EP4687920A2 - Behandlung von fgg-bedingten hörstörungen - Google Patents

Behandlung von fgg-bedingten hörstörungen

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Publication number
EP4687920A2
EP4687920A2 EP24781957.6A EP24781957A EP4687920A2 EP 4687920 A2 EP4687920 A2 EP 4687920A2 EP 24781957 A EP24781957 A EP 24781957A EP 4687920 A2 EP4687920 A2 EP 4687920A2
Authority
EP
European Patent Office
Prior art keywords
nucleoside
modified
oligonucleotide
sense strand
antisense strand
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP24781957.6A
Other languages
English (en)
French (fr)
Inventor
Omri GOTTESMAN
Eric BUSS
Shannon BRUSE
Brian CAJES
David Lewis
Gregory Mcinnes
David Rozema
John VEKICH
Darren H. Wakefield
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Empirico Inc
Original Assignee
Empirico Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Empirico Inc filed Critical Empirico Inc
Publication of EP4687920A2 publication Critical patent/EP4687920A2/de
Pending legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A61K31/713—Double-stranded nucleic acids or oligonucleotides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/745—Blood coagulation or fibrinolysis factors
    • C07K14/75—Fibrinogen
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/10—Type of nucleic acid
    • C12N2310/14—Type of nucleic acid interfering nucleic acids [NA]
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/31—Chemical structure of the backbone
    • C12N2310/315—Phosphorothioates
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/32—Chemical structure of the sugar
    • C12N2310/321—2'-O-R Modification
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/34—Spatial arrangement of the modifications
    • C12N2310/341—Gapmers, i.e. of the type ===---===
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/35—Nature of the modification
    • C12N2310/351—Conjugate

Definitions

  • 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.
  • 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.
  • 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.
  • 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.
  • 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 (Freiburgerptest), brainstem audiometry, or otoacoustic emissions measurement.
  • composition comprising an oligonucleotide that targets FGG and when administered to a subject in an effective amount decreases fibrinogen.
  • the oligonucleotide comprises a modified intemucleoside linkage.
  • the modified intemucleoside linkage comprises alkylphosphonate, phosphorothioate, methylphosphonate, phosphorodithioate, alkylphosphonothioate, phosphoramidate, carbamate, carbonate, phosphate triester, acetamidate, or carboxymethyl ester, or a combination thereof.
  • the modified intemucleoside linkage comprises one or more phosphorothioate linkages.
  • 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.
  • the oligonucleotide comprises a modified nucleoside.
  • 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.
  • the modified nucleoside comprises an LNA.
  • the modified nucleoside comprises a 2’, 4’ constrained ethyl nucleic acid.
  • 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.
  • the modified nucleoside comprises one or more 2’-fluoro modified nucleosides.
  • the modified nucleoside comprises 2’-O-alkyl modified nucleoside.
  • 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.
  • the oligonucleotide comprises a sugar moiety attached at a 3’ or 5’ terminus of the oligonucleotide.
  • the sugar comprises N- acetylgalactosamine (GalNAc), N-acetylglucosamine (GlcNAc), or mannose.
  • the sugar comprises GalNAc.
  • the sugar moiety comprises ETL17.
  • the oligonucleotide comprises a small interfering RNA (siRNA) comprising a sense strand and an antisense strand.
  • the sense strand is 12-30 nucleosides in length.
  • the antisense strand is 12-30 nucleosides in length.
  • 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.
  • 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.
  • 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; all pyrimidines comprise 2’-O-methyl modified pyrimidines,
  • the antisense strand comprises a mixture of 2 ’-fluoro and 2’-O-methyl modified nucleosides.
  • the oligonucleotide comprises an antisense oligonucleotide (ASO).
  • ASO antisense oligonucleotide
  • the ASO is 12-30 nucleosides in length.
  • 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.
  • the composition further comprises a pharmaceutically acceptable carrier.
  • 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.
  • 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.
  • FIG. 2 is an example of a GalNAc ligand.
  • a Genome Wide Association Study 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.
  • OR odds ratios
  • beta beta coefficients
  • 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.”
  • 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.
  • 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.
  • 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.
  • 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).
  • compositions comprising an oligonucleotide.
  • the composition comprises an oligonucleotide that targets FGG.
  • the composition consists of an oligonucleotide that targets FGG.
