aforementioned numbers of carbons. In some embodiments, R comprises or consists of an alkyl group containing 4-18 carbons. Any one of the phosphorami dite reagents may be reacted to a 5’ end of an oligonucleotide to produce an oligonucleotide comprising a hydrophobic moiety. In some embodiments, the phosphorami dite reagents is reacted to a 5’ end of a sense strand of an siRNA. The sense strand may then be hybridized to an antisense strand to form a duplex. The hybridization may be performed by incubating the sense and antisense strands in solution at a given temperature. The temperature may be gradually reduced. The temperature may comprise or include a temperature comprising an annealing temperature for the sense and antisense strands. The temperature may be below or include a temperature below the annealing temperature for the sense and antisense strands. The temperature may be below a melting temperature of the sense and antisense strands.

[0126] The lipid may be attached to the oligonucleotide by a linker. The linker may include a polyethyleneglycol (e.g., tetraethyleneglycol).

[0127] The modifications described herein may be useful for delivery to a cell or tissue, for example, extrahepatic delivery or targeting of an oligonucleotide composition. The modifications described herein may be useful for targeting an oligonucleotide composition to a cell or tissue.2. Sugar moieties

[0128] In some embodiments, the composition comprises an oligonucleotide that inhibits or reduces the expression of HGFAC, wherein the oligonucleotide comprises a sugar moiety. The sugar moiety may include an N-acetyl galactose moiety (e.g., an N-acetylgalactosamine (GalNAc) moiety), an N- acetyl glucose moiety (e.g., an N-acetylglucosamine (GlcNAc) moiety), a fucose moiety, or a mannose moiety. The sugar moiety may include 1, 2, 3, or more sugar molecules. The sugar moiety may be attached at a 3’ or 5’ terminus of the oligonucleotide. The sugar moiety may include an N- acetyl galactose moiety. The sugar moiety may include an N-acetylgalactosamine (GalNAc) moiety. The sugar moiety may include an N-acetyl glucose moiety. The sugar moiety may include N- acetylglucosamine (GlcNAc) moiety. The sugar moiety may include a fucose moiety. The sugarmoiety may include a mannose moiety. N-acetyl glucose, GlcNAc, fucose, or mannose may be useful for targeting macrophages when they target or bind a mannose receptor such as CD206. The sugar moiety may be useful for binding or targeting an asialoglycoprotein receptor such as an asialoglycoprotein receptor of a hepatocyte. The GalNAc moiety may bind to an asialoglycoprotein receptor. The GalNAc moiety may target a hepatocyte.

[0129] In some embodiments, the composition comprises an oligonucleotide that inhibits or reduces the expression of HGFAC, wherein the oligonucleotide comprises an N-acetylgalactosamine (GalNAc) moiety. GalNAc may be useful for hepatocyte targeting. The GalNAc moiety may include a bivalent or trivalent branched linker. The oligo may be attached to 1, 2 or 3 GalNAcs through a bivalent or trivalent branched linker. The GalNAc moiety may include 1, 2, 3, or more GalNAc molecules. The GalNAc moiety may be attached at a 3’ or 5’ terminus of the oligonucleotide.

[0130] In some embodiments, the composition comprises an oligonucleotide that inhibits or reduces the expression of HGFAC, wherein the oligonucleotide comprises an N-acetylgalactosamine (GalNAc) ligand for hepatocyte targeting. In some embodiments, the composition comprises GalNAc. In some embodiments, the composition comprises a GalNAc derivative. In some embodiments, the GalNAc ligand is attached at a 3’ terminus of the oligonucleotide. In some embodiments, the GalNAc ligand is attached at a 5’ terminus of the oligonucleotide. In some embodiments, the composition comprises a sense strand, and the GalNAc ligand is attached to the sense strand (e.g., attached to a 5’ end of the sense strand, or attached to a 3’ end of the sense strand). In some embodiments, the composition comprises an antisense strand, and the GalNAc ligand is attached to the antisense strand (e.g., attached to a 5’ end of the antisense strand, or attached to a 3’ end of the antisense strand). In some embodiments, the composition comprises a GalNAc ligand attached at a 3’ or 5’ terminus of the oligonucleotide.

[0131] Disclosed herein, in some embodiments, are compositions comprising an oligonucleotide that inhibits or reduces the expression of HGFAC, wherein the oligonucleotide comprises a GalNAc moiety. The GalNAc moiety may be included in any formula, structure, or GalNAc moiety shown below. In some embodiments, described herein is a compound (e.g., oligonucleotide) represented by Formula (I) or (II):(II); or a salt thereof, whereinJ is an oligonucleotide; each w is independently selected from any value from 1 to 20; each v is independently selected from any value from 1 to 20; n is selected from any value from 1 to 20; m is selected from any value from 1 to 20; z is selected from any value from 1 to 3, wherein if z is 3, Y is C if z is 2, Y is CR6, or if z is 1, Y is C(R6)2;Q is selected from:C3-10 carbocycle optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, -OR7, -SR7, -N(R7>2, -C(O)R7, -C(O)N(R7)2, -N(R7)C(O)R7, - N(R7)C(O)N(R7)2, -OC(O)N(R7)2, -N(R7)C(O)OR7, -C(O)OR7, -OC(O)R7, -S(O)R7, and Ci-6alkyl, wherein the C1-6alkyl, is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, and -NH2;R1is a linker selected from:-O-, -S-, -N(R7)-, -C(O)-, -C(O)N(R7)-, -N(R7)C(O)- -N(R7)C(O)N(R7)-, -OC(O)N(R7)-, -N(R7)C(O)O-, -C(O)O-, -OC(O)-, -S(O)-, -S(O>-, -OS(O)2-, -OPCOXOR7)©-, -SP(O)(OR7)O-, - OP(S)(OR7)O-, -OP(O)(SR7)O-. -OP(O)(OR7)S-, -OP(O)(O )O-, -SP(O)(Q-)O-, -OP(S)(O )O-, - OP(O)(S )O-, -OP(O)(O )S-, -OP(O)(OR7)NR7-, -OP(O)(N(R7)2)NR7-, -OP(OR7)O-, - OP(N(R7)2)O-, -OP(OR7)N(R7)-, and -OPN(R7)2NR7-; each R2is independently selected from:C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR7, -SR7, -N(R7)2, -C(O)R7, -C(O)N(R7)2, -N(R7)C(O)R7-N(R7)C(O)N(R7)2, - OC(O)N(R7)2, -N(R7)C(O)OR7, -C(O)OR7, -OC(O)R7, and -S(O)R7;R3and R4are each independently selected from:-OR7, -SR7, -N(R7)2, -C(O)R7, -C(O)N(R7)2, -N(R7)C(O)R7, -N(R7)C(O)N(R7)2, - OC(O)N(R7)2, -N(R7)C(O)OR7, -C(O)OR7, -OC(O)R7, and -S(O)R7; each R5is independently selected from:-OC(O)R7, -OC(O)N(R7)2, -N(R7)C(O)R7, -N(R7)C(O)N(R7)2, -N(R7)C(O)OR7, -C(O)R7, -C(O)OR7, and -C(O)N(R7)2; each R6is independently selected from: hydrogen; halogen, -CN, -NO2, -OR7, -SR7, -N(R7)2, -C(O)R7, -C(O)N(R7)2, -N(R7)C(O)R7, - N(R7)C(O)N(R7)2, -OC(O)N(R7)2, -N(R7)C(O)OR7, -C(O)OR7, -OC(O)R7, and -S(O)R7; and Ci -6 alkyl optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, -OR7, -SR7, -N(R7)2, -C(O)R7, -C(O)N(R7)2, -N(R7)C(O)R7, - N(R7)C(O)N(R7)2, -OC(O)N(R7)2, -N(R7)C(O)OR7, -C(O)OR7, -OC(O)R7, and -S(O)R7; each R7is independently selected from: hydrogen; C1-6alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =0, =S, -O-C1-6alkyl, -S-C1-6alkyl, -N(C1-6alkyl)2, -NH(C1-6alkyl), C3-10 carbocycle, and 3- to 10- membered heterocycle; andC3-10 carbocycle, and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, - NO2, -NH2, =0, =S, -O-C1-6alkyl, -S-C1-6alkyl, -N(C1-6alkyl^, -NH(C1-6alkyl), C1-6alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, 3- to 10-membered heterocycle, and Ci-ehaloalkyl.

[0132] 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 C5-6 carbocycle optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, -OR7, -SR7, -N(R7)2, -C(O)R7, -C(O)N(R7)2, -N(R7)C(O)R7, -N(R7)C(O)N(R7)2, -OC(O)N(R7)2, -N(R7)C(O)OR7, -C(O)OR7, - OC(O)R7, and -S(O)R7. In some embodiments, Q is selected from C5-6 carbocycle 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 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, R1is selected from -OP(O)(OR7)O-. -SP(O)(OR7)O- , -OP(S)(OR7)O-, -OP(O)(SR7)O-, -OP(O)(OR7)S-, -OP(O)(O )O-, -SP(O)(O )O-, -OP(S)(O )O-, -OP(O)(S )O-, -OP(O)(O)S-, -OP(O)(OR7)NR7-, -OP(O)(N(R7)2)NR7-, -OPCOR7)O-, -OP(N(R7)2)O-, - OP(OR7)N(R7)-, and -OPN(R7)2NR7. In some embodiments, R1is selected from -OP(O)(OR7)O-, - SP(O)(OR7)O-, -OP(S)(OR7)O-, -OP(O)(SR7)O-, -OP(O)(OR7)S-, -OP(O)(O )O-, -SP(O)(O )O-, - OP(S)(O )O-, -OP(O)(S )O-, -OP(O)(O )S-, and -OP(OR7)O-. In some embodiments, R1is selected from -OP(O)(OR7)O-, -OP(S)(OR7)O-, -OP(O)(O )O-, -OP(S)(O )O-, -OP(O)(S )O-, and -OP(OR7)O- In some embodiments, R1is selected from -OP(O)(OR7)O- and -OP(OR7)O-. In some embodiments, R2is selected from C1-3 alkyl substituted with one or more substituents independently selected from halogen, -OR7, -OC(O)R7, -SR7, -N(R7X, -C(O)R7, and -S(O)R7. In some embodiments, R2is selected from Ci -3 alkyl substituted with one or more substituents independently selected from -OR7, - OC(O)R7, -SR7, and -N(R7)2. In some embodiments, R2is selected from C1-3 alkyl substituted with one or more substituents independently selected from -OR7and -OC(O)R7. In some embodiments, R3is selected from halogen, -OR7, -SR7, -N(R7)2. -C(O)R7, -OC(O)R7, and -S(O)R7. In some embodiments, R3is selected from -OR7-SR7, -OC(O)R7, and -N(R7)2. In some embodiments, R3is selected from - OR7- and -OC(O)R7. In some embodiments, R4is selected from halogen, -OR7, -SR7, -N(R7)2, -C(O)R7, -OC(O)R7, and -S(O)R7. In some embodiments, R4is selected from -OR7-SR7, - OC(O)R7, and -N(R7)2.In some embodiments, R4is selected from -OR7- and -OC(O)R7. In some embodiments, R5is selected from -OC(O)R7, -OC(O)N(R7)2, -N(R7)C(O)R7-N(R7)C(O)N(R7)2, and - N(R7)C(O)OR7. In some embodiments, R5is selected from -OC(O)R7and -N(R7)C(O)R7. In some embodiments, each R7is independently selected from: hydrogen; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =0, =S, -O-C1-6alkyl, -S-C1-6alkyl, -N(C1-6alkyl)2, -NH(C1-6alkyl), C3-10 carbocycle, or 3- to 10- membered heterocycle. In some embodiments, each R7is independently selected from C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -N02, -NH2, =0, =S, -O-C1-6alkyl, -S-C1-6alkyl, -N(C1-6alkyl)2, and -NH(C1-6alkyl). In some embodiments, each R7is independently selected from C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, and -SH. 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 optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -N02. -NH2, and C1.3 alkyl; R1is selected from -OP(O)(OR7)O-, -OP(S)(OR7)O-, -0P(0)(0 )0-, -OP(S)(Q- )0-, -OP(O)(S )O-, and -OP(OR7)O-; R2is Ci alkyl substituted with -OH or -0C(0)CH3;R3is -OH or -OC(O)CH3; R4is -OH or -OC(O)CH3; and R5is -NH(0)CH3. In some embodiments, the

