Modified oligonucleotides

Abstract

Disclosed herein are compositions comprising modified oligonucleotides. In some embodiments, the oligonucleotide includes a hydrophobic moiety. In some embodiments, the oligonucleotide includes a vinyl phosphonate. In some embodiments, the oligonucleotide includes modified oligonucleotide sugars such as 2' modified ribose molecules. In some embodiments, the oligonucleotide includes modified internucleoside linkages such as phosphorothioate linkages. In some embodiments, the oligonucleotide includes an siRNA. In some embodiments, the siRNA comprises a duplex region with overhangs on either end.

Description

Attorney Docket No. 54462-758.601 MODIFIED OLIGONUCLEOTIDES CROSS-REFERENCE

[0001] This application claims the benefit of U.S. Provisional No. 63 / 582,790, filed September 14, 2023, and U.S. Provisional No. 63 / 585,542, filed September 26, 2023, all of which applications 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 54462-758_601_SL.xml, created September 1, 2024, which is 845,570 bytes in size. The information in the electronic format of the Sequence Listing is incorporated by reference in its entirety. BACKGROUND

[0003] There is a need in the art for improved oligonucleotides for reducing gene expression. BRIEF SUMMARY

[0004] Provided herein are compositions comprising: a small interfering RNA (siRNA) comprising a sense strand, an antisense strand, and a lipid moiety connected to the 5’ or 3’ end of the sense strand or antisense strand; wherein the lipid moiety comprises a phenethyl or cyclohexanyl linker, wherein the phenethyl or cyclohexanyl linker is connected to a lipid and to the end of the sense strand or antisense strand, and wherein the lipid comprises a myristyl, lauryl, or stearyl^group. Further provided herein are compositions wherein the lipid and the end of the sense or antisense strand are connected to the phenyl or cyclohexanyl linker in the 1,4; 1,3; or 1,2 substitution pattern. Further provided herein are compositions wherein the lipid and the end of the sense or antisense strand are connected to the phenyl or cyclohexanyl linker in the 1,4 substitution pattern. Further provided herein are compositions wherein thelipid moiety comprises the following structure: ; wherein the dotted line indicates a covalent connection to the end of the sense or antisense strand, with the proviso that R is not an octane. the lipid moiety comprises the followingstructure: ; wherein the dotted line indicates a covalent connection to the end of the sense or antisense strand, n is 2, and R is an alkyl group containing 4-18Attorney Docket No. 54462-758.601 carbons. her provided herein are compositions wherein the lipid moiety comprises the following structure: wherein the dotted line indicates a covalent connection to thesense or n and R is an alkyl group containing 4-18 carbons. her provided herein are compositions wherein the lipid moiety comprises the following structure:; wherein the dotted line indicates a covalent connection to the end of the sense or antisense strand, and R is an alkyl group containing 4-18 carbons. Further provided herein are compositions wherein the composition comprises the structure: ,. Further provided herein are compositions wherein the lipid moiety is connected to the 5’ end of the sense strand or antisense strand. Further provided herein are compositions wherein the lipid moiety is connected through a phosphate to the 5’ end of the sense strand or antisense strand. her provided herein are compositions wherein the lipid moiety is connected to an end of the sense strand. Further provided herein are compositions wherein the antisense strand comprises a 5’ vinyl phosphonate. Further provided herein are compositions wherein the antisense strand comprises one or two 5’ phosphorothioate linkages. Further provided herein are compositions wherein the antisense strand comprises one or two 3’ phosphorothioate linkages. Further provided herein are compositions wherein the sense strand comprises one or two 5’ phosphorothioate linkages. Further provided herein are compositions wherein the sense strand does not comprise one or twoAttorney Docket No. 54462-758.601 5’ phosphorothioate linkages. Further provided herein are compositions wherein the sense strand comprises 5’ phosphate linkages. Further provided herein are compositions wherein the sense strand comprises one or two 3’ phosphorothioate linkages. Further provided herein are compositions wherein any one of the following is true with regard to the sense strand: the sense strand comprises at least three modified nucleosides, wherein the three modifications comprises a 2’-fluoro modified nucleoside, a 2’-O- methyl modified nucleoside, and 2’-O-methoxyethyl; the sense strand comprises at least two modified nucleosides, wherein the two modifications comprises a 2’-fluoro modified nucleoside, a 2’-O-methyl modified nucleoside, and 2’-O-methoxyethyl; or the sense strand comprises at least a 2’-fluoro modified nucleoside, a 2’-O-methyl modified nucleoside, or a 2’-O-methoxyethyl; with the proviso that in any of the foregoing, the sense strand may include a 2’-deoxy nucleoside. Further provided herein are compositions 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 (ii) 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- methoxyethyl 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) 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) 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-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. Further provided herein are compositions wherein the sense strand includes the 2’-deoxy nucleoside. Further provided herein areAttorney Docket No. 54462-758.601 compositions wherein the sense strand does not include the 2’-deoxy nucleoside. Further provided herein are compositions wherein the antisense strand comprises a combination of 2’-fluoro and 2’-O-methyl modifications. Further provided herein are compositions wherein the sense strand and the antisense strand form a duplex. Further provided herein are compositions wherein the duplex comprises at least 10 base pairs, at least 11 base pairs, at least 12 base pairs, at least 13 base pairs, at least 14 base pairs, at least 15 base pairs, at least 16 base pairs, at least 17 base pairs, at least 18 base pairs, at least 19 base pairs, at least 20 base pairs, at least 21 base pairs, at least 22 base pairs, at least 23 base pairs, at least 24 base pairs, or at least 25 base pairs. Further provided herein are compositions wherein the duplex comprises 19 base pairs. Further provided herein are compositions wherein the duplex comprises a sense strand overhang. Further provided herein are compositions wherein the sense strand overhang comprises 1-4 nucleotides. Further provided herein are compositions wherein the sense strand overhang comprises 2 nucleotides. Further provided herein are compositions wherein the sense strand overhang comprises uracil. Further provided herein are compositions wherein the duplex comprises an antisense strand overhang. Further provided herein are compositions wherein the antisense strand overhang comprises 1-4 nucleotides. Further provided herein are compositions wherein the antisense strand overhang comprises 2 nucleotides. Further provided herein are compositions wherein the antisense strand overhang comprises uracil. Further provided herein are compositions wherein the 5’ end of the antisense strand comprises 3 nucleosides separated by the 2 phosphorothioate linkages. Further provided herein are compositions wherein the 3’ end of the antisense strand comprises 3 nucleosides separated by the 2 phosphorothioate linkages. Further provided herein are compositions wherein the sense strand comprises any one of modification patterns 1S- 115S. Further provided herein are compositions wherein the antisense strand comprises any one of modification patterns 1AS-59AS. Further provided herein are compositions further comprising a pharmaceutically acceptable carrier.

[0005] Provided herein are methods of treatment, comprising administering to a subject in need thereof an effective amount of a composition provided herein. Further provided herein are methods wherein the administration comprises intravenous, subcutaneous, parenteral, intramuscular, intraperitoneal, intraparenchymal, intravitreal, intracameral, subconjunctival, intrathecal, intracerebroventricular, intra-articular, intranasal, intratracheal, inhaled, or topical administration. Further provided herein are methods wherein the siRNA targets an mRNA encoding a protein that mediates a disease of the subject. Further provided herein are methods wherein the mRNA is in a tissue of the subject, the tissue comprising a liver, adipose, kidney, heart, vascular, muscle, skin, immune, airway, lung, joint, eye, brain, or spinal cord tissue.

[0006] Provided herein are methods of reducing an amount of a target RNA or protein encoded by the target RNA in a cell, comprising administering a composition provided herein to the cell, wherein the antisense strand comprises a sequence that is complementary to and binds to the RNA. Further provided herein are methods wherein the composition is administered to a subject comprising the cell. Further provided herein are methods wherein the administration comprises intravenous, subcutaneous, parenteral, intramuscular, intraperitoneal, intraparenchymal, intravitreal, intracameral, subconjunctival,Attorney Docket No. 54462-758.601 intrathecal, intracerebroventricular, intra-articular, intranasal, intratracheal, inhaled, or topical administration. Further provided herein are methods wherein the administration reduces a measurement of the target RNA or protein encoded by the RNA, by at least 10% relative to a baseline measurement or control. Further provided herein are methods wherein the cell comprises a liver, adipose, kidney, heart, vascular, muscle, skin, airway, immune, blood, connective tissue, lung, joint, eye, brain, or spinal cord cell. DETAILED DESCRIPTION

[0007] Disclosed herein, in some embodiments, are modified oligonucleotides. The modified oligonucleotide may be an siRNA that includes modifications to the ribose rings, and phosphate linkages. The modifications may be in particular patterns that maximize cell delivery, stability, and efficiency. The siRNA may also include a vinyl phosphonate and a hydrophobic group. These modifications may aid in delivery to a cell or tissue within a subject. The modified oligonucleotide may be used in a method such as a treatment method or a method of reducing gene expression.

[0008] In some embodiments, the oligonucleotide comprises a duplex consisting of 21 nucleotide single strands with base pairing between 19 of the base pairs. In some embodiments, the duplex comprises single-stranded 2 nucleotide overhangs are at the 3’ ends of each strand. One strand (antisense strand) is complementary to target mRNA. Each end of the antisense strand has one to two 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 1-2 phosphorothioates at the 3’ end. In some embodiments, there are 1 or no phosphorothioates at the 5’ end. In some embodiments, there is a hydrophobic conjugate of 12 to 25 carbons attached at the 5’ end via a phosphodiester bond. I. COMPOSITIONS

[0009] Disclosed herein, in some embodiments, are compositions comprising an oligonucleotide. In some embodiments, the composition comprises an oligonucleotide that targets a target oligonucleotide. The target oligonucleotide may include a target RNA. In some embodiments, the composition consists of an oligonucleotide that targets the target RNA. The target RNA may include a target mRNA. In some embodiments, the oligonucleotide reduces a target mRNA expression in the subject. In some embodiments, the oligonucleotide reduces target protein expression in the subject. The oligonucleotide may include an RNA duplex. The oligonucleotide may include a small interfering RNA (siRNA). The oligonucleotide may include an antisense oligonucleotide (ASO). In some embodiments, a composition 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. Some embodiments relate to use of a composition comprising an oligonucleotide, in a method of treating a disorder.

[0010] Targets may be identified by a variety of ways. In some instances, a target oligonucleotide comprises an mRNA that has expression levels that are associated with incidence of a disorder (e.g., an adipose-related, eye-related disorder, neurodegenerative disorder, etc.). In someAttorney Docket No. 54462-758.601 instances, the target oligonucleotide comprises an mRNA that is encoded by a gene that has a particular genotype associated with the disorder. Large-scale human genetic data can improve the success rate of pharmaceutical discovery and development. A Genome Wide Association Study (GWAS) may detect associations between genetic variants and traits in a population sample. A GWAS may enable better understanding of the biology of disease, and provide applicable treatments. A GWAS can utilize 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 said to be associated with disease. Association statistics that may be used in a GWAS are 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.”

[0011] 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.

[0012] 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 the therapeutic insights derived from human genetics, disease biology in patients are 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, lung or eye) and a relevant indication. Such studies may be conducted to identify specific disorder-related targets for siRNA inhibition by a composition or compound described herein. In some cases, the target may be related to a particular tissue.

[0013] Disclosed herein are compositions comprising an oligonucleotide that targets the target RNA. Where inhibition or targeting of target RNA is disclosed, it is contemplated that some embodiments may include inhibiting or targeting a target protein or target RNA. For example, by inhibiting or targeting an RNA (e.g., mRNA) encoded by the target gene using an oligonucleotide described herein, the targetAttorney Docket No. 54462-758.601 protein may be inhibited or targeted as a result of there being less production of the target protein by translation of the target RNA; or a target protein may be targeted or inhibited by an oligonucleotide that binds or interacts with a target RNA and reduces production of the target protein from the target RNA. Thus, targeting may refer to binding a target RNA and reducing target 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 target disorder by providing an oligonucleotide that targets target to a subject in need thereof.

[0014] Some embodiments include a composition comprising an oligonucleotide that targets an mRNA and when administered to a subject in an effective amount decreases target mRNA or protein levels in a cell, fluid or tissue. In some embodiments, the composition comprises an oligonucleotide that targets the target RNA and when administered to a subject in an effective amount decreases target mRNA levels in a cell or tissue. In some embodiments, the target 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 target mRNA levels are decreased by about 10% or more, as compared to prior to administration. In some embodiments, the target 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 target 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 target mRNA levels are decreased by no more than about 10%, as compared to prior to administration. In some embodiments, the target 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 target 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 a range defined by any of the two aforementioned percentages.

[0015] In some embodiments, the composition comprises an oligonucleotide that targets the target mRNA and when administered to a subject in an effective amount decreases target protein levels in a cell, fluid or tissue. In some embodiments, the target 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 target protein levels are decreased by about 10% or more, as compared to prior to administration. In some embodiments, the target 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 target 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 target protein levels are decreased by no more than about 10%, as compared to prior to administration. In some embodiments, the target protein levels are decreased by no more than about 20%, no more than aboutAttorney Docket No. 54462-758.601 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 target 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.

[0016] In some embodiments, the composition comprises an oligonucleotide that targets an mRNA and when administered to a subject in an effective amount diminishes a disease phenotype. In some embodiments, the disease 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 disease phenotype is decreased by about 10% or more, as compared to prior to administration. In some embodiments, the disease 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 disease 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 disease phenotype is decreased by no more than about 10%, as compared to prior to administration. In some embodiments, the disease 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 disease 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.