  • the oligonucleotide reduces FGG mRNA expression in the subject.
  • 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) described herein.
  • 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.
  • 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).
  • a cell e.g., hepatocyte or neuron
  • fluid e.g., blood, serum, plasma, or cerebrospinal fluid (CSF)
  • tissue e.g., brain or liver tissue
  • organ e.g., the brain or liver
  • 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.
  • the cell is a liver cell (e.g., hepatocyte).
  • the cell is a neuron.
  • the tissue is liver tissue.
  • the tissue is neural tissue.
  • the neural tissue is CNS tissue.
  • the neural tissue is brain tissue (e.g., neuronal, glia, or endothelial tissue).
  • the fluid is CSF.
  • 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.
  • 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.
  • 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.
  • the cell is a hepatocyte.
  • the cell is a neural cell (e.g., CNS cell (e.g., brain cell)).
  • the cell is a neuronal cell.
  • the cell is a glial cell.
  • the cell is an endothelial cell.
  • the tissue is liver tissue.
  • the tissue is neural (e.g., CNS (e.g., brain)) tissue.
  • the fluid is CSF.
  • 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, as compared 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.
  • 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.
  • 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).
  • 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.
  • fibrinogen may be lowered enough to have a therapeutic effect on hearing disorders but without significantly affecting coagulation parameters such as PT or aPTT.
  • 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 (Freiburgerptest), brainstem audiometry, or otoacoustic emissions.
  • 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.
  • 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.
  • 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.
  • 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).
  • 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.
  • the hearing is increased by about 10% or more, as compared to prior to administration.
  • 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.
  • 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.
  • 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.
  • 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.
  • the composition comprises an oligonucleotide that targets FGG, wherein the oligonucleotide comprises a small interfering RNA (siRNA).
  • 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.
  • siRNA small interfering RNA
  • 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.
  • 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.
  • the composition comprises an antisense strand is 12-30 nucleosides in length.
  • the composition comprises an antisense strand that is 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleosides in length, or a range defined by any of the two aforementioned numbers.
  • the antisense strand may be 14-30 nucleosides in length.
  • 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.
  • thymine (T) may be replaced with Uracil (U).
  • 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.
  • 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.
  • the first base pair of the double -stranded RNA duplex is an AU base pair.
  • the sense strand further comprises a 3’ overhang.
  • 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.
  • the 3’ overhang comprises 1, 2, or more nucleosides.
  • the 3’ overhang comprises 2 nucleosides.
  • the sense strand further comprises a 5’ overhang.
  • 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.
  • the 5’ overhang comprises 1, 2, or more nucleosides.
  • the 5’ overhang comprises 2 nucleosides.
  • the antisense strand further comprises a 3’ overhang.
  • 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.
  • the 3’ overhang comprises 1, 2, or more nucleosides.
  • the 3’ overhang comprises 2 nucleosides.
  • the antisense strand further comprises a 5’ overhang.
  • 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.
  • the 5’ overhang comprises 1, 2, or more nucleosides.
  • the 5’ overhang comprises 2 nucleosides.
  • 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.
  • 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.
  • 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 17mer in a non -human primate FGG mRNA.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • 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).
  • 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%.
  • 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.
  • 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.
  • the sense strand further comprises a 3’ overhang.
  • 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.
  • the 3’ overhang comprises 1, 2, or more nucleosides.
  • the 3’ overhang comprises 2 nucleosides.
  • the sense strand further comprises a 5’ overhang.
  • 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.
  • 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.
  • 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.
  • thymine (T) may be replaced with Uracil (U).
  • U Uracil
  • 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.
  • 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.
  • 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.
  • 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.
  • position 1 (from the 5’ end) of any one of SEQ ID NOs: 1-1742 is modified to an A.
  • position 6 (from the 5’ end) of any one of SEQ ID NOs: 1-1742 is modified to an A.
  • position 19 (from the 5’ end) of any one of SEQ ID NOs: 1-1742 is modified to an A.
  • 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.
  • position 1 (from the 5’ end) of any one of SEQ ID NOs: 1-1742 is modified to an T or U.
  • position 6 (from the 5’ end) of any one of SEQ ID NOs: 1-1742 is modified to a T or U.
  • position 19 (from the 5’ end) of any one of SEQ ID NOs: 1-1742 is modified to a T or U.
  • 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.