[0133] In some embodiments, the oligonucleotide (J) is attached at a 5’ end or a 3’ end of the oligonucleotide. In some embodiments, the oligonucleotide comprises DNA. In some embodiments, the oligonucleotide comprises RNA. In some embodiments, the oligonucleotide comprises one or more modified intemucleoside linkages. In some embodiments, the one or more modified internucleoside linkages comprise alkylphosphonate, phosphorothioate, methylphosphonate, phosphor odi thioate, alkylphosphonothioate, phosphoramidate, carbamate, carbonate, phosphate triester, acetamidate, or carboxymethyl ester, or a combination thereof. In some embodiments, the oligonucleotide comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 modified internucleoside linkages. In some embodiments, the compound binds to an asialoglycoprotein receptor. In some embodiments, the compound targets a hepatocyte.

[0134] Some embodiments include the following, where J is the oligonucleotide:J may include one or more additional phosphates, or one or more phosphorothioates linking tooligonucleotide. J may include one or more additional phosphates linking to the oligonucleotide, may include one or more phosphorothioates linking to the oligonucleotide.

[0135] Some embodiments include the following, where J is the oligonucleotide:J may include one or more additional phosphates, or one or more phosphorothioates linking to theoligonucleotide. J may include one or more additional phosphates linking to the oligonucleotide. J may include one or more phosphorothioates linking to the oligonucleotide.

[0136] Some embodiments include the following, where J is the oligonucleotide:J may include one or more phosphates or phosphorothioates linking to the oligonucleotide. J may include one or more phosphates linking to the oligonucleotide. J may include a phosphate linking to the oligonucleotide. J may include one or more phosphorothioates linking to the oligonucleotide. J may include a phosphorothioate linking to the oligonucleotide.

[0137] Some embodiments include the following, where J is the oligonucleotide:The structure in this compound attached to the oligonucleotide (J) is an example of a GalNAc moiety. J may include one or more phosphates or phosphorothioates linking to the oligonucleotide. J may include one or more phosphates linking to the oligonucleotide. J may include a phosphate linking to the oligonucleotide. J may include one or more phosphorothioates linking to the oligonucleotide. J may include a phosphorothioate linking to the oligonucleotide.

[0138] Some embodiments include the following, where the phosphate or “5”’ indicates a connection to the oligonucleotide:

[0139] Some embodiments include the following, where the phosphate or “5”’ indicates a connection to the oligonucleotide:

[0140] Some embodiments include the following, where J is the oligonucleotide:include one or more phosphates or phosphorothioates linking to the oligonucleotide. J may include one or more phosphates linking to the oligonucleotide. J may include a phosphate linking to the oligonucleotide. J may include one or more phosphorothioates linking to the oligonucleotide. J may include a phosphorothioate linking to the oligonucleotide.

[0141] Some embodiments include the following, where J is the oligonucleotide:The structure in this compound attached to the oligonucleotide (J) may be referred to as “ETL1,” and is an example of a GalNAc moiety. J may include one or more phosphates or phosphorothioates linking to the oligonucleotide. J may include one or more phosphates linking to the oligonucleotide. J may include a phosphate linking to the oligonucleotide. J may include one or more phosphorothioates linking to the oligonucleotide. J may include a phosphorothioate linking to the oligonucleotide

[0142] Some embodiments include the following, where J is the oligonucleotide:include one or more additional phosphates, or one or more phosphorothioates linking to theoligonucleotide. J may include one or more additional phosphates linking to the oligonucleotide. J may include one or more phosphorothioates linking to the oligonucleotide.

[0143] Some embodiments include the following, where J is the oligonucleotide:J may include one or more additional phosphates, or one or more phosphorothioates linking to the oligonucleotide. J may include one or more additional phosphates linking to the oligonucleotide. J may include one or more phosphorothioates linking to the oligonucleotide.

[0144] Some embodiments include the following, where J is the oligonucleotide:may include one or more phosphates or phosphorothioates linking to the oligonucleotide. J may include one or more phosphates linking to the oligonucleotide. J may include a phosphate linking to the oligonucleotide. J may include one or more phosphorothioates linking to the oligonucleotide. J may include a phosphorothioate linking to the oligonucleotide.

[0145] Some embodiments include the following, where J is the oligonucleotide:The structure in this compound attached to the oligonucleotide (J) may be referred to as “ETL17,” andis an example of a GalNAc moiety. J may include one or more phosphates or phosphorothioates linking to the oligonucleotide. J may include one or more phosphates linking to the oligonucleotide. J may include a phosphate linking to the oligonucleotide. J may include one or more phosphorothioates linking to the oligonucleotide. J may include a phosphorothioate linking to the oligonucleotide.

[0146] Disclosed herein, in some embodiments, are compositions comprising an oligonucleotide that inhibits or reduces the expression of a target gene, wherein the oligonucleotide comprises a GalNAc moiety. The GalNAc moiety may be included in any formula, structure, or GalNAc moiety shown below. In some embodiments, described herein is a compound (e.g., oligonucleotide) represented by Formula (III), (IV), or (V):Formula III,Formula V, or a salt thereof, whereinJ is an oligonucleotide; each w is independently selected from any value from 0 to 20; v is independently selected from any value from 0 to 20; each n is selected from any value from 0 to 20; each m is selected from any value from 0 to 20;each p is selected from any value from 0 to 1; each w is selected from any value from 0 to 20; t is selected from any value from 0 to 1; x is selected from any value from 0 to 1; r is selected from any value from 0 to 20; u is selected from any value from 0 to 20;Q is selected from: C3-20 cyclic, heterocyclic or acyclic linker optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, -OR7, -SR7, -N(R7)2, -C(O)R7, - C(O)N(R7)2, -N(R7)C(O)R7, -N(R7)C(O)N(R7)2, -OC(O)N(R7)2, -N(R7)C(O)OR7, -C(O)OR7, - OC(O)R7, -S(O)R7, and C1-6alkyl, wherein the C1-6alkyl, is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, and -NH2;R1is a linker selected from: -O-, -S-, -N(R7)-, -C(O)-, -C(O)N(R7)-, -N(R7)C(O)-, - N(R7)C(O)N(R7)-, -OC(O)N(R7)-, -N(R7)C(O)O-, -C(O)O-, -OC(O)-, -S(O)-, -S(O)2-, -OS(O)2-, - OP(O)(OR7)O-, -SP(O)(OR7)O-, -OP(S)(OR7)O-, -OP(O)(SR7)O-, -OP(O)(OR7)S-, -OP(O)(O )O-, - SP(O)(O-)O-, -OP(S)(O-)O-, -OP(O)(S-)O-, -OP(O)(O-)S-, -OP(O)(OR7)NR7-, -OP(O)(N(R7)2)NR7-, - OP(OR7)O-, -OP(N(R7)2)O-, -OP(OR7)N(R7)-, and -OPN(R7)2NR7-; each R7is independently selected from: hydrogen, C1-6alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =0, =S, -O-C1-6alkyl, -S-C1-6alkyl, -N(CI-6alkyl)2, -NH(Ci^ alkyl), C3- 10 carbocycle, and 3- to 10-membered heterocycle, C3-10 carbocycle, and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =0, =S, -O-C1-6alkyl, -S-C1-6alkyl, -N(C1-6alkyl)2, -NH(C1-6alkyl), C1-6alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, 3- to 10-membered heterocycle, and C 1 -6 haloalky 1.

[0147] Provided herein are sugar moieties comprising the following structure, where J is an oligonucleotide:

[0148] The structure in this compound attached to the oligonucleotide (J) in some instances is referred to as “L96,” and is an example of a GalNAc moiety. J in some instances comprises one or more phosphates or phosphor othi oates linking to the oligonucleotide. J in some instances comprises one or more phosphates linking to the oligonucleotide. J in some instances comprises a phosphate linking to the oligonucleotide. J in some instances comprises one or more phosphorothi oates linking to the oligonucleotide. J in some instances comprises a phosphorothi oate linking to the oligonucleotide.

[0149] Provided herein are sugar moieties comprising the following structure, where J is an oligonucleotide:

[0150] The structure in this compound attached to the oligonucleotide (J) in some instances is referred to as “NAG37,” and is an example of a GalNAc moiety. J in some instances comprises one or more phosphates or phosphor othi oates linking to the oligonucleotide. J in some instances comprises one or more phosphates linking to the oligonucleotide. J in some instances comprises a phosphate linking to the oligonucleotide. J in some instances comprises one or more phosphorothi oates linking to the oligonucleotide. J in some instances comprises a phosphorothi oate linking to the oligonucleotide. Provided herein are sugar moieties comprising the following structure, where J is an oligonucleotide:The structure in this compound attached to the oligonucleotide (J) in some instances is referred to as “GluGalNAc,” and is an example of a GalNAc moiety. J in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. J in some instances comprises one or more phosphates linking to the oligonucleotide. J in some instances comprises a phosphate linking to the oligonucleotide. J in some instances comprises one or more phosphorothioates linking to the oligonucleotide. J in some instances comprises a phosphorothioate linking to the oligonucleotide.