[0017] In some embodiments, the composition comprises an oligonucleotide that targets an mRNA and when administered to a subject in an effective amount enhances a protective phenotype against a disease in the subject. 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 toAttorney Docket No. 54462-758.601 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 a range defined by any of the two aforementioned percentages. A. siRNAs

[0018] In some embodiments, the composition comprises an oligonucleotide that targets a target RNA such as mRNA, wherein the oligonucleotide comprises a small interfering RNA (siRNA). In some embodiments, the composition comprises an oligonucleotide that targets the target mRNA, wherein the oligonucleotide comprises a small interfering RNA (siRNA) comprising a sense strand and an antisense strand.

[0019] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of the target mRNA, 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 a range defined by any of the two aforementioned numbers. The antisense strand may be 14-30 nucleosides in length.

[0020] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of the target mRNA, 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 a full-length human target mRNA sequence. 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 the target RNA.

[0021] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of a target mRNA, 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.

[0022] 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’ overhangAttorney Docket No. 54462-758.601 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.

[0023] 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.

[0024] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of a target mRNA, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the siRNA binds with a 19mer in a human target 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 human target mRNA.

[0025] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of a target mRNA, 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 target 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 target mRNA.

[0026] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of a target mRNA, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the siRNA binds with a human target 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 target 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 target mRNA and less than or equal to 30 human off-targets, with no more than 2 mismatches in the antisense strand. In some embodiments, the siRNA binds with a human target 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 target 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 target 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 target mRNA and less than or equal to 20 human off-targets, with no more than 3 mismatches in the antisense strand. In some embodiments, theAttorney Docket No. 54462-758.601 siRNA binds with a human target 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 target 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 target mRNA and less than or equal to 50 human off-targets, with no more than 3 mismatches in the antisense strand.

[0027] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of a target mRNA, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, siRNA binds with a human target 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%. B. ASOs

[0028] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of a target mRNA, wherein the oligonucleotide comprises an antisense oligonucleotide (ASO). In some embodiments, the ASO is 12-30 nucleosides in length. In some embodiments, the ASO is 14-30 nucleosides in length. In some embodiments, the ASO is at least about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleosides in length, or a range defined by any 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.

[0029] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of a target mRNA, 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 target mRNA sequence; 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 a target mRNA. C. Modifications

[0030] In some embodiments, the composition comprises (i) an oligonucleotide that inhibits or modifies the expression of a target mRNA, 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 internucleoside linkage. In some embodiments, the modified internucleoside linkage comprises alkylphosphonate, phosphorothioate, methylphosphonate, phosphorodithioate, alkylphosphonothioate, phosphoramidate, carbamate, carbonate, phosphate triester, acetamidate, or carboxymethyl ester, or a combination thereof. In some embodiments, the modifiedAttorney Docket No. 54462-758.601 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 internucleoside linkage may include decreased toxicity or improved pharmacokinetics.

[0031] In some embodiments, the composition comprises an oligonucleotide that inhibits or modifies the expression of a target mRNA, 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 internucleoside linkages. In some embodiments, the oligonucleotide comprises no more than 20 modified internucleoside linkages. In some embodiments, the oligonucleotide comprises 2 or more modified internucleoside linkages, 3 or more modified internucleoside linkages, 4 or more modified internucleoside linkages, 5 or more modified internucleoside linkages, 6 or more modified internucleoside linkages, 7 or more modified internucleoside linkages, 8 or more modified internucleoside linkages, 9 or more modified internucleoside linkages, 10 or more modified internucleoside linkages, 11 or more modified internucleoside linkages, 12 or more modified internucleoside linkages, 13 or more modified internucleoside linkages, 14 or more modified internucleoside linkages, 15 or more modified internucleoside linkages, 16 or more modified internucleoside linkages, 17 or more modified internucleoside linkages, 18 or more modified internucleoside linkages, 19 or more modified internucleoside linkages, or 20 or more modified internucleoside linkages.

[0032] In some embodiments, the composition comprises an oligonucleotide that inhibits or modifies the expression of a target mRNA, wherein the oligonucleotide comprises the modified nucleoside. In some embodiments, the modified nucleoside comprises a locked nucleic acid (LNA), hexitol nucleic acid (HNA), cyclohexene nucleic acid (CeNA), 2'-O-methoxyethyl , 2'-O-alkyl, 2'-O-allyl, 2'-fluoro, or 2'-deoxy, or a combination thereof. In some embodiments, the modified nucleoside comprises a LNA. In some embodiments, the modified nucleoside comprises a 2’,4’ constrained ethyl nucleic acid. In some embodiments, the modified nucleoside comprises HNA. In some embodiments, the modified nucleoside comprises CeNA. In some embodiments, the modified nucleoside comprises a 2'-O- methoxyethyl group. In some embodiments, the modified nucleoside comprises a 2'-O-alkyl group. In some embodiments, the modified nucleoside comprises 2'-O-methoxyethyl. In some embodiments, the modified nucleoside comprises a methoxyethyl. For example, position 4 of the sense strand may comprise a methoxyethyl nucleoside such as a 2'-O-methoxyethyl thymine. In some embodiments, the modified nucleoside comprises 2'-O-methyl. 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'-deoxyfluoro 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 nucleosideAttorney Docket No. 54462-758.601 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 modified nucleoside comprises one or more 2’-fluoro modified nucleosides. In some embodiments, the modified nucleoside comprises a 2'-O-alkyl modified nucleoside. In some embodiments, the modified nucleoside comprises a 2’-O-methyl inosine nucleoside. In some embodiments, the modified nucleoside comprises an acyclic nucleic acid. In some embodiments, the acyclic nucleic is a glycol nucleic acid. In some embodiments, the modified nucleoside comprises an unlocked nucleic acid. Benefits of the modified nucleoside may include decreased toxicity or improved pharmacokinetics.

[0033] In some embodiments, the modified nucleoside comprises a glycol nucleic acid (GNA). A GNA may comprise the following structure:

[0034] 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.

[0035] In some embodiments, the oligonucleotide comprises a modified nucleoside. In some embodiments, the modified nucleoside comprises a locked nucleic acid and an abasic site:Attorney Docket No. 54462-758.601 are independently an H or a 3’ or 5’ linkage to a nucleotide via

[0036] 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:2’-O-methyl uridine).

[0037] 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 phosphorothioates at the 5’ and 3’ ends.

[0038] 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.Attorney Docket No. 54462-758.601

[0039] In some embodiments, the sense strand comprises at least three modified nucleosides, wherein the three modifications comprises 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 comprises a 2’-fluoro modified nucleoside, a 2’-O- methyl modified nucleoside, and 2’-O-methoxyethyl. In some embodiments, each nucleoside of the sense strand comprises a modified nucleoside, wherein the modified nucleosides are selected from the group consisting of a 2’-fluoro modified nucleoside, a 2’-O-methyl modified nucleoside, and 2’-O- methoxyethyl. In some embodiments, the sense strand comprises at least a 2’-fluoro modified nucleoside, a 2’-O-methyl modified nucleoside, and 2’-O-methoxyethyl.

[0040] 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 a 2’-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.

[0041] The oligonucleotide may include purines. Examples of purines include adenine (A), inosine (I), or 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.

[0042] 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-methoxyethyl, 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.

[0043] 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 someAttorney Docket No. 54462-758.601 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 some embodiments, all nucleotides at position 16 to 20 of the sense strand comprise a 2’-O-methyl modified nucleoside.

[0044] 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.

[0045] 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’- fluoro (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’-O-methyl (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 any of the siRNAs comprises a modification pattern which conforms to any or all of these a strand of the oligonucleotide rules.Attorney Docket No. 54462-758.601

[0046] 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’OMe 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.

[0047] In some cases, position 9 of a strand of the oligonucleotide can be a 2’deoxy. In these cases, 2’F and 2’OMe 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.

[0048] 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.

[0049] 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-Attorney Docket No. 54462-758.601 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.

[0050] 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.

[0051] 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 unmodifiedAttorney Docket No. 54462-758.601 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.

[0052] 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.

[0053] 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.

[0054] In 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-vinylphosphate. In some embodiments, the vinyl phosphonate comprises a cis-vinylphosphate. An example of a nucleotide that includes a vinyl phosphonate is shown below.5’ vinylphosphonate 2’-O-methyl uridine

[0055] In 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 aAttorney Docket No. 54462-758.601 phosphatase. In some embodiments, the vinyl phosphonate improves the binding affinity of the oligonucleotide with the siRNA processing machinery.

[0056] 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. D. Hydrophobic moieties

[0057] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of a target mRNA, wherein the oligonucleotide comprises a hydrophobic 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.

[0058] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of the target mRNA, wherein the oligonucleotide comprises a hydrophobic moiety. An oligonucleotide comprising a hydrophobic moiety may include, or be referred to as a hydrophobic conjugate. Hydrophobic moieties may be useful for enhancing cellular uptake. 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. In some embodiments, the hydrophobic moiety includes a cyclohexanyl. In some embodiments, the hydrophobic moiety includes a lipid. In some embodiments, the hydrophobic moiety is used in a specific format described herein. In some embodiments, the hydrophobic moiety is attached at a 5’ end of a sense strand without any phosphorothioate groups or linkages at the 5’ end. The hydrophobic moiety may include an esterified lipid.

[0059] The hydrophobic moiety may be or include a lipid moiety. In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of the target mRNA, wherein the oligonucleotide comprises a lipid attached at a 3’ or 5’ terminus of the oligonucleotide. In some embodiments, the lipid comprises cholesterol, myristyl, palmityl, stearyl, lithocholyl, docosanyl,Attorney Docket No. 54462-758.601 docosahexaenyl, myristyl, palmityl stearyl, or α-tocopheryl, or a combination thereof. In some embodiments, the lipid comprises stearol, t-butylphenol, n-butylphenol, octylphenyl, dodecylphenyl, phenyl n-dodecyl, octadecylbenzamide, hexadecylbenzamide, or octadecylcyclohexyl. In some embodiments, the lipid comprises phenyl para C12. The lipid moiety may be esterified.

[0060] In some embodiments, the oligonucleotide comprises any aspect of the following structure:. In some embodiments, R is not octane. In some embodiments, R is not an octane. In some embodiments, R is an alkyl group containing 4-7 or 9-18 carbons. In some embodiments, the oligonucleotide comprises any aspect of the following structure:some embodiments, the oligonucleotidecomprises any aspect of the following structure: . In some the 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. InAttorney Docket No. 54462-758.601 some embodiments, R is not an octane (C8). In some embodiments, R is C4-7 alkyl. In some embodiments, R is C9-18 alkyl. In some embodiments, R is C4-7 alkyl and C9-18 alkyl. In some embodiments, the alkyl group contains 11 carbons. In some embodiments, the alkyl group contains 12 carbons. In some embodiments, the alkyl group contains 13 carbons. In some embodiments, the alkyl group contains 14 carbons. In some embodiments, the alkyl group contains 15 carbons. In some embodiments, the alkyl group contains 16 carbons. In some embodiments, the alkyl group contains 17 carbons. In some embodiments, the alkyl group contains 18 carbons. In some embodiments, R is not an octane (C8). In some embodiments, R includes a branched carbon chain. In some embodiments, R includes an unbranched carbon chain. In some embodiments, the lipid moiety comprises an alcohol or ether. In some embodiments, the lipid moiety has at least one degree of unsaturation. In some embodiments, the lipid moiety is an omega fatty acid, such as an omega-3, omega-5, omega-6, omega-7, or omega-9 fatty acid.

[0061] In some embodiments, the lipid includes a fatty acid. In some embodiments, the lipid comprises a lipid depicted in Table 1. The example lipid moieties in Table 1 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 1 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 1. Lipid moiety examples D s t nAttorney Docket No. 54462-758.601 o d ( a p o d h aAttorney Docket No. 54462-758.601 o c m m l m p p m p pAttorney Docket No. 54462-758.601

[0062] 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. In some embodiments, the lipid moiety includes 19 carbons. In some embodiments, the lipid moiety includes 20 carbons.

[0063] 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 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. The lipid may be attached to the carbocycle in the in the 1,4 orientation relative to the oligonucleotide. The lipid may be attached to the carbocycle in the in the 1,3 orientation relative to the oligonucleotide. The lipid may be attached to the carbocycle in the in the 1,2 orientation relative to the oligonucleotide.

[0064] The lipid moiety may comprise or consist of the following structure. In some embodiments, the lipid moiety comprises or consists of thefollowing structure: moietycomprises or consists of the following structure: . In some embodiments, the lipid moiety comprises or consist of the following structure:Attorney Docket No. 54462-758.601 some embodiments, the dotted line indicates a covalentan 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, R includes a branched carbon chain. In some embodiments, R includes an unbranched carbon chain. 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 11 carbons. In some embodiments, the alkyl group contains 12 carbons. In some embodiments, the alkyl group contains 13 carbons. In some embodiments, the alkyl group contains 14 carbons. In some embodiments, the alkyl group contains 15 carbons. In some embodiments, the alkyl group contains 16 carbons. In some embodiments, the alkyl group contains 17 carbons. In some embodiments, the alkyl group contains 18 carbons. In some embodiments, R comprises or consists of an alkyl group containing 4-18 carbons. In some embodiments, the lipid moiety is not a phenyloctyl group. In some embodiments, R is not octane. In some embodiments, R is C4-7alkyl. In some embodiments, R is C9-18 alkyl. In some embodiments, R is C4-7 alkyl and C9-18 alkyl. In some embodiments, the lipid moiety is not a phenyloctyl group.

