Treatment of fgg related hearing disorders

Abstract

Disclosed herein are compositions comprising an oligonucleotide that targets FGG. The oligonucleotide may include a small interfering RNA (siRNA) or an antisense oligonucleotide (ASO). Also provided herein are methods of treating a hearing disorder related to FGG. The method may include providing an oligonucleotide to a subject that targets FGG.

Description

TREATMENT OF FGG RELATED HEARING DISORDERSCROSS-REFERENCE

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 455,363, filed March 29, 2023, U.S. Provisional Application No. 63 / 582,784, filed September 14, 2023, and U.S. Provisional Application No. 63 / 585,553, 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 54462-749_601_SL.xml, created March 27, 2024, which is 6,429,668 bytes in size. The information in the electronic format of the Sequence Listing is incorporated by reference in its entirety.BACKGROUND

[0003] Hearing disorders are widely abundant, and improved therapeutics are needed.SUMMARY

[0004] Disclosed herein, in some aspects, are compositions comprising oligonucleotides target FGG. The oligonucleotide may be useful for treating an FGG-related disorder such as hearing loss or another hearing-related disorder. In certain aspects, described herein is a composition comprising an oligonucleotide that targets FGG and when administered to a subject in an effective amount improves a hearing measurement in the subject, relative to a baseline hearing measurement. In certain aspects, described herein is a composition comprising an oligonucleotide that targets FGG and when administered to a subject in an effective amount improves a hearing disorder measurement in the subject, relative to a baseline hearing disorder measurement. In some embodiments, the hearing disorder comprises an idiopathic sudden sensorineural hearing loss (ISSNHL), noise -induced sensorineural hearing loss, hearing loss, sensorineural hearing loss, tinnitus, or conductive hearing loss. In some embodiments, the hearing measurement or the hearing disorder measurement comprises a pure -tone audiometry, pure tone threshold, speech audiometry and speech reception threshold, tympanometry, Stapedius reflex measurements, German speech intelligibility test (Freiburger Sprachtest), brainstem audiometry, or otoacoustic emissions measurement.

[0005] In certain aspects, described herein is a composition comprising an oligonucleotide that targets FGG and when administered to a subject in an effective amount decreases fibrinogen. In some embodiments, the oligonucleotide comprises a modified intemucleoside linkage. In some embodiments, the modified intemucleoside linkage comprises alkylphosphonate, phosphorothioate, methylphosphonate, phosphorodithioate, alkylphosphonothioate, phosphoramidate, carbamate, carbonate, phosphate triester, acetamidate, or carboxymethyl ester, or a combination thereof. In some embodiments, the modified intemucleoside linkage comprises one or more phosphorothioate linkages. In some embodiments, theoligonucleotide comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 modified intemucleoside linkages. In some embodiments, the oligonucleotide comprises a 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, 2'-deoxy, or a combination thereof. In some embodiments, the modified nucleoside comprises an LNA. In some embodiments, the modified nucleoside comprises a 2’, 4’ constrained ethyl nucleic acid. In some embodiments, the modified nucleoside comprises 2'-O-methyl nucleoside, 2'-deoxyfluoro nucleoside, 2'- O-N-methylacetamido (2'-0-NMA) nucleoside, 2'-O-dimethylaminoethoxyethyl (2'-O-DMAEOE) nucleoside, 2'-O-aminopropyl (2'-O-AP) nucleoside, or 2'-ara-F, or a combination thereof. In some embodiments, the modified nucleoside comprises one or more 2’-fluoro modified nucleosides. In some embodiments, the modified nucleoside comprises 2’-O-alkyl modified nucleoside. In some embodiments, the oligonucleotide comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 modified nucleosides. In some embodiments, the oligonucleotide comprises a sugar moiety attached at a 3’ or 5’ terminus of the oligonucleotide. In some embodiments, the sugar comprises N- acetylgalactosamine (GalNAc), N-acetylglucosamine (GlcNAc), or mannose. In some embodiments, the sugar comprises GalNAc. In some embodiments, the sugar moiety comprises ETL17. In some embodiments, the oligonucleotide comprises a small interfering RNA (siRNA) comprising a sense strand and an antisense strand. In some embodiments, the sense strand is 12-30 nucleosides in length. In some embodiments, the antisense strand is 12-30 nucleosides in length. In some embodiments, the oligonucleotide comprises a nucleoside base sequence at least 90% identical to the sequence of any one of SEQ ID NOs: 1-3484. In some embodiments, the oligonucleotide comprises the nucleoside base sequence of any one of SEQ ID NOs: 1-3484.

[0006] In certain aspects, described herein is a composition comprising an oligonucleotide that inhibits the expression of FGG, 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 comprise a nucleoside sequence comprising about 12-30 contiguous nucleosides of SEQ ID NO: 3621. 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, the antisense strand comprises a mixture of 2 ’-fluoro and 2’-O-methyl modified nucleosides. In some embodiments, the oligonucleotide comprises an antisense oligonucleotide (ASO). In some embodiments, the ASO is 12-30 nucleosides in length.

[0007] In certain aspects, described herein is a composition comprising an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an ASO about 12-30 nucleosides in length and a nucleoside sequence complementary to about 12-30 contiguous nucleosides of SEQ ID NO: 3621. In some embodiments, the composition further comprises a pharmaceutically acceptable carrier. In some embodiments, described herein is a method of treating a subject having a hearing disorder, comprising administering an effective amount of the composition described herein to the subject. In some embodiments, the hearing disorder comprises an idiopathic sudden sensorineural hearing loss (ISSNHL), noise-induced sensorineural hearing loss, hearing loss, sensorineural hearing loss, tinnitus, or conductive hearing loss.BRIEF DESCRIPTION OF THE DRAWINGS

[0008] FIG. 1 is an example of a GalNAc ligand.

[0009] FIG. 2 is an example of a GalNAc ligand.DETAILED DESCRIPTION

[0010] Large-scale human genetic data can improve the success rate of pharmaceutical discovery and development. A Genome Wide Association Study (GWAS) detects associations between genetic variants and traits in a population sample, and this improves understanding of the biology of disease and provides evidence of applicable treatments. A GWAS generally utilizes genotyping and / or sequencing data, and often involves an evaluation of millions of genetic variants that are relatively evenly distributed across the genome. The most common GWAS design is the case-control study, which involves comparing variant frequencies in cases versus controls. If a variant has a significantly different frequency in cases versus controls, that variant is considered associated with disease. Association statistics used in a GWAS include p-values, as a measure of statistical significance; odds ratios (OR), as a measure of effect size; or beta coefficients (beta), as a measure of effect size. Researchers often assume an additive genetic model and calculate an allelic odds ratio, which is the increased (or decreased) risk of disease conferred by each additional copy of an allele (compared to carrying no copies of that allele). An additional concept in design and interpretation of GWAS is that of linkage disequilibrium, which is the non-random association of alleles. The presence of linkage disequilibrium can obfuscate which variant is “causal.”

[0011] Functional annotation of variants and / or wet lab experimentation is used to identify the 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 is exogenously ‘programmed’ into replicating the observation from human genetics. There are several options fortherapeutic modalities that may be brought to bear in translating therapeutic targets identified via human genetics into novel medicines. These include well established therapeutic modalities such as small molecules and monoclonal antibodies, maturing modalities such as oligonucleotides, and emerging modalities such as gene therapy and gene editing. The choice of therapeutic modality depends on factors such as the location of a target (for example, intracellular, extracellular, or secreted), a relevant tissue (for example, liver, brain, or neural tissue) and a relevant indication.

[0013] The fibrinogen gamma chain gene, also known as fibrinogen gamma gene (FGG), is located on chromosome 4, and encodes fibrinogen gamma chain (also referred to as FGG protein). The FGG protein may be a gamma component of fibrinogen. FGG protein may include 453 amino acids and have a mass of about 51.5 kDa. An example of a FGG amino acid sequence, and further description of FGG is included at uniprot.org under accession no. P02679 (last modified September 29, 2021). FGG may be secreted and affect hearing. FGG may be secreted by the liver cells such as hepatocytes.

[0014] Here, it is shown that genetic variants causing inactivation of FGG resulted in protective associations for hearing disorders. Therefore, inhibition of FGG may serve as a therapeutic for treatment of hearing disorders (e.g., idiopathic sudden sensorineural hearing loss (ISSNHL), noise-induced sensorineural hearing loss, hearing loss, sensorineural hearing loss, tinnitus, or conductive hearing loss).

[0015] Disclosed herein are compositions comprising an oligonucleotide that targets FGG. Where inhibition or targeting of FGG is disclosed, it is contemplated that some embodiments may include inhibiting or targeting a FGG protein or FGG RNA. For example, by inhibiting or targeting an RNA (e.g., mRNA) encoded by the FGG gene using an oligonucleotide described herein, the FGG protein may be inhibited or targeted as a result of there being less production of the FGG protein by translation of the FGG RNA; or a FGG protein may be targeted or inhibited by an oligonucleotide that binds or interacts with a FGG RNA and reduces production of the FGG protein from the FGG RNA. Thus, targeting FGG may refer to binding a FGG RNA and reducing FGG RNA or protein levels. The oligonucleotide may include a small interfering RNA (siRNA) or an antisense oligonucleotide (ASO).

[0016] Also provided herein are methods of treating a hearing disorder or disease by providing or administering an oligonucleotide that targets FGG in a subject in need thereof. Administration of the oligonucleotide to a subject may improve hearing related traits, such as pure-tone audiometry, pure tone threshold, speech audiometry and speech reception threshold, tympanometry, Stapedius reflex measurements, German speech intelligibility test (Freiburger Sprachtest), brainstem audiometry, or otoacoustic emissions.I. COMPOSITIONS

[0017] Disclosed herein, in some embodiments, are compositions comprising an oligonucleotide. In some embodiments, the composition comprises an oligonucleotide that targets FGG. In some embodiments, the composition consists of an oligonucleotide that targets FGG. In some embodiments, the oligonucleotide reduces FGG mRNA expression in the subject. In some embodiments, the oligonucleotide reduces FGG protein expression in the subject. The oligonucleotide may include a small interfering RNA (siRNA) described herein. The oligonucleotide may include an antisense oligonucleotide (ASO) describedherein. In some embodiments, a composition described herein is used in a method of treating a disorder in a subject in need thereof. Some embodiments relate to a composition comprising an oligonucleotide for use in a method of treating a disorder as described herein. Some embodiments relate to use of a composition comprising an oligonucleotide, in a method of treating a disorder (e.g., hearing disorder) as described herein.

[0018] Some embodiments include a composition comprising an oligonucleotide that targets FGG and when administered to a subject in an effective amount decreases FGG mRNA or protein levels in a cell (e.g., hepatocyte or neuron), fluid (e.g., blood, serum, plasma, or cerebrospinal fluid (CSF)), tissue (e.g., brain or liver tissue), or organ (e.g., the brain or liver).

[0019] In some embodiments, the composition comprises an oligonucleotide that targets FGG and when administered to a subject in an effective amount decreases FGG mRNA levels in a cell or tissue. In some embodiments, the cell is a liver cell (e.g., hepatocyte). In some embodiments, the cell is a neuron. In some embodiments, the tissue is liver tissue. In some embodiments, the tissue is neural tissue. In some embodiments, the neural tissue is CNS tissue. In some embodiments, the neural tissue is brain tissue (e.g., neuronal, glia, or endothelial tissue). In some embodiments, the fluid is CSF. In some embodiments, the FGG 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 FGG mRNA levels are decreased by about 10% or more, as compared to prior to administration. In some embodiments, the FGG 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 FGG 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 FGG mRNA levels are decreased by no more than about 10%, as compared to prior to administration. In some embodiments, the FGG 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 FGG 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.

[0020] In some embodiments, the composition comprises an oligonucleotide that targets FGG and when administered to a subject in an effective amount decreases FGG protein levels in a cell, fluid (e.g., CSF) or tissue. In some embodiments, the cell is a hepatocyte. In some embodiments, the cell is a neural cell (e.g., CNS cell (e.g., brain cell)). In some embodiments, the cell is a neuronal cell. In some embodiments, the cell is a glial cell. In some embodiments, the cell is an endothelial cell. In some embodiments, the tissue is liver tissue. In some embodiments, the tissue is neural (e.g., CNS (e.g., brain)) tissue. In some embodiments, the fluid is CSF. In some embodiments, the FGG 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 FGG protein levels are decreased by about 10% or more, ascompared to prior to administration. In some embodiments, the FGG 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 FGG 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 FGG protein levels are decreased by no more than about 10%, as compared to prior to administration. In some embodiments, the FGG protein levels are decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration. In some embodiments, the FGG 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.

[0021] In some embodiments, the composition comprises an oligonucleotide that targets FGG and when administered to a subject in an effective amount diminishes a hearing disorder or disease phenotype, such as a hearing disorder phenotype. A disorder may include a disease. The hearing disease or disorder may include hearing disorders (e.g., idiopathic sudden sensorineural hearing loss (ISSNHL), noise - induced sensorineural hearing loss, hearing loss, sensorineural hearing loss, tinnitus, or conductive hearing loss). For hearing indications, fibrinogen may be lowered enough to have a therapeutic effect on hearing disorders but without significantly affecting coagulation parameters such as PT or aPTT.

[0022] In some embodiments, the composition comprises an oligonucleotide that targets FGG and when administered to a subject in an effective amount decreases a hearing disease phenotype. The hearing disease phenotype may include a pure-tone audiometry, pure tone threshold, speech audiometry and speech reception threshold, tympanometry, Stapedius reflex measurements, German speech intelligibility test (Freiburger Sprachtest), brainstem audiometry, or otoacoustic emissions. In some embodiments, the hearing 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 hearing disease phenotype is decreased by about 10% or more, as compared to prior to administration. In some embodiments, the hearing 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 hearing 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 hearing disease phenotype is decreased by no more than about 10%, as compared to prior to administration. In some embodiments, the hearing 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 hearing 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.

[0023] In some embodiments, the composition comprises an oligonucleotide that targets FGG and when administered to a subject in an effective amount increases hearing (e.g., as determined by a hearing measurement). In some embodiments, the hearing 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 hearing is increased by about 10% or more, as compared to prior to administration. In some embodiments, the hearing 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 hearing 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 hearing 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 hearing is increased by no more than about 10%, as compared to prior to administration. In some embodiments, the hearing is increased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100%, as compared to prior to administration. In some embodiments, the hearing 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 hearing 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

[0024] In some embodiments, the composition comprises an oligonucleotide that targets FGG, wherein the oligonucleotide comprises a small interfering RNA (siRNA). In some embodiments, the composition comprises an oligonucleotide that targets FGG, wherein the oligonucleotide comprises a small interfering RNA (siRNA) comprising a sense strand and an antisense strand.

[0025] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, 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 30nucleosides in length, or a range defined by any of the two aforementioned numbers. The antisense strand may be 14-30 nucleosides in length.

[0026] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, 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 FGG mRNA sequence such as SEQ ID NO: 3621. In SEQ ID NO: 3621, thymine (T) may be replaced with Uracil (U). In some embodiments, at least one of the sense strand and the antisense strand comprise a nucleoside sequence comprising at least about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or more contiguous nucleosides of one of SEQ ID NO: 3621.

[0027] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, 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.

[0028] In some embodiments, the sense strand further comprises a 3’ overhang. In some embodiments, the 3’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 3’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 3’ overhang comprises 2 nucleosides. In some embodiments, the sense strand further comprises a 5’ overhang. In some embodiments, the 5’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 5’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 5’ overhang comprises 2 nucleosides.

[0029] 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.

[0030] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the siRNA binds with a 19mer in a human FGG 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 FGG mRNA.

[0031] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an siRNA comprising a sense strand and anantisense strand, wherein the siRNA binds with a 17mer in a non -human primate FGG 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 FGG mRNA.

[0032] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the siRNA binds with a human FGG 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 FGG 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 FGG 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 FGG 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 FGG 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 FGG 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 FGG mRNA and less than or equal to 20 human off- targets, with no more than 3 mismatches in the antisense strand. In some embodiments, the siRNA binds with a human FGG 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 FGG 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 FGG mRNA and less than or equal to 50 human off- targets, with no more than 3 mismatches in the antisense strand.

[0033] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, siRNA binds with a human FGG 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%.