[0151] Provided herein are sugar moieties comprising the following structure, where J and K are independently H, a GalNAc moiety or oligonucleotides:

[0152] The structures in these compounds in some instances are attached to the oligonucleotide (J or K) and referred to as “ademA GalNAc, ademG GalNAc, ademC GalNAc, or ademU GalNAc” depending on the base used in the nucleotide. In some instances, 2-4 GalNAc moi eties are attached to the oligonucleotide. The placement of the GalNAc moieties in some instances is at the 3 or 5’ ends (J or K = H) or internal (J and K are oligonucleotides) of the oligonucleotide strand. J and K may in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. J and K in some instances comprises one or more phosphates linking to the oligonucleotide. J and K in some instances comprises a phosphate linking to the oligonucleotide. J and K in some instances comprises one or more phosphorothioates linking to the oligonucleotide. J and K in some instances comprises a phosphorothioate linking to the oligonucleotide.

[0153] Provided herein are sugar moieties comprising the following structure, where R is an oligonucleotide:

[0154] The structure in this compound attached to the oligonucleotide (R) in some instances is referred to as Hl, H2, H3, H4, H5, H6, H7, or H9, and are examples of GalNAc moieties. R in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. R in some instances comprises one or more phosphates linking to the oligonucleotide. R in some instances comprises a phosphate linking to the oligonucleotide. R in some instances comprises one or more phosphorothioates linking to the oligonucleotide. R in some instances comprises a phosphorothioate linking to the oligonucleotide.

[0155] Provided herein are sugar moieties comprising the following structure, where J is an oligonucleotide:The structure in this compound attached to the oligonucleotide (J) may be referred to as ”K2GalN Ac.' and is an example of a GalNAc moiety. J in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. J in some instances comprises one or more phosphates linking to the oligonucleotide. J in some instances comprises a phosphate linking to the oligonucleotide. J in some instances comprises one or more phosphorothioates linking to the oligonucleotide. J in some instances comprises a phosphorothioate linking to the oligonucleotide.

[0156] Provided herein are sugar moieties comprising the following structure, where J is an oligonucleotide and X is S or O:. The structure in this compound attached to the oligonucleotide (J) in some instances is referred to as “ST23,” and is an example of a GalNAc moiety. J in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. J in some instances comprises one or more phosphates linking to the oligonucleotide. J in some instances comprises a phosphate linking to theoligonucleotide. J in some instances comprises one or more phosphorothioates linking to the oligonucleotide. J in some instances comprises a phosphorothioate linking to the oligonucleotide.

[0157] Provided herein are sugar moieties comprising the following structure, where J is an oligonucleotide:. The structure in this compound attached to the oligonucleotide (J) in some instances is referred to as “GalNAc23,” and is an example of a GalNAc moiety. J in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. J in some instances comprises one or more phosphates linking to the oligonucleotide. J in some instances comprises a phosphate linking to the oligonucleotide. J in some instances comprises one or more phosphorothioates linking to the oligonucleotide. J in some instances comprises a phosphorothioate linking to the oligonucleotide.

[0158] Provided herein are sugar moieties comprising the following structure, where J or K comprises an oligonucleotide:

[0159] The structures in these compounds in some instances are attached to the oligonucleotide (J or K), referred to as “PyrGalNAc”, “PipGalNAc” and “TEG-GalNAc” are examples of GalNAc moieties. In some instances, 2-4 GalNAc moieties are attached oligonucleotide. The placement of the GalNAc moieties may be at the 3 or 5 ’ ends (J or K = H) or internal (J and K are oligonucleotides) of the oligonucleotide strand. J and K in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. J and K in some instances comprises one or more phosphates linking to the oligonucleotide. J and K in some instances comprises a phosphate linking to the oligonucleotide. J and K in some instances comprises one or more phosphorothioates linking to the oligonucleotide. J and K in some instances comprises a phosphorothioate linking to the oligonucleotide.

[0160] Provided herein are sugar moieties comprising the following structure, where J is an oligonucleotide:

[0161] The structure in this compound attached to the oligonucleotide (J) in some instances is referred to as “THA,” and is an example of a GalNAc moiety. J in some instances comprises one or more phosphates or phosphor othi oates linking to the oligonucleotide. J in some instances comprises one or more phosphates linking to the oligonucleotide. J in some instances comprises a phosphate linking to the oligonucleotide. J in some instances comprises one or more phosphorothi oates linking to the oligonucleotide. J in some instances comprises a phosphorothi oate linking to the oligonucleotide.

[0162] Provided herein are sugar moieties comprising the following structure, where Nu is an oligonucleotide:

[0163] The structure in this compound attached to the oligonucleotide (Nu) in some instances is referred to as “L-9” and is an example of a GalNAc moiety. Nu in some instances comprises one ormore phosphates or phosphorothioates linking to the oligonucleotide. Nu in some instances comprises one or more phosphates linking to the oligonucleotide. Nu in some instances comprises a phosphate linking to the oligonucleotide. Nu in some instances comprises one or more phosphorothioates linking to the oligonucleotide. Nu in some instances comprises a phosphorothioate linking to the oligonucleotide.

[0164] Provided herein are sugar moieties comprising the following structure, where J is an oligonucleotide:

[0165] The structure in this compound attached to the oligonucleotide (J) in some instances is referred to as “Sirius GalNAc,” and is an example of a GalNAc moiety. J in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. J in some instances comprises one or more phosphates linking to the oligonucleotide. J in some instances comprises a phosphate linking to the oligonucleotide. J in some instances comprises one or more phosphorothioates linking to the oligonucleotide. J in some instances comprises a phosphor othioate linking to the oligonucleotide.

[0166] Provided herein are sugar moieties comprising the following structures, where J is an oligonucleotide:

[0167] The structures in this compound attached to the oligonucleotide (J) in some instances are referred to as GLS-5 and GLS-15 and are examples of GalNAc moieties. J in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. J in some instances comprises one or more phosphates linking to the oligonucleotide. J in some instances comprises a phosphate linking to the oligonucleotide. J in some instances comprises one or more phosphorothioates linking to the oligonucleotide. J in some instances comprises a phosphorothioate linking to the oligonucleotide.

[0168] Provided herein are sugar moieties comprising the following structure, where J is an oligonucleotide:

[0169] The structure in this compound attached to the oligonucleotide (J) in some instances is referred to as “Olix GalNAc,” and is an example of a GalNAc moiety. J in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. J in some instances comprises one or more phosphates linking to the oligonucleotide. J in some instances comprises a phosphate linking to the oligonucleotide. J in some instances comprises one or more phosphorothioates linking to the oligonucleotide. J in some instances comprises a phosphorothioate linking to the oligonucleotide.

[0170] Provided herein are sugar moieties comprising the following structure, where J and J’ is an oligonucleotide or a GalNAc moiety:

[0171] The structure in this compound attached to the oligonucleotide or a GalNAc moiety (J or J’) in some instances is referred to as “GalNAc Gib,” and is an example of a GalNAc moiety. J or J’ in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. J or J’ in some instances comprises one or more phosphates linking to the oligonucleotide. J or J’ in some instances comprises a phosphate linking to the oligonucleotide. J or J’ in some instances comprises one or more phosphorothioates linking to the oligonucleotide. J or J’ in some instances comprises a phosphorothioate linking to the oligonucleotide.

[0172] Provided herein are sugar moieties comprising the following structure, where B is a nucleic acid base, and J and J’ is an oligonucleotide or a GalNAc moiety:

[0173] The structure in this compound attached to the oligonucleotide or a GalNAc moiety (J or J’) in some instances is referred to as “lgT3,” and is an example of a GalNAc moiety. J or J’ in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. J or J’ in some instances comprises one or more phosphates linking to the oligonucleotide. J or J’ in some instances comprises a phosphate linking to the oligonucleotide. J or J’ in some instances comprises one or more phosphorothioates linking to the oligonucleotide. J or J’ in some instances comprises a phosphorothioate linking to the oligonucleotide.

[0174] Provided herein are sugar moieties comprising the following structure, where J is an oligonucleotide and X is an optional linker:The structure in this compound attached to the oligonucleotide (J) in some instances is referred to as “5gn2c6,” and is an example of a GalNAc moiety. J in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. J in some instances comprises one or more phosphates linking to the oligonucleotide. J in some instances comprises a phosphate linking to the oligonucleotide. J in some instances comprises one or more phosphorothioates linking to the oligonucleotide. J in some instances comprises a phosphorothioate linking to the oligonucleotide. X is a carbon or heteroatom linker to J. In some instances, the heteroatom in linker X is an N or O.

[0175] Provided herein are sugar moieties comprising the following structure, where J is an oligonucleotide:The structure in this compound attached to the oligonucleotide (J) in some instances is referred to as “[Gal-6]s[Gal-6]s[Gal-6],” and is an example of a GalNAc moiety. J in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. J in some instances comprises one or more phosphates linking to the oligonucleotide. J in some instances comprises a phosphate linking to the oligonucleotide. J in some instances comprises one or more phosphorothioates linking to the oligonucleotide. J in some instances comprises a phosphorothioate linking to the oligonucleotide.

[0176] Provided herein are sugar moieties comprising the following structure, where J is an oligonucleotide:The structure in this compound attached to the oligonucleotide (J) in some instances is referred to as “Janssen,” and is an example of a GalNAc moiety. J in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. J in some instances comprises one or more phosphates linking to the oligonucleotide. J in some instances comprises a phosphate linking to the oligonucleotide. J in some instances comprises one or more phosphorothioates linking to the oligonucleotide. J in some instances comprises a phosphorothioate linking to the oligonucleotide.

[0177] Provided herein are sugar moieties comprising the following structure, where J is an oligonucleotide:The structure in this compound attached to the oligonucleotide (J) in some instances is referred to as “Arbutus,” and is an example of a GalNAc moiety. J in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. J in some instances comprises one or more phosphates linking to the oligonucleotide. J in some instances comprises a phosphate linking to the oligonucleotide. J in some instances comprises one or more phosphorothioates linking to the oligonucleotide. J in some instances comprises a phosphorothioate linking to the oligonucleotide

[0178] Provided herein are sugar moieties comprising the following structure, where J is an oligonucleotide; Y is C, N or O; R is F, H, OH or NHCOCH3; and X is an optional linker:The structure in this compound attached to the oligonucleotide (J) in some instances is referred to as “Hepagenel,” and is an example of a GalNAc moiety. J in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. J in some instances comprises one or more phosphates linking to the oligonucleotide. J in some instances comprises a phosphate linking to the oligonucleotide. J in some instances comprises one or more phosphorothioates linking to the oligonucleotide. J in some instances comprises a phosphorothioate linking to the oligonucleotide. X is a carbon or heteroatom linker to J. In some instances, the heteroatom in linker X is an N or O.

[0179] Provided herein are sugar moieties comprising the following structure, where J is an oligonucleotide; Y is C, N or O; R is F, H, OH or NHCOCH3; and X is an optional linker:The structure in this compound attached to the oligonucleotide (J) in some instances is referred to as “Hepagene2,” and is an example of a GalNAc moiety. J in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. J in some instances comprises one or more phosphates linking to the oligonucleotide. J in some instances comprises a phosphate linking to the oligonucleotide. J in some instances comprises one or more phosphorothioates linking to the oligonucleotide. J in some instances comprises a phosphorothioate linking to the oligonucleotide. X is a carbon or heteroatom linker to J. In some instances, the heteroatom in linker X is an N or O.