[0065] In some embodiments, the 5’ hydrophobic moiety comprises any one of the following structures:, or , wherein the dotted line indicates a covalent connection to the end of the 5’ end of the sense strand, n is 1-3, and R is an alkyl group containing 4-18 carbons. In some embodiments, R is not an octane. In some embodiments, the alkyl group contains 4–7 or 9–18 carbons. In some embodiments, the alkyl group contains 14 carbons.Attorney Docket No. 54462-758.601 In some embodiments, the alkyl group contains 15 carbons. In some embodiments, the alkyl group contains 16 carbons. In some embodiments, the alkyl group contains 17 carbons. In some embodiments, the alkyl group contains 18 carbons. In some embodiments, the 5’ hydrophobic moiety comprises a hydrophobic moiety in Table 1. In some embodiments, the 5’ hydrophobic moiety comprises phenyl para C12. In some embodiments, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14. In some embodiments, n is 0–3. In some embodiments, n is 1–3. In some embodiments, n is 1. In some embodiments n is 2. In some embodiments, the hydrophobic moiety comprises an alcohol or an ether. In some embodiments, R is an unsaturated alkyl group. In some embodiments, the unsaturated alkyl group may be monounsaturated. In some embodiments, the unsaturated alkyl group may be unsaturated at the omega-3, position, omega-4 position, omega-5 position, omega-6 position, omega-7 position, omega-8 position, omega-9 position, or a combination thereof. In some embodiments, the 5’ hydrophobic moiety is not a phenyloctyl group.

[0066] 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 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. The lipid may be attached to the carbocycle in the in the 1,4 orientation relative to the oligonucleotide. The lipid may be attached to the carbocycle in the in the 1,3 orientation relative to the oligonucleotide. The lipid may be attached to the carbocycle in the in the 1,2 orientation relative to the oligonucleotide.

[0067] 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 the oligonucleotide, 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 aAttorney Docket No. 54462-758.601 modification such as a sulfur in place of an oxygen. In some embodiments, the oligonucleotide is not d(pT-G-G-G-G-G).

[0068] 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.

[0069] 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 phosphoramidite 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:. 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, R comprises or consists of an alkyl group containing 4-18 carbons. Any one of the phosphoramidite reagents may be reacted to a 5’ end of an oligonucleotide to produce an oligonucleotide comprising a hydrophobic moiety. In some embodiments,Attorney Docket No. 54462-758.601 the phosphoramidite 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.

[0070] 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.

[0071] In 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’ O Methyl Uridine

[0072] In 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.

[0073] 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.Attorney Docket No. 54462-758.601

[0074] The oligonucleotide may include purines. Examples of purines include adenine (A), guanine (G), inosine (I), or modified versions thereof. The oligonucleotide may include pyrimidines. Examples of pyrimidines include cytosine (C), thymine (T), or uracil (U), or modified versions thereof.

[0075] 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.

[0076] 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.

[0077] 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 a mixture 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.

[0078] In some embodiments, all purines of the oligonucleotide comprise 2’-fluoro modified purines, and all pyrimidines of the oligonucleotide comprise a mixture of 2’-fluoro and 2’-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.Attorney Docket No. 54462-758.601 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.

[0079] 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, 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.

[0080] 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, 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.Attorney Docket No. 54462-758.601

[0081] 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, 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.

[0082] 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, 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.

[0083] 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. E. Modified siRNAs

[0084] In some embodiments, the composition comprises an oligonucleotide that inhibits 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 1S: 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,Attorney Docket No. 54462-758.601 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 some embodiments, the moiety in modification pattern 4S or 5S is a lipid moiety. In some embodiments, the sense strand comprises modification pattern 6S: 5’- NfsnsNfnNfnNfnNfnNfnNfnNfnNfnNfsnsn-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’-nsnsnnnNfNfNfNfnnnnnnnnnnsnsn-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 11S: 5’-nsnsNfnNfnNfnNfnNfnNfnnnNfnNfsnsn-3’. In some embodiments, the sense strand comprises modification pattern 12S: 5’-NfsnsNfnNfnNfnNfnNfnnnNfnNfnNfsnsn-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’-snnnnnnNfNfNfNfnnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 15S: 5’-snnnnNfNfNfNfNfnnnnnnnnnnsnsn-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’-snnnnnNfNfnNfnnnnnnnnnnsnsn-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’-snnnnNfnNfnNfnNfnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 20S: 5’-snnnnNfnNfnNfnnnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 21S: 5’-snnnnNfNfnnNfNfnnnnnnnnnsnsn- 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’-snnnnnNfnNfNfnnnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 24S: 5’-snnnnnnnNfNfNfNfnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 25S: 5’-snnnnnNfNfNfNfNfnnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 26S: 5’-snnnnnNfNfNfNfnnnnnnnnnnsnsn- 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’-snnnnnnnnNfnNfnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 30S: 5’-snnnnNfNfnnNfnNfnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 31S: 5’-snnnnNfNfnNfNfnnnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 32S: 5’- snnnnnnNfNfdNNfnnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modificationAttorney Docket No. 54462-758.601 pattern 33S: 5'-snnnnNfnNfnNfNfnnnnnnnnnsnsn-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'-snnnnnnNfNfNfNfnNfnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 36S: 5'- snnnnnNfNfNfNfnNfnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 37S: 5'-snnnnNfnNfNfdTNfnnnnnnnnnsnsn-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 41S: 5’-snnnnnnnnNfNfnnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 42S: 5'- snnnnNfnNfNfdTnNfnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 43S: 5'-snnnnnnNfnNfnNfnnnnnnnnsnsn-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'-snnnnnNfnnNfNfnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 46S: 5'-snnnnnnNfNfNfNfNfnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 47S: 5'-snnnnnNfNfnNfnNfnnnnnnnnsnsn- 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'- nnnnnNfNfNfNfNfnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 51S: 5'- nnnnNfNfNfNfNfnnnnnnnnnnsnsn-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'-snnnnmnNfNfNfNfnnnnmnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 55S: 5'-snnnnmnNfNfNfNfnnnmnnnnnnnsnsn-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'-snnnnnmNfNfNfNfnnnnmnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 58S: 5'- nnnnmnNfNfNfNfnnnnmnnnnnnsnsn-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'- snnnnmnnNfNfNfNfnnnmnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 61S: 5'- snnnnmNfnNfNfNfNfnnnmnnnnnnsnsn-3'. In some 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'-Attorney Docket No. 54462-758.601 nnnnmnnNfNfNfNfnnnmnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 65S: 5'- nsnsnnmnN(C16)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'- nnnnNfnnNfNfnnnnnnnnnnsnsn-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'-nnnnnNfnnNfNfnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 90S: 5'-nnnnnNfnNfNfNfNfnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 91S: 5'-nnnnnNfNfnNfNfnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 92S: 5'-nnnnNfnnnNfNfnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 93S: 5'- nnnnNfnnNfNfNfNfnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 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 pattern 96S: 5'-nnnnNfNfnnNfNfnnnnnnnnnsnsn-3'. In some embodiments,Attorney Docket No. 54462-758.601 the sense strand comprises modification pattern 97S: 5'-nnnnnnnNfNfnnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 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 pattern 100S: 5'-nnnnNfnNfNfdTnNfnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 101S: 5'-nnnnNfnNfNfdNnNfnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 102S: 5'-nnnnNfnNfNfdTnnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 103S: 5'- snnnnnNfnNfNfnNfnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 104S: 5'-snnnnNfNfnnNfnnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 105S: 5'-snnnnNfnnNfNfnNfnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 106S: 5'-snnnnNfnnNfNfnnnnnnnnnnsnsnm-3'. In some embodiments, the sense strand comprises modification pattern 107S: 5'-snnnnNfnnnNfNfnnnnnnnnnsnsn- 3'. In some embodiments, the sense strand comprises modification pattern 108S: 5’- snNfnNfnNfnNfNfnnnnnNfnNfNfnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 109S: 5’-snnnnnmNfNfNfNfnnnnnmnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 110S: 5'-nnnnnNfNfnNfnnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 111S: 5’-NfsnNfnNfnNfnNfnNfnNfnNfnNfnNfsnsn-3’. In some embodiments, the sense strand comprises modification pattern 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 pattern 114S: 5’-snnnnmnNfNfNfNfnnmnnnnnnnnsnsn -3’. In some embodiments, the sense strand comprises modification pattern 115S: 5’- nNfnNfnNfnNfNfnnnnnNfnNfNfnsnsn-3’. In all the above modification patterns, 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-methoxyethyl 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.

[0085] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of MTRES1, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the antisense strand comprises modification pattern 1AS: 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 3AS: 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 5AS: 5’-nsNfsnnnnnnnnnnnNfnNfnnnsnsn-3’. In some embodiments, the antisenseAttorney Docket No. 54462-758.601 strand comprises modification pattern 6AS: 5’-nsNfsnnnNfnnNfnnnnNfnNfnnnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 7AS: 5’- nsNfsnNfnNfnNfnNfnNfnNfnNfnNfnsnsn-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’- nsNfsnNfsnNfnNfnNfnNfnNfnNfnNfnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 11AS: 5'-nsNfsnnnNfnNfnNfnnnNfnNfnNfnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 12AS: 5'-nsNfsnnnNfnNfnNfnNfnNfnNfnNfnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 13AS: 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'-nsNfsnNfnnNfnnNfnNfnNfnNfnNfnsnsn-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 21AS: 5'-nsNfsnnnnNfnNfnnnnNfnNfnNfnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 22AS: 5'- nsNfsnNfnNfnNfnnnnnNfnNfnNfnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 23AS: 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 31AS: 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'-Attorney Docket No. 54462-758.601 nsNfsnnNfnNfNfnnnNfnNfnNfnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 35AS: 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 41AS: 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 45AS: 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'-nsNfsnnnnNfNfnNfnNfnNfnNfnNfnsnsn-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'-nsNfsnnNfnNfnNfnnNfnNfnNfnNfnsnsn-3'. In some embodiments, the antisense strand comprises modification pattern 51AS: 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 some embodiments, the antisense strand comprises modification pattern 54AS: 5'-nsNfsnnnnNfNfnnnNfnNfnNfnnnsnsn-3'. In some embodiments, the antisense strand comprises modification pattern 55AS: 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-methoxyethyl 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,Attorney Docket No. 54462-758.601 “[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.

[0086] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of MTRES1, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises pattern 1S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 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 2S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 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 3S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 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 4S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 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 5S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 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 6S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 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 7S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 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,Attorney Docket No. 54462-758.601 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 8S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 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 9S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 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.S. In some embodiments, the sense strand comprises pattern 10S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 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 11S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 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 12S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 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 13S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 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 14S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 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 15S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS,Attorney Docket No. 54462-758.601 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 16S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 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 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 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 18S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 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 19S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 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 20S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 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 21S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 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 22S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 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 23S and the antisense strand comprises pattern 1AS,Attorney Docket No. 54462-758.601 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 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 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 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 25S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 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 26S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 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 27S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 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 28S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 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 29S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 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 30S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS,Attorney Docket No. 54462-758.601 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 31S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 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 32S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 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 33S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 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 34S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 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 35S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 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 36S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 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 37S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 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 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS,Attorney Docket No. 54462-758.601 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 39S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 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 40S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 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 41S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 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 42S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 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 43S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 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 44S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 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 45S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 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 someAttorney Docket No. 54462-758.601 embodiments, the sense strand comprises pattern 46S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 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 47S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 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 48S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 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 49S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 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 50S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 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 51S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 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 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 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 53S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS,Attorney Docket No. 54462-758.601 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 54S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 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 55S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 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 56S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 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 57S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 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 58S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 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 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, or 40AS. In some embodiments, the sense strand comprises pattern 60S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 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 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS,Attorney Docket No. 54462-758.601 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 62S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 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 63S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 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 64S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 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 65S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 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 66S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 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 67S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 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 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 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 69S and the antisense strand comprises pattern 1AS,Attorney Docket No. 54462-758.601 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 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 70S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 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 71S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 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 72S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 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 73S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 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 74S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 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 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 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 76S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS,Attorney Docket No. 54462-758.601 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 77S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 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 78S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 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 79S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 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 80S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 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 81S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 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 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 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 83S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 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 84S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS,Attorney Docket No. 54462-758.601 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 85S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 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 86S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 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 87S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 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 88S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 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 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 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 90S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 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 91S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 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 someAttorney Docket No. 54462-758.601 embodiments, the sense strand comprises pattern 92S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 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 93S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 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 94S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 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 95S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 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 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 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 97S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 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 98S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 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 99S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS,Attorney Docket No. 54462-758.601 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 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 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 101S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 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 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 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 103S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 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 104S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 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 105S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 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 106S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 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 107S and the antisense strand comprises pattern 1AS,Attorney Docket No. 54462-758.601 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 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 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 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 109S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 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 110S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 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 111S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 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 112S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 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 113S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 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 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42AS, 43AS, 44AS, 45AS, 46AS, 47AS,Attorney Docket No. 54462-758.601 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, or 59AS. In some embodiments, the sense strand comprises pattern 115S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 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 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 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 1AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 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 2AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 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 3AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 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 4AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 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,Attorney Docket No. 54462-758.601 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 5AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 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 6AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 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 7AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 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 8AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S. 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 9AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 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 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S,Attorney Docket No. 54462-758.601 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 11AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 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 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 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 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 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 14AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 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 15AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 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,Attorney Docket No. 54462-758.601 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 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 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 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 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 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 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 19AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 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 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 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 pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S,Attorney Docket No. 54462-758.601 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 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 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 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 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 pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 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 25AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 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 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 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,Attorney Docket No. 54462-758.601 108S, 109S, 110S, 111S, 112S, 113S, 114S, or 115S and the antisense strand comprises pattern 27AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 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 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 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 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 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 30AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 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 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 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 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S,Attorney Docket No. 54462-758.601 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 33AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 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 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 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 35AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 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 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 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 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 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 theAttorney Docket No. 54462-758.601 antisense strand comprises pattern 38AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 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 pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 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 40AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 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 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 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 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 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 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S , 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S,Attorney Docket No. 54462-758.601 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 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 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 45AS.In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 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 46AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 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 47AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 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 48AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 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 49AS. In some embodiments,Attorney Docket No. 54462-758.601 the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 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 50AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 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 51AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 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 52AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 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 53AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 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 54AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 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,Attorney Docket No. 54462-758.601 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 55AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 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 56AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 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 57AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 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 58AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 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 59AS.