  • position 1 (from the 5’ end) of any one of SEQ ID NOs: 1-1742 is modified to an G.
  • position 6 (from the 5’ end) of any one of SEQ ID NOs: 1-1742 is modified to an G.
  • position 19 (from the 5’ end) of any one of SEQ ID NOs: 1- 1742 is modified to an G.
  • 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.
  • position 1 (from the 5’ end) of any one of SEQ ID NOs: 1-1742 is modified to an C.
  • position 6 (from the 5’ end) of any one of SEQ ID NOs: 1- 1742 is modified to an C.
  • position 19 (from the 5’ end) of any one of SEQ ID NOs: 1-1742 is modified to an C.
  • 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.
  • 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.
  • the antisense strand further comprises a 3’ overhang.
  • 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.
  • the 3’ overhang comprises 1, 2, or more nucleosides.
  • the 3’ overhang comprises 2 nucleosides.
  • the antisense strand further comprises a 5’ overhang.
  • 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.
  • the 5’ overhang comprises 1, 2, or more nucleosides.
  • the 5’ overhang comprises 2 nucleosides.
  • 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.
  • 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.
  • thymine (T) may be replaced with Uracil (U).
  • U Uracil
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • position 1 (from the 5 ’ end) of any one of SEQ ID NOs: 1743-3484 is modified to an A.
  • position 14 (from the 5’ end) of the sense strand of any one of SEQ ID NOs: 1743-3484 is modified to an A.
  • position 19 (from the 5’ end) of any one of SEQ ID NOs: 1743-3484 is modified to an A.
  • 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.
  • position 1 (from the 5’ end of any one of SEQ ID NOs: 1743-3484 is modified to a T or U.
  • position 14 (from the 5’ end) of any one of SEQ ID NOs: 1743-3484 is modified to a T or U.
  • position 19 (from the 5’ end) of any one of SEQ ID NOs: 1743-3484 is modified to a T or U.
  • 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.
  • position 1 (from the 5’ end) of any one of SEQ ID NOs: 1743-3484 is modified to an G.
  • position 14 (from the 5’ end) of any one of SEQ ID NOs: 1743-3484 is modified to an G.
  • position 19 (from the 5’ end) of any one of SEQ ID NOs: 1743-3484 is modified to an G.
  • 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.
  • position 1 (from the 5’ end) of any one of SEQ ID NOs: 1743-3484 is modified to an C.
  • position 14 (from the 5’ end) of any one of SEQ ID NOs: 1743-3484 is modified to an C.
  • position 19 (from the 5’ end) of any one of SEQ ID NOs: 1743-3484 is modified to an C.
  • 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.
  • 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.
  • 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.
  • the sense strand further comprises a 3’ overhang.
  • 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.
  • the 3’ overhang comprises 1, 2, or more nucleosides.
  • the 3’ overhang comprises 2 nucleosides.
  • the sense strand further comprises a 5’ overhang.
  • 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.
  • 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.
  • thymine (T) may be replaced with Uracil (U).
  • U Uracil
  • 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.
  • 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.
  • 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.
  • 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.
  • position 1 (from the 5’ end) of any one of SEQ ID NOs: 3713-3748 is modified to an A.
  • position 6 (from the 5’ end) of any one of SEQ ID NOs: 3713- 3748 is modified to an A.
  • position 19 (from the 5’ end) of any one of SEQ ID NOs: 3713-3748 is modified to an A.
  • 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.
  • position 1 (from the 5’ end) of any one of SEQ ID NOs: 3713-3748 is modified to an T or U.
  • position 6 (from the 5’ end) of any one of SEQ ID NOs: 3713-3748 is modified to a T or U.
  • position 19 (from the 5’ end) of any one of SEQ ID NOs: 3713-3748 is modified to a T or U.
  • 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.
  • position 1 (from the 5’ end) of any one of SEQ ID NOs: 3713-3748 is modified to an G.
  • position 6 (from the 5’ end) of any one of SEQ ID NOs: 3713-3748 is modified to an G.
  • position 19 (from the 5’ end) of any one of SEQ ID NOs: 3713-3748 is modified to an G.
  • 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.
  • position 1 (from the 5’ end) of any one of SEQ ID NOs: 3713-3748 is modified to an C.
  • position 6 (from the 5’ end) of any one of SEQ ID NOs: 3713-3748 is modified to an C.