[0034] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1-1742, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1-1742, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand further comprises a 3’ overhang. In some embodiments, the 3’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of theaforementioned numbers. In some embodiments, the 3’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 3’ overhang comprises 2 nucleosides. In some embodiments, the sense strand further comprises a 5’ overhang. In some embodiments, the 5’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 5’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 5’ overhang comprises 2 nucleosides. In some embodiments, the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1-1742, or a nucleic acid sequence thereof having 1 or 2 nucleoside additions at the 3’ end. In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1-1742. In any of SEQ ID NOs: 1-1742, thymine (T) may be replaced with Uracil (U). Any of the aforementioned siRNAs may include an antisense strand where the 5’ nucleoside has been modified to an A. Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5 ’ nucleoside has been modified to a U or T. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 1- 1742 is modified to an A, T, C, U, or G. In some embodiments, position 6 (from the 5’ end) of any one of SEQ ID NOs: 1-1742 is modified to an A, T, C, U, or G. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 1-1742 is modified to an A, T, C, U, or G. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 1-1742 is modified to an A. In some embodiments, position 6 (from the 5’ end) of any one of SEQ ID NOs: 1-1742 is modified to an A. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 1-1742 is modified to an A. In some embodiments, position 1 and position 6, position 1 and position 19, position 6 and position 19, or position 1, position 6, and position 19 of any one of SEQ ID NOs: 1-1742 is modified to an A. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 1-1742 is modified to an T or U. In some embodiments, position 6 (from the 5’ end) of any one of SEQ ID NOs: 1-1742 is modified to a T or U. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 1-1742 is modified to a T or U. In some embodiments, position 1 and position 6, position 1 and position 19, position 6 and position 19, or position 1, position 6, and position 19 of any one of SEQ ID NOs: 1-1742 is modified to a T or U. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 1-1742 is modified to an G. In some embodiments, position 6 (from the 5’ end) of any one of SEQ ID NOs: 1-1742 is modified to an G. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 1- 1742 is modified to an G. In some embodiments, position 1 and position 6, position 1 and position 19, position 6 and position 19, or position 1, position 6, and position 19 of any one of SEQ ID NOs: 1-1742 is modified to an G. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 1-1742 is modified to an C. In some embodiments, position 6 (from the 5’ end) of any one of SEQ ID NOs: 1- 1742 is modified to an C. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 1-1742 is modified to an C. In some embodiments, position 1 and position 6, position 1 and position19, position 6 and position 19, or position 1, position 6, and position 19 of any one of SEQ ID NOs: 1-1742 is modified to an C.

[0035] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the antisense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1743-3484, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1743-3484 or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand further comprises a 3’ overhang. In some embodiments, the 3’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 3’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 3’ overhang comprises 2 nucleosides. In some embodiments, the antisense strand further comprises a 5’ overhang. In some embodiments, the 5’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 5’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 5’ overhang comprises 2 nucleosides. In some embodiments, the antisense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1743-3484, or a nucleic acid sequence thereof having 1 or 2 nucleoside additions at the 3’ end. In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the antisense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1743-3484. In any of SEQ ID NOs: 1743-3484, thymine (T) may be replaced with Uracil (U). Any of the aforementioned siRNAs may include a sense strand wherein the 3’ nucleoside has been modified to an A. Any one of the aforementioned siRNAs may include a sense strand sequence wherein the 5’ nucleoside has been modified to a T or U. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 1743-3484 is modified to an A, T, C, U, or G. In some embodiments, position 14 (from the 5’ end) of any one of SEQ ID NOs: 1743-3484 is modified to an A, T, C, U, or G. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 1743-3484 is modified to an A, T, C, U, or G. In some embodiments, position 1 and position 14, position 1 and position 19, position 14 and position 19, or position 1, position 14, and position 19 of any one of SEQ ID NOs: 1743-3484 is modified to an A, T, C, U, or G. In some embodiments, position 1 (from the 5 ’ end) of any one of SEQ ID NOs: 1743-3484 is modified to an A. In some embodiments, position 14 (from the 5’ end) of the sense strand of any one of SEQ ID NOs: 1743-3484 is modified to an A. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 1743-3484 is modified to an A. In some embodiments, position 1 and position 14, position 1 and position 19, position 14 and position 19, or position 1, position 14, and position 19 of any one of SEQ ID NOs: 1743-3484 is modified to an A. In some embodiments, position 1 (from the 5’ end of any one of SEQ ID NOs: 1743-3484 is modified to a T or U. In someembodiments, position 14 (from the 5’ end) of any one of SEQ ID NOs: 1743-3484 is modified to a T or U. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 1743-3484 is modified to a T or U. In some embodiments, position 1 and position 14, position 1 and position 19, position 14 and position 19, or position 1, position 14, and position 19 of any one of SEQ ID NOs: 1743- 3484 is modified to a T or U. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 1743-3484 is modified to an G. In some embodiments, position 14 (from the 5’ end) of any one of SEQ ID NOs: 1743-3484 is modified to an G. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 1743-3484 is modified to an G. In some embodiments, position 1 and position 14, position 1 and position 19, position 14 and position 19, or position 1, position 14, and position 19 of any one of SEQ ID NOs: 1743-3484 is modified to an G. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 1743-3484 is modified to an C. In some embodiments, position 14 (from the 5’ end) of any one of SEQ ID NOs: 1743-3484 is modified to an C. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 1743-3484 is modified to an C. In some embodiments, position 1 and position 14, position 1 and position 19, position 14 and position 19, or position 1, position 14, and position 19 of any one of SEQ ID NOs: 1743-3484 is modified to an C.

[0036] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 3713-3748, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 3713-3748, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand further comprises a 3’ overhang. In some embodiments, the 3’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 3’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 3’ overhang comprises 2 nucleosides. In some embodiments, the sense strand further comprises a 5’ overhang. In some embodiments, the 5’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 5’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 5’ overhang comprises 2 nucleosides. In some embodiments, the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 3713-3748, or a nucleic acid sequence thereof having 1 or 2 nucleoside additions at the 3’ end. In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 3713-3748. In any of SEQ ID NOs: 3713-3748, thymine (T) may be replaced with Uracil (U). Any of the aforementioned siRNAs may include an antisense strand where the 5 ’ nucleoside has been modified to an A. Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’nucleoside has been modified to a U or T. In some embodiments, position 1 (from the 5 ’ end) of any one of SEQ ID NOs: 3713-3748 is modified to an A, T, C, U, or G. In some embodiments, position 6 (from the 5’ end) of any one of SEQ ID NOs: 3713-3748 is modified to an A, T, C, U, or G. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 3713-3748 is modified to an A, T, C, U, or G. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 3713-3748 is modified to an A. In some embodiments, position 6 (from the 5’ end) of any one of SEQ ID NOs: 3713- 3748 is modified to an A. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 3713-3748 is modified to an A. In some embodiments, position 1 and position 6, position 1 and position 19, position 6 and position 19, or position 1, position 6, and position 19 of any one of SEQ ID NOs: 3713-3748 is modified to an A. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 3713-3748 is modified to an T or U. In some embodiments, position 6 (from the 5’ end) of any one of SEQ ID NOs: 3713-3748 is modified to a T or U. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 3713-3748 is modified to a T or U. In some embodiments, position 1 and position 6, position 1 and position 19, position 6 and position 19, or position 1, position 6, and position 19 of any one of SEQ ID NOs: 3713-3748 is modified to a T or U. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 3713-3748 is modified to an G. In some embodiments, position 6 (from the 5’ end) of any one of SEQ ID NOs: 3713-3748 is modified to an G. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 3713-3748 is modified to an G. In some embodiments, position 1 and position 6, position 1 and position 19, position 6 and position 19, or position 1, position 6, and position 19 of any one of SEQ ID NOs: 3713-3748 is modified to an G. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 3713-3748 is modified to an C. In some embodiments, position 6 (from the 5’ end) of any one of SEQ ID NOs: 3713-3748 is modified to an C. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 3713- 3748 is modified to an C. In some embodiments, position 1 and position 6, position 1 and position 19, position 6 and position 19, or position 1, position 6, and position 19 of any one of SEQ ID NOs: 3713- 3748 is modified to an C.

[0037] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the antisense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 3749-3784, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 3749-3784 or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand further comprises a 3’ overhang. In some embodiments, the 3’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 3’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 3’ overhang comprises 2 nucleosides. In some embodiments, the antisense strand further comprises a 5’ overhang. In some embodiments, the 5’overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 5’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 5’ overhang comprises 2 nucleosides. In some embodiments, the antisense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 3749-3784, or a nucleic acid sequence thereof having 1 or 2 nucleoside additions at the 3’ end. In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the antisense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 3749-3784. In any of SEQ ID NOs: 3749-3784, thymine (T) may be replaced with Uracil (U). Any of the aforementioned siRNAs may include a sense strand wherein the 3’ nucleoside has been modified to an A. Any one of the aforementioned siRNAs may include a sense strand sequence wherein the 5’ nucleoside has been modified to a T or U. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 3749-3784 is modified to an A, T, C, U, or G. In some embodiments, position 14 (from the 5’ end) of any one of SEQ ID NOs: 3749-3784 is modified to an A, T, C, U, or G. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 3749-3784 is modified to an A, T, C, U, or G. In some embodiments, position 1 and position 14, position 1 and position 19, position 14 and position 19, or position 1, position 14, and position 19 of any one of SEQ ID NOs: 3749-3784 is modified to an A, T, C, U, or G. In some embodiments, position 1 (from the 5 ’ end) of any one of SEQ ID NOs: 3749-3784 is modified to an A. In some embodiments, position 14 (from the 5’ end) of the sense strand of any one of SEQ ID NOs: 3749-3784 is modified to an A. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 3749-3784 is modified to an A. In some embodiments, position 1 and position 14, position 1 and position 19, position 14 and position 19, or position 1, position 14, and position 19 of any one of SEQ ID NOs: 3749-3784 is modified to an A. In some embodiments, position 1 (from the 5’ end of any one of SEQ ID NOs: 3749-3784 is modified to a T or U. In some embodiments, position 14 (from the 5’ end) of any one of SEQ ID NOs: 3749-3784 is modified to a T or U. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 3749-3784 is modified to a T or U. In some embodiments, position 1 and position 14, position 1 and position 19, position 14 and position 19, or position 1, position 14, and position 19 of any one of SEQ ID NOs: 3749- 3784 is modified to a T or U. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 3749-3784 is modified to an G. In some embodiments, position 14 (from the 5’ end) of any one of SEQ ID NOs: 3749-3784 is modified to an G. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 3749-3784 is modified to an G. In some embodiments, position 1 and position 14, position 1 and position 19, position 14 and position 19, or position 1, position 14, and position 19 of any one of SEQ ID NOs: 3749-3784 is modified to an G. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 3749-3784 is modified to an C. In some embodiments, position 14 (from the 5’ end) of any one of SEQ ID NOs: 3749-3784 is modified to an C. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 3749-3784 is modified to an C. In some embodiments,position 1 and position 14, position 1 and position 19, position 14 and position 19, or position 1, position 14, and position 19 of any one of SEQ ID NOs: 3749-3784 is modified to an C.

[0038] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 3879-3941 or 4020-4021, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 3879-3941 or 4020-4021, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand further comprises a 3’ overhang. In some embodiments, the 3’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 3’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 3’ overhang comprises 2 nucleosides. In some embodiments, the sense strand further comprises a 5’ overhang. In some embodiments, the 5’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 5’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 5’ overhang comprises 2 nucleosides. In some embodiments, the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 3879-3941 or 4020-4021, or a nucleic acid sequence thereof having 1 or 2 nucleoside additions at the 3’ end. In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 3879-3941 or 4020-4021. In any of SEQ ID NOs: 3879-3941 or 4020-4021, thymine (T) may be replaced with Uracil (U). Any of the aforementioned siRNAs may include an antisense strand where the 5’ nucleoside has been modified to an A. Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5 ’ nucleoside has been modified to a U or T. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 3879-3941 or 4020-4021 is modified to an A, T, C, U, or G. In some embodiments, position 6 (from the 5’ end) of any one of SEQ ID NOs: 3879-3941 or 4020-4021 is modified to an A, T, C, U, or G. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 3879-3941 or 4020-4021 is modified to an A, T, C, U, or G. In some embodiments, position 1 (from the 5 ’ end) of any one of SEQ ID NOs: 3879-3941 or 4020-4021 is modified to an A. In some embodiments, position 6 (from the 5’ end) of any one of SEQ ID NOs: 3879-3941 or 4020-4021 is modified to an A. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 3879-3941 or 4020-4021 is modified to an A. In some embodiments, position 1 and position 6, position 1 and position 19, position 6 and position 19, or position 1, position 6, and position 19 of any one of SEQ ID NOs: 3879-3941 or 4020-4021 is modified to an A. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 3879-3941 or 4020-4021 is modified to an T or U. In some embodiments, position 6 (from the 5’ end) of any one of SEQ ID NOs:3879-3941 or 4020-4021 is modified to a T or U. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 3879-3941 or 4020-4021 is modified to a T or U. In some embodiments, position 1 and position 6, position 1 and position 19, position 6 and position 19, or position 1, position 6, and position 19 of any one of SEQ ID NOs: 3879-3941 or 4020-4021 is modified to a T or U. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 3879-3941 or 4020-4021 is modified to an G. In some embodiments, position 6 (from the 5’ end) of any one of SEQ ID NOs: 3879- 3941 or 4020-4021 is modified to an G. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 3879-3941 or 4020-4021 is modified to an G. In some embodiments, position 1 and position 6, position 1 and position 19, position 6 and position 19, or position 1, position 6, and position 19 of any one of SEQ ID NOs: 3879-3941 or 4020-4021 is modified to an G. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 3879-3941 or 4020-4021 is modified to an C. In some embodiments, position 6 (from the 5’ end) of any one of SEQ ID NOs: 3879-3941 or 4020-4021 is modified to an C. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 3879- 3941 or 4020-4021 is modified to an C. In some embodiments, position 1 and position 6, position 1 and position 19, position 6 and position 19, or position 1, position 6, and position 19 of any one of SEQ ID NOs: 3879-3941 or 4020-4021 is modified to an C.

[0039] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the antisense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 3942-4002 or 4022-4023, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 3942-4002 or 4022-4023 or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand further comprises a 3’ overhang. In some embodiments, the 3’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 3’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 3’ overhang comprises 2 nucleosides. In some embodiments, the antisense strand further comprises a 5’ overhang. In some embodiments, the 5’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 5’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 5’ overhang comprises 2 nucleosides. In some embodiments, the antisense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 3942-4002 or 4022-4023, or a nucleic acid sequence thereof having 1 or 2 nucleoside additions at the 3’ end. In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the antisense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 3942-4002 or 4022-4023. In any of SEQ ID NOs: 3942-4002 or 4022-4023, thymine (T) may be replaced with Uracil (U). Any ofthe aforementioned siRNAs may include a sense strand wherein the 3 ’ nucleoside has been modified to an A. Any one of the aforementioned siRNAs may include a sense strand sequence wherein the 5’ nucleoside has been modified to a T or U. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 3942-4002 or 4022-4023 is modified to an A, T, C, U, or G. In some embodiments, position 14 (from the 5’ end) of any one of SEQ ID NOs: 3942-4002 or 4022-4023 is modified to an A, T, C, U, or G. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 3942-4002 or 4022-4023 is modified to an A, T, C, U, or G. In some embodiments, position 1 and position 14, position 1 and position 19, position 14 and position 19, or position 1, position 14, and position 19 of any one of SEQ ID NOs: 3942-4002 or 4022-4023 is modified to an A, T, C, U, or G. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 3942-4002 or 4022-4023 is modified to an A. In some embodiments, position 14 (from the 5’ end) of the sense strand of any one of SEQ ID NOs: 3942-4002 or 4022-4023 is modified to an A. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 3942-4002 or 4022-4023 is modified to an A. In some embodiments, position 1 and position 14, position 1 and position 19, position 14 and position 19, or position 1, position 14, and position 19 of any one of SEQ ID NOs: 3942-4002 or 4022-4023 is modified to an A. In some embodiments, position 1 (from the 5’ end of any one of SEQ ID NOs: 3942-4002 or 4022-4023 is modified to a T or U. In some embodiments, position 14 (from the 5’ end) of any one of SEQ ID NOs: 3942-4002 or 4022-4023 is modified to a T or U. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 3942-4002 or 4022-4023 is modified to a T or U. In some embodiments, position 1 and position 14, position 1 and position 19, position 14 and position 19, or position 1, position 14, and position 19 of any one of SEQ ID NOs: 3942-4002 or 4022-4023 is modified to a T or U. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 3942-4002 or 4022-4023 is modified to an G. In some embodiments, position 14 (from the 5’ end) of any one of SEQ ID NOs: 3942-4002 or 4022-4023 is modified to an G. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 3942- 4002 or 4022-4023 is modified to an G. In some embodiments, position 1 and position 14, position 1 and position 19, position 14 and position 19, or position 1, position 14, and position 19 of any one of SEQ ID NOs: 3942-4002 or 4022-4023 is modified to an G. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 3942-4002 or 4022-4023 is modified to an C. In some embodiments, position 14 (from the 5’ end) of any one of SEQ ID NOs: 3942-4002 or 4022-4023 is modified to an C. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 3942-4002 or 4022-4023 is modified to an C. In some embodiments, position 1 and position 14, position 1 and position 19, position 14 and position 19, or position 1, position 14, and position 19 of any one of SEQ ID NOs: 3942-4002 or 4022-4023 is modified to an C. In some embodiments, the sense and / or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and / or antisense strand sequence in any of Tables 3-7. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in any Tables 3-7, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sensestrand and / or the antisense strand sequence of an siRNA in any Tables 3-7, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in any Tables 3-7. In some embodiments, the siRNA is cross-reactive with a non-human primate (NHP) FGG mRNA. The siRNA may include one or more intemucleoside linkages and / or one or more nucleoside modifications. In some embodiments, a sense strand sequence of an siRNA in any one of Tables 3-7 is modified by substitution of the 3’ nucleoside to an A. In some embodiments, a sense strand sequence of an siRNA in any one of Tables 3-6 is modified by substitution of the nucleoside to an A at position 19 (from the 5’ end). In some embodiments, an antisense strand sequence of an siRNA in any one of Tables 3-7 is modified by substitution of the 3’ nucleoside to an U. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A at position 19 (from the 5’ end). Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5 ’ nucleoside has been modified to a U.