[0087] In some embodiments, the sense strand comprises any one of modification patters 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, or 9S. In some embodiments, the sense strand comprises any one of modification patters 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 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,Attorney Docket No. 54462-758.601 102S, 103S, 104S, 105S, 106S, 107S, 108S, 109S, 110S, 111S, 112S, 113S, 114S, or 115S. In some embodiments, the sense strand comprises modification pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, or 8AS. In some embodiments, the antisense strand comprises modification pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 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.

[0088] In some embodiments, the siRNA comprises a sense strand, an antisense strand, and a lipid moiety connected to an end of the sense or antisense strand; wherein the lipid moiety comprises a phenyl or cyclohexanyl linker, wherein the linker is connected to a lipid and to the end of the sense or antisense strand. 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 (vi) 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-methoxyethyl modified pyrimidines; (iii) a mixture of 2’-fluoro and 2’-O-methoxyethyl modified pyrimidines; or (iv) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O-methoxyethyl modified pyrimidines; (e) all purines comprise a mixture of 2’-fluoro and 2'-O- methoxyethyl modified purines and all pyrimidines 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) 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) 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-methoxyethyl modified pyrimidines; (iv) a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; (v) a mixture of 2’-O-methyl and 2’-O-methoxyethyl modified pyrimidines; (vi) a mixture of 2’-fluoro and 2’-O-methoxyethyl modified pyrimidines; or (vii) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O-methoxyethyl modified pyrimidines. In some embodiments, 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; allAttorney Docket No. 54462-758.601 purines comprise 2’-O-methyl modified purines, and all pyrimidines comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; all purines comprise 2’-O-methyl modified purines, and all pyrimidines comprise 2’-fluoro modified pyrimidines; all pyrimidines comprise 2’-fluoro modified pyrimidines, and all purines comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines; all pyrimidines comprise 2’-O-methyl modified pyrimidines, and all purines comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines; or all pyrimidines comprise 2’-O-methyl modified pyrimidines, and all purines comprise 2’-fluoro modified purines. In some embodiments, the siRNA comprises comprising a sense strand and an antisense strand; wherein the antisense strand comprises a 5’ end comprising a vinyl phosphonate and 2 phosphorothioate linkages, and a 3’ end comprising 2 phosphorothioate linkages; wherein the sense strand comprises (a) all purines comprise fluoro modified purines and all pyrimidines comprise (i) a mixture of 2’-O-methyl and 2’-O-methoxyethyl modified pyrimidines; or (ii) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O-methoxyethyl modified pyrimidines; (b) all purines comprise 2'-O- methyl modified purines and all pyrimidines comprise (vi) 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- methoxyethyl modified pyrimidines; (iii) a mixture of 2’-fluoro and 2’-O-methoxyethyl modified pyrimidines; or (iv) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O-methoxyethyl modified pyrimidines; (e) all purines comprise a mixture of 2’-fluoro and 2'-O-methoxyethyl modified purines and all pyrimidines 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) 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) 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-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; and 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 purinesAttorney Docket No. 54462-758.601 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.

[0089] 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 (vi) 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-methoxyethyl modified pyrimidines; (iii) a mixture of 2’-fluoro and 2’-O-methoxyethyl modified pyrimidines; or (iv) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O-methoxyethyl modified pyrimidines; (e) all purines comprise a mixture of 2’-fluoro and 2'-O- methoxyethyl modified purines and all pyrimidines 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) 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) 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-methoxyethyl modified pyrimidines; (iv) a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; (v) a mixture of 2’-O-methyl and 2’-O-methoxyethyl modified pyrimidines; (vi) a mixture of 2’-fluoro and 2’-O-methoxyethyl modified pyrimidines; or (vii) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O-methoxyethyl modified pyrimidines. In some embodiments, a deoxy nucleoside may be included in the sense strand. In some embodiments, the sense strand includes the deoxy nucleoside. The deoxy nucleoside may be at nucleoside position 9 of the sense strand. In some embodiments, the sense strand does not include a deoxy nucleoside. The deoxy nucleoside of the sense strand may be otherwise unmodified.

[0090] In some embodiments, purines of the sense strand comprise 2’-fluoro modified purines. In some embodiments, purines of the sense strand comprise 2’-O-methyl modified purines. In some embodiments, purines of the sense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modifiedAttorney Docket No. 54462-758.601 purines. In some embodiments, all purines of the sense strand comprise 2’-fluoro modified purines. In some embodiments, all purines of the sense strand comprise 2’-O-methyl modified purines. In some embodiments, all purines of the sense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines.

[0091] In some embodiments, pyrimidines of the sense strand comprise 2’-fluoro modified pyrimidines. In some embodiments, pyrimidines of the sense strand comprise 2’-O-methyl modified pyrimidines. In some embodiments, pyrimidines of the sense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines. In some embodiments, all pyrimidines of the sense strand comprise 2’-fluoro modified pyrimidines. In some embodiments, all pyrimidines of the sense strand comprise 2’-O- methyl modified pyrimidines. In some embodiments, all pyrimidines of the sense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines.

[0092] In some embodiments, purines of the sense strand comprise 2’-fluoro modified purines, and pyrimidines of the sense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines. In some embodiments, purines of the sense strand comprise 2’-O-methyl modified purines, and pyrimidines of the sense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines. In some embodiments, purines of the sense strand comprise 2’-fluoro modified purines, and pyrimidines of the sense strand comprise 2’-O-methyl modified pyrimidines. In some embodiments, purines of the sense strand comprise 2’-O-methyl modified purines, and pyrimidines of the sense strand comprise 2’-fluoro modified pyrimidines. In some embodiments, pyrimidines of the sense strand comprise 2’-fluoro modified pyrimidines, and purines of the sense strand comprise a mixture of 2’-fluoro and 2’-O- methyl modified purines. In some embodiments, pyrimidines of the sense strand comprise 2’-O-methyl modified pyrimidines, and purines of the sense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines. In some embodiments, pyrimidines of the sense strand comprise 2’-fluoro modified pyrimidines, and purines of the sense strand comprise 2’-O-methyl modified purines. In some embodiments, pyrimidines of the sense strand comprise 2’-O-methyl modified pyrimidines, and purines of the sense strand comprise 2’-fluoro modified purines.

[0093] In some embodiments, all purines of the sense strand comprise 2’-fluoro modified purines, and all pyrimidines of the sense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines. In some embodiments, all purines of the sense strand comprise 2’-O-methyl modified purines, and all pyrimidines of the sense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines. In some embodiments, all purines of the sense strand comprise 2’-fluoro modified purines, and all pyrimidines of the sense strand comprise 2’-O-methyl modified pyrimidines. In some embodiments, all purines of the sense strand comprise 2’-O-methyl modified purines, and all pyrimidines of the sense strand comprise 2’-fluoro modified pyrimidines. In some embodiments, all pyrimidines of the sense strand comprise 2’-fluoro modified pyrimidines, and all purines of the sense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines. In some embodiments, all pyrimidines of the sense strand comprise 2’-O-methyl modified pyrimidines, and all purines of the sense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines. In some embodiments, all pyrimidines of theAttorney Docket No. 54462-758.601 sense strand comprise 2’-fluoro modified pyrimidines, and all purines of the sense strand comprise 2’-O- methyl modified purines. In some embodiments, all pyrimidines of the sense strand comprise 2’-O-methyl modified pyrimidines, and all purines of the sense strand comprise 2’-fluoro modified purines.

[0094] In some embodiments, purines of the antisense strand comprise 2’-fluoro modified purines. In some embodiments, purines of the antisense strand comprise 2’-O-methyl modified purines. In some embodiments, purines of the antisense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines. In some embodiments, all purines of the antisense strand comprise 2’-fluoro modified purines. In some embodiments, all purines of the antisense strand comprise 2’-O-methyl modified purines. In some embodiments, all purines of the antisense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines.

[0095] In some embodiments, pyrimidines of the antisense strand comprise 2’-fluoro modified pyrimidines. In some embodiments, pyrimidines of the antisense strand comprise 2’-O-methyl modified pyrimidines. In some embodiments, pyrimidines of the antisense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines. In some embodiments, all pyrimidines of the antisense strand comprise 2’-fluoro modified pyrimidines. In some embodiments, all pyrimidines of the antisense strand comprise 2’-O-methyl modified pyrimidines. In some embodiments, all pyrimidines of the antisense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines.

[0096] In some embodiments, purines of the antisense strand comprise 2’-fluoro modified purines, and pyrimidines of the antisense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines. In some embodiments, purines of the antisense strand comprise 2’-O-methyl modified purines, and pyrimidines of the antisense strand comprise a mixture of 2’-fluoro and 2’-O- methyl modified pyrimidines. In some embodiments, purines of the antisense strand comprise 2’-fluoro modified purines, and pyrimidines of the antisense strand comprise 2’-O-methyl modified pyrimidines. In some embodiments, purines of the antisense strand comprise 2’-O-methyl modified purines, and pyrimidines of the antisense strand comprise 2’-fluoro modified pyrimidines. In some embodiments, pyrimidines of the antisense strand comprise 2’-fluoro modified pyrimidines, and purines of the antisense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines. In some embodiments, pyrimidines of the antisense strand comprise 2’-O-methyl modified pyrimidines, and purines of the antisense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines. In some embodiments, pyrimidines of the antisense strand comprise 2’-fluoro modified pyrimidines, and purines of the antisense strand comprise 2’-O-methyl modified purines. In some embodiments, pyrimidines of the antisense strand comprise 2’-O-methyl modified pyrimidines, and purines of the antisense strand comprise 2’-fluoro modified purines.

[0097] In some embodiments, all purines of the antisense strand comprise 2’-fluoro modified purines, and all pyrimidines of the antisense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines. In some embodiments, all purines of the antisense strand comprise 2’-O-methyl modified purines, and all pyrimidines of the antisense strand comprise a mixture of 2’-fluoro and 2’-O- methyl modified pyrimidines. In some embodiments, all purines of the antisense strand comprise 2’-fluoroAttorney Docket No. 54462-758.601 modified purines, and all pyrimidines of the antisense strand comprise 2’-O-methyl modified pyrimidines. In some embodiments, all purines of the antisense strand comprise 2’-O-methyl modified purines, and all pyrimidines of the antisense strand comprise 2’-fluoro modified pyrimidines. In some embodiments, all pyrimidines of the antisense strand comprise 2’-fluoro modified pyrimidines, and all purines of the antisense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines. In some embodiments, all pyrimidines of the antisense strand comprise 2’-O-methyl modified pyrimidines, and all purines of the antisense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines. In some embodiments, all pyrimidines of the antisense strand comprise 2’-fluoro modified pyrimidines, and all purines of the antisense strand comprise 2’-O-methyl modified purines. In some embodiments, all pyrimidines of the antisense strand comprise 2’-O-methyl modified pyrimidines, and all purines of the antisense strand comprise 2’-fluoro modified purines.

[0098] In some embodiments, the siRNA comprises a sense strand, an antisense strand, and a lipid moiety connected to an end of the sense or antisense strand; wherein the lipid moiety comprises a phenyl or cyclohexanyl linker, wherein the linker is connected to a lipid and to the end of the sense or antisense strand. In some embodiments, any one of the following is true with regard to the sense 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’-fluoro modified purines, and all pyrimidines comprise 2’-O-methyl 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’-fluoro modified pyrimidines, and all purines comprise 2’-O-methyl modified purines. 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 siRNA comprises comprising a sense strand and an antisense strand; wherein the antisense strand comprises a 5’ end comprising a vinyl phosphonate and 2 phosphorothioate linkages, and a 3’ end comprising 2 phosphorothioate linkages; wherein the sense strand comprises a 5’ end comprising a hydrophobic moiety, and a 3’ end comprising 2 phosphorothioate linkages; wherein any one of the following is true with regard to the sense 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 pyrimidinesAttorney Docket No. 54462-758.601 comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines, all purines comprise 2’-fluoro modified purines, and all pyrimidines comprise 2’-O-methyl 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’-fluoro modified pyrimidines, and all purines comprise 2’-O-methyl modified purines; and 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.

[0099] In some embodiments, any one of the following is true with regard to the sense 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’-fluoro modified purines, and all pyrimidines comprise 2’-O-methyl 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’-fluoro modified pyrimidines, and all purines comprise 2’-O-methyl modified purines; with the proviso that in any of the foregoing, the sense strand may include a deoxy nucleoside. In some embodiments, all purines comprise 2’-fluoro modified purines, and all pyrimidines comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; with the proviso that a deoxy nucleoside may be included in the sense strand. In some embodiments, in the sense strand, all purines comprise 2’-O-methyl modified purines, and all pyrimidines comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; with the proviso that a deoxy nucleoside may be included in the sense strand. In some embodiments, in the sense strand, all purines comprise 2’-fluoro modified purines, and all pyrimidines comprise 2’-O-methyl modified pyrimidines; with the proviso that a deoxy nucleoside may be included in the sense strand. In some embodiments, all pyrimidines comprise 2’-fluoro modified pyrimidines, and all purines comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines; with the proviso that a deoxy nucleoside may be included in the sense strand. In some embodiments, in the sense strand, all pyrimidines comprise 2’-O-methyl modified pyrimidines, and all purines comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines; with the proviso that a deoxy nucleoside may be included in the sense strand. In some embodiments, in the sense strand, all pyrimidines comprise 2’-fluoro modified pyrimidines, and all purines comprise 2’-O-methylAttorney Docket No. 54462-758.601 modified purines; with the proviso that a deoxy nucleoside may be included in the sense strand. In some embodiments, the sense strand includes the deoxy nucleoside. The deoxy nucleoside may be at nucleoside position 9 of the sense strand. In some embodiments, the sense strand does not include a deoxy nucleoside. The deoxy nucleoside of the sense strand may be otherwise unmodified.