  • position 19 (from the 5’ end) of any one of SEQ ID NOs: 3713- 3748 is modified to an C.
  • 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.
  • 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.
  • 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.
  • the antisense strand further comprises a 3’ overhang.
  • 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.
  • the 3’ overhang comprises 1, 2, or more nucleosides.
  • the 3’ overhang comprises 2 nucleosides.
  • the antisense strand further comprises a 5’ overhang.
  • 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.
  • the 5’ overhang comprises 1, 2, or more nucleosides.
  • the 5’ overhang comprises 2 nucleosides.
  • 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.
  • 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.
  • thymine (T) may be replaced with Uracil (U).
  • U Uracil
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • position 1 (from the 5 ’ end) of any one of SEQ ID NOs: 3749-3784 is modified to an A.
  • position 14 (from the 5’ end) of the sense strand of any one of SEQ ID NOs: 3749-3784 is modified to an A.
  • position 19 (from the 5’ end) of any one of SEQ ID NOs: 3749-3784 is modified to an A.
  • 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.
  • position 1 (from the 5’ end of any one of SEQ ID NOs: 3749-3784 is modified to a T or U.
  • position 14 (from the 5’ end) of any one of SEQ ID NOs: 3749-3784 is modified to a T or U.
  • position 19 (from the 5’ end) of any one of SEQ ID NOs: 3749-3784 is modified to a T or U.
  • 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.
  • position 1 (from the 5’ end) of any one of SEQ ID NOs: 3749-3784 is modified to an G.
  • position 14 (from the 5’ end) of any one of SEQ ID NOs: 3749-3784 is modified to an G.
  • position 19 (from the 5’ end) of any one of SEQ ID NOs: 3749-3784 is modified to an G.
  • 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.
  • position 1 (from the 5’ end) of any one of SEQ ID NOs: 3749-3784 is modified to an C.
  • position 14 (from the 5’ end) of any one of SEQ ID NOs: 3749-3784 is modified to an C.
  • position 19 (from the 5’ end) of any one of SEQ ID NOs: 3749-3784 is modified to an C.
  • 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.
  • 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.
  • 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.
  • the sense strand further comprises a 3’ overhang.
  • 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.
  • the 3’ overhang comprises 1, 2, or more nucleosides.
  • the 3’ overhang comprises 2 nucleosides.
  • the sense strand further comprises a 5’ overhang.
  • 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.
  • the 5’ overhang comprises 1, 2, or more nucleosides.
  • the 5’ overhang comprises 2 nucleosides.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • position 1 (from the 5 ’ end) of any one of SEQ ID NOs: 3879-3941 or 4020-4021 is modified to an A.
  • position 6 (from the 5’ end) of any one of SEQ ID NOs: 3879-3941 or 4020-4021 is modified to an A.
  • position 19 (from the 5’ end) of any one of SEQ ID NOs: 3879-3941 or 4020-4021 is modified to an A.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • position 1 (from the 5’ end) of any one of SEQ ID NOs: 3879-3941 or 4020-4021 is modified to an G.
  • position 6 (from the 5’ end) of any one of SEQ ID NOs: 3879- 3941 or 4020-4021 is modified to an G.
  • position 19 (from the 5’ end) of any one of SEQ ID NOs: 3879-3941 or 4020-4021 is modified to an G.
  • 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.
  • position 1 (from the 5’ end) of any one of SEQ ID NOs: 3879-3941 or 4020-4021 is modified to an C.
  • position 6 (from the 5’ end) of any one of SEQ ID NOs: 3879-3941 or 4020-4021 is modified to an C.
  • position 19 (from the 5’ end) of any one of SEQ ID NOs: 3879- 3941 or 4020-4021 is modified to an C.
  • 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.
  • 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.
  • 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.
  • the antisense strand further comprises a 3’ overhang.
  • 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.
  • the 3’ overhang comprises 1, 2, or more nucleosides.
  • the 3’ overhang comprises 2 nucleosides.
  • the antisense strand further comprises a 5’ overhang.
  • 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.
  • the 5’ overhang comprises 1, 2, or more nucleosides.
  • the 5’ overhang comprises 2 nucleosides.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • position 1 (from the 5’ end) of any one of SEQ ID NOs: 3942-4002 or 4022-4023 is modified to an A.
  • 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.