[0040] In some embodiments, the sense and / or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and / or antisense strand sequence in Table 66B. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 66B, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 66B, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 66B. In some embodiments, the siRNA is cross- reactive with a non-human primate (NHP) FGG mRNA. The siRNA may include one or more intemucleoside linkages and / or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A at position 19 (from the 5’ end). Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U.

[0041] In some embodiments, the sense and / or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and / or antisense strand sequence in Table 79. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 79, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 79, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 79. In some embodiments, the siRNA is cross-reactive with a non-human primate (NHP) FGG mRNA. The siRNA may include one or more intemucleoside linkages and / or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A at position 19 (from the 5’ end). Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U.

[0042] In some embodiments, the sense and / or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and / or antisense strand sequence in Table 83. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 83, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 83, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 83. In some embodiments, the siRNA is cross- reactive with a non-human primate (NHP) FGG mRNA. The siRNA may include one or more intemucleoside linkages and / or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A at position 19 (from the 5’ end). Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U.

[0043] In some embodiments, the sense and / or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and / or antisense strand sequence in Table 87. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 87, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 87, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 87. In some embodiments, the siRNA is cross- reactive with a non-human primate (NHP) FGG mRNA. The siRNA may include one or more intemucleoside linkages and / or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A at position 19 (from the 5’ end). Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U.

[0044] In some embodiments, the sense and / or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90%identical, or at least 95% identical, to a sense and / or antisense strand sequence in Table 93. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 93, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 93, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 93. In some embodiments, the siRNA is cross- reactive with a non-human primate (NHP) FGG mRNA. The siRNA may include one or more intemucleoside linkages and / or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A at position 19 (from the 5’ end). Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U.

[0045] In some embodiments, the sense and / or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and / or antisense strand sequence in Table 97. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 97, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 97, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 97. In some embodiments, the siRNA is cross- reactive with a non-human primate (NHP) FGG mRNA. The siRNA may include one or more intemucleoside linkages and / or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A at position 19 (from the 5’ end). Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U.

[0046] In some embodiments, the sense and / or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and / or antisense strand sequence in Table 101. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 101, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 101, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 101. In some embodiments, the siRNA is cross- reactive with a non-human primate (NHP) FGG mRNA. The siRNA may include one or moreintemucleoside linkages and / or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A at position 19 (from the 5’ end). Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U.

[0047] In some embodiments, the sense and / or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and / or antisense strand sequence in Table 105. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 105, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 105, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 105. In some embodiments, the siRNA is cross- reactive with a non-human primate (NHP) FGG mRNA. The siRNA may include one or more intemucleoside linkages and / or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A at position 19 (from the 5’ end). Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U.

[0048] In some embodiments, the sense and / or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and / or antisense strand sequence in Table 109. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 109, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 109, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 109. In some embodiments, the siRNA is cross- reactive with a non-human primate (NHP) FGG mRNA. The siRNA may include one or more intemucleoside linkages and / or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A at position 19 (from the 5’ end). Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U.

[0049] In some embodiments, the sense and / or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and / or antisense strand sequence in Table 113. In someembodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 113, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 113, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 113. In some embodiments, the siRNA is cross- reactive with a non-human primate (NHP) FGG mRNA. The siRNA may include one or more intemucleoside linkages and / or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A at position 19 (from the 5’ end). Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U.

[0050] In some embodiments, the sense and / or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and / or antisense strand sequence in Table 117. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 117, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 117, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 117. In some embodiments, the siRNA is cross- reactive with a non-human primate (NHP) FGG mRNA. The siRNA may include one or more intemucleoside linkages and / or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A at position 19 (from the 5’ end). Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U.

[0051] In some embodiments, the sense and / or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and / or antisense strand sequence in Table 121. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 121, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 121, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 121. In some embodiments, the siRNA is cross- reactive with a non-human primate (NHP) FGG mRNA. The siRNA may include one or more intemucleoside linkages and / or one or more nucleoside modifications. Any of the aforementioned siRNAsmay include a sense strand where the 3’ nucleoside has been modified to an A. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A at position 19 (from the 5’ end). Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U.

[0052] In some embodiments, the sense and / or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and / or antisense strand sequence in Table 125. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 125, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 125, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 125. In some embodiments, the siRNA is cross- reactive with a non-human primate (NHP) FGG mRNA. The siRNA may include one or more intemucleoside linkages and / or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A at position 19 (from the 5’ end). Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U.

[0053] In some embodiments, the sense and / or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and / or antisense strand sequence in Table 166. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 166, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 166, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 166. In some embodiments, the siRNA is cross- reactive with a non-human primate (NHP) FGG mRNA. The siRNA may include one or more intemucleoside linkages and / or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A at position 19 (from the 5’ end). Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U.

[0054] In some embodiments, the sense and / or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and / or antisense strand sequence in Table 170. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA inTable 170, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 170, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 170. In some embodiments, the siRNA is cross- reactive with a non-human primate (NHP) FGG mRNA. The siRNA may include one or more intemucleoside linkages and / or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A at position 19 (from the 5’ end). Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U.

[0055] In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of subset A, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of subset A, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of subset A. The siRNA may include one or more intemucleoside linkages and / or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A at position 19 (from the 5’ end). Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U.

[0056] In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of subset B, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of subset B, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of subset B. The siRNA may include one or more intemucleoside linkages and / or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A at position 19 (from the 5’ end). Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U.

[0057] In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of subset C, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of subset C, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sensestrand and / or the antisense strand sequence of an siRNA of subset C. The siRNA may include one or more intemucleoside linkages and / or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A at position 19 (from the 5’ end). Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of subset D, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of subset D, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of subset D. The siRNA may include one or more intemucleoside linkages and / or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand where the 3 ’ nucleoside has been modified to an A. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A at position 19 (from the 5’ end). Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U.

[0058] In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of subset E, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of subset E, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of subset E. The siRNA may include one or more intemucleoside linkages and / or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A at position 19 (from the 5’ end). Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U.

[0059] In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of subset G, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of subset G, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of subset G. The siRNA may include one or more intemucleoside linkages and / or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A at position 19 (from the 5’ end). Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U.

[0060] In some embodiments, the sense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to any one of SEQ ID NOs: 352, 1003, 1011, 1278, or 3785. In some embodiments, the sense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 352, 1003, 1011, 1278, 3785, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 352, 1003, 1011, 1278, 3785, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 352, 1003, 1011, 1278, or 3785. The sense strand may include any intemucleoside linkages or nucleoside modifications described herein. The sense strand may include an overhang (e.g., 2 bases on a 5 or 3’ end when paired with an antisense strand). The sense strand may include a GalNAc moiety connected at one of the ends (e.g., 5’ end).

[0061] In some embodiments, the sense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 352. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 352, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 352, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 352. The sense strand may include any intemucleoside linkages or nucleoside modifications described herein. The sense strand may include an overhang (e.g., 2 bases on a 5’ or 3’ end when paired with an antisense strand). The sense strand may include a GalNAc moiety connected at one of the ends (e.g., 5’ end).

[0062] In some embodiments, the sense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 1003. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 1003, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 1003, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 1003. The sense strand may include any intemucleoside linkages or nucleoside modifications described herein. The sense strand may include an overhang (e.g., 2 bases on a 5’ or 3’ end when paired with an antisense strand). The sense strand may include a GalNAc moiety connected at one of the ends (e.g., 5’ end).

[0063] In some embodiments, the sense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 1011. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 1011, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 1011, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 1011. The sense strand may include any intemucleoside linkages or nucleoside modifications described herein. The sense strand may include anoverhang (e.g., 2 bases on a 5’ or 3’ end when paired with an antisense strand). The sense strand may include a GalNAc moiety connected at one of the ends (e.g., 5’ end).

[0064] In some embodiments, the sense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 1278. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 1278, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 1278, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 1278. The sense strand may include any intemucleoside linkages or nucleoside modifications described herein. The sense strand may include an overhang (e.g., 2 bases on a 5’ or 3’ end when paired with an antisense strand). The sense strand may include a GalNAc moiety connected at one of the ends (e.g., 5’ end).

[0065] In some embodiments, the sense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 3785. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3785, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3785, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3785. The sense strand may include any intemucleoside linkages or nucleoside modifications described herein. The sense strand may include an overhang (e.g., 2 bases on a 5’ or 3’ end when paired with an antisense strand). The sense strand may include a GalNAc moiety connected at one of the ends (e.g., 5’ end).

[0066] In some embodiments, the antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to any one of SEQ ID NOs: 2094, 2745, 2753, or 3020. In some embodiments, the antisense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 2094, 2745, 2753, or 3020, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 2094, 2745, 2753, or 3020, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 2094, 2745, 2753, or 3020. The antisense strand may include any intemucleoside linkages or nucleoside modifications described herein. The antisense strand may include an overhang (e.g., 2 bases on a 5’ or 3’ end when paired with a sense strand). The antisense strand may include a GalNAc moiety connected at one of the ends (e.g., 5’ end or 3’ end).

[0067] In some embodiments, the antisense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 2094. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 2094, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 2094, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 2094. The antisensestrand may include any intemucleoside linkages or nucleoside modifications described herein. The antisense strand may include an overhang (e.g., 2 bases on a 5’ or 3’ end when paired with a sense strand). The sense strand may include a GalNAc moiety connected at one of the ends.

[0068] In some embodiments, the antisense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 2745. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 2745, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 2745, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 2745. The antisense strand may include any intemucleoside linkages or nucleoside modifications described herein. The antisense strand may include an overhang (e.g., 2 bases on a 5’ or 3’ end when paired with a sense strand). The sense strand may include a GalNAc moiety connected at one of the ends.

[0069] In some embodiments, the antisense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 2753. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 2753, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 2753, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 2753. The antisense strand may include any intemucleoside linkages or nucleoside modifications described herein. The antisense strand may include an overhang (e.g., 2 bases on a 5’ or 3’ end when paired with a sense strand). The sense strand may include a GalNAc moiety connected at one of the ends.

[0070] In some embodiments, the antisense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 3020. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3020, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3020, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3020. The antisense strand may include any intemucleoside linkages or nucleoside modifications described herein. The antisense strand may include an overhang (e.g., 2 bases on a 5 or 3’ end when paired with a sense strand). The sense strand may include a GalNAc moiety connected at one of the ends.

[0071] In some embodiments, the sense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to any one of SEQ ID NOs: 3723, 3724, 3726, or 3747. In some embodiments, the sense strand comprises the nucleoside sequence of any one of SEQ ID NOS: 3723, 3724, 3726, or 3747, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of any one of SEQ ID NOS: 3723, 3724, 3726, or 3747, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of any one of SEQ ID NOS: 3723, 3724, 3726, or3747. The sense strand may include any intemucleoside linkages or nucleoside modifications described herein. The sense strand may include an overhang (e.g., 2 bases on a 5 or 3’ end when paired with an antisense strand). The sense strand may include a GalNAc moiety connected at one of the ends (e.g., 5’ end).

[0072] In some embodiments, the sense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 3723. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3723, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO:3723, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3723. The sense strand may include any intemucleoside linkages or nucleoside modifications described herein. The sense strand may include an overhang (e.g., 2 bases on a 5’ or 3’ end when paired with an antisense strand). The sense strand may include a GalNAc moiety connected at one of the ends (e.g., 5’ end).

[0073] In some embodiments, the sense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 3724. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3724, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO:3724, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3724. The sense strand may include any intemucleoside linkages or nucleoside modifications described herein. The sense strand may include an overhang (e.g., 2 bases on a 5’ or 3’ end when paired with an antisense strand). The sense strand may include a GalNAc moiety connected at one of the ends (e.g., 5’ end).

[0074] In some embodiments, the sense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 3726. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3726, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3726, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3726. The sense strand may include any intemucleoside linkages or nucleoside modifications described herein. The sense strand may include an overhang (e.g., 2 bases on a 5’ or 3’ end when paired with an antisense strand). The sense strand may include a GalNAc moiety connected at one of the ends (e.g., 5’ end).

[0075] In some embodiments, the sense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 3747. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3747, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3747, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3747. The sense strand may include any intemucleoside linkages or nucleoside modifications described herein. The sense strand may include anoverhang (e.g., 2 bases on a 5’ or 3’ end when paired with an antisense strand). The sense strand may include a GalNAc moiety connected at one of the ends (e.g., 5’ end).

[0076] In some embodiments, the antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to any one of SEQ ID NOs: 3759, 3760, 3762, 3783, or 3790. In some embodiments, the antisense strand comprises the nucleoside sequence of any one of SEQ ID NOS: 3759, 3760, 3762, 3783, or 3790, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of any one of SEQ ID NOS: 3759, 3760, 3762, 3783, or 3790 and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of any one of SEQ ID NOS: 3759, 3760, 3762, 3783, or 3790. The antisense strand may include any intemucleoside linkages or nucleoside modifications described herein. The antisense strand may include an overhang (e.g., 2 bases on a 5’ or 3’ end when paired with a sense strand). The antisense strand may include a GalNAc moiety connected at one of the ends (e.g., 5’ end or 3’ end).

[0077] In some embodiments, the antisense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 3759. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3759, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3759, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3759. The antisense strand may include any intemucleoside linkages or nucleoside modifications described herein. The antisense strand may include an overhang (e.g., 2 bases on a 5’ or 3’ end when paired with a sense strand). The sense strand may include a GalNAc moiety connected at one of the ends.

[0078] In some embodiments, the antisense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 3760. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3760, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3760, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3760. The antisense strand may include any intemucleoside linkages or nucleoside modifications described herein. The antisense strand may include an overhang (e.g., 2 bases on a 5’ or 3’ end when paired with a sense strand). The sense strand may include a GalNAc moiety connected at one of the ends.

[0079] In some embodiments, the antisense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 3762. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3762, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3762, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3762. The antisensestrand may include any intemucleoside linkages or nucleoside modifications described herein. The antisense strand may include an overhang (e.g., 2 bases on a 5’ or 3’ end when paired with a sense strand). The sense strand may include a GalNAc moiety connected at one of the ends.

[0080] In some embodiments, the antisense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 3783. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3783, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3783, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3783. The antisense strand may include any intemucleoside linkages or nucleoside modifications described herein. The antisense strand may include an overhang (e.g., 2 bases on a 5’ or 3’ end when paired with a sense strand). The sense strand may include a GalNAc moiety connected at one of the ends.

[0081] In some embodiments, the antisense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 3790. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3790, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3790, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3790. The antisense strand may include any intemucleoside linkages or nucleoside modifications described herein. The antisense strand may include an overhang (e.g., 2 bases on a 5’ or 3’ end when paired with a sense strand). The sense strand may include a GalNAc moiety connected at one of the ends.B. ASOs

[0082] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, 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.

[0083] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, 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 FGG mRNA sequence such as SEQ ID NO: 3621; wherein (i) the oligonucleotide comprises a modification comprising a modified nucleoside and / or a modified intemucleoside linkage, and / or (ii) the composition comprises a pharmaceutically acceptable carrier. In some embodiments, the ASO comprise a nucleoside sequence complementary to at least about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or more contiguous nucleosides of one of SEQ ID NO: 3621.C. Modification patterns

[0084] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises a modification comprising a modified nucleoside and / or a modified intemucleoside 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 intemucleoside linkage. In some embodiments, the oligonucleotide comprises a modified intemucleoside linkage. In some embodiments, the modified intemucleoside linkage comprises alkylphosphonate, phosphorothioate, methylphosphonate, phosphorodithioate, alkylphosphonothioate, phosphoramidate, carbamate, carbonate, phosphate triester, acetamidate, or carboxymethyl ester, or a combination thereof. In some embodiments, the modified intemucleoside 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 intemucleoside linkages may be included in siRNAs or ASOs. Benefits of the modified intemucleoside linkage may include decreased toxicity or improved pharmacokinetics.

[0085] 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.

[0086] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises a modified intemucleoside 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 intemucleoside linkages, or a range of modified intemucleoside linkages defined by any two of the aforementioned numbers. In some embodiments, the oligonucleotide comprises no more than 18 modified intemucleoside linkages. In some embodiments, the oligonucleotide comprises no more than 20 modified intemucleoside linkages. In some embodiments, the oligonucleotide comprises 2 or more modified intemucleoside linkages, 3 or more modified intemucleoside linkages, 4 or more modified intemucleoside linkages, 5 or more modified intemucleoside linkages, 6 or more modified intemucleoside linkages, 7 or more modified intemucleoside linkages, 8 or more modified intemucleoside linkages, 9 or more modified intemucleoside linkages, 10 or more modified intemucleoside linkages, 11 or more modified intemucleoside linkages, 12 or more modified intemucleoside linkages, 13 or more modified intemucleoside linkages, 14 or more modified intemucleoside linkages, 15 or more modified intemucleoside linkages, 16 or more modified intemucleoside linkages, 17 or more modified intemucleoside linkages, 18 or more modified intemucleoside linkages, 19 or more modified intemucleoside linkages, or 20 or more modified intemucleoside linkages.

[0087] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, 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 an 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'-0-NMA) nucleoside, a 2'-O-dimethylaminoethoxyethyl (2'-O-DMAEOE) nucleoside, 2'-O-aminopropyl (2'-O-AP) nucleoside, or 2'-ara-F, or a combination thereof. In some embodiments, the modified nucleoside comprises a 2'-O-methyl nucleoside. In some embodiments, the modified nucleoside comprises a 2'- deoxyfluoro nucleoside. In some embodiments, the modified nucleoside comprises a 2'-0-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.