[0100] 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; with the proviso that in any of the foregoing, the sense strand may include a deoxy nucleoside. In some embodiments, all purines comprise 2’-fluoro modified purines, and all pyrimidines comprise a mixture of 2’-fluoro and 2’- O-methyl modified pyrimidines; with the proviso that a deoxy nucleoside may be included in the antisense strand. In some embodiments, in the antisense strand, all purines comprise 2’-O-methyl modified purines, and all pyrimidines comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; with the proviso that a deoxy nucleoside may be included in the antisense strand. In some embodiments, in the antisense strand, all purines comprise 2’-O-methyl modified purines, and all pyrimidines comprise 2’-fluoro modified pyrimidines; with the proviso that a deoxy nucleoside may be included in the antisense strand. In some embodiments, in the antisense strand, all pyrimidines comprise 2’-fluoro modified pyrimidines, and all purines comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines; with the proviso that a deoxy nucleoside may be included in the antisense strand. In some embodiments, in the antisense strand, all pyrimidines comprise 2’-O-methyl modified pyrimidines, and all purines comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines; with the proviso that a deoxy nucleoside may be included in the antisense strand. In some embodiments, in the antisense strand, all pyrimidines comprise 2’-O-methyl modified pyrimidines, and all purines comprise 2’-fluoro modified purines; with the proviso that a deoxy nucleoside may be included in the antisense strand. In some embodiments, the antisense strand includes the deoxy nucleoside. The deoxy nucleoside may be at nucleoside position 9 of the antisense strand. In some embodiments, the antisense strand does not include a deoxy nucleoside. The deoxy nucleoside of the antisense strand may be otherwise unmodified.

[0101] In some embodiments, any one of the following is true with regard to the sense 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’-fluoro modified purines, and all pyrimidines comprise 2’-O-methyl modified pyrimidines; all pyrimidines comprise 2’-fluoro modified pyrimidines, and all purines comprise a mixture of 2’-fluoro and 2’-O-methylAttorney Docket No. 54462-758.601 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’-fluoro modified pyrimidines, and all purines comprise 2’-O-methyl modified purines; with the proviso that in any of the foregoing, the sense strand may include a deoxy nucleoside or a 2’-O-methoxyethyl nucleoside. In some embodiments, all purines comprise 2’-fluoro modified purines, and all pyrimidines comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; with the proviso that a deoxy nucleoside or a 2’-O- methoxyethyl nucleoside may be included in the sense strand. In some embodiments, in the sense strand, all purines comprise 2’-O-methyl modified purines, and all pyrimidines comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; with the proviso that a deoxy nucleoside or a 2’-O-methoxyethyl nucleoside may be included in the sense strand. In some embodiments, in the sense strand, all purines comprise 2’-fluoro modified purines, and all pyrimidines comprise 2’-O-methyl modified pyrimidines; with the proviso that a deoxy nucleoside or a 2’-O-methoxyethyl nucleoside may be included in the sense strand. In some embodiments, all pyrimidines comprise 2’-fluoro modified pyrimidines, and all purines comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines; with the proviso that a deoxy nucleoside or a 2’-O-methoxyethyl nucleoside may be included in the sense strand. In some embodiments, in the sense strand, all pyrimidines comprise 2’-O-methyl modified pyrimidines, and all purines comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines; with the proviso that a deoxy nucleoside or a 2’- O-methoxyethyl nucleoside may be included in the sense strand. In some embodiments, in the sense strand, all pyrimidines comprise 2’-fluoro modified pyrimidines, and all purines comprise 2’-O-methyl modified purines; with the proviso that a deoxy nucleoside or a 2’-O-methoxyethyl nucleoside may be included in the sense strand. In some embodiments, the sense strand includes the deoxy nucleoside. The deoxy nucleoside may be at nucleoside position 9 of the sense strand. In some embodiments, the sense strand does not include a deoxy nucleoside. The deoxy nucleoside of the sense strand may be otherwise unmodified. In some embodiments, the sense strand includes a 2’-O-methoxyethyl nucleoside. The 2’-O- methoxyethyl nucleoside may be at nucleoside position 4 of the sense strand. The 2’-O-methoxyethyl nucleoside may include a 2’-O-methoxyethyl thymine nucleoside. In some embodiments, the sense strand does not include a 2’-O-methoxyethyl nucleoside. The 2’-O-methoxyethyl nucleoside of the sense strand may be otherwise unmodified.

[0102] 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; with the proviso that in any of the foregoing, the sense strand may include a deoxy nucleoside or a 2’-O-methoxyethylAttorney Docket No. 54462-758.601 nucleoside. In some embodiments, all purines comprise 2’-fluoro modified purines, and all pyrimidines comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; with the proviso that a deoxy nucleoside or a 2’-O-methoxyethyl nucleoside may be included in the antisense strand. In some embodiments, in the antisense strand, all purines comprise 2’-O-methyl modified purines, and all pyrimidines comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; with the proviso that a deoxy nucleoside or a 2’-O-methoxyethyl nucleoside may be included in the antisense strand. In some embodiments, in the antisense strand, all purines comprise 2’-O-methyl modified purines, and all pyrimidines comprise 2’-fluoro modified pyrimidines; with the proviso that a deoxy nucleoside or a 2’-O- methoxyethyl nucleoside may be included in the antisense strand. In some embodiments, in the antisense strand, all pyrimidines comprise 2’-fluoro modified pyrimidines, and all purines comprise a mixture of 2’- fluoro and 2’-O-methyl modified purines; with the proviso that a deoxy nucleoside or a 2’-O- methoxyethyl nucleoside may be included in the antisense strand. In some embodiments, in the antisense strand, all pyrimidines comprise 2’-O-methyl modified pyrimidines, and all purines comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines; with the proviso that a deoxy nucleoside or a 2’-O- methoxyethyl nucleoside may be included in the antisense strand. In some embodiments, in the antisense strand, all pyrimidines comprise 2’-O-methyl modified pyrimidines, and all purines comprise 2’-fluoro modified purines; with the proviso that a deoxy nucleoside or a 2’-O-methoxyethyl nucleoside may be included in the antisense strand. In some embodiments, the antisense strand includes the deoxy nucleoside. The deoxy nucleoside may be at nucleoside position 9 of the antisense strand. In some embodiments, the antisense strand does not include a deoxy nucleoside. The deoxy nucleoside of the antisense strand may be otherwise unmodified. In some embodiments, the antisense strand includes a 2’- O-methoxyethyl nucleoside. The 2’-O-methoxyethyl nucleoside may be at nucleoside position 4 of the sense strand. The 2’-O-methoxyethyl nucleoside may include a 2’-O-methoxyethyl thymine nucleoside. In some embodiments, the antisense strand does not include a 2’-O-methoxyethyl nucleoside. The 2’-O- methoxyethyl nucleoside of the antisense strand may be otherwise unmodified.

[0103] In some embodiments, any one of the following is true with regard to the sense 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’-fluoro modified purines, and all pyrimidines comprise 2’-O-methyl 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’-fluoro modified pyrimidines, and all purines comprise 2’-O-methyl modified purines; with the proviso that in any of the foregoing, the sense strand may include a 2’-O-methoxyethyl nucleoside. In some embodiments, all purines comprise 2’-fluoro modified purines, and all pyrimidines comprise a mixture of 2’-fluoro and 2’- O-methyl modified pyrimidines; with the proviso that a 2’-O-methoxyethyl nucleoside may be included in the sense strand. In some embodiments, in the sense strand, all purines comprise 2’-O-methyl modifiedAttorney Docket No. 54462-758.601 purines, and all pyrimidines comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; with the proviso that a 2’-O-methoxyethyl nucleoside may be included in the sense strand. In some embodiments, in the sense strand, all purines comprise 2’-fluoro modified purines, and all pyrimidines comprise 2’-O-methyl modified pyrimidines; with the proviso that a 2’-O-methoxyethyl nucleoside may be included in the sense strand. In some embodiments, all pyrimidines comprise 2’-fluoro modified pyrimidines, and all purines comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines; with the proviso that a 2’-O-methoxyethyl nucleoside may be included in the sense strand. In some embodiments, in the sense strand, all pyrimidines comprise 2’-O-methyl modified pyrimidines, and all purines comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines; with the proviso that a 2’-O-methoxyethyl nucleoside may be included in the sense strand. In some embodiments, in the sense strand, all pyrimidines comprise 2’-fluoro modified pyrimidines, and all purines comprise 2’-O-methyl modified purines; with the proviso that a 2’-O-methoxyethyl nucleoside may be included in the sense strand. In some embodiments, the sense strand includes a 2’-O-methoxyethyl nucleoside. The 2’-O-methoxyethyl nucleoside may be at nucleoside position 4 of the sense strand. The 2’-O-methoxyethyl nucleoside may include a 2’-O-methoxyethyl thymine nucleoside. In some embodiments, the sense strand does not include a 2’-O-methoxyethyl nucleoside. The 2’-O-methoxyethyl nucleoside of the sense strand may be otherwise unmodified.

[0104] 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; with the proviso that in any of the foregoing, the sense strand may include a deoxy nucleoside or a 2’-O-methoxyethyl nucleoside. In some embodiments, all purines comprise 2’-fluoro modified purines, and all pyrimidines comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; with the proviso that a 2’-O- methoxyethyl nucleoside may be included in the antisense strand. In some embodiments, in the antisense strand, all purines comprise 2’-O-methyl modified purines, and all pyrimidines comprise a mixture of 2’- fluoro and 2’-O-methyl modified pyrimidines; with the proviso that a 2’-O-methoxyethyl nucleoside may be included in the antisense strand. In some embodiments, in the antisense strand, all purines comprise 2’- O-methyl modified purines, and all pyrimidines comprise 2’-fluoro modified pyrimidines; with the proviso that a 2’-O-methoxyethyl nucleoside may be included in the antisense strand. In some embodiments, in the antisense strand, all pyrimidines comprise 2’-fluoro modified pyrimidines, and all purines comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines; with the proviso that a 2’-O- methoxyethyl nucleoside may be included in the antisense strand. In some embodiments, in the antisenseAttorney Docket No. 54462-758.601 strand, all pyrimidines comprise 2’-O-methyl modified pyrimidines, and all purines comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines; with the proviso that a 2’-O-methoxyethyl nucleoside may be included in the antisense strand. In some embodiments, in the antisense strand, all pyrimidines comprise 2’-O-methyl modified pyrimidines, and all purines comprise 2’-fluoro modified purines; with the proviso that a 2’-O-methoxyethyl nucleoside may be included in the antisense strand. In some embodiments, the antisense strand includes a 2’-O-methoxyethyl nucleoside. The 2’-O-methoxyethyl nucleoside may be at nucleoside position 4 of the sense strand. The 2’-O-methoxyethyl nucleoside may include a 2’-O-methoxyethyl thymine nucleoside. In some embodiments, the antisense strand does not include a 2’-O-methoxyethyl nucleoside. The 2’-O-methoxyethyl nucleoside of the antisense strand may be otherwise unmodified.

[0105] In some embodiments, any one of the following is true with regard to the sense strand, with the proviso that the sense strand may include a 2’-deoxy nucleoside: 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’-fluoro, and all pyrimidine nucleosides comprise 2’-O-methyl, 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’-fluoro, and all purine nucleosides comprise 2’-O-methyl. In some embodiments, in the sense strand, all purine nucleosides comprise 2’-fluoro, and all pyrimidine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methyl, with the proviso that the sense strand may include a 2’- deoxy nucleoside. In some embodiments, in the sense strand, all purine nucleosides comprise 2’-O- methyl, and all pyrimidine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methyl, with the proviso that the sense strand may include a 2’-deoxy nucleoside. In some embodiments, in the sense strand, all purine nucleosides comprise 2’-fluoro, and all pyrimidine nucleosides comprise 2’-O-methyl, with the proviso that the sense strand may include a 2’-deoxy nucleoside. In some embodiments, in the sense strand, all pyrimidine nucleosides comprise 2’-fluoro, and all purine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methyl, with the proviso that the sense strand may include a 2’-deoxy nucleoside. In some embodiments, in the sense strand, all pyrimidine nucleosides comprise 2’-O-methyl, and all purine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methyl, with the proviso that the sense strand may include a 2’-deoxy nucleoside. In some embodiments, in the sense strand, all pyrimidine nucleosides comprise 2’-fluoro, and all purine nucleosides comprise 2’-O-methyl, with the proviso that the sense strand may include a 2’-deoxy nucleoside. In some embodiments, the sense strand includes the 2’-deoxy nucleoside. In some embodiments, the sense strand does not include the 2’-deoxy nucleoside. Some embodiments include a proviso that the sense strand may include a 2’-O-methoxyethyl nucleoside (e.g., at position 4, counting from 5’ to 3’). Some embodiments include the 2’-O-methoxyethyl nucleoside in the sense strand. Some embodiments do not include the 2’-O-methoxyethyl nucleoside in the sense strand.Attorney Docket No. 54462-758.601

[0106] In some embodiments, any one of the following is true with regard to the sense 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’-fluoro, and all pyrimidine nucleosides comprise 2’-O-methyl, 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’-fluoro, and all purine nucleosides comprise 2’-O- methyl. In some embodiments, in the sense strand, 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, in the sense strand, all purine nucleosides comprise 2’-O-methyl, and all pyrimidine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methyl. In some embodiments, in the sense strand, all purine nucleosides comprise 2’-fluoro, and all pyrimidine nucleosides comprise 2’-O-methyl. In some embodiments, in the sense strand, all pyrimidine nucleosides comprise 2’-fluoro, and all purine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methyl. In some embodiments, in the sense strand, 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, in the sense strand, all pyrimidine nucleosides comprise 2’-fluoro, and all purine nucleosides comprise 2’-O-methyl. Some embodiments include a proviso that the sense strand may include a 2’-O-methoxyethyl nucleoside (e.g., at position 4, counting from 5’ to 3’). Some embodiments include the 2’-O-methoxyethyl nucleoside in the sense strand. Some embodiments do not include the 2’-O-methoxyethyl nucleoside in the sense strand.