  • position 19 (from the 5’ end) of any one of SEQ ID NOs: 3942-4002 or 4022-4023 is modified to an A.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • position 1 (from the 5’ end) of any one of SEQ ID NOs: 3942-4002 or 4022-4023 is modified to an G.
  • position 14 (from the 5’ end) of any one of SEQ ID NOs: 3942-4002 or 4022-4023 is modified to an G.
  • position 19 (from the 5’ end) of any one of SEQ ID NOs: 3942- 4002 or 4022-4023 is modified to an G.
  • 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.
  • position 1 (from the 5’ end) of any one of SEQ ID NOs: 3942-4002 or 4022-4023 is modified to an C.
  • position 14 (from the 5’ end) of any one of SEQ ID NOs: 3942-4002 or 4022-4023 is modified to an C.
  • position 19 (from the 5’ end) of any one of SEQ ID NOs: 3942-4002 or 4022-4023 is modified to an C.
  • 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.
  • 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.
  • 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 sense strand 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.
  • NHS non-human primate
  • the siRNA may include one or more intemucleoside linkages and/or one or more nucleoside modifications.
  • 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.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • NEP non-human primate
  • 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.
  • 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.
  • 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.
  • 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.
  • NEP non-human primate
  • 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.
  • 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.
  • 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.
  • 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.
  • NEP non-human primate
  • 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.
  • 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.
  • 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.
  • 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.
  • NEP non-human primate
  • 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.
  • 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.
  • 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.
  • 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.
  • NEP non-human primate
  • 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.
  • 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.
  • 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.
  • 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.
  • NEP non-human primate
  • 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.
  • 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.
  • 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.
  • 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 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.
  • NEP non-human primate
  • 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.
  • 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.
  • 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.
  • 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.
  • NEP non-human primate
  • 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.
  • 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.
  • 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.
  • 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.
  • NEP non-human primate
  • 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.
  • 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.
  • 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.
  • 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.
  • NEP non-human primate
  • 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.
  • 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.
  • 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.
  • 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.
  • NEP non-human primate
  • 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.
  • 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.
  • 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.
  • 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 siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A.
  • NEP non-human primate
  • 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.
  • 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.
  • 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.
  • 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.
  • NEP non-human primate
  • 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.
  • 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.
  • 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.
  • 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.
  • NEP non-human primate
  • 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.
  • 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.
  • 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 3 or 4 nucleoside substitutions, additions, or deletions.
  • 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.
  • NEP non-human primate
  • 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.
  • 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.
  • 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.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA of subset C, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA of subset C, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA of subset C.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • 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).
  • the sense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 1003.
  • 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.
  • the sense strand comprises the nucleoside sequence of SEQ ID NO: 1003, and 3 or 4 nucleoside substitutions, additions, or deletions.
  • 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).
  • 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 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).
  • 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).
  • 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 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.
  • 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.
  • 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).
  • 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 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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, or 3747.
  • 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).
  • 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:
  • 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).
  • 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:
  • 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).
  • 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).
  • 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).
  • 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.
  • 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.
  • 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).
  • 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.
  • 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.
  • 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 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.
  • 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.
  • the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an antisense oligonucleotide (ASO).
  • ASO antisense oligonucleotide
  • 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.
  • 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.
  • 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
  • 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.
  • 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.
  • 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.
  • position 4 of the sense strand may comprise a methoxyethyl nucleoside such as a 2’-O-methoxyethyl thymine.
  • the modified nucleoside comprises 2'-O-methyl.
  • the modified nucleoside comprises a 2'-O-allyl group.
  • the modified nucleoside comprises a 2'-fluoro group.
  • the modified nucleoside comprises a 2'-deoxy group.
  • 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.
  • the modified nucleoside comprises a glycol nucleic acid (GNA).
  • GNA glycol nucleic acid
  • the oligonucleotide comprises a modified nucleoside.
  • 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.
  • 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.
  • 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.
  • 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.
  • the antisense strand is combination of 2’-fluoro and 2’-O-methyl modifications.
  • 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.
  • the sense strand comprises at least a 2 ’-fluoro modified nucleoside and a 2’-O-methyl modified nucleoside.
  • the oligonucleotide may include purines.
  • 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.
  • the sense strand comprises purines and pyrimidines.