[0088] In some embodiments, the modified nucleoside comprises a glycol nucleic acid (GNA). A GNA may comprise the following structure:

[0089] In some embodiments, the modified nucleoside comprises an unlocked nucleic acid. An unlocked nucleic acid may comprise the following structure: 3’ nucleotidewherein the base can be any pyrimidine or purine.

[0090] In some embodiments, the oligonucleotide comprises a modified nucleoside. In some embodiments, the modified nucleoside comprises a locked nucleic acid and an abasic site:are independently an H or a 3 ’ or 5 ’ linkage to a nucleotide via a phosphodiester or phosphorothioate bond.

[0091] In some embodiments, the oligonucleotide comprises a phosphate mimic. In some embodiments, the phosphate mimic comprises methylphosphonate. An example of a nucleotide that comprises a methylphosphonate is shown below:’ methylphosphonate 2’-0-methyl uridine).

[0092] 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.

[0093] 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.

[0094] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises a moiety attached at a 3 ’ or 5 ’ terminus of the oligonucleotide. Examples of moieties include a hydrophobic moiety or a sugar moiety, or a combination thereof. In some embodiments, the oligonucleotide is an siRNA having a sense strand, and the moiety is attached to a 5’ end of the sense strand. In some embodiments, the oligonucleotide is an siRNA having a sense strand, and the moiety is attached to a 3’ end of the sense strand. In some embodiments, the oligonucleotide is an siRNA having an antisense strand, and the moiety is attached to a 5 ’ end of the antisense strand. In some embodiments, the oligonucleotide is an siRNA having an antisense strand, and the moiety is attached to a 3’ end of the antisense strand. In some embodiments, the oligonucleotide is anASO, 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.

[0095] In some embodiments, the sense strand comprises at least three modified nucleosides, wherein the three modifications comprise a 2’-fluoro modified nucleoside, a 2’-O-methyl modified nucleoside, and 2’-O-methoxyethyl. In some embodiments, the sense strand comprises at least two modified nucleosides, wherein the two modifications comprise a 2 ’-fluoro modified nucleoside, a 2’-O- methyl modified nucleoside, and 2’-O-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.

[0096] 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.

[0097] The oligonucleotide may include purines. Examples of purines include adenine (A), guanine (G), or 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.

[0098] 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.

[0099] 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 ’-fluoromodified 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 to20 of the sense strand comprises a 2’-O-methyl modified nucleoside. In some embodiments, at least two nucleotides at position 16 to 20 of the sense strand comprise a 2’-O-methyl modified nucleoside. In some embodiments, at least three nucleotides at position 16 to 20 of the sense strand comprise a 2’-O-methyl modified nucleoside. In some embodiments, at least four nucleotides at position 16 to 20 of the sense strand comprise a 2’-O-methyl modified nucleoside. In some embodiments, all nucleotides at position 16 to 20 of the sense strand comprise a 2’-O-methyl modified nucleoside.

[0100] 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.

[0101] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises a hydrophobic moiety. The hydrophobic moiety may be attached at a 3’ or 5’ terminus of the oligonucleotide. The hydrophobic moiety may include a lipid such as a fatty acid. The hydrophobic moiety may include a hydrocarbon. The hydrocarbon may be linear. The hydrocarbon may be non-linear. The hydrophobic moiety may include a lipid moiety or a cholesterol moiety, or a combination thereof.

[0102] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises a lipid attached at a 3 ’ or 5 ’ terminus of the oligonucleotide. In some embodiments, the lipid comprises cholesterol, myristoyl, palmitoyl, stearoyl, lithocholoyl, docosanoyl, docosahexaenoyl, myristyl, palmityl stearyl, or a-tocopherol, or a combination thereof.

[0103] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises a sugar moiety. The sugar moiety may include an N-acetyl galactose moiety (e.g., a N-acetylgalactosamine (GalNAc) moiety), an N-acetyl glucose moiety (e.g., an N-acetylglucosamine (GlcNAc) moiety), a fucose moiety, or a mannose moiety. Thesugar moiety may include 1, 2, 3, or more sugar molecules. The sugar moiety may be attached at a 3’ or 5’ terminus of the oligonucleotide. The sugar moiety may include an N-acetyl galactose moiety. The sugar moiety may include an N-acetylgalactosamine (GalNAc) moiety. The sugar moiety may include an N- acetyl glucose moiety. The sugar moiety may include N-acetylglucosamine (GlcNAc) moiety. The sugar moiety may include a fucose moiety. The sugar moiety may include a mannose moiety. N-acetyl glucose, GlcNAc, fucose, or mannose may be useful for targeting macrophages since they may target or bind a mannose receptor such as CD206.

[0104] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an N-acetylgalactosamine (GalNAc) moiety. GalNAc may be useful for hepatocyte targeting, neural (e.g., CNS (e.g., brain), or CSF targeting. . The GalNAc moiety may include a bivalent or trivalent branched linker. The oligo may be attached to 1, 2 or 3 GalNAcs through a bivalent or trivalent branched linker. The GalNAc moiety may include 1, 2, 3, or more GalNAc molecules. The GalNAc moiety may be attached at a 3’ or 5’ terminus of the oligonucleotide.

[0105] Non-limiting examples of GalNAc ligands are shown in FIG. 1 and FIG. 2. In some embodiments, the oligonucleotide is conjugated to the GalNAc ligand in FIG. 1. In the GalNAc ligand shown in FIG. 1, J indicates a point of attachment to an oligonucleotide. In some embodiments, J is at a 5’ end of the oligonucleotide. In some embodiments, J is at a 3’ end of the oligonucleotide. In the GalNAc ligand shown in FIG. 1, n may be any number. For example, n may be 1-10. In some embodiments, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or a range defined by any two of the aforementioned integers. In some embodiments, n is 2. In embodiments in which n is 2 and the oligonucleotide is connected at J, the GalNAc moiety may be referred to as “GalNAc# 1” or “GalNAc 1.”

[0106] In some embodiments, the oligonucleotide is conjugated to the GalNAc ligand in FIG. 2. The wavy line in FIG. 1 indicates a point of attachment to an oligonucleotide. In some embodiments, the wavy line is at a 5’ end of the oligonucleotide. In some embodiments, the wavy line is at a 3’ end of the oligonucleotide. In embodiments in which the oligonucleotide is connected at the wavy line, the GalNAc moiety may be referred to as “GalNAc#23” or “GalNAc23.”

[0107] The oligonucleotide may include purines. Examples of purines include adenine (A), guanine (G), or 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.

[0108] 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. 2’-O-methyl may include 2’-O-methyl. Where 2’-O-methyl modifications are described, it is contemplated that a 2’ -methyl modification may be included, and vice versa.

[0109] 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.

[0110] 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.

[0111] 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. 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.

[0112] In some cases, the oligonucleotide comprises a particular modification pattern. In some embodiments, position 9 counting from the 5’ end of the of a strand of the oligonucleotide may have a 2’F modification. In some embodiments, when position 9 of a strand of the oligonucleotide is a pyrimidine, then all purines in a strand of the oligonucleotide have a 2’0Me 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.

[0113] In some embodiments, when position 9 of a strand of the oligonucleotide is a purine, then all purines in a strand of the oligonucleotide have a 2’0Me modification. In some embodiments, when position 9 is the only purine between positions 5 and 11 of the sense stand, then position 9 is the only position with a 2’F modification in a strand of the oligonucleotide. In some embodiments, when position 9 and only one other base between positions 5 and 11 of a strand of the oligonucleotide are purines, then both of these purines are the only two positions with a 2’F modification in a strand of the oligonucleotide. In some embodiments, when position 9 and only two other bases between positions 5 and 11 of a strand of the oligonucleotide are purines, and those two other purines are in adjacent positions so that there would be not three 2’F modifications in a row, then any combination of 2’F modifications can be made that give three 2’F modifications in total. In some embodiments, when there are more than 2 purines between positions 5 and 11 of a strand of the oligonucleotide, then all combinations of purines having the 2’F modification are allowed that have three to five 2’F modifications in total, provided that a strand of the oligonucleotide does not have three 2’F modifications in a row. In some cases, a strand of the oligonucleotide of any of the siRNAs comprises a modification pattern which conforms to any or all of these a strand of the oligonucleotide rules.

[0114] In some cases, position 9 of a strand of the oligonucleotide can be a 2’deoxy. In these cases, 2’F and 2’0Me modifications may occur at the other positions of a strand of the oligonucleotide. In some cases, a strand of the oligonucleotide of any of the siRNAs comprises a modification pattern which conforms to these a strand of the oligonucleotide rules.

[0115] 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 ’-fluoromodified 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.

[0116] In some embodiments, position nine of the sense strand comprises a 2’-fluoro-modified purine. In some embodiments, all pyrimidines of the sense strand comprise 2’-O-methyl modified purines. In some embodiments, 1, 2, 3, 4, or 5 purines between positions 5 and 11 comprise a 2’-fluoro-modified purine, provided there are not three 2’-fluoro-modified purine in a row. In some embodiments, the odd- numbered positions of the antisense strand comprise 2’-O-methyl modified nucleotides. In some embodiments, the even -numbered positions of the antisense strand comprise 2’-fluoro-modified nucleotides and unmodified deoxyribonucleotide. In some embodiments, the even -numbered positions of the antisense strand comprise 2’-fluoro-modified nucleotides, 2’-O-methyl modified nucleotides and unmodified deoxyribonucleotide. In some embodiments, position nine of the sense strand comprises a 2’- fluoro -modified purine; all pyrimidine of the sense strand comprises 2’-O-methyl modified pyrimidines;1, 2, 3, 4, or 5 purines between positions 5 and 11 comprise a 2’-fluoro-modified purines, provided there are not three 2’-fluoro-modified purines in a row; the odd-numbered positions of the antisense strand comprise 2’-O-methyl modified nucleotides; and the even-numbered positions of the antisense strand comprise 2 ’-fluoro -modified nucleotides and unmodified deoxyribonucleotides. In some embodiments, there are not three 2’-fluoro-modified purines in a row. In some embodiments, there are not three 2’- fluoro -modified pyrimidines in a row.

[0117] 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 unmodifieddeoxyribonucleotides. 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.

[0118] In some embodiments, position nine of the sense strand comprises an unmodified deoxyribonucleotide. In some embodiments, positions 5, 7, and 8 of the sense strand comprise 2’-fluoro- modifed nucleotides. In some embodiments, all purines in positions 10 to 21 of the sense strand comprise 2’-O-methyl modified purines and all pyrimidines in positions 10 to 21 of the comprise 2’-O-methyl modified pyrimidines or 2’-fluoro-modified pyrimidines. In some embodiments, the odd-numbered positions of the antisense strand comprise 2’-O-methyl modified nucleotides. In some embodiments, the even-numbered positions of the antisense strand comprise 2’-fluoro-modified nucleotides and unmodified deoxyribonucleotides. In some embodiments, the even-numbered positions of the antisense strand comprise 2 ’-fluoro -modified nucleotides, 2’-O-methyl modified nucleotides and unmodified deoxyribonucleotides. In some embodiments, position nine of the sense strand comprises an unmodified deoxyribonucleotide; positions 5, 7, and 8 of the sense strand comprise 2’-fluoro-modifed nucleotides; all purines in positions 10 to 21 of the sense strand comprise 2’-O-methyl modified purines and all pyrimidines in positions 10 to 21 of the comprise 2’-O-methyl modified pyrimidines or 2’-fluoro- modified pyrimidines; the odd-numbered positions of the antisense strand comprise 2’-O-methyl modified nucleotides; and the even-numbered positions of the antisense strand comprise 2’-fluoro-modified nucleotides and unmodified deoxyribonucleotide.

[0119] 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.

[0120] 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.

[0121] 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 atrans-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

[0122] 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.

[0123] In some embodiments, the oligonucleotide includes 1 vinyl phosphonate. In some embodiments, the oligonucleotide includes 2 vinyl phosphonates. In some embodiments, the oligonucleotide includes 3 vinyl phosphonates. In some embodiments, the oligonucleotide includes 4 vinyl phosphonates. In some embodiments, the antisense strand of the oligonucleotide comprises a vinyl phosphonate at the 5’ end. In some embodiments, the antisense strand of the oligonucleotide comprises a vinyl phosphonate at the 3’ end. In some embodiments, the sense strand of the oligonucleotide comprises a vinyl phosphonate at the 5’ end. In some embodiments, the sense strand of the oligonucleotide comprises a vinyl phosphonate at the 3’ end.1. Hydrophobic moieties

[0124] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises a hydrophobic moiety. The hydrophobic moiety may be attached at a 3’ or 5’ terminus of the oligonucleotide. The hydrophobic moiety may include a lipid such as a fatty acid. The hydrophobic moiety may include a hydrocarbon. The hydrocarbon may be linear. The hydrocarbon may be non-linear. The hydrophobic moiety may include a lipid moiety or a cholesterol moiety, or a combination thereof.

[0125] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises a lipid attached at a 3 ’ or 5 ’ terminus of the oligonucleotide. In some embodiments, the lipid comprises cholesterol, myristoyl, palmitoyl, stearoyl, lithocholoyl, docosanoyl, docosahexaenoyl, myristyl, palmityl, stearyl, or a-tocopherol, or a combination thereof.

[0126] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises a hydrophobic ligand or moiety. In some embodiments, the hydrophobic ligand or moiety comprises cholesterol. In some embodiments, the hydrophobic ligand or moiety comprises a cholesterol derivative. In some embodiments, the hydrophobic ligand or moiety is attached at a 3’ terminus of the oligonucleotide. In some embodiments, the hydrophobic ligand or moiety is attached at a 5’ terminus of the oligonucleotide. In some embodiments, the composition comprises a sense strand, and the hydrophobic ligand or moiety is attached to the sense strand (e.g., attached to a 5’ end of the sense strand, or attached to a 3’ end of the sense strand). In some embodiments, the composition comprises an antisense strand, and the hydrophobic ligand or moiety is attached to the antisense strand (e.g., attached to a 5’ end of the antisense strand, or attached to a 3’ end of the antisense strand). In some embodiments, the composition comprises a hydrophobic ligand or moiety attached at a 3’ or 5’ terminus of the oligonucleotide.

[0127] In some embodiments, a hydrophobic moiety is attached to the oligonucleotide (e.g., a sense strand and / or an antisense strand of a siRNA). In some embodiments, a hydrophobic moiety is attached at a 3’ terminus of the oligonucleotide. In some embodiments, a hydrophobic moiety is attached at a 5’ terminus of the oligonucleotide. In some embodiments, the hydrophobic moiety comprises cholesterol. In some embodiments, the hydrophobic moiety includes a cyclohexanyl. The hydrophobic moiety may include an esterified lipid.

[0128] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises a lipid attached at a 3 ’ or 5 ’ terminus of the oligonucleotide. In some embodiments, a lipid is attached at a 3’ terminus of the oligonucleotide. In some embodiments, a lipid is attached at a 5’ terminus of the oligonucleotide. In some embodiments, the lipid comprises cholesterol, myristoyl, palmitoyl, stearoyl, lithocholoyl, docosanoyl, docosahexaenoyl, myristyl, palmityl, stearyl, or a-tocopherol, or a combination thereof. In some embodiments, the lipid comprises stearyl, lithocholyl, docosanyl, docosahexaenyl, or myristyl. In some embodiments, the lipid comprises cholesterol. In some embodiments, the lipid includes a sterol such as cholesterol. In some embodiments, the lipid comprises stearyl, t-butylphenol, n-butylphenol, octylphenol, dodecylphenol, phenyl n-dodecyl, octadecylbenzamide, hexadecylbenzamide, or octadecylcyclohexyl. In some embodiments, the lipid comprises phenyl para C12. The lipid moiety may be esterified.

[0129] In some embodiments, the oligonucleotide comprises any aspect of the following structure:. In some embodiments, the oligonucleotide comprises any aspect5' oligonucleotide of the following structure:. In some embodiments, the oligonucleotide comprises any aspect of the following structure:some embodiments, the oligonucleotide comprises any aspect of the following structure:some embodiments, the oligonucleotide comprises any aspect of the following structure: The aspect included in the oligonucleotide may include the entire structure, or may include the lipid moiety, of any of the structures shown. In some embodiments, n is 1-3. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, R is an alkyl group. In some embodiments, the alkyl group contains 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbons. In some embodiments, the alkyl group contains 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 carbons, or a range defined by any two of the aforementioned numbers of carbons. In some embodiments, the alkyl group contains 4-18 carbons. In some embodiments, the lipid moiety comprises an alcohol or ether.

[0130] 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: Hydrophobic moiety examples

[0131] 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.

[0132] The hydrophobic moiety may include a linker that comprises a carbocycle. The carbocycle may be six-membered. Some examples of a carbocycle include phenyl or cyclohexyl. The linker may include a phenyl. The linker may include a cyclohexyl. The lipid may be attached to the carbocycle, which may in turn be attached at a phosphate (e.g., 5’ or 3’ phosphate) of the oligonucleotide. In some embodiments, the lipid or hydrocarbon, and the end of the sense are connected to the phenyl or cyclohexyl linker in the 1,4; 1,3; or 1,2 substitution pattern (e.g., the para, meta, or ortho phenyl configuration). In some embodiments, the lipid or hydrocarbon, and the end of the sense are connected to the phenyl or cyclohexyl linker in the 1,4 substitution pattern (e.g., the para phenyl configuration). The lipid may be attached to the carbocycle in the 1,4 substitution pattern relative to the oligonucleotide. The lipid may be attached to the carbocycle in the 1,3 substitution pattern relative to the oligonucleotide. The lipid may be attached to the carbocycle in the 1,2 substitution pattern relative to the oligonucleotide. The lipid may be attached to the carbocycle in the ortho orientation relative to the oligonucleotide. The lipid may be attached to the carbocycle in the para orientation relative to the oligonucleotide. The lipid may be attached to the carbocycle in the meta orientation relative to the oligonucleotide.