[0107] In some embodiments, any one of the following is true with regard to the antisense strand, with the proviso that the antisense strand may include a 2’-deoxy nucleoside: 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, in 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, with the proviso that the antisense strand may include a 2’-deoxy nucleoside. In some embodiments, in the antisense strand, all purine nucleosides comprise 2’-O-methyl, and all pyrimidine nucleosides are modified with a mixture of 2’- fluoro and 2’-O-methyl, with the proviso that the antisense strand may include a 2’-deoxy nucleoside. In some embodiments, in the antisense strand, all purine nucleosides comprise 2’-fluoro, and all pyrimidine nucleosides comprise 2’-O-methyl, with the proviso that the antisense strand may include a 2’-deoxy nucleoside. In some embodiments, in the antisense strand, all pyrimidine nucleosides comprise 2’-fluoro,Attorney Docket No. 54462-758.601 and all purine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methyl, with the proviso that the antisense strand may include a 2’-deoxy nucleoside. In some embodiments, in the antisense strand, all pyrimidine nucleosides comprise 2’-O-methyl, and all purine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methyl, with the proviso that the antisense strand may include a 2’-deoxy nucleoside. In some embodiments, in the antisense strand, all pyrimidine nucleosides comprise 2’-fluoro, and all purine nucleosides comprise 2’-O-methyl, with the proviso that the antisense strand may include a 2’- deoxy nucleoside. In some embodiments, the antisense strand includes the 2’-deoxy nucleoside. In some embodiments, the antisense strand does not include the 2’-deoxy nucleoside. Some embodiments include a proviso that the antisense strand may include a 2’-O-methoxyethyl nucleoside (e.g., at position 4, counting from 5’ to 3’). Some embodiments include the 2’-O-methoxyethyl nucleoside in the antisense strand. Some embodiments do not include the 2’-O-methoxyethyl nucleoside in the antisense strand.

[0108] In some embodiments, any one of the following is true with regard 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, in 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. In some embodiments, in the antisense strand, all purine nucleosides comprise 2’-O-methyl, and all pyrimidine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methyl. In some embodiments, in the antisense strand, all purine nucleosides comprise 2’-fluoro, and all pyrimidine nucleosides comprise 2’-O-methyl. In some embodiments, in the antisense strand, all pyrimidine nucleosides comprise 2’-fluoro, and all purine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methyl. In some embodiments, in the antisense strand, 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, in the antisense strand, all pyrimidine nucleosides comprise 2’-fluoro, and all purine nucleosides comprise 2’-O-methyl. Some embodiments include a proviso that the antisense strand may include a 2’-O-methoxyethyl nucleoside (e.g., at position 4, counting from 5’ to 3’). Some embodiments include the 2’-O-methoxyethyl nucleoside in the antisense strand. Some embodiments do not include the 2’-O-methoxyethyl nucleoside in the antisense strand.

[0109] In some embodiments, the antisense strand comprises one or two 3’ phosphorothioate linkages. For example, there may be a phosphorothioate linkage between the first and second nucleotides from the 3’ end of the antisense strand, or there may be phosphorothioate linkages between the first, second and third nucleotides from the 3’ end of the antisense strand. In some embodiments, the sense strand comprises one or two 5’ phosphorothioate linkages. For example, there may be a phosphorothioateAttorney Docket No. 54462-758.601 linkage between the first and second nucleotides from the 5’ end of the sense strand, or there may be phosphorothioate linkages between the first, second and third nucleotides from the 5’ end of the sense strand. In some embodiments, the sense strand does not comprise one or two 5’ phosphorothioate linkages. For example, in some embodiments, there are no phosphorothioate linkages between the last 3 nucleotides at the 5’ end of the sense strand. In some embodiments, the sense strand comprises 5’ phosphate linkages. In some embodiments, the sense strand comprises one or two 3’ phosphorothioate linkages. For example, there may be a phosphorothioate linkage between the first and second nucleotides from the 3’ end of the sense strand, or there may be phosphorothioate linkages between the first, second and third nucleotides from the 3’ end of the sense strand.

[0110] In some embodiments, the antisense strand comprises a 5’ end comprising 2 phosphorothioate linkages. The 5’ end may comprise 3 nucleosides separated by the 2 phosphorothioate linkages. In some embodiments, the antisense strand comprises a 3’ end comprising 2 phosphorothioate linkages. The 3’ end may comprise 3 nucleosides separated by the 2 phosphorothioate linkages.

[0111] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of a target nucleic acid, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the oligonucleotide comprises a hydrophobic moiety. In some embodiments, the hydrophobic moiety may be attached at the 5’ end of the sense strand. In some embodiments, the hydrophobic moiety may be attached at the 3’ end of the sense strand. In some embodiments, the hydrophobic moiety may be attached at the 5’ end of the antisense strand. In some embodiments, the hydrophobic moiety may be attached at the 3’ end of the antisense strand.

[0112] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of a target nucleic acid, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the oligonucleotide comprises one or more vinyl phosphonate. In some embodiments, the one or more vinyl phosphonate may be attached at the 5’ end of the sense strand. In some embodiments, the one or more vinyl phosphonate may be attached at the 3’ end of the sense strand. In some embodiments, the one or more vinyl phosphonate may be attached at the 5’ end of the antisense strand. In some embodiments, the one or more vinyl phosphonate may be attached at the 3’ end of the antisense strand.

[0113] In some embodiments, the sense strand comprises or consists of RNA or modified RNA nucleotides. In some embodiments, the sense strand comprises a deoxy nucleoside. The deoxy nucleoside may include a DNA nucleoside. In some embodiments, the deoxy nucleoside comprises or consists of a 2’-deoxy nucleoside. The deoxy nucleoside may be at a position within the sense strand (5’ to 3’, where the 5’ position is 1). The position within the sense strand may be or include position 2, 4, 6, 8, 9, 10, 12, 14, 16, or 18, or a combination of said positions. The position within the sense strand may be or include position 2, 4, 6, 8, 10, 12, 14, 16, or 18, or a combination of said positions. The position within the sense strand may be or include position 2, 6, 9, 10, 14, or 18, or a combination of said positions. The position within the sense strand may be or include position 2, 6, 10, 14, or 18, or a combination of said positions. The position within the sense strand may be or include position 4, 8, 9, 12, or 16, or a combination of saidAttorney Docket No. 54462-758.601 positions. The position within the sense strand may be or include position 4, 8, 12, or 16, or a combination of said positions. The position within the sense strand may include position 9. The position within the sense strand may be position 9. The sense strand may include 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 deoxy nucleosides. In some embodiments, the sense strand includes 1 deoxy nucleoside. The sense strand may include 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 deoxy nucleosides, or a range of deoxy nucleosides defined by any two of the aforementioned numbers of deoxy nucleosides. The sense strand may include deoxy nucleosides at all even positions. The sense strand may include deoxy nucleosides at some even positions. The sense strand may include deoxy nucleosides at every other even position. The sense strand may include 1 deoxy nucleoside. The sense strand may include at least 1 deoxy nucleoside. The sense strand may include at least 2 deoxy nucleosides. The sense strand may include at least 3 deoxy nucleosides. The sense strand may include at least 4 deoxy nucleosides. The sense strand may include at least 5 deoxy nucleosides. The sense strand may include at least 6 deoxy nucleosides. The sense strand may include at least 7 deoxy nucleosides. The sense strand may include at least 8 deoxy nucleosides. The sense strand may include at least 9 deoxy nucleosides. The sense strand may include at least 10 deoxy nucleosides. The sense strand may include no greater than 2 deoxy nucleosides. The sense strand may include no greater than 3 deoxy nucleosides. The sense strand may include no greater than 4 deoxy nucleosides. The sense strand may include no greater than 5 deoxy nucleosides. The sense strand may include no greater than 6 deoxy nucleosides. The sense strand may include no greater than 7 deoxy nucleosides. The sense strand may include no greater than 8 deoxy nucleosides. The sense strand may include no greater than 9 deoxy nucleosides. The sense strand may include no greater than 10 deoxy nucleosides.

[0114] In some embodiments, the antisense strand comprises or consists of RNA or modified RNA nucleotides. In some embodiments, the antisense strand comprises a deoxy nucleoside. The deoxy nucleoside may include a DNA nucleoside. In some embodiments, the deoxy nucleoside comprises or consists of a 2’-deoxy nucleoside. The antisense strand may include 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 deoxy nucleosides, or a range of deoxy nucleosides defined by any two of the aforementioned numbers of deoxy nucleosides.

[0115] In some embodiments in which a deoxy nucleoside is included in the sense strand (e.g., at the 9th nucleotide counting from 5’ end), nucleosides at positions 1-8 include a mixture of 2’-fluoro and 2’-O-methyl modified nucleosides. In some embodiments in which a deoxy nucleoside is included in the sense strand, purines at positions 1-8 include a mixture of 2’-fluoro and 2’-O-methyl modified nucleosides. In some embodiments in which a deoxy nucleoside is included in the sense strand, pyrimidines at positions 1-8 include a mixture of 2’-fluoro and 2’-O-methyl modified nucleosides. In some embodiments in which a deoxy nucleoside is included in the sense strand, nucleosides at positions 1-8 all include 2’-O-methyl modified nucleosides. In some embodiments in which a deoxy nucleoside is included in the sense strand, purines at positions 1-8 all include 2’-O-methyl modified nucleosides. In some embodiments in which a deoxy nucleoside is included in the sense strand, pyrimidines at positions 1-8 all include 2’-O-methyl modified nucleosides. In some embodiments in which a deoxy nucleoside isAttorney Docket No. 54462-758.601 included in the sense strand, purines at positions 1-8 include a mixture of 2’-fluoro and 2’-O-methyl modified nucleosides, and pyrimidines at positions 1-8 all include 2’-O-methyl modified nucleosides. In some embodiments in which a deoxy nucleoside is included in the sense strand, pyrimidines at positions 1-8 include a mixture of 2’-fluoro and 2’-O-methyl modified nucleosides, and purines at positions 1-8 all include 2’-O-methyl modified nucleosides.

[0116] An antisense strand may start with an alternating pattern wherein the even numbered nucleosides include 2’-fluoro modified nucleosides, and odd numbered nucleosides include 2’-O-methyl modified nucleosides. The sense strand may then be optimized by replacing some 2’-fluoro modifications with 2’-O-methyl modifications. The antisense strand may include a mixture of 2’-fluoro modifications and 2’-O-methyl modifications. F. Modified ASOs

[0117] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of a target nucleic acid, wherein the oligonucleotide comprises an antisense oligonucleotide (ASO). In some embodiments, the ASO comprises modification pattern 1S, 2S, 3S, 4S, 1AS, or 2AS, or any other combination of modifications described herein. In some embodiments, the ASO comprises modification pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 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, 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 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. G. Formulations

[0118] In some embodiments, the composition is a pharmaceutical composition. In some embodiments, the composition is sterile. In some embodiments, the composition further comprises a pharmaceutically acceptable carrier.

[0119] In some embodiments, the pharmaceutically acceptable carrier comprises water. In some embodiments, the pharmaceutically acceptable carrier comprises a buffer. In some embodiments, the pharmaceutically acceptable carrier comprises a saline solution. In some embodiments, the pharmaceutically acceptable carrier comprises water, a buffer, or a saline solution. In some embodiments, the composition comprises a liposome. In some embodiments, the pharmaceutically acceptable carrier comprises liposomes, lipids, nanoparticles, proteins, protein-antibody complexes, peptides, cellulose, nanogel, or a combination thereof.Attorney Docket No. 54462-758.601

[0120] In some embodiments, the composition is formulated to cross the blood brain barrier. In some embodiments, the composition is formulated for central nervous system (CNS) delivery. In some embodiments, the composition includes a lipophilic compound. The lipophilic compound may be useful for crossing the blood brain barrier or for CNS delivery.

[0121] In some embodiments, the composition is formulated for administration. The administration may be systemic. In some embodiments, the administration is intravenous. In some embodiments, the administration is by injection. In some embodiments, the injection is subcutaneous. In some embodiments, the injection is subcutaneous. In some embodiments, the injection is intraperitoneal. In some embodiments, the injection is intramuscular. In some embodiments, the injection is intrathecal. The administration may be to an eye (e.g., intravitreal). The administration may be to a neural tissue. The administration may be to a brain. The administration may be intracerebroventricular. The administration may be intrathecal. The administration may be to a spinal cord or a spinal canal. In some embodiments, the formulation allows for delivery of a compound such as an oligonucleotide to an eye cell. In some embodiments, the formulation allows for delivery of a compound such as an oligonucleotide to a neural cell. H. Kits

[0122] Described herein, in some embodiments, are kits. The kit may include an oligonucleotide such as an siRNA described herein. The oligonucleotide may be conjugated to a lipid moiety. The kit may include a lipid moiety described herein. The oligonucleotide may comprise nucleoside modifications or modified internucleoside linkages. The oligonucleotide may include any modifications described herein, such as modifications from a base sequence. The kit may include a delivery reagent such as a needle. The kit may include instructions for use, such as methods for use in a method described herein. II. METHODS AND USES

[0123] Disclosed herein, in some embodiments, are methods of administering a composition described herein to a subject. Some embodiments relate to use a composition described herein, such as administering the composition to a subject.