[0180] Provided herein are sugar moieties comprising the following structure, where J is an oligonucleotide; Y is C, N or O; R and R’ are independently F, H, OH or NHCOCH3; and X is an optional linker:The structure in this compound attached to the oligonucleotide (J) in some instances is referred to as “Hepagene3,” and is an example of a GalNAc moiety. J in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. J in some instances comprises one or more phosphates linking to the oligonucleotide. J in some instances comprises a phosphate linking to the oligonucleotide. J in some instances comprises one or more phosphorothioates linking to the oligonucleotide. J in some instances comprises a phosphorothioate linking to the oligonucleotide. X is a carbon or heteroatom linker to J. In some instances, the heteroatom in linker X is an N or O.

[0181] Provided herein are sugar moieties comprising the following structure, where J is an oligonucleotide; Y is C, N or O; R is F, H, OH or NHCOCH3; and X is an optional linker:The structure in this compound attached to the oligonucleotide (J) in some instances is referred to as “Hepagene4,” and is an example of a GalNAc moiety. J in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. J in some instances comprises one or more phosphates linking to the oligonucleotide. J in some instances comprises a phosphate linking to the oligonucleotide. J in some instances comprises one or more phosphorothioates linking to the oligonucleotide. J in some instances comprises a phosphorothioate linking to the oligonucleotide. X is a carbon or heteroatom linker to J. In some instances, the heteroatom in linker X is an N or O.3. Modified siRNAs

[0182] In some embodiments, the composition comprises an oligonucleotide that inhibits or reduces the expression of target nucleic acid, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises modification pattern IS: 5’ - NfsnNfnNfnNfNfNfnNfnNfnNfnNfnNfsnsn -3. In some embodiments, the sense strand comprises modification pattern 2S: 5'-nsnsnnNfnNfNfNfnnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 3S: 5’-nsnsnnNfnNfnNfnnnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 4S: 5’- NfsnsNfnNfnNfNfNfnNfnNfnNfnNfnNfsnsnN-moiety-3’. In some embodiments, the sense strand comprises modification pattern 5S: 5’-nsnsnnNfnNfNfNfnnnnnnnnnnsnsnN-moiety-3’. In some embodiments, the moiety in modification pattern 4S or 5S is a lipophilic moiety. In someembodiments, the moiety in modification pattern 4S or 5S is a lipid moiety. In some embodiments, the sense strand comprises modification pattern 6S: 5’-NfsnsNfnNfnNfnNfiiNfnNfhNfhNfnNfsnsn-3’. In some embodiments, the sense strand comprises modification pattern 7S: 5’- nsnsnnNfNfNfNfNfnnnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 8S: 5’-nsnsnrmNfNfNfNfnnnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 9S: 5'-nsnsnnnnNfNfNfNfnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 10S: 5’ - NfsnsnnNfnNfnNfnNfnNfnNfnNfnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 1 IS: 5’- nsnsNfnNfnNfiiNfnNfnNfiinnNfhNfsnsn-3’. In some embodiments, the sense strand comprises modification pattern 12S: 5’- NfsnsNfnNfnNfhNfnNfnnnNfhNfnNfsnsn-3’. In some embodiments, the sense strand comprises modification pattern 13S: 5’ - nsnsnnnnNfnNfnNfnNfnNfnNfnNfsnsn-3 ’ . In some embodiments, the sense strand comprises modification pattern 14S: 5’- srmnrmnNfNfNfNfiiririnnririnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 15S: 5’- snrmnNfNfNfNfNfimnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 16S: 5’- snnnnNfnNfNfdNnnnnnnnnnnsnsn-3 ’ . In some embodiments, the sense strand comprises modification pattern 17S: 5'-snnnnnN[WnNfiinnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 18S: 5'-snnnnnnNfnNfNfnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 19S: 5’- srmnnNfnNfnNfnNfnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 20S: 5’-snnnnNfnNfnNfnnnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 21 S: 5'-snnnnNIWnnN[Wnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 22S: 5' -snnnnNfnnNfNfNfNfnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 23S: 5’- snnnnnNfiiNIWnnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 24S: 5’-snnrmnrmNfNfNfNfnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 25S: 5’-snnrmnNfNfNfNfNfnnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 26S: 5’- snnnnnNfNrNrNfnnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 27S: 5’-snnnnnnnNfNfnNfnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 28S: 5’-snnnnNfNfnNfNfnNfnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 29S: 5’- snnnnnnnnNfiiNfiinnnnnnnsnsn-3 ’ . In some embodiments, the sense strand comprises modification pattern 30S: 5'-snnnnN[WnnNfiiNfnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 3 IS: 5'-snnnnNIWnN[Wnnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 32S: 5'-snnnnnnNfNfdNNfnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 33 S: 5'-snnnnNfnNfnNrNfnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 34S:5'-snnnnNfnNfNfdNNfnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 35S:5'-snnnnnnNfNfNfNfiiNfnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 36S:5'-srmnrmNfNfNfNfnNfnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 37S :5'- srmrmNfiiNfNfdTNfnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 38S:5'-snnnnNfnNfNfNfnnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 39S:5'-snnnnNfnNfNfdTnnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 40S:5'- snnnnNfnNfNfdNnNfnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 41 S: 5’- snnrmnrmnNfNfimnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 42S:5'-snnnnNfnNfNfdTnNfnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 43 S: 5'- snnnnnnNfiiNfiiNfnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 44S:5'-snnnnNfnNfNfNfNfnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 45S:5'-snnnnnNfimNfWnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 46S:5'-srmnrmnNfNfNfNfNfnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 47S:5'- snnnnnNfWnNfiiNfiinnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 48S :5'- nnNfnNfnNfnNfnNfnNfnnnNfnNfsnsn-3'. In some embodiments, the sense strand comprises modification pattern 49S:5'- NfnNfnNfnNfNfNfnNfnNfnNfnNfnNfsnsn-3'. In some embodiments, the sense strand comprises modification pattern 50S :5'- nnrmnNfNfNfNfNfimnnnrinrinsnsn-3'. In some embodiments, the sense strand comprises modification pattern 51 S :5'- nrmnNfNfNfNfNfiinnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 52S:5'-snnnnmnNfNfNfNfnnnnnnmnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 53S :5'- snnnnmnNfNfNfNfnnnnnmnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 54S:5'-snrmnrnnNfNfNfNfnnnnrnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 55S:5'-snnnnmnNrNfNrNfnnnmnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 56S :5'- snnnnnmNfNfNfNfnnnmnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 57S:5'-snrmrmmNfNfNfNfnnnnrnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 58S : 5'- nnnnmnNfNfNrNfnnnnmnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 59S :5'- snsnnnnNfNfNfNfNfnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 60S:5'- srmrmrnnnNfNfNfNfiinnmnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 61 S :5'- snnrmmNfiiNfNfNfNfnrinrnrinririnnsnsn-3'. Insome embodiments, the sense strand comprises modification pattern 62S:5'- snnnnmnNfNfNfNfnnnnmnnnninsnsn-3'. In some embodiments, the sense strand comprises modification pattern 63S :5'- snnnnmnNfNfNfNfnnnnmnninnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 64S:5'- rmrmmrmNfNfNfNlhnnrnrinrinrinsnsn-3'. In some embodiments, the sense strand comprises modification pattern 65S :5'- nsnsnnmnN(C 16)NfNfNfnnnnmnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 66S: 5'-nnnnnnnnNfNfnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 67S: 5'-nnnnNfnNfNfdNNfnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 68S: 5'- nnnnnnnNfNfnNfnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 69S: 5'-nnnnnNfnnNfnNfnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 70S: 5'-nnnnnNfnNfNfnnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 71S: 5'-nnnnnNfnNfNfnNfnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 72S: 5'- nnnnnnNfnNfNfnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 73S: 5'-nnnnNfnNfnNfnnnnnnnnnnsnsn-3. In some embodiments, the sense strand comprises modification pattern 74S: 5'-nnnnNfNfnnNfnnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 75S: 5'-nnnnNfnnnNfnNfnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 76S: 5'- nnnnNfNfnnNfnNfnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 77S: 5'-nnnnnnNfnNfnNfnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 78S: 5'-nnnnnNfNfnNfnNfnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 79S: 5'-nnnnnNfNfNfNfnnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 80S: 5'- nnnnnNfNfNfNfnNfnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 81S: 5'-nnnnNNnnNfWnnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 82S: 5'-nnnnNfnnNfNfnNfnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 83S: 5'-nnnnNfnNfnNfnNfnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 84S: 5'- nnnnNfNfnNfNfnnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 85S: 5'-nnnnNfNfnNfNfnNfnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 86S: 5'-nnnnnnnNfNfNfNfnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 87S: 5'-nnnnnnNfNfNfNfnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 88S: 5'- nnnnnnNfNfNfNfNfnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 89S: 5'-nnnnnNfnnNfWnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 90S: 5'-nnnnnNfnNfNfNfNfnnnnnnnnsnsn-3'. In some embodiments, the sensestrand comprises modification patern 91S: 5'-nnnnnNfNfnNfNfnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification patern 92S: 5'- nnrmNfimnNfNfimnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification patern 93S: 5'-nrmnNfrinNfNfNfNfnririnririnnsnsn-3'. In some embodiments, the sense strand comprises modification patern 94S: 5'-nnnnNfnNfnNfNfnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 95S: 5'-nnnnNfnNfNfNfNfnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification patern 96S: 5'- nnrmNfNfimNfNfimnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification patern 97S: 5'-nrmnrmnNfNfimnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification patern 98S: 5'-nnnnNfnNfNfdNnnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 99S: 5'-nnnnnnnnNfnNfnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification patern 100S: 5'- nnnnNfnNfNfdTnNfnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification patern 101 S: 5'-nnnnNfnNfNfdNnNfnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 102S: 5'-nnnnNfnNfWdTnnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 103S: 5'-snnnnnNfnNfWnNfnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification patern 104S: 5'- snnnnNfWnnNfnnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification patern 105S: 5'-snrmnNfimNfNfnNfnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 106S: 5'-snnnnNfnnNfWnnnnnnnnnnsnsnm-3'. In some embodiments, the sense strand comprises modification pattern 107S: 5'-snnnnNfnnnNfWnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification patern 108S: 5’- snNfnNfnNfnNfNfnnnnnNfnNfNfnsnsn-3 ’ . . In some embodiments, the sense strand comprises modification patern 109S: 5’- snrmrmmNfNfNfNfimnnnmnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 110S: 5'-nnnnnNfWnNfnnnnnnnnnnsnsn-3' In some embodiments, the sense strand comprises modification patern 11 IS: 5’ - NfsnNfnNfnNfnNfnNfnNfnNfnNfnNfsnsn-3’. In some embodiments, the sense strand comprises modification patern 112S: 5’-NfnNfnNfnNfnNfnNfnNfnNfnNfnNfsnsn-3’. In some embodiments, the sense strand comprises modification pattern 113S: 5' - nnnnnnNfnNfnnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification patern 114S: 5’ - snnnnmnNPNfN fN fnnmnnnnnnnnsnsn -3 ’ . In some embodiments, the sense strand comprises modification patern 115S: 5’- nNfnNfnNfnNfNfnnnnnNfnNfNfnsnsn-3’. In all the above modification patern, wherever they occur, “Nf” is a 2’ -fluoro-modified nucleoside, “n” is a 2’-O- methyl modified nucleoside, “s” is a phosphorothioate or phosphate linkage, “dN” is a 2’ -deoxymodified nucleoside or a 2’ -deoxy nucleoside, “nm” is a 2’ -O-methoxy ethyl modified nucleoside, “i” is an inosine, “ni” is a 2’-O-methyl inosine nucleoside, N(C16) is 2’-O-hexadecate modification and N comprises one or more nucleosides. In some modifications N(C16) is a 2'-O-hexadecyl adenylate.