[0133] The lipid moiety may comprise or consist of the following structuresome embodiments, the lipid moiety comprises or consists of the following structure:some embodiments, the lipid moiety comprises the following structure:some embodiments, the lipid moiety comprises or consist of the following structure:In some embodiments, the dotted line indicates a covalent connection. The covalent connection may between an end of the sense or antisense strand. For example, the connection may be to the 5’ end of the sense strand. In some embodiments, n is 0-3. In some embodiments, n is 1-3. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, 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.

[0134] 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 a modification such as a sulfur in place of an oxygen.

[0135] 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.

[0136] 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:. n 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, 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.

[0137] The lipid may be attached to the oligonucleotide by a linker. The linker may include a polyethyleneglycol (e.g., tetraethyleneglycol).

[0138] The modifications described herein may be useful for delivery to a cell or tissue, for example, extrahepatic delivery or targeting of an oligonucleotide composition. The modifications described herein may be useful for targeting an oligonucleotide composition to a cell or tissue.2. Sugar moieties

[0139] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises a sugar moiety. The sugar moiety may include an N-acetyl galactose moiety (e.g., an N-acetylgalactosamine (GalNAc) moiety), an N-acetyl glucose moiety (e.g., an N-acetylglucosamine (GlcNAc) moiety), a fucose moiety, or a mannose moiety. The sugar moiety may include 1, 2, 3, or more sugar molecules. The sugar moiety may be attached at a 3’ or 5’ terminus of the oligonucleotide. The sugar moiety may include an N-acetyl galactose moiety. The sugar moiety may include an N-acetylgalactosamine (GalNAc) moiety. The sugar moiety may include an N- acetyl glucose moiety. The sugar moiety may include N-acetylglucosamine (GlcNAc) moiety. The sugar moiety may include a fucose moiety. The sugar moiety may include a mannose moiety. N-acetyl glucose, GlcNAc, fucose, or mannose may be useful for targeting macrophages when they target or bind a mannose receptor such as CD206. The sugar moiety may be useful for binding or targeting an asialoglycoprotein receptor such as an asialoglycoprotein receptor of a hepatocyte. The GalNAc moiety may bind to an asialoglycoprotein receptor. The GalNAc moiety may target a hepatocyte.

[0140] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an N-acetylgalactosamine (GalNAc) moiety. GalNAc may be useful for hepatocyte targeting. The GalNAc moiety may include a bivalent or tri valent branched linker. The oligo may be attached to 1, 2 or 3 GalNAcs through a bivalent or trivalent branched linker. The GalNAc moiety may include 1, 2, 3, or more GalNAc molecules. The GalNAc moiety may be attached at a 3’ or 5’ terminus of the oligonucleotide.

[0141] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an N-acetylgalactosamine (GalNAc) ligand for hepatocyte targeting. In some embodiments, the composition comprises GalNAc. In some embodiments, the composition comprises a GalNAc derivative. In some embodiments, the GalNAc ligand is attached at a 3’ terminus of the oligonucleotide. In some embodiments, the GalNAc ligand is attached at a 5’ terminus of the oligonucleotide. In some embodiments, the composition comprises a sense strand, and the GalNAc ligand is attached to the sense strand (e.g., attached to a 5’ end of the sense strand, or attached to a 3’ end of the sense strand). In some embodiments, the composition comprises an antisense strand, and the GalNAc ligand is attached to the antisense strand (e.g., attached to a 5’ end of the antisense strand, or attached to a 3’ end of the antisense strand). In some embodiments, the composition comprises a GalNAc ligand attached at a 3’ or 5’ terminus of the oligonucleotide.

[0142] Disclosed herein, in some embodiments, are compositions comprising an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises a GalNAc moiety. The GalNAc moiety may be included in any formula, structure, or GalNAc moiety shown below. In some embodiments, described herein is a compound (e.g., oligonucleotide) represented by Formula (I) or (II):or a salt thereof, whereinJ is an oligonucleotide; each w is independently selected from any value from 1 to 20; each v is independently selected from any value from 1 to 20; n is selected from any value from 1 to 20; m is selected from any value from 1 to 20; z is selected from any value from 1 to 3, wherein if z is 3, Y is C if z is 2, Y is CR6, or if z is 1, Y is C(R6)2;Q is selected from:C3-10 carbocycle optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, -OR7, -SR7, -N(R7)2, -C(O)R7, -C(O)N(R7)2, -N(R7)C(O)R7- N(R7)C(O)N(R7)2, -OC(O)N(R7)2, -N(R7)C(O)OR7, -C(O)OR7, -OC(O)R7, -S(O)R7, and Ci6alkyl, wherein the C1-6 alkyl, is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, and -NH2;R1is a linker selected from:-O-, -S-, -N(R7)-, -C(O)-, -C(O)N(R7)-, -N(R7)C(O)-_ -N(R7)C(O)N(R7)-, -OC(O)N(R7)-, - N(R7)C(O)O-, -C(O)O-, -OC(O)-, -S(O)-, -S(O)2-, -OS(O)2-, -OP(O)(OR7)O-, -SP(O)(OR7)O-, - OP(S)(OR7)O-, -OP(O)(SR7)O-, -OP(O)(OR7)S-, -OP(O)(O )O-, -SP(O)(O )O-, -OP(S)(O )O-, - OP(O)(S )O-, -OP(O)(O )S-, -OP(O)(OR7)NR7-, -OP(O)(N(R7)2)NR7-, -OP(OR7)O-, - OP(N(R7)2)O-, -OP(OR7)N(R7)-, and -OPN(R7)2NR7-; each R2is independently selected from:C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR7, -SR7, -N(R7)2, -C(O)R7, -C(O)N(R7)2, -N(R7)C(O)R7-N(R7)C(O)N(R7)2, - OC(O)N(R7)2, -N(R7)C(O)OR7, -C(O)OR7, -OC(O)R7, and -S(O)R7;R3and R4are each independently selected from:-OR7, -SR7, -N(R7)2, -C(O)R7, -C(O)N(R7)2, -N(R7)C(O)R7-N(R7)C(O)N(R7)2, - OC(O)N(R7)2, -N(R7)C(O)OR7, -C(O)OR7, -OC(O)R7, and -S(O)R7; each R5is independently selected from:-OC(O)R7, -OC(O)N(R7)2, -N(R7)C(O)R7-N(R7)C(O)N(R7)2, - N(R7)C(O)OR7, -C(O)R7, -C(O)OR7, and -C(O)N(R7)2; each R6is independently selected from: hydrogen; halogen, -CN, -NO2, -OR7, -SR7, -N(R7)2, -C(O)R7, -C(O)N(R7)2, -N(R7)C(O)R7- N(R7)C(O)N(R7)2, -OC(O)N(R7)2, -N(R7)C(O)OR7, -C(O)OR7, -OC(O)R7, and -S(O)R7; and Ci-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, -OR7, -SR7, -N(R7)2, -C(O)R7, -C(O)N(R7)2, -N(R7)C(O)R7- N(R7)C(O)N(R7)2, -OC(O)N(R7)2, -N(R7)C(O)OR7, -C(O)OR7, -OC(O)R7, and -S(O)R7; each R7is independently selected from: hydrogen;Ci-6 alkyl, C2-6 alkenyl, and C2.e alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =0, =S, - O-Ci-6 alkyl, -S-Ci-6 alkyl, -N(Ci-e alkyl)2, -NH(Ci-e alkyl), C3-10 carbocycle, and 3- to 10- membered heterocycle; andC3-10 carbocycle, and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, - N02, -NH2, =0, =S, -O-C1-6 alkyl, -S-Ci-e alkyl, -N(Ci-e alkyl)2, -NH(Ci-e alkyl), C1-6 alkyl, C2.e alkenyl, C2.„ alkynyl, C3-10 carbocycle, 3- to 10-membered heterocycle, and Ci-ehaloalkyl.

[0143] In some embodiments, each w is independently selected from any value from 1 to 10. In some embodiments, each w is independently selected from any value from 1 to 5. In some embodiments, each w is 1. In some embodiments, each v is independently selected from any value from 1 to 10. In some embodiments, each v is independently selected from any value from 1 to 5. In some embodiments, each v is 1. In some embodiments, n is selected from any value from 1 to 10. In some embodiments, n is selected from any value from 1 to 5. In some embodiments, n is 2. In some embodiments, m is selected from any value from 1 to 10. In some embodiments, m is selected from any value from 1 to 5. In some embodiments, m is selected from 1 and 2. In some embodiments, z is 3 and Y is C. In some embodiments, Q is selected from C5-6 carbocycle optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, -OR7, -SR7, -N(R7)2, -C(O)R7, -C(O)N(R7)2, -N(R7)C(O)R7- N(R7)C(O)N(R7)2, -OC(O)N(R7)2, -N(R7)C(O)OR7, -C(O)OR7, -OC(O)R7, and -S(O)R7. In some embodiments, Q is selected from C5-6 carbocycle optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, and -NH2. In some embodiments, Q is selected from phenyl and cyclohexyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, and -NH2. In some embodiments, Q is selected from phenyl. In some embodiments, Q is selected from cyclohexyl. In some embodiments, R1is selected from -OP(O)(OR7)O-, -SP(O)(OR7)O-, -OP(S)(OR7)O-, -OP(O)(SR7)O-, - OP(O)(OR7)S-, -OP(O)(O )O-, -SP(O)(O )O-, -OP(S)(O )O-, -OP(O)(S )O-, -OP(O)(O )S-, - OP(O)(OR7)NR7-, -OP(O)(N(R7)2)NR7-, -OP(OR7)O-, -OP(N(R7)2)O-, -OP(OR7)N(R7)-, and -OPN(R7)2.NR7. In some embodiments, R1is selected from -OP(O)(OR7)O-, -SP(O)(OR7)O-, -OP(S)(OR7)O-, - OP(O)(SR7)O-, -OP(O)(OR7)S-, -OP(O)(O )O-, -SP(O)(O )O-, -OP(S)(O )O-, -OP(O)(S )O-, -OP(O)(O )S-, and -OP(OR7)O-. In some embodiments, R1is selected from -OP(O)(OR7)O-, -OP(S)(OR7)O-, - OP(O)(O )O-, -OP(S)(O )O-, -OP(O)(S )O-, and -OP(OR7)O-. In some embodiments, R1is selected from - OP(O)(OR7)O- and -OP(OR7)O-. In some embodiments, R2is selected from C1-3 alkyl substituted with one or more substituents independently selected from halogen, -OR7, -OC(O)R7, -SR7, -N(R7)2, -C(O)R7, and -S(O)R7. In some embodiments, R2is selected from C1-3 alkyl substituted with one or more substituents independently selected from -OR7, -OC(O)R7, -SR7, and -N(R7)2. In some embodiments, R2is selected from C1-3 alkyl substituted with one or more substituents independently selected from -OR7and - OC(O)R7. In some embodiments, R3is selected from halogen, -OR7, -SR7, -N(R7)2, -C(O)R7, -OC(O)R7, and -S(O)R7In some embodiments, R3is selected from -OR7-SR7, -OC(O)R7, and -N(R7)2. In some embodiments, R3is selected from -OR7- and -OC(O)R7. In some embodiments, R4is selected from halogen, -OR7, -SR7, -N(R7)2, -C(O)R7, -OC(O)R7, and -S(O)R7In some embodiments, R4is selected from -OR7-SR7, -OC(O)R7, and -N(R7)2 In some embodiments, R4is selected from -OR7- and -OC(O)R7. In some embodiments, R5is selected from -OC(O)R7, -OC(O)N(R7)2, -N(R7)C(O)R7-N(R7)C(O)N(R7)2, and -N(R7)C(O)OR7. In some embodiments, R5is selected from -OC(O)R7and -N(R7)C(O)R7. In some embodiments, each R7is independently selected from: hydrogen; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =0, =S, -O- C1-6 alkyl, -S-C1-6 alkyl, -N(CI-6 alkyl)2, -NH(CI-6 alkyl), C3-10 carbocycle, or 3- to 10-membered heterocycle. In some embodiments, each R7is independently selected from C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, - NH2, =0, =S, -O-C1.6 alkyl, -S-C1-6 alkyl, -N(CI-6 alkyl)2, and -NH(CI-6 alkyl). In some embodiments, each R7is independently selected from C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, and -SH. In some embodiments, w is 1; v is 1; n is 2; m is 1 or 2; z is 3 and Y is C; Q is phenyl or cyclohexyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, and C1-3 alkyl; R1is selected from -OP(O)(OR7)O-, -OP(S)(OR7)O-, -0P(0)(0 )0-, -OP(S)(O )0-, -OP(O)(S )0-, and - OP(OR7)O-; R2is Ci alkyl substituted with -OH or -0C(0)CH3;R3is -OH or -0C(0)C some embodiments, the compound comprises:

[0144] In some embodiments, the oligonucleotide (J) is attached at a 5’ end or a 3’ end of the oligonucleotide. In some embodiments, the oligonucleotide comprises DNA. In some embodiments, the oligonucleotide comprises RNA. In some embodiments, the oligonucleotide comprises one or more modified intemucleoside linkages. In some embodiments, the one or more modified intemucleoside linkages comprise alkylphosphonate, phosphorothioate, methylphosphonate, phosphorodithioate, alkylphosphonothioate, phosphoramidate, carbamate, carbonate, phosphate triester, acetamidate, or carboxymethyl ester, or a combination thereof. In some embodiments, the oligonucleotide comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 modified intemucleoside linkages. In some embodiments, the compound binds to an asialoglycoprotein receptor. In some embodiments, the compound targets a hepatocyte.

[0145] Some embodiments include the following, where J is the oligonucleotide:include one or more additional phosphates, or one or more phosphorothioates linking to the oligonucleotide. J may include one or more additional phosphates linking to the oligonucleotide. J may include one or more phosphorothioates linking to the oligonucleotide.

[0146] Some embodiments include the following, where J is the oligonucleotide:J may include one or more additional phosphates, or one or more phosphorothioates linking to the oligonucleotide. J may include one or more additional phosphates linking to the oligonucleotide. J may include one or more phosphorothioates linking to the oligonucleotide.

[0147] Some embodiments include the following, where J is the oligonucleotide:include one or more phosphates or phosphorothioates linking to the oligonucleotide. J may include one or more phosphates linking to the oligonucleotide. J may include a phosphate linking to the oligonucleotide. J may include one or more phosphorothioates linking to the oligonucleotide. J may include a phosphorothioate linking to the oligonucleotide.

[0148] Some embodiments include the following, where J is the oligonucleotide:The structure in this compound attached to the oligonucleotide (J) may be referred to as “ETL17,” and isan example of a GalNAc moiety. J may include one or more phosphates or phosphorothioates linking to the oligonucleotide. J may include one or more phosphates linking to the oligonucleotide. J may include a phosphate linking to the oligonucleotide. J may include one or more phosphorothioates linking to the oligonucleotide. J may include a phosphorothioate linking to the oligonucleotide.

[0149] Some embodiments include the following, where the phosphate or “5”’ indicates a connection to the oligonucleotide:

[0150] Some embodiments include the following, where the phosphate or “5”’ indicates a connection to the oligonucleotide:

[0151] Some embodiments include the following, where J is the oligonucleotide:include one or more phosphates or phosphorothioates linking to the oligonucleotide. J may include one or more phosphates linking to the oligonucleotide. J may include a phosphate linking to the oligonucleotide.J may include one or more phosphorothioates linking to the oligonucleotide. J may include a phosphorothioate linking to the oligonucleotide.

[0152] Some embodiments include the following, where J is the oligonucleotide:The structure in this compound attached to the oligonucleotide (J) may be referred to as “ETL1,” and is an example of a GalNAc moiety. J may include one or more phosphates or phosphorothioates linking to the oligonucleotide. J may include one or more phosphates linking to the oligonucleotide. J may include aphosphate linking to the oligonucleotide. J may include one or more phosphorothioates linking to the oligonucleotide. J may include a phosphorothioate linking to the oligonucleotide.