[0124] Some embodiments relate to a method of treating a disorder in a subject in need thereof. Some embodiments relate to use of a composition described herein in the method of treatment. Some embodiments include administering a composition described herein to a subject with the disorder. In some embodiments, the administration treats the disorder in the subject. In some embodiments, the composition treats the disorder in the subject.

[0125] In some embodiments, the treatment comprises prevention, inhibition, or reversion of the disorder in the subject. Some embodiments relate to use of a composition described herein in the method of preventing, inhibiting, or reversing the disorder. Some embodiments relate to a method of preventing, inhibiting, or reversing a disorder a disorder in a subject in need thereof. Some embodiments include administering a composition described herein to a subject with the disorder. In some embodiments, the administration prevents, inhibits, or reverses the disorder in the subject. In some embodiments, the composition prevents, inhibits, or reverses the disorder in the subject.Attorney Docket No. 54462-758.601

[0126] Some embodiments relate to a method of preventing a disorder a disorder in a subject in need thereof. Some embodiments relate to use of a composition described herein in the method of preventing the disorder. Some embodiments include administering a composition described herein to a subject with the disorder. In some embodiments, the administration prevents the disorder in the subject. In some embodiments, the composition prevents the disorder in the subject.

[0127] Some embodiments relate to a method of inhibiting a disorder a disorder in a subject in need thereof. Some embodiments relate to use of a composition described herein in the method of inhibiting the disorder. Some embodiments include administering a composition described herein to a subject with the disorder. In some embodiments, the administration inhibits the disorder in the subject. In some embodiments, the composition inhibits the disorder in the subject.

[0128] Some embodiments relate to a method of reversing a disorder a disorder in a subject in need thereof. Some embodiments relate to use of a composition described herein in the method of reversing the disorder. Some embodiments include administering a composition described herein to a subject with the disorder. In some embodiments, the administration reverses the disorder in the subject. In some embodiments, the composition reverses the disorder in the subject.

[0129] In some embodiments, the administration is systemic. In some embodiments, the administration is by parenteral administration. In some embodiments, the administration is local (e.g., to a particular organ or tissue). In some embodiments, the administration is by inhalation. In some embodiments, the administration is topical. In some embodiments, the administration is by infusion. In some embodiments, the administration is by injection. In some embodiments, the administration is intravenous (e.g., by intravenous injection or infusion). In some embodiments, the administration is subcutaneous (e.g., by subcutaneous injection). In some embodiments, the administration is intraperitoneal. In some embodiments, the administration is intraparenchymal. In some embodiments, the administration is intramuscular (e.g., by intramuscular injection). In some embodiments, the administration may be to an eye tissue (e.g., by intravitreal, intracameral or subconjunctival injection, or by topical administration to the eye). In some embodiments, the administration may be to a central nervous system tissue (e.g., brain or spinal cord or spinal canal). In some embodiments, the administration is intracerebroventricular or intrathecal (e.g., by intrathecal injection or infusion). In some embodiments, the administration may be to joint tissue (e.g., by intra-articular injection). In some embodiments, the administration may be to airway or lung tissue (e.g., by intranasal, intratracheal or inhaled administration). In some embodiments, the administration may be to skin or connective tissue (e.g., by topical administration or injection to the skin).

[0130] Disclosed herein, in some embodiments, are methods of targeting an siRNA to a cell or tissue. The method may include conjugating the siRNA (e.g., the sense strand of the siRNA) to a lipid moiety described herein. The method may comprise delivering the siRNA conjugated to the lipid moiety to the tissue or cell. The method may comprise contacting the tissue or cell with the siRNA conjugated to the lipid moiety.Attorney Docket No. 54462-758.601

[0131] Disclosed herein, in some embodiments, are methods of reducing an amount of a target RNA or protein in a cell or tissue, comprising administering or delivering a composition described herein the cell or tissue. The composition may include an siRNA with an antisense strand that has a sequence complementary to the RNA. The antisense strand may bind to the RNA.

[0132] Disclosed herein, in some embodiments, are methods of making an siRNA composition. The method may include conjugating an siRNA to a lipid moiety. The siRNA and lipid moiety may include any siRNA or lipid moiety described herein. The method may include synthesizing the siRNA. The method may include synthesizing the lipid moiety. A. Disorders

[0133] Some embodiments of the methods described herein include treating a disorder in a subject in need thereof. In some embodiments, the disorder is an ocular disorder. In some embodiments, the disorder is an adipose-related or metabolic disorder. In some embodiments, the disorder is a kidney disorder. In some embodiments, the disorder is a brain disorder. In some embodiments, the disorder is a vascular or heart disorder. In some embodiments, the disorder is a muscle disorder. In some embodiments, the disorder is a lung or airway disorder. In some embodiments, the disorder is a joint disorder. In some embodiments, the disorder is an immune or inflammatory disorder. In some embodiments, the disorder is a neoplastic disorder. In some embodiments, the disorder is a connective tissue disorder. In some embodiments, the disorder is a skeletal disorder. In some embodiments, the disorder is a disorder of the male or female genital tracts or reproductive systems. In some embodiments, the disorder is an endocrine disorder. In some embodiments, the disorder is a psychiatric disorder. In some embodiments, the disorder is a liver disorder. In some embodiments, the disorder is a disorder of the digestive system. In some embodiments, the disorder is an infectious disorder. In some embodiments, the disorder is a blood disorder. In some embodiments, the disorder is a skin disorder. In some embodiments, the disorder is a urinary system disorder. In some embodiments, the disorder is an ear disorder. In some embodiments, the disorder is a nervous system disorder. B. Subjects

[0134] Some embodiments of the methods described herein include treatment of a subject. Non- limiting examples of subjects include vertebrates, animals, mammals, dogs, cats, cattle, rodents, mice, rats, primates, monkeys, and humans. In some embodiments, the subject is a vertebrate. In some embodiments, the subject is an animal. In some embodiments, the subject is a mammal. In some embodiments, the subject is a dog. In some embodiments, the subject is a cat. In some embodiments, the subject is a cattle. In some embodiments, the subject is a mouse. In some embodiments, the subject is a rat. In some embodiments, the subject is a primate. In some embodiments, the subject is a monkey. In some embodiments, the subject is an animal, a mammal, a dog, a cat, cattle, a rodent, a mouse, a rat, a primate, or a monkey. In some embodiments, the subject is a human. In some embodiments, the subject is male. In some embodiments, the subject is female. In some embodiments, the subject is an adult (e.g., at least 18 years old).Attorney Docket No. 54462-758.601 C. Baseline measurements

[0135] Some embodiments of the methods described herein include obtaining a baseline measurement from a subject. For example, in some embodiments, a baseline measurement is obtained from the subject prior to treating the subject. In some embodiments, the baseline measurement is obtained directly from the subject. In some embodiments, the baseline measurement is obtained by observation, for example by observation of the subject or of the subject’s tissue. In some embodiments, the baseline measurement is obtained noninvasively using an imaging device. In some embodiments, the baseline measurement is obtained in a sample from the subject. In some embodiments, the baseline measurement is obtained in one or more histological tissue sections. In some embodiments, the baseline measurement is obtained by performing an assay such as an immunoassay, a colorimetric assay, or a fluorescence assay, on the sample obtained from the subject. In some embodiments, the baseline measurement is obtained by an immunoassay, a colorimetric assay, a fluorescence assay, or a chromatography (e.g., HPLC) assay. In some embodiments, the baseline measurement is obtained by PCR. In some embodiments, the baseline measurement is a baseline target protein measurement. In some embodiments, the baseline target protein measurement comprises a baseline target protein level. In some embodiments, the baseline target protein level is indicated as a mass or percentage of target protein per sample weight. In some embodiments, the baseline target protein level is indicated as a mass or percentage of target protein per sample volume. In some embodiments, the baseline target protein level is indicated as a mass or percentage of target protein per total protein within the sample. In some embodiments, the baseline target protein measurement is a baseline circulating / tissue target protein measurement. In some embodiments, the baseline target protein measurement is obtained by an assay such as an immunoassay, a colorimetric assay, or a fluorescence assay. In some embodiments, the baseline measurement is a baseline target mRNA measurement. In some embodiments, the baseline target mRNA measurement comprises a baseline target mRNA level. In some embodiments, the baseline target mRNA level is indicated as an amount or percentage of target mRNA per sample weight. In some embodiments, the baseline target mRNA level is indicated as an amount or percentage of target mRNA per sample volume. In some embodiments, the baseline target mRNA level is indicated as an amount or percentage of target mRNA per total mRNA within the sample. In some embodiments, the baseline target mRNA level is indicated as an amount or percentage of target mRNA per total nucleic acids within the sample. In some embodiments, the baseline target mRNA level is indicated relative to another mRNA level, such as an mRNA level of a housekeeping gene, within the sample. In some embodiments, the baseline target mRNA measurement is a baseline tissue target mRNA measurement. In some embodiments, the baseline target mRNA measurement is obtained by an assay such as a polymerase chain reaction (PCR) assay. In some embodiments, the PCR comprises quantitative PCR (qPCR). In some embodiments, the PCR comprises reverse transcription of the target mRNA. Some embodiments of the methods described herein include obtaining a sample from a subject. In some embodiments, the baseline measurement is obtained in a sample obtained from the subject. In some embodiments, the sample is obtained from the subject prior to administration or treatment of the subject with a composition described herein. In some embodiments, a baseline measurement is obtained in aAttorney Docket No. 54462-758.601 sample obtained from the subject prior to administering the composition to the subject. In some embodiments, the sample is obtained from the subject in a fasted state. In some embodiments, the sample is obtained from the subject after an overnight fasting period. In some embodiments, the sample is obtained from the subject in a fed state.

[0136] In some embodiments, the sample comprises a fluid. In some embodiments, the sample is a fluid sample. In some embodiments, the sample is a blood, plasma, or serum sample. In some embodiments, the sample comprises blood. In some embodiments, the sample is a blood sample. In some embodiments, the sample is a whole-blood sample. In some embodiments, the blood is fractionated or centrifuged. In some embodiments, the sample comprises plasma. In some embodiments, the sample is a plasma sample. A blood sample may be a plasma sample. In some embodiments, the sample comprises serum. In some embodiments, the sample is a serum sample. A blood sample may be a serum sample. In some embodiments, the sample comprises sputum. In some embodiments, the fluid comprises synovial fluid. In some embodiments, the fluid comprises bronchoalveolar lavage fluid. In some embodiments, the fluid comprises cerebrospinal fluid (CSF). For example, the fluid may be obtained by a spinal tap. In some embodiments, the fluid comprises spinal fluid. In some embodiments, the fluid comprises cerebral fluid. In some embodiments, the fluid comprises cerebral fluid. In some embodiments, the sample comprises a tissue. In some embodiments, the sample is a tissue sample. In some embodiments, the tissue comprises liver, adipose, kidney, heart, vascular, muscle, skin, immune, airway, lung, joint, eye, brain, or spinal cord tissue. For example, the baseline target mRNA measurement, or the baseline target protein measurement, may be obtained in a liver, adipose, kidney, heart, vascular, muscle, skin, immune, airway, lung, joint, eye, brain, or spinal cord sample obtained from the patient. In some embodiments, the tissue comprises kidney tissue. The kidney tissue may include renal medullary cells, or renal proximal tubule cells. In some embodiments, the tissue comprises adipose tissue. In some embodiments, the adipose tissue comprises white adipose tissue. The adipose tissue may include adipocytes. In some embodiments, the tissue comprises liver tissue. The liver may include hepatocytes. In some embodiments, the tissue is non-liver tissue. In some embodiments, the tissue comprises eye tissue. In some embodiments, the eye tissue comprises retinal tissue. In some embodiments, the tissue comprises brain tissue. The brain tissue may include neurons or glial cells. The brain tissue may comprise cerebellum. The brain tissue may comprise frontal cortex. The brain tissue may comprise temporal cortex. The brain tissue may comprise tissue from the right hemisphere of the brain (e.g., right frontal cortex or right temporal cortex). The brain tissue may comprise tissue from the left hemisphere of the brain (e.g., left frontal cortex or left temporal cortex). The brain tissue may comprise hippocampal tissue. In some embodiments, the tissue comprises nerve tissue. In some embodiments, the tissue comprises a nerve. In some embodiments, the tissue comprises spinal tissue. In some embodiments, the tissue comprises tissue of the spinal cord or spinal canal. In some embodiments, the tissue comprises lung tissue, In some embodiments, the tissue comprises vascular tissue. The vascular tissue may include vascular endothelial cells.

[0137] In some embodiments, the sample includes cells. In some embodiments, the sample comprises a cell. In some embodiments, the cell comprises a liver cell, adipose cell, kidney cell, heart cell,Attorney Docket No. 54462-758.601 vascular cell, muscle cell, skin cell, airway cell, immune cell, blood cell, connective tissue cell, lung cell, joint cell, eye cell, brain cell, or spinal cord cell. In some embodiments, the cell is a renal cell. In some embodiments, the renal cell is a renal medullary cell. In some embodiments, the renal cell is a renal proximal tubule cell. In some embodiments, the cell is an adipose cell. In some embodiments, the adipose cell is an adipocyte. In some embodiments, the cell is a liver cell. In some embodiments, the liver cell is a hepatocyte. In some embodiments, the cell is a non-liver cell, or is not a hepatocyte. In some embodiments, the cell is an eye cell. In some embodiments, the eye cell is a retinal cell. In some embodiments, the eye cell is a rod cell. In some embodiments, the eye cell is a cone cell. In some embodiments, the cell is a brain cell. In some embodiments, the brain cell is from a brain tissue such as cerebellum, cortex, hippocampal tissue. In some embodiments, the brain cell is a neuron. In some embodiments, the brain cell is a glial cell. In some embodiments, the cell is a spinal cell. In some embodiments, the cell is a spinal cord cell. In some embodiments, the cell is a lung cell. In some embodiments, the cell is a vasculature cell. In some embodiments, the vasculature cell is an endothelial cell. D. Effects

[0138] In some embodiments, the composition or administration of the composition affects a measurement such as a target protein measurement or a target mRNA measurement, relative to the baseline measurement.