  • all purine nucleosides comprise 2’-fluoro, and all pyrimidine nucleosides are modified with a mixture of 2’-O-methyl and 2’-O-methoxyethyl.
  • all purine nucleosides comprise 2’-O-methyl, and all pyrimidine nucleosides are modified with a mixture of 2’-fluoro and 2’-O- methoxyethyl.
  • 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.
  • all pyrimidine nucleosides comprise 2’-O-methoxyethyl, and all purine nucleosides are modified with a mixture of 2 ’-fluoro and 2’-O-methyl.
  • the sense strand may include a 2’ deoxy nucleoside.
  • At least one nucleotide at position 4 or 5 of the sense strand comprises a 2’-O-methoxyethyl modified nucleoside.
  • at least one nucleotide of the sense strand from position 6 to 9 comprise a 2’-fluoro-modified nucleoside.
  • at least two nucleotides of the sense strand at position 6 to 9 comprise a 2’-fluoro-modified nucleoside.
  • at least three nucleotides of the sense strand at positions 6 to 9 comprise a 2 ’-fluoromodified nucleoside.
  • each nucleotide from positions 6 to 9 of the sense strand comprise a 2’-fluoro-modified nucleoside.
  • at least one nucleotide at position 16 to 20 of the sense strand comprises a 2’-O-methyl modified nucleoside.
  • at least two nucleotides at position 16 to 20 of the sense strand comprise a 2’-O-methyl modified nucleoside.
  • at least three nucleotides at position 16 to 20 of the sense strand comprise a 2’-O-methyl modified nucleoside.
  • at least four nucleotides at position 16 to 20 of the sense strand comprise a 2’-O-methyl modified nucleoside.
  • all nucleotides at position 16 to 20 of the sense strand comprise a 2’-O-methyl modified nucleoside.
  • 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; all pyrimidine nucleo
  • 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.
  • 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.
  • 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.
  • the sugar moiety may include 1, 2, 3, or more sugar molecules.
  • the sugar moiety may be attached at a 3’ or 5’ terminus of the oligonucleotide.
  • the sugar moiety may include an N-acetyl galactose moiety.
  • the sugar moiety may include an N-acetylgalactosamine (GalNAc) moiety.
  • the sugar moiety may include an N- acetyl glucose moiety.
  • the sugar moiety may include N-acetylglucosamine (GlcNAc) moiety.
  • the sugar moiety may include a fucose moiety.
  • the sugar moiety may include a mannose moiety. N-acetyl glucose, GlcNAc, fucose, or mannose may be useful for targeting macrophages since they may target or bind a mannose receptor such as CD206.
  • 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.
  • Non-limiting examples of GalNAc ligands are shown in FIG. 1 and FIG. 2.
  • the oligonucleotide is conjugated to the GalNAc ligand in FIG. 1.
  • J indicates a point of attachment to an oligonucleotide.
  • J is at a 5’ end of the oligonucleotide.
  • J is at a 3’ end of the oligonucleotide.
  • n may be any number. For example, n may be 1-10.
  • 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.”
  • the oligonucleotide may include purines.
  • 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.
  • 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.
  • 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.
  • pyrimidines of the oligonucleotide comprise 2 ’-fluoro modified pyrimidines. In some embodiments, pyrimidines of the oligonucleotide comprise 2’-O-methyl modified pyrimidines.
  • 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.
  • 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.
  • 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.
  • 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.
  • pyrimidines of the oligonucleotide comprise 2’ -fluoro modified pyrimidines, and purines of the oligonucleotide comprise 2’- O-methyl modified purines.
  • pyrimidines of the oligonucleotide comprise 2’-O- methyl modified pyrimidines, and purines of the oligonucleotide comprise 2’-fluoro modified purines.
  • 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.
  • 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.
  • 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.
  • 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. [00112] 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.
  • position 9 of a strand of the oligonucleotide 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.
  • 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.
  • position 9 of a strand of the oligonucleotide 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.
  • 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.
  • position 9 of a strand of the oligonucleotide can be a 2’deoxy.
  • 2’F and 2’0Me modifications may occur at the other positions of a strand of the oligonucleotide.
  • a strand of the oligonucleotide of any of the siRNAs comprises a modification pattern which conforms to these a strand of the oligonucleotide rules.
  • position nine of the sense strand comprises a 2’-fluoro-modified pyrimidine.