[0183] In some embodiments, the composition comprises an oligonucleotide that inhibits or reduces the expression of HGFAC, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the antisense strand comprises modification pattern IAS: 5’ - nsNfsnNfnNfnNfnNfnnnNfnNfnNfnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 2AS: 5'-nsNfsnnnNfnNfNfnnnnNfnNfnnnsnsn-3'. In some embodiments, the antisense strand comprises modification pattern 3 AS: 5’-nsNfsnnnNfnnnnnnnNfnNfnnnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 4AS: 5’- nsNfsnNfnNfnnnnnnnNfnNfnnnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 5 AS: 5'-nsNfsnnnnnnnnnnnNfnNfnnnsnsn-3'. In some embodiments, the antisense strand comprises modification pattern 6AS: 5’-nsNfsnnnNfnnNfnnnnNfnNfnnnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 7 AS: 5’- nsNfsnNfnNfnNfnNfnNfnNfiiNfnNfnsnsn-3 ’ . In some embodiments, the antisense strand comprises modification pattern 8AS: 5'-nsNfsnnnnnnnnnnnNfnnnnnsnsn-3'. In some embodiments, the antisense strand comprises modification pattern 9AS: 5’- nsNfsnnnNfnNfnnnnnNfnNfnnnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 10AS: 5’ - nsNfsnNfsnNfnNfnNfnNfnNfnNfiiNfnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern l lAS:5'-nsNfsnnnNfnNfnNfnnnNfnNfnNfnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 12AS:5'-nsNfsnnnNfnNfnNfiiNfnNfiiNfnNfnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 13 AS: 5'- nsNfsnnNfnNfnnNfnNfnNfnNfnNfnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 14AS:5'-nsNfsnnNfnNfnNfnnnnNfnNfnNfnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 15AS:5'-nsNfsnNfnnNfnNfnnnnNfnNfnNfnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 16AS:5'- nsNfsnnnNfnNfnnnNfnNfnNfnNfnsnsn-3 ’ . In some embodiments, the antisense strand comprises modification pattern 17AS:5'-nsNfsnNfnnNfimNfiiNfnNfhNfnNfnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 18AS:5'-nsNfsnNfnnNfnnNfnnnNfnNfnNfnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 19AS:5'- nsNfsnnnnNfnnNfnNfnNfnNfnNfnsnsn-3 ’ . In some embodiments, the antisense strand comprises modification pattern 20AS:5'-nsNfsnnnnNfnNfnnNfnNfnNfnNfnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 21 AS:5'-nsNfsnnnnNfnNfnnnnNfnNfiiNfnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 22AS:5'- nsNfsnNfnNfnNfnnnnnNfnNfnNfnsnsn-3 ’ . In some embodiments, the antisense strand comprises modification pattern 23 AS: 5'- VPnsNfsnnnNfnNfnnnnnNfnNfnnnsnsn-3'. In some embodiments, the antisense strand comprises modification pattern 24AS:5'- VPnsNfsnNfnNfnNfnNfnNfnNfnNfnNfnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 25AS:5'- VPnsNfsnnnNfnNfnNfnNfnNfnNfnNfnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 26AS:5'-VPnsNfsnnNfnNfnnNfnNfnNfnNfnNfnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 27AS:5'- VPnsNfsnNfnnNfnNfnnnnNfnNfnNfnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 28AS: 5'-nsNfsnnNfnNfnnNfnnnNfnNfnNfnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 29AS: 5'- nsNfsnnNfnNfnnNfnnnNfnNfnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 30AS: 5'-nsNfsnnnNfnNfnNfnNfnNfnNfnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 3 IAS: 5'-nsNfsnnNfnNfnnNfnNfnNfnNfnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 32AS: 5'- nsNfsnnnNfNfnnNfnNfnNfnNfnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 33AS: 5'-nsNfsnnNfnNfNfnNfnnnNfnNfnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 34AS: 5'-nsNfsnnNfnNfNfnnnNfnNfnNfnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 35 AS: 5'- nsNfsnnnNfNfnnNfnnnNfnNfnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 36AS: 5'-nsNfsnnnnNfNfnNfnnnNfnNfnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 37AS: 5'-nsNfsnnNfn| NUNA|nnNfnnnNfnNfnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 38AS: 5'- nsNfsnnNf|NUNA|NfnnNfnnnNfnNfnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 39AS: 5'-5VPnsNfsnnNfnNfnnNfnnnNfnNfnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 40AS: 5'- 5VPnsNfsnnNfnNfnnNfnNfnNfnNfnnnsnsn-3'. In some embodiments, the antisense strand comprises modification pattern 41 AS: 5'-nnnNfnNfnNfnNfnNfnNfnNfnNfnsnsn-3'. In some embodiments, the antisense strand comprises modification pattern 42AS: 5'-nsNfsnnnNfnNfnNfnnnNfnNfnnnsnsn-3'. In some embodiments, the antisense strand comprises modification pattern 43AS: 5'- nsNfsnnnNfNfnnNfnNfnNfnNfnNfnsnsn-3'. In some embodiments, the antisense strand comprises modification pattern 44AS: 5'-nsNfsnnnNfnnnNfnnnNfnNfnNfnsnsn-3'. In some embodiments, the antisense strand comprises modification pattern 45 AS: 5'-nsNfsnnnNfNfnnNfnnnNfnNfnNfnsnsn-3'. In some embodiments, the antisense strand comprises modification pattern 46AS: 5'- nsNfsnnnnNfnnNfnnnNfnNfnnnsnsn-3'. In some embodiments, the antisense strand comprises modification pattern 47AS: 5'-nsNfsnnnnNfNfiiNfnNfhNfnNfnNfhsnsn-3'. In some embodiments, the antisense strand comprises modification pattern 48AS: 5'-nsNfsnnNfnNfNfnNfnNfnNfnNfnNfnsnsn- 3'. In some embodiments, the antisense strand comprises modification pattern 49AS: 5'- nsNfsnnNfnNfNfnnnNfnNfnNfnNfnsnsn-3'. In some embodiments, the antisense strand comprises modification pattern 50AS: 5'-nsNfsnnNfnNfnNfnnNfhNfnNfnNfhsnsn-3'. In some embodiments, the antisense strand comprises modification pattern 51 AS: 5'-nsNfsnNfnNfnNfnNfnNfnNfnNfnnnsnsn-3'. In some embodiments, the antisense strand comprises modification pattern 52AS: 5'- nsNfsnNfnNf[UNA]NfnNfnNfnNfnNfnnnsnsn-3'. In some embodiments, the antisense strand comprises modification pattern 53AS: 5'-nsNfsnnnnNfNfnNfnNfnNfnNfnnnsnsn-3'. In someembodiments, the antisense strand comprises modification pattern 54AS: 5'- nsNfsnnnnNfNfnnnNfnNfnNfnnnsnsn-3'. In some embodiments, the antisense strand comprises modification pattern 55 AS: 5'-nsNfsnnnn[UNA]NfnnnNfnNfnNfnnnsnsn-3'. In some embodiments, the antisense strand comprises modification pattern 56AS: 5’- nsnsnNfnNfnNfnNfnNfnNfnNfnNfnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 57AS: 5’-nsNfsnNfnnNfnnNfnNfnNfnnnnnsnsn 3’. In some embodiments, the antisense strand comprises modification pattern 58AS: 5’-nsNfsnnnNfnNfnNfnNfnNfnnnnnsnsn 3’. In some embodiments, the antisense strand comprises modification pattern 59AS:5’-nsNfsnNfnnNfnnnnNfnNfnNfnNfnsnsn 3 ’.In all the above modification pattern, wherever they occur, “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, “s” is a phosphorothioate or phosphate linkage, “dN” is a 2’ -deoxy-modified nucleoside or a 2’ -deoxy nucleoside, “nm” is a 2’ -O-methoxy ethyl modified nucleoside, “i” is an inosine, “ni” is a 2’ -O-methyl inosine nucleoside, N(C16) is 2’-O-hexadecate modification, VP is a 5'- vinyl phosphonate, “[NUNA]” is an unlocked nucleic acid, “[UNA]” is an unlocked nucleic acid and N comprises one or more nucleosides. In some modifications N(C16) is a 2'-O-hexadecyl adenylate.