[0153] Disclosed herein, in some embodiments, are compositions comprising an oligonucleotide that inhibits the expression of a target gene, wherein the oligonucleotide comprises a GalNAc moiety. The GalNAc moiety may be included in any formula, structure, or GalNAc moiety shown below. In some embodiments, described herein is a compound (e.g., oligonucleotide) represented by Formula (III), (IV), or (V):Formula IV, orFormula V, or a salt thereof, whereinJ is an oligonucleotide; each w is independently selected from any value from 0 to 20; v is independently selected from any value from 0 to 20; each n is selected from any value from 0 to 20; each m is selected from any value from 0 to 20; each p is selected from any value from 0 to 1 ; each w is selected from any value from 0 to 20; t is selected from any value from 0 to 1; x is selected from any value from 0 to 1; r is selected from any value from 0 to 20; u is selected from any value from 0 to 20;Q is selected from: C3-20 cyclic, heterocyclic or acyclic linker optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, -OR7, -SR7, -N(R7)2, -C(O)R7, - C(O)N(R7)2, -N(R7)C(O)R7-N(R7)C(O)N(R7)2, -OC(O)N(R7)2, -N(R7)C(O)OR7, -C(O)OR7, -OC(O)R7, - S(O)R7, and Ci-e alkyl, wherein the C1-6 alkyl, is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, and -NH2;R1is a linker selected from: -O-, -S-, -N(R7)-, -C(O)-, -C(O)N(R7)-, -N(R7)C(O)-_ -N(R7)C(O)N(R7)-, -OC(O)N(R7)-, -N(R7)C(O)O-, -C(O)O-, -OC(O)-, -S(O)-, -S(O)2-, -OS(O)2-, -OP(O)(OR7)O-, - SP(O)(OR7)O-, -OP(S)(OR7)O-, -OP(O)(SR7)O-, -OP(O)(OR7)S-, -OP(O)(O )O-, -SP(O)(O )O-, - OP(S)(O )O-, -OP(O)(S )O-, -OP(O)(O )S-, -OP(O)(OR7)NR7-, -OP(O)(N(R7)2)NR7-, -OP(OR7)O-, - OP(N(R7)2)O-, -OP(OR7)N(R7)-, and -OPN(R7)2NR7-;each R7is independently selected from: hydrogen, Ci-6 alkyl, C2-6 alkenyl, and C2-ealkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, - OH, -SH, -NO2, -NH2, =0, =S, -O-C1.6 alkyl, -S-C1.6 alkyl, -N(CI-6alkyl)2, -NH(CI-6alkyl), C3-10 carbocycle, and 3- to 10-membered heterocycle, C3-10 carbocycle, and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =0, =S, -O-Ci.6alkyl, -S-C1.6 alkyl, -N(CI-6alkyl)2, -NH(CI-6alkyl), C1-6 alkyl, C2-6 alkenyl, C2-e alkynyl, C3-10 carbocycle, 3- to 10-membered heterocycle, and C1-6 haloalkyl.

[0154] Provided herein are sugar moieties comprising the following structure, where J is an oligonucleotide:

[0155] The structure in this compound attached to the oligonucleotide (J) in some instances is referred to as “L96,” and is an example of a GalNAc moiety. J in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. J in some instances comprises one or more phosphates linking to the oligonucleotide. J in some instances comprises a phosphate linking to the oligonucleotide. J in some instances comprises one or more phosphorothioates linking to the oligonucleotide. J in some instances comprises a phosphorothioate linking to the oligonucleotide.

[0156] Provided herein are sugar moieties comprising the following structure, where J is an oligonucleotide:

[0157] The structure in this compound attached to the oligonucleotide (J) in some instances is referred to as “NAG37,” and is an example of a GalNAc moiety. J in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. J in some instances comprises one or more phosphates linking to the oligonucleotide. J in some instances comprises a phosphate linking to the oligonucleotide. J in some instances comprises one or more phosphorothioates linking to the oligonucleotide. J in some instances comprises a phosphorothioate linking to the oligonucleotide.

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

[0159] The structure in this compound attached to the oligonucleotide (J) in some instances is referred to as “GluGalNAc,” and is an example of a GalNAc moiety. J in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. J in some instances comprises oneor more phosphates linking to the oligonucleotide. J in some instances comprises a phosphate linking to the oligonucleotide. J in some instances comprises one or more phosphorothioates linking to the oligonucleotide. J in some instances comprises a phosphorothioate linking to the oligonucleotide.

[0160] Provided herein are sugar moieties comprising the following structure, where J and K are independently H, a GalNAc moiety or oligonucleotides:

[0161] The structures in these compounds in some instances are attached to the oligonucleotide (J or K) and referred to as “ademA GalNAc, ademG GalNAc, ademC GalNAc, or ademU GalNAc” depending on the base used in the nucleotide. In some instances, GalNAc moieties are attached to the oligonucleotide. The placement of the GalNAc moieties in some instances is at the 3 or 5’ ends (J or K = H) or internal (J and K are oligonucleotides) of the oligonucleotide strand. J and K may in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. J and K in someinstances comprises one or more phosphates linking to the oligonucleotide. J and K in some instances comprises a phosphate linking to the oligonucleotide. J and K in some instances comprises one or more phosphorothioates linking to the oligonucleotide. J and K in some instances comprises a phosphorothioate linking to the oligonucleotide.

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

[0163] The structure in this compound attached to the oligonucleotide (R) in some instances is referred to as Hl, H2, H3, H4, H5, H6, H7, or H9, and are examples of GalNAc moieties. R in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. R in some instances comprises one or more phosphates linking to the oligonucleotide. R in some instances comprises a phosphate linking to the oligonucleotide. R in some instances comprises one or more phosphorothioates linking to the oligonucleotide. R in some instances comprises a phosphorothioate linking to the oligonucleotide.

[0164] Provided herein are sugar moieties comprising the following structure, where J is an oligonucleotide:The structure in this compound attached to the oligonucleotide (J) may be referred to as “K2GalNAc,” and is an example of a GalNAc moiety. J in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. J in some instances comprises one or more phosphates linking to the oligonucleotide. J in some instances comprises a phosphate linking to the oligonucleotide. J in some instances comprises one or more phosphorothioates linking to the oligonucleotide. J in some instances comprises a phosphorothioate linking to the oligonucleotide.

[0165] Provided herein are sugar moieties comprising the following structure, where J is an oligonucleotide and X is S or O:. The structure in this compound attached to the oligonucleotide (J) in some instances is referred to as “ST23,” and is an example of a GalNAc moiety. J in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. J in some instances comprises one or more phosphates linking to the oligonucleotide. J in some instances comprises a phosphate linking to the oligonucleotide. J in some instances comprises one or more phosphorothioates linking to the oligonucleotide. J in some instances comprises a phosphorothioate linking to the oligonucleotide.

[0166] Provided herein are sugar moieties comprising the following structure, where J is an oligonucleotide:. The structure in this compound atached to the oligonucleotide (J) in some instances is referred to as “GalNAc23,” and is an example of a GalNAc moiety. J in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. J in some instances comprises one or more phosphates linking to the oligonucleotide. J in some instances comprises a phosphate linking to the oligonucleotide. J in some instances comprises one or more phosphorothioates linking to the oligonucleotide. J in some instances comprises a phosphorothioate linking to the oligonucleotide.

[0167] Provided herein are sugar moieties comprising the following structure, where J or K comprises an oligonucleotide:

[0168] The structures in these compounds in some instances are attached to the oligonucleotide (J orK), referred to as “PyrGalNAc”, “PipGalNAc” and “TEG-GalNAc” are examples of GalNAc moieties. In some instances, 2-4 GalNAc moieties are attached oligonucleotide. The placement of the GalNAc moieties may be at the 3 ’ or 5 ’ ends (J or K = H) or internal (J and K are oligonucleotides) of the oligonucleotide strand. J and K in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. J and K in some instances comprises one or more phosphates linking to the oligonucleotide. J and K in some instances comprises a phosphate linking to the oligonucleotide. J and K in some instances comprises one or more phosphorothioates linking to the oligonucleotide. J and K in some instances comprises a phosphorothioate linking to the oligonucleotide.

[0169] Provided herein are sugar moieties comprising the following structure, where J is an oligonucleotide:

[0170] The structure in this compound attached to the oligonucleotide (J) in some instances is referred to as “THA,” and is an example of a GalNAc moiety. J in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. J in some instances comprises one or more phosphates linking to the oligonucleotide. J in some instances comprises a phosphate linking to the oligonucleotide. J in some instances comprises one or more phosphorothioates linking to the oligonucleotide. J in some instances comprises a phosphorothioate linking to the oligonucleotide.

[0171] Provided herein are sugar moieties comprising the following structure, where Nu is an oligonucleotide:

[0172] The structure in this compound attached to the oligonucleotide (Nu) in some instances is referred to as “L-9” and is an example of a GalNAc moiety. Nu in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. Nu in some instances comprises one or more phosphates linking to the oligonucleotide. Nu in some instances comprises a phosphate linking tothe oligonucleotide. Nu in some instances comprises one or more phosphorothioates linking to the oligonucleotide. Nu in some instances comprises a phosphorothioate linking to the oligonucleotide.

[0173] Provided herein are sugar moieties comprising the following structure, where J is an oligonucleotide:

[0174] The structure in this compound attached to the oligonucleotide (J) in some instances is referred to as “Sirius GalNAc,” and is an example of a GalNAc moiety. J in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. J in some instances comprises one or more phosphates linking to the oligonucleotide. J in some instances comprises a phosphate linking to the oligonucleotide. J in some instances comprises one or more phosphorothioates linking to the oligonucleotide. J in some instances comprises a phosphorothioate linking to the oligonucleotide.3. siRNA modification patterns

[0175] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises modification pattern IS: 5’-NfsnsNfiiNfiiNfNfNfhNfiiNfnNfiiNfiiNfsnsn-3’, wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 2S: 5 ’ -nsnsnnNfiiNfNfNfnnnnnnnnnnsnsn- 3’, wherein “Nf’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 3S: 5’-nsnsnnNfhNfiiNfimnnnnnnnnsnsn-3’, wherein “Nf’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 4S: 5’-NfsnsNfhNfiiNfNfNfiiNfiiNfnNfiiNfiiNfsnsnN-moiety-3’, wherein “Nf’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, “s” is a phosphorothioate or phosphate linkage, and N comprises one or more nucleosides. In some embodiments, the sense strand comprises modification pattern 5S: 5’-nsnsnnNfiiNfNfNfnnnnnnnnnnsnsnN-moiety-3’, wherein “Nf’ is a 2’-fhioro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, “s” is a phosphorothioate or phosphate linkage, and N comprises one or more nucleosides. In some embodiments, the moiety in modification pattern 4S or 5Sis a lipid moiety. In some embodiments, the moiety in modification pattern 4S or 5S is a sugar moiety. In some embodiments, the sense strand comprises modification pattern 6S: 5’-NfsnsNfiiNfiiNfnNfnNfhNfiiNfnNfiiNfsnsn-3’, wherein “Nf’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 7S: 5’-nsnsnnNfNfNfNfNfnnnnnnnnnnsnsn-3’, wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’- O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 8S: 5’-nsnsnnnNfNfNfNfnnnnnnnnnnsnsn-3’, wherein “Nf ’ is a 2 ’-fluoro -modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 9S: 5’-nsnsnnnnNfNfNfNfnnnnnnnnnsnsn-3’, wherein “Nf’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern IOS: 5'- nsnsnnNfNfiiNfNfnnnnnnnnnnsnsn-3', wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O- methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 1 IS: 5'-nsnsnnNfnnnNfnnnnnnnnnnsnsn-3', wherein “Nf’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 12S: 5'-snnnnNfNfnNfNfnnnnNfimNfimsnsn-3', wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 13S: 5'- snnnnNfNfnNfdNnNfNfimNfimnnsnsn-3', wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O- methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 14S: 5'-snnNfNfimnnNfimnnNfiiNfNfnnsnsn-3', wherein “Nf ’ is a 2 ’-fluoro -modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 15S: 5'-snnNfiiNfnNfNfdNnNfNfnnNfnnnnsnsn-3', wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 16S: 5'- snnnnNfnNfNfNfNfimnnnnnnnsnsn-3', wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O- methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 17S: 5'-snnnnnNfNfNfNfnnnnnnnnnnsnsn-3', wherein “Nf ’ is a 2 ’-fluoro -modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 18S: 5'-snnnnNfNfnNfNfnnnnnnnnnnsnsn-3', wherein “Nf’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 19S: 5'-snnnnNfnnnNfnnnnnnnnnnsnsn-3', wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is aphosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 20S: 5'-snnnnnNfNfNfNfnNfimnnnnnnsnsn-3', wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 2 IS: 5'- snnnnnnNfNfNfNfNfimnnnnnnsnsn-3', wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O- methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 22S: 5'-snnnnNfNfhNfNfnNfimnnnnnnsnsn-3', wherein “Nf ’ is a 2 ’-fluoro -modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 23S: 5'-snnnnNfhNfNfdTnnnnnnnnnnsnsn-3', wherein “dT” is deoxythymidine, “Nf ’ is a 2’- fluoro -modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 24S: 5'- snnnnNfNfnnNfNfimnnnnnnnsnsn-3', wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O- methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 25S: 5'-snnnnnNfNfhNfimnnnnnnnnsnsn-3', wherein “Nf’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 26S: 5'-snnnnnnNfhNfNfimnnnnnnnsnsn-3', wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 27S: 5'-snnnnnnnNfNfnNfimnnnnnnsnsn- 3', wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 28S: 5'-snnnnnnnnNfiiNfnNfhnnnnnsnsn-3', wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 29S: 5'-snnnnnnnNfNfNfNfnnnnnnnnsnsn- 3', wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 30S: 5'-snnnnmnNfNfNfNfimnnmnnnnnnsnsn-3’, wherein “nm” is a 2 ’-O-methoxyethyl -modified nucleoside, “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 3 IS: 5'-snnnnmnNfNfNfNfimnmnnnnnnnsnsn-3’, wherein “nm” is a 2 ’-O-methoxyethyl -modified nucleoside, “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 32S: 5'-snnnnmnNfNfNfNfhtmnnnnnnnnsnsn-3’, wherein “nm” is a 2 ’-O-methoxyethyl -modified nucleoside, “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 33S: 5'-snnnnnmNfNfNfNfimnmnnnnnnnsnsn-3’, wherein “nm” is a 2 ’-O-methoxyethyl -modified nucleoside, “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” isa phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 34S: 5'-snnnnmnNfNfNfNfimnnnnmnnnnsnsn-3’, wherein “nm” is a 2 ’-O-methoxyethyl -modified nucleoside, “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 35S: 5'-snnnnmnNfNfNfNfimnnnmnnnnnsnsn-3’, wherein “nm” is a 2 ’-O-methoxyethyl -modified nucleoside, “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 36S: 5'-snnnnmnNfNfNfNfimnntmnnnnnsnsn-3’, wherein “nm” is a 2 ’-O-methoxyethyl -modified nucleoside, “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 37S: 5'-snnnnmnNfNfNfNfimnnmnnnnnnsnsn-3’, wherein “Nf’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 38S: 5'- snnnnmNfiiNfNfNfNfimnmnnnnnnsnsn-3’, wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’- O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 39S: 5'-snnnnmnNfNfNfNfimmnnnnnnnnsnsn-3’, wherein “Nf ’ is a 2’-fhioro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 40S: 5'-snnnnNfhNfNfNfdnnnnnnnnnnsnsn-3’, wherein “Nf’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 4 IS: 5'- snnnnmnNfNfNfNfnnnmnnnnnnnsnsn-3’, wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’- O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 42S: 5'-snnnnnNfnnNfhNfimnnnnnnsnsn-3’, wherein “Nf ’ is a 2 ’-fluoro -modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 43S: 5'-snnnnNfimNfNfNfNfimnnnnnnsnsn-3’, wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 44S: 5'- snnnnNfNfNfNfNfnnnnnnnnnnsnsn-3’, wherein “Nf’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O- methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 45S: 5'-snnnnNfnnNfNfiiNfnnnnnnnnsnsn-3’, wherein “Nf ’ is a 2 ’-fluoro -modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 46S: 5'-snnnnmNfhNfNfNfNfnntmnnnnnnsnsn-3’, wherein “Nf’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 47S: 5'- snnnnmnNfNfNfNfnnntmnnnnnnsnsn-3’, wherein “Nf’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 48S: 5'-snnnnmnNfNfNfNfimtmnnnnnnnsnsn-3’, wherein “Nf” is a 2 ’-fluoro -modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 49S: 5'-snnnnNfNfnnNfhNfnnnnnnnnsnsn-3’, wherein “Nf’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 50S: 5'-snnnnnnNfNfNfNfnnnnnnnnnsnsn- 3’, wherein “Nf’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 5 IS: 5'-snnnnNfiiNfiiNfhnnnnnnnnnsnsn-3’, wherein “Nf’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 52S: 5'- snnnnmnNfNfNfNfnnnnnmnnnnnsnsn-3’, wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’- O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 53S: 5'-snnnnnnNfNfNfNfnnnnnnnnsnsn-3’, wherein “Nf ’ is a 2 ’-fluoro -modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 54S: 5'-snnnmnNfNfNfNfnnnnmnnnnnnsnsn-3’, wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 55S: 5'- snnnnNfnnNfNfNfNfimnnnnnnsnsn-3’, wherein “Nf’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O- methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 56S: 5'-snnnnNfNfNfNfNfimnnnnnnnnsnsn-3’, wherein “Nf ’ is a 2 ’-fluoro -modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 57S: 5'-snnnnNfimNfNfhNfnnnnnnnnsnsn-3’, wherein “Nf’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 58S: 5'- snnnnNfnNfNfNfdNnnnnnnnnnsnsn-3’, wherein “Nf’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O- methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 59S: 5'-snnnnNfnNfNfNfdTnnnnnnnnnsnsn-3’, wherein “Nf ’ is a 2 ’-fluoro -modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 60S: 5'-snnnnNfhNfiiNfNfnnnnnnnnnsnsn-3’, wherein “Nf’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 6 IS: 5'-snnnnNfimNfNfimnnnnnnnnsnsn- 3’, wherein “Nf’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modificationpatem 62S: 5'-snnnnNfnnnNfNfnnnnnnnnnsnsn-3'. wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 63S: 5'-snnnnnnNfNfNfNfimnnnnnnnsnsn- 3’, wherein “Nf’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 64S: 5'-snnnnNfhNfiiNfimnnnnnnnnsnsn-3’, wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 65S: 5'- snnnnmNfiiNfNfNfNfimnmnnnnnnsnsn-3’, wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’- O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 66S: 5'-snnnmnNfNfNfNfnnnnmnnnnnnsnsn-3’, wherein “Nf ’ is a 2 ’-fluoro -modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage.