[0139] Some embodiments of the methods described herein include obtaining the measurement from a subject. For example, the measurement may be obtained from the subject after treating the subject. In some embodiments, the measurement is obtained in a second sample (such as a fluid or tissue sample described herein) obtained from the subject after the composition is administered to the subject. In some embodiments, the measurement is an indication that the disorder has been treated.

[0140] In some embodiments, the measurement is obtained directly from the subject. In some embodiments, the measurement is obtained noninvasively using an imaging device. In some embodiments, the measurement is obtained in a second sample from the subject. In some embodiments, the measurement is obtained in one or more histological tissue sections. In some embodiments, the measurement is obtained by performing an assay on the second sample obtained from the subject. In some embodiments, the measurement is obtained by an assay, such as an assay described herein. In some embodiments, the assay is an immunoassay, a colorimetric assay, a fluorescence assay, a chromatography (e.g., HPLC) assay, or a PCR assay. In some embodiments, the measurement is obtained by an assay such as an immunoassay, a colorimetric assay, a fluorescence assay, or a chromatography (e.g., HPLC) assay. In some embodiments, the measurement is obtained by PCR. In some embodiments, the measurement is obtained by histology. In some embodiments, the measurement is obtained by observation. In some embodiments, additional measurements are made, such as in a 3rd sample, a 4th sample, or a fifth sample.

[0141] In some embodiments, the measurement is obtained within 1 hour, within 2 hours, within 3 hours, within 4 hours, within 5 hours, within 6 hours, within 12 hours, within 18 hours, or within 24 hours after the administration of the composition. In some embodiments, the measurement is obtainedAttorney Docket No. 54462-758.601 within 1 day, within 2 days, within 3 days, within 4 days, within 5 days, within 6 days, or within 7 days after the administration of the composition. In some embodiments, the measurement is obtained within 1 week, within 2 weeks, within 3 weeks, within 1 month, within 2 months, within 3 months, within 6 months, within 1 year, within 2 years, within 3 years, within 4 years, or within 5 years after the administration of the composition. In some embodiments, the measurement is obtained after 1 hour, after 2 hours, after 3 hours, after 4 hours, after 5 hours, after 6 hours, after 12 hours, after 18 hours, or after 24 hours after the administration of the composition. In some embodiments, the measurement is obtained after 1 day, after 2 days, after 3 days, after 4 days, after 5 days, after 6 days, or after 7 days after the administration of the composition. In some embodiments, the measurement is obtained after 1 week, after 2 weeks, after 3 weeks, after 1 month, after 2 months, after 3 months, after 6 months, after 1 year, after 2 years, after 3 years, after 4 years, or after 5 years, following the administration of the composition.

[0142] In some embodiments, the composition reduces the measurement relative to the baseline measurement. In some embodiments, the reduction is measured in a second sample obtained from the subject after administering the composition to the subject. In some embodiments, the reduction is measured directly in the subject after administering the composition to the subject. In some embodiments, the measurement is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline measurement. In some embodiments, the measurement is decreased by about 10% or more, relative to the baseline measurement. In some embodiments, the measurement is decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, relative to the baseline measurement. In some embodiments, the measurement is decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, relative to the baseline measurement. In some embodiments, the measurement is decreased by no more than about 10%, relative to the baseline measurement. In some embodiments, the measurement 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%, no more than about 90%, or no more than about 100% relative to the baseline measurement. In some embodiments, the measurement is decreased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or by a range defined by any of the two aforementioned percentages.

[0143] In some embodiments, the composition increases the measurement relative to the baseline measurement. In some embodiments, the increase is measured in a second sample obtained from the subject after administering the composition to the subject. In some embodiments, the increase is measured directly in the subject after administering the composition to the subject. In some embodiments, the measurement is increased by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline measurement. In some embodiments, the measurement is increased by about 10% or more, relative to the baseline measurement. In some embodiments, the measurement 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, relative to the baseline measurement. In some embodiments, the measurement is increased by about 100% or more, increased by about 250% or more,Attorney Docket No. 54462-758.601 increased by about 500% or more, increased by about 750% or more, or increased by about 1000% or more, relative to the baseline measurement. In some embodiments, the measurement is increased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, relative to the baseline measurement. In some embodiments, the measurement is increased by no more than about 10%, relative to the baseline measurement. In some embodiments, the measurement 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% relative to the baseline measurement. In some embodiments, the measurement is increased by no more than about 100%, increased by no more than about 250%, increased by no more than about 500%, increased by no more than about 750%, or increased by no more than about 1000%, relative to the baseline measurement. In some embodiments, the measurement is increased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 250%, 500%, 750%, or 1000%, or by a range defined by any of the two aforementioned percentages.

[0144] In some embodiments, the measurement is an target protein measurement. In some embodiments, the target protein measurement comprises an target protein level. In some embodiments, the target protein level is indicated as a mass or percentage of target protein per sample weight. In some embodiments, the target protein level is indicated as a mass or percentage of target protein per sample volume. In some embodiments, the target protein level is indicated as a mass or percentage of target protein per total protein within the sample. In some embodiments, the target protein measurement is a circulating / tissue target protein measurement. In some embodiments, the target protein measurement is obtained by an assay such as an immunoassay, a colorimetric assay, or a fluorescence assay.

[0145] In some embodiments, the composition reduces the target protein measurement relative to the baseline target protein measurement. In some embodiments, the composition reduces circulating target protein levels relative to the baseline target protein measurement. In some embodiments, the composition reduces tissue target protein levels relative to the baseline target protein measurement. In some embodiments, the reduced target protein levels are measured in a second sample obtained from the subject after administering the composition to the subject. In some embodiments, the target protein measurement is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline target protein measurement. In some embodiments, the target protein measurement is decreased by about 10% or more, relative to the baseline target protein measurement. In some embodiments, the target protein measurement is decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, relative to the baseline target protein measurement. In some embodiments, the ...

Claims

Attorney Docket No. 54462-758.601 CLAIMS What is claimed is:

1. A composition comprising: a small interfering RNA (siRNA) comprising a sense strand, an antisense strand, and a lipid moiety connected to the 5’ or 3’ end of the sense strand or antisense strand; wherein the lipid moiety comprises a phenethyl or cyclohexanyl linker, wherein the phenethyl or cyclohexanyl linker is connected to a lipid and to the end of the sense strand or antisense strand, and wherein the lipid comprises a myristyl, lauryl, or stearyl^group.

2. The composition of claim 1, wherein the lipid and the end of the sense or antisense strand are connected to the phenyl or cyclohexanyl linker in the 1,4; 1,3; or 1,2 substitution pattern.

3. The composition of claim 1, wherein the lipid and the end of the sense or antisense strand are connected to the phenyl or cyclohexanyl linker in the 1,4 substitution pattern.

4. The composition of claim 1, wherein the lipid moiety comprises the following structure:wherein the dotted line indicates a covalent connection to the end of the sense or antisense strand, with the proviso that R is not an octane.

5. The composition of claim 1, wherein the lipid moiety comprises the following structure:; wherein the dotted line indicates a covalent connection to the end of the sense or antisense strand, n is 2, and R is an alkyl group containing 4-18 carbons. 1, wherein the lipid moiety comprises the following structure:; wherein the dotted line indicates a covalent connection to the end of the sense or antisense strand, n is 2, and R is an alkyl group containing 4-18 carbons.

7. The composition of claim 1, wherein the lipid moiety comprises the following structure:Attorney Docket No. 54462-758.601 ;wherein the dotted line indicates a covalent connection to the end of the sense or antisense strand, and R is an alkyl group containing 4-18 carbons.

8. The composition of claim 1, wherein the composition comprises the structure: ,.

9. The composition of claim 1, wherein the lipid moiety is connected to the 5’ end of the sense strand or antisense strand.

10. The composition of claim 1, wherein the lipid moiety is connected through a phosphate to the 5’ end of the sense strand or antisense strand.

11. The composition of claim 1, wherein the lipid moiety is connected to an end of the sense strand.

12. The composition of claim 1, wherein the antisense strand comprises a 5’ vinyl phosphonate.

13. The composition of claim 1, wherein the antisense strand comprises one or two 5’ phosphorothioate linkages.

14. The composition of claim 1, wherein the antisense strand comprises one or two 3’ phosphorothioate linkages.

15. The composition of claim 1, wherein the sense strand comprises one or two 5’ phosphorothioate linkages.

16. The composition of claim 1, wherein the sense strand does not comprise one or two 5’Attorney Docket No. 54462-758.601 phosphorothioate linkages.

17. The composition of claim 1, wherein the sense strand comprises 5’ phosphate linkages.

18. The composition of claim 1, wherein the sense strand comprises one or two 3’ phosphorothioate linkages.

19. The composition of claim 1, wherein any one of the following is true with regard to the sense strand: the sense strand comprises at least three modified nucleosides, wherein the three modifications comprises a 2’-fluoro modified nucleoside, a 2’-O-methyl modified nucleoside, and 2’-O-methoxyethyl; the sense strand comprises at least two modified nucleosides, wherein the two modifications comprises a 2’-fluoro modified nucleoside, a 2’-O-methyl modified nucleoside, and 2’-O-methoxyethyl; or the sense strand comprises at least a 2’-fluoro modified nucleoside, a 2’-O-methyl modified nucleoside, or a 2’-O-methoxyethyl; with the proviso that in any of the foregoing, the sense strand may include a 2’-deoxy nucleoside.

20. The composition of claim 1, 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 (ii) 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-methoxyethyl 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) 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) a mixture of 2’-fluoro and 2’-O-methoxyethylAttorney Docket No. 54462-758.601 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.

21. The composition of claim 19 or 20, wherein the sense strand includes the 2’-deoxy nucleoside.

22. The composition of claim 19 or 20, wherein the sense strand does not include the 2’- deoxy nucleoside.

23. The composition of claim 1, wherein the antisense strand comprises a combination of 2’- fluoro and 2’-O-methyl modifications.

24. The composition of claim 1, wherein the sense strand and the antisense strand form a duplex.

25. The composition of claim 24, wherein the duplex comprises at least 10 base pairs, at least 11 base pairs, at least 12 base pairs, at least 13 base pairs, at least 14 base pairs, at least 15 base pairs, at least 16 base pairs, at least 17 base pairs, at least 18 base pairs, at least 19 base pairs, at least 20 base pairs, at least 21 base pairs, at least 22 base pairs, at least 23 base pairs, at least 24 base pairs, or at least 25 base pairs.

26. The composition of claim 24, wherein the duplex comprises 19 base pairs.

27. The composition of claim 24, wherein the duplex comprises a sense strand overhang.

28. The composition of claim 27, wherein the sense strand overhang comprises 1-4 nucleotides.

29. The composition of claim 27, wherein the sense strand overhang comprises 2 nucleotides.

30. The composition of claim 27, wherein the sense strand overhang comprises uracil.

31. The composition of claim 24, wherein the duplex comprises an antisense strand overhang.

32. The composition of claim 31, wherein the antisense strand overhang comprises 1-4 nucleotides.

33. The composition of claim 31, wherein the antisense strand overhang comprises 2 nucleotides.

34. The composition of claim 31, wherein the antisense strand overhang comprises uracil.

35. The composition of claim 24, wherein the 5’ end of the antisense strand comprises 3 nucleosides separated by the 2 phosphorothioate linkages.

36. The composition of claim 24, wherein the 3’ end of the antisense strand comprises 3Attorney Docket No. 54462-758.601 nucleosides separated by the 2 phosphorothioate linkages.

37. The composition of claim 24, wherein the sense strand comprises any one of modification patterns 1S-115S.

38. The composition of claim 24, wherein the antisense strand comprises any one of modification patterns 1AS-59AS.

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

40. A method of treatment, comprising administering to a subject in need thereof an effective amount of the composition of any one of claims 1-39.

41. The method of claim 40, wherein the administration comprises intravenous, subcutaneous, parenteral, intramuscular, intraperitoneal, intraparenchymal, intravitreal, intracameral, subconjunctival, intrathecal, intracerebroventricular, intra-articular, intranasal, intratracheal, inhaled, or topical administration.

42. The method of claim 40, wherein the siRNA targets an mRNA encoding a protein that mediates a disease of the subject.

43. The method of claim 42, wherein the mRNA is in a tissue of the subject, the tissue comprising a liver, adipose, kidney, heart, vascular, muscle, skin, immune, airway, lung, joint, eye, brain, or spinal cord tissue.

44. A method of reducing an amount of a target RNA or protein encoded by the target RNA in a cell, comprising administering the composition of any one of claims 1-39 to the cell, wherein the antisense strand comprises a sequence that is complementary to and binds to the RNA.

45. The method of claim 44, wherein the composition is administered to a subject comprising the cell.

46. The method of claim 44, wherein the administration comprises intravenous, subcutaneous, parenteral, intramuscular, intraperitoneal, intraparenchymal, intravitreal, intracameral, subconjunctival, intrathecal, intracerebroventricular, intra-articular, intranasal, intratracheal, inhaled, or topical administration.

47. The method of claim 44, wherein the administration reduces a measurement of the target RNA or protein encoded by the RNA, by at least 10% relative to a baseline measurement or control.

48. The method of claim 44, wherein the cell comprises a liver, adipose, kidney, heart, vascular, muscle, skin, airway, immune, blood, connective tissue, lung, joint, eye, brain, or spinal cord cell.

Images