[0184] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of HGFAC, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises pattern IS and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13AS, MAS. 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45 AS, 46 AS, 47AS, 48AS, 49AS, 50As, 5 IAS, 52AS, 53AS, 54AS 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 2S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25 AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45 AS, 46AS, 47 AS, 48AS, 49AS, 50As, 51 AS, 52AS, 53AS, 54AS 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 3S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41 AS, 42As, 43 AS, 44AS, 45AS, 46AS, 47 AS, 48AS, 49 AS, 50AS, 5 IAS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 4S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15 AS. 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25 AS, 26AS, 27 AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35 AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45AS, 46AS, 47 AS, 48AS, 49AS, 50AS, 51AS,52AS, 53AS, 54AS, 55 AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 5S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. MAS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25 AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 5 IAS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 6S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23 AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45AS, 46AS, 47 AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 7S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, I 3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49 AS, 50AS, 5 IAS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 8S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, I 3AS. 14AS, 15 AS. 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33 AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41 AS, 42As, 43 AS, 44AS, 45AS, 46AS, 47 AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 9S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25 AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 10S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, I 3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27 AS, 28AS, 29 AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41 AS, 42As, 43 AS, 44AS, 45AS, 46AS, 47 AS, 48AS, 49 AS, 50AS, 5 IAS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 1 IS and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15 AS. 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25 AS, 26AS, 27 AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35 AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45AS, 46AS, 47 AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strandcomprises pattern 12S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5 AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25 AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45AS, 46AS, 47 AS, 48AS, 49AS, 50AS, 5 IAS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 13S and the antisense strand comprises pattern IAS, 2AS, 3 AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21 AS, 22AS, 23 AS, 24AS, 25AS, 26AS, 27 AS, 28AS, 29 AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45AS, 46AS, 47 AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 14S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, I 3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49 AS, 50AS, 5 IAS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 15S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, I 3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41 AS, 42As, 43 AS, 44AS, 45AS, 46AS, 47 AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 16S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 17S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, I 3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27 AS, 28AS, 29 AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41 AS, 42As, 43 AS, 44AS, 45AS, 46AS, 47 AS, 48AS, 49 AS, 50AS, 5 IAS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 18S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25 AS, 26AS, 27 AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35 AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45AS, 46AS, 47 AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 19S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS,7 AS, 8AS, 9AS, 10AS, HAS, 12AS, 13AS, MAS, 15 AS. 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25 AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 5 IAS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 20S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21 AS, 22AS, 23 AS, 24AS, 25AS, 26AS, 27 AS, 28AS, 29 AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45AS, 46AS, 47 AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 21 S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, I 3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49 AS, 50AS, 5 IAS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 22S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33 AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41 AS, 42As, 43 AS, 44AS, 45AS, 46AS, 47 AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 23S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23 AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 24S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, I 3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27 AS, 28AS, 29 AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41 AS, 42As, 43 AS, 44AS, 45AS, 46AS, 47 AS, 48AS, 49 AS, 50AS, 5 IAS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 25S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25 AS, 26AS, 27 AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35 AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41 AS, 42As, 43 AS, 44AS, 45AS, 46AS, 47 AS, 48AS, 49 AS, 50AS, 5 IAS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 26S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15 AS. 16AS, 17AS, 18AS, 19AS, 20AS, 21AS,22AS, 23AS, 24AS, 25 AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 5 IAS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 27S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21 AS, 22AS, 23 AS, 24AS, 25AS, 26AS, 27 AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45AS, 46AS, 47 AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 28S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, I 3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49 AS, 50AS, 5 IAS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 29S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, I 3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33 AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41 AS, 42As, 43 AS, 44AS, 45AS, 46AS, 47 AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 30S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45 AS, 46AS, 47AS, 48AS, 49AS, 50AS, 5 IAS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 31S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, I 3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25 AS, 26AS, 27 AS, 28AS, 29 AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41 AS, 42As, 43 AS, 44AS, 45AS, 46AS, 47 AS, 48AS, 49 AS, 50AS, 5 IAS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 32S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25 AS, 26AS, 27 AS, 28AS, 29 AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35 AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45AS, 46AS, 47 AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 33S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25 AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS,36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 5 IAS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 34S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21 AS, 22AS, 23 AS, 24AS, 25AS, 26AS, 27 AS, 28AS, 29 AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45AS, 46AS, 47 AS, 48AS, 49 AS, 50AS, 5 IAS, 52AS, 53AS, 54AS, 55 AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 35S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, I 3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49 AS, 50AS, 5 IAS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 36S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, I 3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33 AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41 AS, 42As, 43 AS, 44AS, 45AS, 46AS, 47 AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 37S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 38S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, I 3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27 AS, 28AS, 29 AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41 AS, 42As, 43 AS, 44AS, 45AS, 46AS, 47 AS, 48AS, 49 AS, 50AS, 5 IAS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 39S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25 AS, 26AS, 27 AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35 AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41 AS, 42As, 43AS, 44AS, 45AS, 46AS, 47 AS, 48AS, 49 AS, 50AS, 5 IAS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 40S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25 AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS,50AS, 5 IAS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 41 S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5 AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27 AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45AS, 46AS, 47 AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 42S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5 AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, I 3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49 AS, 50AS, 5 IAS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 43 S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, I 3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33 AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 4 IAS, 42As, 43 AS, 44AS, 45AS, 46AS, 47 AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 44S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5 AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, I 3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43 AS, 44AS, 45 AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51 AS, 52AS, 53AS, 54AS, 55 AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 45S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, I 3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25 AS, 26AS, 27 AS, 28AS, 29 AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41 AS, 42As, 43 AS, 44AS, 45AS, 46AS, 47 AS, 48AS, 49 AS, 50AS, 5 IAS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 46S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25 AS, 26AS, 27 AS, 28AS, 29 AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35 AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45AS, 46AS, 47 AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 47S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25 AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 5 IAS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, thesense strand comprises pattern 48S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13AS, MAS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21 AS, 22AS, 23 AS, 24AS, 25AS, 26AS, 27 AS, 28AS, 29 AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45AS, 46AS, 47 AS, 48AS, 49 AS, 50AS, 5 IAS, 52AS, 53AS, 54AS, 55 AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 49S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, I 3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49 AS, 50AS, 5 IAS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 50S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, I 3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33 AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41 AS, 42As, 43 AS, 44AS, 45AS, 46AS, 47 AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 51S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 52S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, I 3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27 AS, 28AS, 29 AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41 AS, 42As, 43 AS, 44AS, 45AS, 46AS, 47 AS, 48AS, 49 AS, 50AS, 5 IAS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 53S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15 AS. 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25 AS, 26AS, 27 AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33 AS, 34AS, 35 AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45AS, 46AS, 47 AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 54S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15 AS. 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25 AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 5 IAS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 55S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS,5 AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13AS, MAS, 15 AS. 16AS, 17AS, 18AS, 19AS, 20AS, 21 AS, 22AS, 23 AS, 24AS, 25AS, 26AS, 27 AS, 28AS, 29 AS, 3OAS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45AS, 46AS, 47 AS, 48AS, 49AS, 5OAS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 56S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5 AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, I 3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49 AS, 50AS, 5 IAS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 57S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, I 3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33 AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41 AS, 42As, 43 AS, 44AS, 45AS, 46AS, 47 AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 58S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5 AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 59S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5 AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, I 3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33 AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, or 40AS. In some embodiments, the sense strand comprises pattern 60S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5 AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 61S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5 AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, I 3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27 AS, 28AS, 29 AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 62S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5 AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, I 5AS. 16AS, 17AS, 18AS, 19AS, 20AS, 21 AS, 22AS, 23AS, 24AS, 25 AS, 26AS, 27 AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35 AS, 36AS, 37AS,38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45AS, 46AS, 47 AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS.. In some embodiments, the sense strand comprises pattern 63S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5 AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25 AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 5 IAS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 64S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21 AS, 22AS, 23 AS, 24AS, 25AS, 26AS, 27 AS, 28AS, 29 AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 65S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, I 3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49 AS, 50AS, 5 IAS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 66S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, I 3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33 AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41 AS, 42As, 43 AS, 44AS, 45AS, 46AS, 47 AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 67S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, I 3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 68S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, I 3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27 AS, 28AS, 29 AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41 AS, 42As, 43 AS, 44AS, 45AS, 46AS, 47 AS, 48AS, 49 AS, 50AS, 5 IAS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 69S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25 AS, 26AS, 27 AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33 AS, 34AS, 35 AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45AS, 46AS, 47 AS, 48AS, 49AS, 50AS, 51AS,52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 70S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5 AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. MAS, 15 AS. 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25 AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 5 IAS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 71S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, I 3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21 AS, 22AS, 23 AS, 24AS, 25AS, 26AS, 27 AS, 28AS, 29 AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45AS, 46AS, 47 AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 72S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, I 3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49 AS, 50AS, 5 IAS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 73 S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, I 3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33 AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41 AS, 42As, 43 AS, 44AS, 45AS, 46AS, 47 AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 74S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, I 3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 75S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8 AS, 9AS, 10AS, HAS, 12AS, I 3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27 AS, 28AS, 29 AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43 AS, 44AS, 45AS, 46AS, 47 AS, 48AS, 49 AS, 50AS, 5 IAS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 76S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25 AS, 26AS, 27 AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35 AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45AS, 46AS, 47 AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strandcomprises pattern 77S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5 AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23 AS, 24AS, 25 AS, 26 AS, 27AS, 28AS, 29 AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35 AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 5 IAS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 78S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21 AS, 22AS, 23 AS, 24AS, 25AS, 26AS, 27 AS, 28AS, 29 AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 79S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 5 IAS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 80S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, I 3AS. 14AS, 15AS, 16AS , 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33 AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41 AS, 42As, 43 AS, 44AS, 45AS, 46AS, 47 AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 81S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, I 3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27 AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 82S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, I 3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27 AS, 28AS, 29 AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41 AS, 42As, 43 AS, 44AS, 45AS, 46AS, 47 AS, 48AS, 49 AS, 50AS, 5 IAS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 83S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25 AS, 26AS, 27 AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35 AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 84S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS,7 AS, 8AS, 9AS, 10AS, HAS, 12AS, 13AS, MAS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25 AS, 26AS, 27AS, 28AS, 29AS, 3OAS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 5OAS, 5 IAS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 85S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23 AS, 24AS, 25 AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45AS, 46AS, 47 AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 86S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, I 3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49 AS, 50AS, 5 IAS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 87S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, I 3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33 AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41 AS, 42As, 43 AS, 44AS, 45AS, 46AS, 47 AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 88S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, I 3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 89S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, I 3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27 AS, 28AS, 29 AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41 AS, 42As, 43 AS, 44AS, 45AS, 46AS, 47 AS, 48AS, 49 AS, 50AS, 5 IAS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 90S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15 AS. 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25 AS, 26AS, 27 AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33 AS, 34AS, 35 AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45AS, 46AS, 47 AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 91 S and the antisense strand comprises pattern IAS, 2AS, 3 AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15 AS. 16AS, 17AS, 18AS, 19AS, 20AS, 21AS,22AS, 23AS, 24AS, 25 AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 5 IAS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 92S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, I 3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21 AS, 22AS, 23 AS, 24AS, 25AS, 26AS, 27 AS, 28AS, 29 AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45AS, 46AS, 47 AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 93S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, I 3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49 AS, 50AS, 5 IAS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 94S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, I 3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33 AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41 AS, 42As, 43 AS, 44AS, 45AS, 46AS, 47 AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 95S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, I 3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 96S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8 AS, 9AS, 10AS, HAS, 12AS, I 3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27 AS, 28AS, 29 AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43 AS, 44AS, 45AS, 46AS, 47 AS, 48AS, 49 AS, 50AS, 5 IAS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 97S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25 AS, 26AS, 27 AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35 AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45AS, 46AS, 47 AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 98S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23 AS, 24AS, 25 AS, 26 AS, 27AS, 28AS, 29 AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35 AS,36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 5 IAS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 99S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5 AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21 AS, 22AS, 23 AS, 24AS, 25AS, 26AS, 27 AS, 28AS, 29 AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 100S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, I 3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33 AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41 AS, 42As, 43 AS, 44AS, 45AS, 46AS, 47 AS, 48AS, 49AS, 50AS, 5 IAS, 52AS, 53AS, 54AS, 55 AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 101 S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, I 3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25 AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 102S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, I 3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27 AS, 28AS, 29 AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41 AS, 42As, 43 AS, 44AS, 45AS, 46AS, 47 AS, 48AS, 49 AS, 50AS, 5 IAS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 103S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25 AS, 26AS, 27 AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35 AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45AS, 46AS, 47 AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 104S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25 AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 5 IAS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 105S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21 AS, 22AS, 23 AS, 24AS, 25AS, 26AS, 27 AS, 28AS, 29 AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45AS, 46AS, 47 AS,48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 106S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, I 3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25 AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33 AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41 AS, 42As, 43 AS, 44AS, 45AS, 46AS, 47 AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 107S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, I 3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 108S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, I 3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27 AS, 28AS, 29 AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 109S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25 AS, 26AS, 27 AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35 AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45AS, 46AS, 47 AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 110S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23 AS, 24AS, 25 AS, 26AS, 27 AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35 AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 5 IAS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 111 S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21 AS, 22AS, 23 AS, 24AS, 25AS, 26AS, 27 AS, 28AS, 29 AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45AS, 46AS, 47 AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 112S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, I 3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33 AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41 AS, 42As, 43 AS, 44AS, 45AS, 46AS, 47 AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or59AS. In some embodiments, the sense strand comprises pattern 113S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5 AS, 6AS, 7AS, 8AS, 9AS, 10AS, H AS, 12AS, 13 AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 114S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5 AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, I 3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21 AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27 AS, 28AS, 29 AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41 AS, 42As, 43 AS, 44AS, 45AS, 46AS, 47 AS, 48AS, 49 AS, 50AS, 5 IAS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 115S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5 AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25 AS, 26AS, 27 AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35 AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45AS, 46AS, 47 AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. \