[0176] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the antisense strand comprises modification pattern IAS: 5’-nsNfsnNfiiNfiiNfiiNfnnnNfnNfiiNfnsnsn-3’, wherein “Nf’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the antisense strand comprises modification pattern 2AS: 5’-nsNfsnnnNfiiNfNfimnnNfhNfnnnsnsn-3’, wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’- O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the antisense strand comprises modification pattern 3 AS: 5’-nsNfsnnnNfnnnnnnnNfiiNfnnnsnsn-3’, wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the antisense strand comprises modification pattern 4AS: 5’-nsNfsnNfiiNfnnnnnnnNfiiNfimnsnsn-3’, wherein “Nf ’ is a 2’-fluoro- modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the antisense strand comprises modification pattern 5 AS: 5’-nsNfsnnnnnnnnnnnNfhNfiinnsnsn-3’, wherein “Nf’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O- methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the antisense strand comprises modification pattern 6AS: 5’-nsNfsnnnNfnnNfimnnNfnNfimnsnsn-3’, wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the antisense strand comprises modification pattern 7AS: 5’-nsNfsnNfiiNfnNfiiNfiiNfnNfhNfnNfnsnsn-3’, wherein “Nf’ is a 2’-fluoro- modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the antisense strand comprises modification pattern 8 AS: 5’-nsNfsnnnnnnnnnnnNfimnnnsnsn-3’, wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O- methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the antisense strand comprises modification pattern 9AS: 5’-nNfiiNfiiNfnNfiiNfhNfiiNfiiNfnNfnsnsn-3’,wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the antisense strand comprises modification pattern 10AS: 5'-nsNfsnNfimnNfhNfiiNfiiNfnNfiiNfnsnsn-3', wherein “Nf ’ is a 2 ’-fluoromodified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the antisense strand comprises modification pattern 1 IAS: 5'- nsNfsnNfnnNfnnNfnNfiiNfiiNfiiNfnsnsn-3', wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’- O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the antisense strand comprises modification pattern 12AS: 5'-nsNfsndTndNnNfhNfhdNnNfndNnNfhsnsn- 3', wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “dT” is deoxythymidine, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the antisense strand comprises modification pattern HAS: 5'-nsNfsndTndNnNfnNfndNndTndNndTnsnsn-3', wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “dT” is deoxythymidine, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the antisense strand comprises modification pattern 14AS: 5'-nsNfsnnnNfnnnNfiiNfiiNfiiNfiiNfiisnsn-3', wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the antisense strand comprises modification pattern 15AS: 5'-dTsNfsnnnNfiiNfiiNfnNfnNfnNfhNfiisnsn-3', wherein “Nf ’ is a 2’-fluoro- modified nucleoside, “dT” is deoxythymidine, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the antisense strand comprises modification pattern 16As: 5'-NfsNfsnnnNfiiNfhNfiiNfiiNfnNfiiNfnsnsn-3', wherein “Nf ’ is a 2’-fluoro- modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the antisense strand comprises modification pattern 17AS: 5'- nsNfsnnnNfiiNfnNfnNfiiNfiiNfiiNfnsnsn-3', wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’- O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the antisense strand comprises modification pattern 18AS: 5'-nsNfsnNfnNfimnNfiiNfhNfiiNfnNfnsnsn-3', wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the antisense strand comprises modification pattern 19AS: 5'-nsNfsnNfimNfNfiiNfnNfnNfiiNfnNfnsnsn-3', wherein “Nf ’ is a 2 ’-fluoromodified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the antisense strand comprises modification pattern 20AS: 5'- nsNfsnNfnnNfnnnnNfnNfiiNfnNfiisnsn-3', wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’- O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the antisense strand comprises modification pattern 21AS: 5'-nsNfsnnnNfiiNfnnnNfnNfiiNfiiNfiisnsn-3', wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 22AS: 5'-nsNfsnNfimNfnnNfnNfnNfimnnnsnsn-3’, wherein “Nf’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 23AS: 5'-nsNfsnnnNfiiNfnNfnNfiiNfiiNfimnsnsn-3’, wherein “Nf’ is a 2’-fluoro-modified nucleoside, “n” is a 2’- O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 24AS: 5'-nsNfsnnnNfhNfhNfnNfiiNfimnnnsnsn-3’, wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 25 AS: 5'-nsNfsnnNfhNfimNfiiNfnNfiiNfiiNfnsnsn-3’, wherein “Nf’ is a 2’-fluoro-modified nucleoside, “n” is a 2’ O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 26AS: 5'- nsNfsnnNfnNfNfimnNfiiNfiiNfiiNfnsnsn-3’, wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’ O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 27AS: 5'-nsNfsnNfhNfnNfnNfiiNfiiNfiiNfnnnsnsn-3’, wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’ O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 28AS: 5'-nsNfsnnnNfNfimNfnNfnNfhNfiiNfnsnsn-3’, wherein “Nf’ is a 2’-fluoro-modified nucleoside, “n” is a 2’ O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 29AS: 5'- nsNfsnnnNfNfnnnnNfnNfiiNfnNfiisnsn-3’, wherein “Nf’ is a 2’-fhioro-modified nucleoside, “n” is a 2’ O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 30AS: 5'-nsNfsnnNfiiNfNfnNfhNfiiNfiiNfnNfnsnsn-3’, wherein “Nf ’ is a 2’-fhioro-modified nucleoside, “n” is a 2’ O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 3 IAS: 5'-nsNfsnnNfiiNfimNfimnNfnNfnNfhsnsn-3’, wherein “Nf’ is a 2’-fluoro-modified nucleoside, “n” is a 2’ O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 32AS: 5'- nsNfsnnNfnNfNfiiNfimnNfiiNfiiNfnsnsn-3’, wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’ O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 33AS: 5'-nsNfsnnnnNfimnnNfhNfiiNfiiNfnsnsn-3’, wherein “Nf ’ is a 2’-fhioro-modified nucleoside, “n” is a 2’ O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 34AS: 5'-nsNfsnnNfhNfiiNfnnNfnNfiiNfiiNfnsnsn-3’, wherein “Nf’ is a 2’-fluoro-modified nucleoside, “n” is a 2’ O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 35AS: 5'- nsNfsnNfnnNfnnnnNfnNfiiNfnNfsn-3’, wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’ O- methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 36AS: 5'-nsNfsnNfimNfnnnnNfnNfhNfnsNfsn-3’, wherein “Nf ’ is a 2’-fhioro-modified nucleoside, “n” is a 2’ O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 37AS: 5'-nsNfsnNfimNfnnnnNfiiNfnNfiisnsn-3’, wherein “Nf’ is a 2’-fluoro-modified nucleoside,“n” is a 2’ O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 38AS: 5'- nsNfsnNfimNfimnnNfiiNfirNfsnsn-3’, wherein “Nf’ is a 2’-fluoro-modified nucleoside, “n” is a 2’ O- methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 39AS: 5'-nsNfsnNfimNfnnNfnNfhNfnNfiiNfsn-3’, wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’ O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 40AS: 5'-nsNfsnNfimNfnnNfnNfnNfiiNfhsnsn-3’, wherein “Nf’ is a 2’-fluoro-modified nucleoside, “n” is a 2’ O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 41AS: 5'- nsNfsnNfnnnfimNfnnfnNfiiNfsnsn-3’, wherein “Nf ’ is a 2’-fluoro-modified nucleoside, “n” is a 2’ O- methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage.

[0177] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises pattern IS and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, WAS, HAS, 12AS, I 3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS. In some embodiments, the sense strand comprises pattern 2S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, WAS, HAS, 12AS, I 3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS. In some embodiments, the sense strand comprises pattern 3S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, I 3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS. In some embodiments, the sense strand comprises pattern 4S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, WAS, HAS, 12AS, I 3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS. In some embodiments, the sense strand comprises pattern 5S and the antisense strand comprises pattern IAS, 2AS, 3 AS, 4AS, 5 AS, 6AS, 7AS, 8AS, 9AS, WAS, HAS, 12AS, I 3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS. In some embodiments, the sense strand comprises pattern 6S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, I 3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS. In some embodiments, the sense strand comprises pattern 7S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, WAS, HAS, 12AS, I 3AS. 14AS, 15AS, 16AS, 17AS,18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS. In some embodiments, the sense strand comprises pattern 8S and the antisense strand comprises pattern IAS, 2AS, 3 AS, 4AS, 5 AS, 6AS, 7AS, 8AS, 9AS, WAS, HAS, 12AS, I3AS. 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, or 41AS. In some embodiments, the sense strand comprises pattern 9S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, I3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS. In some embodiments, the sense strand comprises pattern IOS and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, WAS, HAS, 12AS, I3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS. In some embodiments, the sense strand comprises pattern 1 IS and the antisense strand comprises pattern IAS, 2AS, 3 AS, 4AS, 5 AS, 6AS, 7AS, 8AS, WAS, HAS, 12AS, I3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 4 IAS. In some embodiments, the sense strand comprises pattern 12S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 10AS, HAS, 12AS, HAS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS. In some embodiments, the sense strand comprises pattern 13S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, WAS, HAS, 12AS, I3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS. In some embodiments, the sense strand comprises pattern 14S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, WAS, HAS, 12AS, I3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS. In some embodiments, the sense strand comprises pattern 15S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 10AS, HAS, 12AS, HAS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS. In some embodiments, the sense strand comprises pattern 16S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, WAS, HAS, 12AS, BAS, 14AS, BAS, 16AS, 17AS, 18AS, WAS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS. In some embodiments, the sense strand comprises pattern 17S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, WAS, HAS, 12AS, BAS, 14AS, BAS, 16AS, WAS, 18AS, WAS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS,39AS, 40AS, or 4 IAS. In some embodiments, the sense strand comprises pattern 18S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 10AS, HAS, 12AS, HAS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS. In some embodiments, the sense strand comprises pattern 19S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, WAS, HAS, 12AS, I3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS. In some embodiments, the sense strand comprises pattern 20S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, WAS, HAS, 12AS, I3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 4 IAS. In some embodiments, the sense strand comprises pattern 21S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 10AS, HAS, 12AS, HAS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS. In some embodiments, the sense strand comprises pattern 22S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, WAS, HAS, 12AS, BAS, 14AS, BAS, 16AS, 17AS, 18AS, WAS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS. In some embodiments, the sense strand comprises pattern 23 S and the antisense strand comprises pattern IAS, 2AS, 3 AS, 4AS, 5 AS, 6AS, 7AS, 8AS, WAS, HAS, 12AS, BAS, 14AS, BAS, 16AS, WAS, 18AS, WAS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 4 IAS. In some embodiments, the sense strand comprises pattern 24S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, WAS, HAS, 12AS, BAS, 14AS, BAS, 16AS, WAS. 18AS, WAS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS. In some embodiments, the sense strand comprises pattern 25 S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, WAS, HAS, BAS, BAS, 14AS, BAS, 16AS, WAS, 18AS, WAS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS. In some embodiments, the sense strand comprises pattern 26S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, WAS, HAS, 12AS, BAS, 14AS, BAS, 16AS, WAS, 18AS, WAS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 4 IAS. In some embodiments, the sense strand comprises pattern 27S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, WAS, HAS, 12AS, BAS, 14AS, BAS, 16AS, WAS, 18AS, WAS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS. In some embodiments, the sense strand comprises pattern 28S and the antisense strand comprises pattern IAS,2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, WAS, HAS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 3OAS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS. In some embodiments, the sense strand comprises pattern 29S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, WAS, HAS, 12AS, I3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 4 IAS. In some embodiments, the sense strand comprises pattern 30S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 10AS, HAS, 12AS, HAS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS. In some embodiments, the sense strand comprises pattern 3 IS and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, WAS, HAS, 12AS, I3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS. In some embodiments, the sense strand comprises pattern 32S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, WAS, HAS, 12AS, I3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS. In some embodiments, the sense strand comprises pattern 33S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 10AS, HAS, 12AS, HAS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS. In some embodiments, the sense strand comprises pattern 34S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, WAS, HAS, 12AS, BAS, 14AS, BAS, 16AS, 17AS, 18AS, WAS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS. In some embodiments, the sense strand comprises pattern 35S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, WAS, HAS, 12AS, BAS, 14AS, BAS, 16AS, WAS, 18AS, WAS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 4 IAS. In some embodiments, the sense strand comprises pattern 36S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, WAS, HAS, 12AS, BAS, 14AS, BAS, 16AS, WAS. 18AS, WAS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS. In some embodiments, the sense strand comprises pattern 37S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, WAS, HAS, BAS, BAS, 14AS, BAS, 16AS, WAS, 18AS, WAS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS. In some embodiments, the sense strand comprises pattern 38S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, WAS, HAS, 12AS, BAS, 14AS, BAS, 16AS, WAS, 18AS, WAS, 20AS, 21AS, 22AS, 23AS,24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 4 IAS. In some embodiments, the sense strand comprises pattern 39S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 10AS, HAS, 12AS, HAS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS. In some embodiments, the sense strand comprises pattern 40S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, WAS, HAS, 12AS, I3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS. In some embodiments, the sense strand comprises pattern 41S and the antisense strand comprises pattern IAS, 2AS, 3 AS, 4AS, 5 AS, 6AS, 7AS, 8AS, WAS, HAS, 12AS, I3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 4 IAS. In some embodiments, the sense strand comprises pattern 42S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 10AS, HAS, 12AS, HAS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS. In some embodiments, the sense strand comprises pattern 43 S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, WAS, HAS, 12AS, BAS, 14AS, BAS, 16AS, 17AS, 18AS, WAS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS. In some embodiments, the sense strand comprises pattern 44S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, WAS, HAS, 12AS, BAS, 14AS, BAS, 16AS, WAS, 18AS, WAS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS. In some embodiments, the sense strand comprises pattern 45S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, WAS, 1 IAS, 12AS, BAS, 14AS, BAS, 16AS, WAS. 18AS, WAS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS. In some embodiments, the sense strand comprises pattern 46S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, WAS, HAS, BAS, BAS, 14AS, BAS, 16AS, WAS, 18AS, WAS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS. In some embodiments, the sense strand comprises pattern 47S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, WAS, HAS, 12AS, BAS, 14AS, BAS, 16AS, WAS, 18AS, WAS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 4 IAS. In some embodiments, the sense strand comprises pattern 48S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, WAS, HAS, 12AS, BAS, 14AS, BAS, 16AS, WAS, 18AS, WAS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS. In someembodiments, the sense strand comprises pattern 49S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, WAS, HAS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS. In some embodiments, the sense strand comprises pattern 50S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, WAS, HAS, 12AS, I3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 4 IAS. In some embodiments, the sense strand comprises pattern 5 IS and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 10AS, HAS, 12AS, HAS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS. In some embodiments, the sense strand comprises pattern 52S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, WAS, HAS, 12AS, I3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS. In some embodiments, the sense strand comprises pattern 53S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, WAS, HAS, 12AS, I3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 4 IAS. In some embodiments, the sense strand comprises pattern 54S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 10AS, HAS, 12AS, HAS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS. In some embodiments, the sense strand comprises pattern 55S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, WAS, HAS, 12AS, BAS, 14AS, BAS, 16AS, 17AS, 18AS, WAS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS. In some embodiments, the sense strand comprises pattern 56S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, WAS, HAS, 12AS, BAS, 14AS, BAS, 16AS, WAS, 18AS, WAS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 4 IAS. In some embodiments, the sense strand comprises pattern 57S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, WAS, HAS, 12AS, BAS, 14AS, BAS, 16AS, WAS. 18AS, WAS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS. In some embodiments, the sense strand comprises pattern 58S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, WAS, HAS, BAS, BAS, 14AS, BAS, 16AS, WAS, 18AS, WAS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS. In some embodiments, the sense strand comprises pattern 59S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS,8AS, WAS, HAS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 3OAS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 4 IAS. In some embodiments, the sense strand comprises pattern 60S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 10AS, HAS, 12AS, HAS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS. In some embodiments, the sense strand comprises pattern 61S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, WAS, HAS, 12AS, I 3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS. In some embodiments, the sense strand comprises pattern 62S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, WAS, HAS, 12AS, I 3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS. In some embodiments, the sense strand comprises pattern 63S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 10AS, HAS, 12AS, HAS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS. In some embodiments, the sense strand comprises pattern 64S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, WAS, HAS, 12AS, BAS, 14AS, BAS, 16AS, 17AS, 18AS, WAS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS. In some embodiments, the sense strand comprises pattern 65 S and the antisense strand comprises pattern IAS, 2AS, 3 AS, 4AS, 5 AS, 6AS, 7AS, 8AS, WAS, HAS, 12AS, BAS, 14AS, BAS, 16AS, WAS, 18AS, WAS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 4 IAS. In some embodiments, the sense strand comprises pattern 66S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, WAS, HAS, 12AS, BAS, 14AS, BAS, 16AS, WAS. 18AS, WAS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS.