[0185] In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, I IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S, 90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, or ! 15S, and the antisense strand comprises pattern IAS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, I IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S, 90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, or ! 15S, and the antisense strand comprises pattern 2AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, I IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S, 90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, or ! 15S, and the antisense strand comprises pattern 3 AS.In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, I IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S,31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S,51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S,71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S, 90S,91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 1O3S, 104S, 1O5S, 106S, 107S, 1O8S, 109S, 11OS, 111S, 112S, 113S, 114S, or 111S, and the antisense strand comprises pattern 4AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, I IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S,31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S,51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S,71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S, 90S,91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, or l l5S, and the antisense strand comprises pattern 5 AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S,31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S,51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S,71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S, 90S,91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, or l l5S, and the antisense strand comprises pattern 6AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, I IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S,31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S,51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S,71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S, 90S,91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, or l l5S, and the antisense strand comprises pattern 7 AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, I IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S,31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S,51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S,71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S, 90S,91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, or l l5S, and the antisense strand comprises pattern 8 AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S,31S, 32S, 33S, 34S. 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S,50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S,70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S,90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 1O1S, 102S, 1O3S, 104S, 1O5S, 106S, 107S,1O8S, 109S, 11OS, 111S, 112S, 113S, 114S, or 115S, and the antisense strand comprises pattern 9 AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, I IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S, 90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, or 115S, and the antisense strand comprises pattern 10AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, I IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S,30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S,50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S,70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S,90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, or 115S, and the antisense strand comprises pattern HAS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, I IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S,30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S,50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S,70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S,90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, or 115S, and the antisense strand comprises pattern 12AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, I IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S,30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S,50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S,70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S,90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, or 115S, and the antisense strand comprises pattern 13AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, I IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S,70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S, 90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 1O1S, 102S, 1O3S, 104S, 1O5S, 106S, 107S, 108S, 109S, 11OS, 111S, 112S, 113S, 114S, or 115S, and the antisense strand comprises pattern 14AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, I IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S,30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S,50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S,70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S,90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101 S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, or 115S, and the antisense strand comprises pattern 15AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, I IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S,30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S,50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S,70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S,90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, or 115S, and the antisense strand comprises pattern 16AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, I IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S,30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S,50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S,70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S,90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, or 115S, and the antisense strand comprises pattern 17AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, I IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S,30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S,50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S,70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S,90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, or 115S, and the antisense strand comprises pattern 18AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, I IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S,30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S,50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S,70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S,90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S,108S, 109S, 110S, 111S, 112S, 113S, 114S, or 115S, and the antisense strand comprises patern 19AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, I IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S,30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S,50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S,70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S,90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, or 115S, and the antisense strand comprises pattern 20AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, I IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S,30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S,50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S,70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S,90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, or 115S, and the antisense strand comprises pattern 21AS. In some embodiments, the sense strand comprises patern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, I IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S,30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S,50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S,70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S,90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, or 115S, and the antisense strand comprises pattern 22AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, I IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S,30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S,50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S,70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S,90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, or 115S, and the antisense strand comprises pattern 23AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, I IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S,30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S,50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S,70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S,90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, or 115S, and the antisense strand comprises pattern 24AS. In some embodiments, the sense strand comprises patern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S,10S, IIS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S,3OS, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S,5OS, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S,70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S,90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 1OOS, 1O1S, 102S, 1O3S, 104S, 1O5S, 106S, 107S, 1O8S, 109S, 11OS, 111S, 112S, 113S, 114S, or 115S, and the antisense strand comprises patern 25AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S , 10S, I IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S, 90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, or 115S, and the antisense strand comprises pattern 26AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, I IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S, 90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, or 115S, and the antisense strand comprises pattern 27AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, I IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S,30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S,50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S,70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S,90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, or 115S, and the antisense strand comprises pattern 28AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, I IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S, 70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S, 90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, or 115S, and the antisense strand comprises pattern 29AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, I IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S,50S, 51 S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S,70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S,90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 1O1S, 102S, 1O3S, 104S, 1O5S, 106S, 107S,1O8S, 109S, 11OS, 111S, 112S, 113S, 114S, or 115S, and the antisense strand comprises patern 30AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, I IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S,30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S,50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S,70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S,90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, or 115S, and the antisense strand comprises pattern 31AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, I IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S,30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S,50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S,70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S,90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, or 115S, and the antisense strand comprises pattern 32AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, I10, I IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S,30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S,50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S,70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S,90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101 S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, or 115S, and the antisense strand comprises pattern 33AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, I IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S,30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S,50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S,70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S,90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, or 115S, and the antisense strand comprises pattern 34AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, I IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S,30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S,50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S,70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S,90S, 91 S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 1O1S, 102S, 1O3S, 104S, 1O5S, 106S, 107S, 1O8S, 109S, 11OS, 111S, 112S, 113S, 114S, or 115S, and the antisense strand comprises patern 35AS. In some embodiments, the sense strand comprises patern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, I IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S,30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S,50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S,70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S,90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, or 115S, and the antisense strand comprises pattern 36AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, I IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S,30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S,50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S,70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S,90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, or 115S, and the antisense strand comprises pattern 37AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, I IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S,30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S,50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S,70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S,90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, or 115S, and the antisense strand comprises pattern 38AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, I IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S,30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S,50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S,70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S,90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, or 115S, and the antisense strand comprises pattern 39AS. In some embodiments, the sense strand comprises patern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, I IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S,30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S,50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S,70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S,90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, or 115S, and the antisense strand comprises pattern40AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, I IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S,30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S,50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S,70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S,90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, or 115S, and the antisense strand comprises pattern 41AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, I IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S,30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S,50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S,70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S,90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, or 115S, and the antisense strand comprises pattern 42AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, I IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S,30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S,50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S,70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S,90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, or 115S, and the antisense strand comprises pattern 43AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S , 10S, I IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S,30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S,50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S,70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S,90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, or 115S, and the antisense strand comprises pattern 44AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, I IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S,30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S,50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, 66S, 67S, 68S, 69S,70S, 71S, 72S, 73S, 74S, 75S, 76S, 77S, 78S, 79S, 80S, 81S, 82S, 83S, 84S, 85S, 86S, 87S, 88S, 89S,90S, 91S, 92S, 93S, 94S, 95S, 96S, 97S, 98S, 99S, 100S, 101S, 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S...

Claims

CLAIMSWhat is claimed is:

1. A composition comprising an siRNA that targets hepatocyte growth factor activator (HGFAC) wherein the siRNA comprises a sense strand and an antisense strand, wherein the sense strand comprises a modification pattern selected from the list consisting of 54S, 55S, 20S, 43S, 16S, 62S, 61 S, and 63 S; or the antisense strand comprises a modification pattern selected from the list consisting of 12AS, 14AS, 44AS, 45AS, 35AS, 46AS, 29AS, 47 AS, 48AS, 49 AS, 50AS, 51AS, 52AS, 53AS, 54AS, and 55AS.

2. A composition comprising an siRNA that targets HGFAC and when administered to a subject in an effective amount alters an immune cell measurement in a subject, wherein the siRNA comprises a sense strand and an antisense strand, wherein the sense strand comprises a modification pattern selected from the list consisting of 54S, 55S, 20S, 43S, 16S, 62S, 61S, and 63S ; or the antisense strand comprises a modification pattern selected from the list consisting of 12AS, 14AS, 29 AS, 35AS, 44AS, 45 AS, 46AS, 47 AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, and 55AS .

3. The composition of claim 2, wherein the immune cell measurement is altered by about 10% or more, as compared to prior to administration.

4. The composition of claim 2, wherein the immune cell measurement comprises a myeloid derived suppressor cell or subpopulation count, CD8+ tumor infiltrating lymphocyte count, leukocyte count, T lymphocyte count, activated T lymphocyte count, B lymphocyte count, activated B lymphocyte count, monocyte count, macrophage count, activated macrophage count, dendritic cell count, neutrophil count, eosinophil count, basophil count, or mast cell count.

5. A composition comprising an siRNA that targets HGFAC and when administered to a subject in an effective amount increases an antibody level in a subject, wherein the siRNA comprises a sense strand and an antisense strand, wherein the sense strand comprises a modification pattern selected from the list consisting of 54S, 55S, 20S, 43S, 16S, 62S, 61S, and 63S; or the antisense strand comprises a modification pattern selected from the list consisting of 12AS, 14AS, 29AS, 35AS, 44AS, 45 AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, and 55AS.

6. The composition of claim 5, wherein the antibody level is increased by about 10% or more, as compared to prior to administration.

7. The composition of claim 5, wherein the antibody level comprises an IgA level, IgG level, or IgM level.

8. A composition comprising an siRNA that targets HGFAC and when administered to a subject in an effective amount decreases a tumor marker level in a subject, wherein the siRNA comprises a sense strand and an antisense strand, wherein the sense strand comprises a modification pattern selected from the list consisting of 54S, 55S, 20S, 43S, 16S, 62S, 61S, and 63S; or the antisense strand comprises a modification pattern selected from the list consisting of 12AS, 14AS, 29AS, 35AS, 44AS, 45 AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, and 55AS.

9. The composition of claim 8, wherein the tumor marker level is decreased by about 10% or more, as compared to prior to administration.

10. The composition of claim 8, wherein the tumor marker comprises CEA, PSA, CA 125, CA 15-3, CA 19-9, CA 27.29, CA 72-4, AFP, hCG, B2M, BTA, Calcitonin, CgA, CELLSEARCH, DCP, Gastrin, HE4, LDH, NSE, NMP22, or PAP.