[0178] In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S,IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S,30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S,50S, 5 IS, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, or 66S and the antisense strand comprises pattern IAS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, HS, 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, or 66S and the antisense strand comprises pattern 2AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S,24S, 25S, 26S, 27S, 28S, 29S, 30S, 3 IS, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S,44S, 45S, 46S, 47S, 48S, 49S, 50S, 5 IS, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S,64S, 65S, or 66S and the antisense strand comprises pattern 3AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S,40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S,60S, 61S, 62S, 63S, 64S, 65S, or 66S and the antisense strand comprises pattern 4AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S,34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S,54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, or 66S and the antisense strand comprises pattern 5AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S,IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S,30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S,50S, 5 IS, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, or 66S and the antisense strand comprises pattern 6AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, or 66S and the antisense strand comprises pattern 7AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S,44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S,64S, 65S, or 66S and the antisense strand comprises pattern 8AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S,40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S,60S, 61S, 62S, 63S, 64S, 65S, or 66S and the antisense strand comprises pattern 9AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, or 66S and the antisense strand comprises pattern 10AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 5 IS, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, or 66S and the antisense strand comprises pattern 1 IAS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S,27S, 28S, 29S, 30S, 3 IS, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51 S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, or 66S and the antisense strand comprises pattern 12AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S,42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S,62S, 63S, 64S, 65S, or 66S and the antisense strand comprises pattern 13AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S,18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S,38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S,58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, or 66S and the antisense strand comprises pattern 14AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, or 66S and the antisense strand comprises pattern 15AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S,50S, 5 IS, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, or 66S and the antisense strand comprises pattern 16AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S,47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, or 66S and the antisense strand comprises pattern 17AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S,42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S,62S, 63S, 64S, 65S, or 66S and the antisense strand comprises pattern 18AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S,18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S,38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S,58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, or 66S and the antisense strand comprises pattern 19AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, or 66S and the antisense strand comprises pattern 20AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S,30S, 3 IS, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 5 IS, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, or 66S and the antisense strand comprises pattern 2 IAS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, or 66S and the antisense strand comprises pattern 22AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S,42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S,62S, 63S, 64S, 65S, or 66S and the antisense strand comprises pattern 23AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S,18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S,38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S,58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, or 66S and the antisense strand comprises pattern 24AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, or 66S and the antisense strand comprises pattern 25AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 5 IS, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, or 66S and the antisense strand comprises pattern 26AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, or 66S and the antisense strand comprises pattern 27AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S,42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S,62S, 63S, 64S, 65S, or 66S and the antisense strand comprises pattern 28AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S,18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S,38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S,58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, or 66S and the antisense strand comprises pattern 29AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S,34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 5 IS, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, or 66S and the antisense strand comprises pattern 30AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 5 IS, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, or 66S and the antisense strand comprises pattern 3 IAS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, or 66S and the antisense strand comprises pattern 32AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S,42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S,62S, 63S, 64S, 65S, or 66S and the antisense strand comprises pattern 33AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S,18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S,38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S,58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, or 66S and the antisense strand comprises pattern 34AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, or 66S and the antisense strand comprises pattern 35AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 5 IS, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, or 66S and the antisense strand comprises pattern 36AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, or 66S and the antisense strand comprises pattern 37AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S,42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S,62S, 63S, 64S, 65S, or 66S and the antisense strand comprises pattern 38AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S,18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S,38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 5 IS, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, or 66S and the antisense strand comprises pattern 39AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S,34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S,54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, or 66S and the antisense strand comprises pattern 40AS. In some embodiments, the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S,9S, IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 5 IS, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, or 66S and the antisense strand comprises pattern 4 IAS.

[0179] In some embodiments, the sense strand comprises modification pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, WAS, HAS, 12AS, I 3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 2 IAS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS. In some embodiments, the antisense strand comprises modification pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, 65S, or 66S . In some embodiments, the sense strand or the antisense strand comprises modification pattern ASO 1 .

[0180] 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 modified 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.

[0181] 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.

[0182] 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 someembodiments, 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.

[0183] 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 the 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.

[0184] 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.

[0185] 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 strandcomprise 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.

[0186] 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.

[0187] 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’-fluoro 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.

[0188] 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 indelivery 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.

[0189] 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 a FGG 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 FGG mRNA or a target protein. In some embodiments, the sense strand has the same sequence as the FGG 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.

[0190] In some cases, the sense strand of any of the siRNAs comprises siRNA with a particular modification pattern. In some embodiments of the modification pattern, position 9 counting from the 5’ end of the sense strand may have a 2’F modification. In some embodiments, when position 9 of the sense strand is a pyrimidine, then all purines in the sense strand have a 2’0Me 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 the sense strand. In some embodiments, when position 9 and only one other base between positions 5 and 11 of the sense strand are pyrimidines, then both of these pyrimidines are the only two positions with a 2’F modification in the sense strand. In some embodiments, when position 9 and only two other bases between positions 5 and 11 of the sense strand 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 the sense strand, then all combinations of pyrimidines having the 2’F modification are allowed that have three to five 2’F modifications in total, provided that the sense strand does not have three 2’F modifications in a row. In some cases, the sense strand of any of the siRNAs comprises a modification pattern which conforms to any or all of these sense strand rules.

[0191] In some embodiments, when position 9 of the sense strand is a purine, then all purines in the sense strand have a 2’0Me modification. In some embodiments, when position 9 is the only purine between positions 5 and 11 of the sense stand, then position 9 is the only position with a 2’F modification in the sense strand. In some embodiments, when position 9 and only one other base between positions 5 and 11 of the sense strand are purines, then both of these purines are the only two positions with a 2’F modification in the sense strand. In some embodiments, when position 9 and only two other bases between positions 5 and 11 of the sense strand 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 the sense strand, then all combinations of purineshaving the 2’F modification are allowed that have three to five 2’F modifications in total, provided that the sense strand does not have three 2’F modifications in a row. In some cases, the sense strand of any of the siRNAs comprises a modification pattern which conforms to any or all of these sense strand rules.

[0192] In some cases, position 9 of the sense strand can be a 2’deoxy. In these cases, 2’F and 2’OMe modifications may occur at the other positions of the sense strand. In some cases, the sense strand of any of the siRNAs comprises a modification pattern which conforms to these sense strand rules.

[0193] In some cases, the sense strand of any of the siRNAs comprises a modification pattern which conforms to these sense strand rules.

[0194] Disclosed herein, in some embodiments are compositions comprising an oligonucleotide that targets FGG and when administered to a cell decreases expression of FGG, wherein the oligonucleotide comprises a small interfering RNA (siRNA) comprising a sense strand and an antisense strand, wherein the sense strand comprises a sense strand sequence described herein in which at least one intemucleoside linkage is modified and at least one nucleoside is modified, or an sense strand sequence comprising 1 or 2 nucleoside substitutions, additions, or deletions of the oligonucleotide sequence in which at least one intemucleoside linkage is modified and at least one nucleoside is modified, and wherein the antisense strand comprises an antisense strand sequence described herein in which at least one intemucleoside linkage is modified and at least one nucleoside is modified, or an oligonucleotide sequence comprising 1 or 2 nucleoside substitutions, additions, or deletions of the antisense strand sequence in which at least one intemucleoside linkage is modified and at least one nucleoside is modified. Some embodiments relate to methods that include administering the composition to a subject.

[0195] 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 (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. 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) 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; 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.

[0196] In some embodiments, any one of the following is true with regard to the sense strand: (a) all purines comprise fluoro modified purines and all pyrimidines comprise (i) a mixture of 2’-O-methyl and 2’-O-methoxyethyl modified pyrimidines; or (ii) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O- methoxyethyl modified pyrimidines; (b) all purines comprise 2'-O-methyl modified purines and all pyrimidines comprise (i) all pyrimidines of the sense strand comprise a mixture of 2 ’-fluoro and 2’-O- 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-methoxyethylmodified 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.

[0197] In some embodiments, the sense and / or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and / or antisense strand sequence in any of Tables 8A, 18A, 22A, 26A, 31A, 33A, 37A, 42A, 47A, 66A, 78 or 82. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in any of Tables 8A, 18A, 22A, 26A, 31A, 33A, 37A, 42A, 47A, 66A, 78 or 82or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in any of Tables 8A, 18A, 22A, 26A, 31A, 33A, 37A, 42A, 47A, 66A, 78 or 82 or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in any of Tables 8A, 18A, 22A, 26A, 31A, 33A, 37A, 42A, 47A, 66A, 78 or 82. The siRNA may include the same intemucleoside linkage modifications or nucleoside modifications as those in any of 8A, 18A, 22A, 26A, 31A, 33A, 37A, 42A, 47A, 66A, 78 or 82. The siRNA may include any different intemucleoside linkage modifications or nucleoside modifications different from those in any of Tables 88A, 18A, 22A, 26A, 31A, 33A, 37A, 42A, 47A, 66A, 78 or 82. The siRNA may include some unmodified intemucleoside linkages or nucleosides.

[0198] In some embodiments, the sense and / or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and / or antisense strand sequence in Table 8A. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 8A or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 8A or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 8A. The siRNA may include the same intemucleoside linkage modifications or nucleoside modifications as those in Table 8A. The siRNA may include any different intemucleoside linkage modifications or nucleoside modifications different from those in Table 8A. The siRNA may include some unmodified intemucleoside linkages or nucleosides.

[0199] In some embodiments, the sense and / or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and / or antisense strand sequence in Table 8B. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 8B or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 8B or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 8B. The siRNA may include the same intemucleoside linkage modifications or nucleoside modifications as those in Table 8B. The siRNA may include any different intemucleoside linkage modifications or nucleoside modifications different from those in Table 8B. The siRNA may include some unmodified intemucleoside linkages or nucleosides.

[0200] In some embodiments, the sense and / or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and / or antisense strand sequence in Table 18A. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 18A or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 18A or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 18A. The siRNA may include the same intemucleoside linkage modifications or nucleoside modifications as those in Table 18A. The siRNA may include any different intemucleoside linkage modifications or nucleoside modifications different from those in Table 18A. The siRNA may include some unmodified intemucleoside linkages or nucleosides.

[0201] In some embodiments, the sense and / or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and / or antisense strand sequence in Table 22A. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 22A or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 22A or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 22A. The siRNA may include the same intemucleoside linkage modifications or nucleoside modifications as those in Table 22A. The siRNA may include any different intemucleoside linkage modifications or nucleoside modifications different from those in Table 22A. The siRNA may include some unmodified intemucleoside linkages or nucleosides.

[0202] In some embodiments, the sense and / or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90%identical, or at least 95% identical, to a sense and / or antisense strand sequence in Table 26A. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 26A or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 26A or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 26A. The siRNA may include the same intemucleoside linkage modifications or nucleoside modifications as those in Table 26A. The siRNA may include any different intemucleoside linkage modifications or nucleoside modifications different from those in Table 26A. The siRNA may include some unmodified intemucleoside linkages or nucleosides.

[0203] In some embodiments, the sense and / or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and / or antisense strand sequence in Table 31A. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 31 A or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 31 A or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 31A. The siRNA may include the same intemucleoside linkage modifications or nucleoside modifications as those in Table 31A. The siRNA may include any different intemucleoside linkage modifications or nucleoside modifications different from those in Table 31A. The siRNA may include some unmodified intemucleoside linkages or nucleosides.

[0204] In some embodiments, the sense and / or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and / or antisense strand sequence in Table 33A. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 33A or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 33A or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 33A. The siRNA may include the same intemucleoside linkage modifications or nucleoside modifications as those in Table 33A. The siRNA may include any different intemucleoside linkage modifications or nucleoside modifications different from those in Table 33A. The siRNA may include some unmodified intemucleoside linkages or nucleosides.

[0205] In some embodiments, the sense and / or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and / or antisense strand sequence in Table 37A. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA inTable 37A or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 37A or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 37A. The siRNA may include the same intemucleoside linkage modifications or nucleoside modifications as those in Table 37A. The siRNA may include any different intemucleoside linkage modifications or nucleoside modifications different from those in Table 37A. The siRNA may include some unmodified intemucleoside linkages or nucleosides.

[0206] In some embodiments, the sense and / or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and / or antisense strand sequence in Table 42A. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 42A or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 42A or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 42A. The siRNA may include the same intemucleoside linkage modifications or nucleoside modifications as those in Table 42A. The siRNA may include any different intemucleoside linkage modifications or nucleoside modifications different from those in Table 42A. The siRNA may include some unmodified intemucleoside linkages or nucleosides.

[0207] In some embodiments, the sense and / or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and / or antisense strand sequence in Table 47A. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 47A or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 47A or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 47A. The siRNA may include the same intemucleoside linkage modifications or nucleoside modifications as those in Table 47A. The siRNA may include any different intemucleoside linkage modifications or nucleoside modifications different from those in Table 47A. The siRNA may include some unmodified intemucleoside linkages or nucleosides.

[0208] In some embodiments, the sense and / or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and / or antisense strand sequence in Table 66B. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 66B or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strandsequence of an siRNA in Table 66B or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 66B. The siRNA may include the same intemucleoside linkage modifications or nucleoside modifications as those in Table 66B. The siRNA may include any different intemucleoside linkage modifications or nucleoside modifications different from those in Table 66B. The siRNA may include some unmodified intemucleoside linkages or nucleosides.

[0209] In some embodiments, the sense and / or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and / or antisense strand sequence in Table 78. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 78 or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 78 or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 78. The siRNA may include the same intemucleoside linkage modifications or nucleoside modifications as those in Table 78. The siRNA may include any different intemucleoside linkage modifications or nucleoside modifications different from those in Table 78. The siRNA may include some unmodified intemucleoside linkages or nucleosides.

[0210] In some embodiments, the sense and / or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and / or antisense strand sequence in Table 82. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 82 or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 82 or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 82. The siRNA may include the same intemucleoside linkage modifications or nucleoside modifications as those in Table 82. The siRNA may include any different intemucleoside linkage modificatio...

Claims

CLAIMSWhat is claimed is:

1. A composition comprising an oligonucleotide that targets FGG and when administered to a subject in an effective amount improves a hearing measurement in the subject, relative to a baseline hearing measurement.

2. The composition of claim 1, wherein the hearing measurement comprises a pure-tone audiometry, pure tone threshold, speech audiometry and speech reception threshold, tympanometry, Stapedius reflex measurements, German speech intelligibility test (Freiburger Sprachtest), brainstem audiometry, or otoacoustic emissions measurement.

3. The composition of any one of the preceding claims, wherein the hearing measurement is improved by at least 10%.

4. The composition of any one of the preceding claims, wherein the oligonucleotide inhibits the expression of FGG.

5. The composition of any one of the preceding claims, wherein the oligonucleotide comprises a nucleoside sequence complementary to 12-30 contiguous nucleosides of SEQ ID NO: 3621.

6. The composition of any one of the preceding claims, wherein the oligonucleotide comprises a nucleoside base sequence at least 90% identical to the sequence of any one of SEQ ID NOs: 1-3484.

7. The composition of any one of the preceding claims, wherein the oligonucleotide comprises the nucleoside base sequence of any one of SEQ ID NOs: 1-3484.

8. The composition of any one of the preceding claims, wherein the oligonucleotide comprises a modified intemucleoside linkage.

9. The composition of claim 8, wherein the modified intemucleoside linkage comprises alkylphosphonate, phosphorothioate, methylphosphonate, phosphorodithioate, alkylphosphonothioate, phosphoramidate, carbamate, carbonate, phosphate triester, acetamidate, or carboxymethyl ester, or a combination thereof.

10. The composition of claim 8, wherein the modified intemucleoside linkage comprises a phosphorothioate linkage.

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

12. The composition of any one of the preceding claims, wherein the oligonucleotide comprises a modified nucleoside.

13. The composition of claim 12, wherein 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, 2'-deoxy, or a combination thereof.

14. The composition of claim 12, wherein the modified nucleoside comprises 2'-O-methyl nucleoside, 2'-deoxyfluoro nucleoside, 2'-O-N-methylacetamido (2'-0-NMA) nucleoside, 2'-O- dimethylaminoethoxyethyl’(2'-O-DMAEOE) nucleoside, 2'-O-aminopropyl (2'-O-AP) nucleoside, or 2'- ara-F, or a combination thereof.

15. The composition of claim 12, wherein the modified nucleoside comprises a 2 ’-fluoro modified nucleoside.

16. The composition of claim 12, wherein the modified nucleoside comprises a 2’-O-alkyl modified nucleoside.

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

18. The composition of any one of the preceding claims, wherein the oligonucleotide comprises a sugar moiety attached at a 3’ or 5’ terminus of the oligonucleotide.

19. The composition of claim 18, wherein the sugar comprises N-acetylgalactosamine (GalNAc), N-acetylglucosamine (GlcNAc), or mannose.

20. The composition of claim 18, wherein the sugar comprises GalNAc.

21. The composition of claim 18, wherein the sugar moiety comprises ETL17.

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

23. The composition of any one of claims 1-21, wherein the oligonucleotide comprises an antisense oligonucleotide (ASO).

24. The composition of any one of the preceding claims, further comprising a pharmaceutically acceptable carrier.

25. A method of treating a subject having a hearing disorder, comprising administering an effective amount of the composition of any one of the preceding claims to the subject.

26. The method of claim 25, wherein the hearing disorder comprises an idiopathic sudden sensorineural hearing loss (ISSNHL), noise-induced sensorineural hearing loss, hearing loss, sensorineural hearing loss, tinnitus, or conductive hearing loss.

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