11. The composition of any one of claims 1-10, wherein the oligonucleotide comprises a modified intemucleoside linkage.

12. The composition of claim 11, wherein the modified internucleoside linkage comprises alkylphosphonate, phosphorothioate, methylphosphonate, phosphorodithioate, alkylphosphonothioate, phosphorami date, carbamate, carbonate, phosphate triester, acetamidate, or carboxymethyl ester, or a combination thereof.

13. The composition of claim 11, wherein the modified intemucleoside linkage comprises one or more phosphorothioate linkages.

14. The composition of any one of claims 1-10, 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 intemucleoside linkages.

15. The composition of any one of claims 1-10, wherein the oligonucleotide comprises a modified nucleoside.

16. The composition of claim 15, wherein the modified nucleoside comprises a locked nucleic acid (LNA), hexitol nucleic acid (HLA), cyclohexene nucleic acid (CeNA), 2'-methoxy ethyl, 2'-O-alkyl, 2'-O-allyl, 2'-O-allyl, 2'-fluoro, or 2'-deoxy, or a combination thereof.

17. The composition of claim 15, wherein the modified nucleoside comprises an LNA.

18. The composition of claim 15, wherein the modified nucleoside comprises a 2’, 4’ constrained ethyl nucleic acid.

19. The composition of claim 15, wherein the modified nucleoside comprises a 2'-O-methyl nucleoside, 2'- deoxy fluoro nucleoside, 2'-O-N-methylacetamido (2-0-NMA) nucleoside, a 2'-O- dimethylaminoethoxyethyl (2-O-DMAEOE) nucleoside, 2'-O-aminopropyl (2-O-AP) nucleoside, or 2'- ara-F, or a combination thereof.

20. The composition of claim 15, wherein the modified nucleoside comprises one or more 2’- fluoro modified nucleosides.

21. The composition of claim 15, wherein the modified nucleoside comprises a 2’-O-alkyl modified nucleoside.

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

23. The composition of any one of claims 1-10, wherein the oligonucleotide comprises a lipid attached at a 3’ or 5’ terminus of the oligonucleotide.

24. The composition of claim 23, wherein the lipid comprises cholesterol, myristoyl, palmitoyl, stearoyl, lithocholoyl, docosanoyl, docosahexaenoyl, myristyl, palmityl stearyl, or a-tocopherol, or a combination thereof.

25. The composition of any one of claims 1-10, wherein the oligonucleotide comprises a sugar moiety attached at a 3’ or 5’ terminus of the oligonucleotide.

26. The composition of claim 25, wherein the sugar comprises N-acetylgalactosamine (GalNAc), N-acetylglucosamine (GlcNAc), or mannose.

27. The composition of any one of claims 1-10, wherein the oligonucleotide comprises a small interfering RNA (siRNA) comprising a sense strand and an antisense strand.

28. The composition of claim 27, wherein the sense strand is 12-30 nucleosides in length.

29. The composition of claim 27, wherein the antisense strand is 12-30 nucleosides in length.

30. A composition comprising an oligonucleotide that inhibits the expression of HGFAC, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, each strand is independently 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 SEQ ID NO: 4803, wherein the sense strand comprises a modification pattern selected from the list consisting of 54S, 55S, 20S, 43S, 16S, 62S, 61S, and 63S; or the antisense strand comprises a modification pattern selected from the list consisting of 12AS, 14AS, 29 AS, 35AS, 44AS, 45 AS, 46AS, 47AS, 48AS, 49 AS, 50AS, 51AS, 52AS, 53AS, 54AS, and 55AS.

31. The composition of claim 27, wherein any one of the following is true with regard to the sense strand:(a) all purines comprise fluoro modified purines and all pyrimidines comprise (i) a mixture of 2’-O-methyl and 2’-O-methoxyethyl modified pyrimidines; or (ii) a mixture of 2’- fluoro, 2’-O-methyl, and 2’-O-methoxyethyl modified pyrimidines;(b) all purines comprise 2'-O-methyl modified purines and all pyrimidines comprise (i) all pyrimidines of the sense strand comprise a mixture of 2’ -fluoro and 2’-O-methoxyethyl modified pyrimidines; or (ii) a mixture of 2’ -fluoro, 2’-O-methyl, and 2’-O-methoxyethyl modified pyrimidines;(c) all purines comprise 2'-O-methoxyethyl modified purines and all pyrimidines comprise (i) a mixture of 2’ -fluoro and 2’-O-methyl modified pyrimidines; or (vii) a mixture of 2’ -fluoro, 2’-O-methyl, and 2’-O-methoxyethyl modified pyrimidines;(d) all purines comprise a mixture of 2’ -fluoro and 2'-O-methyl modified purines and all pyrimidines comprise (i) 2’-O-methoxyethyl modified pyrimidines; (ii) a mixture of 2’-O-methyl and 2’-O-methoxy ethyl modified pyrimidines; (iii) amixture of 2’-fluoro and 2’-O-methoxyethyl modified pyrimidines; or (iv) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O-methoxyethyl modified pyrimidines;(e) all purines comprise a mixture of 2’ -fluoro and 2'-O-methoxy ethyl modified purines and all pyrimidines of the sense strand comprise (i) 2’ -O-methyl modified pyrimidines; (ii) a mixture of 2’ -fluoro and 2’ -O-methyl modified pyrimidines; (iii) a mixture of 2 ’-O-methyl and 2’-O-methoxyethyl modified pyrimidines; or (iv) amixture of 2’ -fluoro, 2’ -O-methyl, and 2’-O- methoxyethyl modified pyrimidines;(f) all purines comprise a mixture of 2'-O-methyl and 2'-O-methoxy ethyl modified purines and all pyrimidines comprise (i) 2’ -fluoro modified pyrimidines; (ii) a mixture of 2’- fluoro and 2’-O-methyl modified pyrimidines; (iii) a mixture of 2’ -fluoro and 2’-O-methoxyethyl modified pyrimidines; or (iv) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O-methoxyethyl modified pyrimidines; or(g) all purines comprise a mixture of 2’ -fluoro, 2’-O-methyl, and 2’-O-methoxyethyl modified purines and all pyrimidines comprise (i) 2’-fluoro modified pyrimidines; (ii) 2’-O- methyl modified pyrimidines; (iii) 2’ -O-methox ethyl modified pyrimidines; (iv) a mixture of 2’ - fluoro and 2’-O-methyl modified pyrimidines; (v) a mixture of 2’-O-methyl and 2’-O- methoxy ethyl modified pyrimidines; (vi) a mixture of 2’-fluoro and 2’ -O-methoxy ethyl modified pyrimidines; or (vii) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O-methoxyethyl modified pyrimidines; with the proviso that in any of the foregoing, the sense strand may include a 2’ -deoxy nucleoside.

32. The composition of claim 27, wherein any one of the following is true with regard to the antisense strand: all purines comprise 2’ -fluoro modified purines, and all pyrimidines comprise a mixture of 2’ -fluoro and 2’-O-methyl modified pyrimidines; all purines comprise 2’-O-methyl modified purines, and all pyrimidines comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; all purines comprise 2’-O-methyl modified purines, and all pyrimidines comprise 2’- fluoro modified pyrimidines; all pyrimidines comprise 2’-fluoro modified pyrimidines, and all purines comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines; all pyrimidines comprise 2’-O-methyl modified pyrimidines, and all purines comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines; or all pyrimidines comprise 2’-O-methyl modified pyrimidines, and all purines comprise 2’- fluoro modified purines.

33. The composition of any one of claims 1-10, wherein the oligonucleotide comprises an antisense oligonucleotide (ASO).

34. The composition of claim 33, wherein the ASO is 12-30 nucleosides in length.

35. A composition comprising an oligonucleotide that inhibits the expression of HGFAC, wherein the oligonucleotide comprises an ASO about 12-30 nucleosides in length and a nucleoside sequence complementary to about 12-30 contiguous nucleosides of SEQ ID NO: 4803.

36. The composition of claim 30, wherein the sense strand comprises an oligonucleotide sequence of SEQ ID NO: 4599, 4597 or 4581; and the antisense strand comprises an oligonucleotide sequence of SEQ ID NO: 4654, 4652 or 4636.

37. The composition of claim 36, whereina) the sense strand comprises modification pattern 20S, 43S, or 16S (SEQ ID NO: 4809,4558 or 4519); b) the antisense strand comprises modification pattern 14AS, 35AS, or 49AS (SEQ ID NO: 4817, 4839 or 4846); or c) both (a) and (b).

38. The composition of any one of claims 1-10, further comprising a pharmaceutically acceptable carrier.

39. A method of treating a subject having cancer, comprising administering an effective amount of the composition of any one of claims 1-10 to the subject.

40. The method of claim 39, further comprising administering a checkpoint inhibitor to the subject.

41. The method of claim 40, wherein the checkpoint inhibitor comprises a PD1 inhibitor, a PDL1 inhibitor, a CTLA4 inhibitor or a combination thereof.

42. The method of claim 39, further comprising administering radiotherapy to the subject.

43. The method of claim 39, wherein the cancer comprises a malignant neoplasm, a solid tumor, or a hematological cancer.

44. The method of claim 39, wherein the cancer comprises a malignant neoplasm of a urinary tract, malignant neoplasm of an endocrine gland, malignant neoplasm of a soft tissue, malignant neoplasm of skin, malignant neoplasm of a skeletal system, malignant neoplasm of a respiratory organ, malignant neoplasm of an intrathoracic organ, malignant neoplasm of a genital organ, malignant neoplasm of a lip, malignant neoplasm of an oral cavity, malignant neoplasm of a pharynx, malignant neoplasm of an eye, malignant neoplasm of a central nervous system, malignant neoplasm of a brain, malignant neoplasm of a digestive system, malignant neoplasm of a breast, malignant neoplasm of a pancreas, or a malignant melanoma.

45. The method of claim 39, wherein the administration improves a clinical response related to the cancer.

46. The method of claim 45, wherein the improved clinical response comprises at least a 10% increase in a clinical response measurement relative to a baseline clinical response measurement obtained from the subject prior to administration of the composition.

47. The method of claim 45, wherein the clinical response comprises progression free survival, duration of response, disease control rate, health-related quality of life, milestone survival, clinical benefit rate, pathological complete response, complete response, objective response rate, duration of clinical benefit, time to next treatment, time to treatment failure, disease-free survival, or time to cancer progression.

48. A method of treating cancer in a subject in need thereof, the method comprising administering the subject an effective amount of a composition that inhibits HGFAC.

49. The method of claim 48, wherein the composition comprises an oligonucleotide.

50. The method of claim 49, wherein the oligonucleotide comprises an siRNA.

51. A method of treating cancer in a subject in need thereof, the method comprising administering the subject an effective amount of an siRNA that targets HGFAC.

52. The method of claim 51, wherein the administration reduces a symptom or a clinical finding associated with the cancer by at least 10%.

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