  • all purines of the sense strand comprise 2’-O-methyl modified purines.
  • 1, 2, 3, 4, or 5 pyrimidines between positions 5 and 11 comprise a 2 ’-fluoromodified 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.
  • 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.
  • 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.
  • position nine of the sense strand comprises a 2’-fluoro-modified purine.
  • all pyrimidines of the sense strand comprise 2’-O-methyl modified purines.
  • 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.
  • the odd- numbered positions of the antisense strand comprise 2’-O-methyl modified nucleotides.
  • the even -numbered positions of the antisense strand comprise 2’-fluoro-modified nucleotides and unmodified deoxyribonucleotide.
  • the even -numbered positions of the antisense strand comprise 2’-fluoro-modified nucleotides, 2’-O-methyl modified nucleotides and unmodified deoxyribonucleotide.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the oligonucleotide includes a phosphate mimic.
  • the phosphate mimic comprises vinyl phosphonate.
  • the vinyl phosphonate comprises atrans-vinylphosphonate.
  • the vinyl phosphonate comprises a cis-vinylphosphonate.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the lipid comprises cholesterol, myristoyl, palmitoyl, stearoyl, lithocholoyl, docosanoyl, docosahexaenoyl, myristyl, palmityl, stearyl, or a-tocopherol, or a combination thereof.
  • the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises a hydrophobic ligand or moiety.
  • the hydrophobic ligand or moiety comprises cholesterol.
  • the hydrophobic ligand or moiety comprises a cholesterol derivative.
  • 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.
  • 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).
  • 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).
  • the composition comprises a hydrophobic ligand or moiety attached at a 3’ or 5’ terminus of the oligonucleotide.
  • 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.
  • 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.
  • the lipid comprises cholesterol, myristoyl, palmitoyl, stearoyl, lithocholoyl, docosanoyl, docosahexaenoyl, myristyl, palmityl, stearyl, or a-tocopherol, or a combination thereof.
  • the lipid comprises stearyl, lithocholyl, docosanyl, docosahexaenyl, or myristyl.
  • the lipid comprises cholesterol.
  • the lipid includes a sterol such as cholesterol.
  • the lipid comprises stearyl, t-butylphenol, n-butylphenol, octylphenol, dodecylphenol, phenyl n-dodecyl, octadecylbenzamide, hexadecylbenzamide, or octadecylcyclohexyl.
  • the lipid comprises phenyl para C12. The lipid moiety may be esterified.
  • the oligonucleotide comprises any aspect of the following structure:
  • the oligonucleotide comprises any aspect 5' 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.
  • 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.
  • the lipid moiety comprises an alcohol or ether. [00130] 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.
  • a lipid moiety in Table 1 may be attached at a different point of attachment than shown.
  • the point of attachment of any of the lipid moieties in the table may be at a 3’ oligonucleotide end.
  • the lipid is used for targeting the oligonucleotide to a non-hepatic cell or tissue.
  • Table 1 Hydrophobic moiety examples [00131]
  • the lipid or lipid moiety includes 16 to 18 carbons.
  • 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.
  • 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.
  • 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).
  • 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.
  • the lipid moiety may comprise or consist of the following structure some 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.
  • 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.
  • n is 5. In some embodiments, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
  • 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.
  • 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.
  • 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.
  • 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.
  • phosphoramidite reagents that may be used to produce a hydrophobic conjugate are provided as follows:
  • 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.
  • 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.
  • 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.
  • 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.
  • the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an N-acetylgalactosamine (GalNAc) ligand for hepatocyte targeting.
  • the composition comprises GalNAc.
  • the composition comprises a GalNAc derivative.
  • the GalNAc ligand is attached at a 3’ terminus of the oligonucleotide.
  • the GalNAc ligand is attached at a 5’ terminus of the oligonucleotide.
  • 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).
  • 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).
  • the composition comprises a GalNAc ligand attached at a 3’ or 5’ terminus of the oligonucleotide.
  • 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.
  • described herein is a compound (e.g., oligonucleotide) represented by Formula (I) or (II):
  • Q is selected from:
  • C3-10 carbocycle optionally substituted with one or more substituents independently selected from halogen, -CN, -NO 2 , -OR 7 , -SR 7 , -N(R 7 ) 2 , -C(O)R 7 , -C(O)N(R 7 ) 2 , -N(R 7 )C(O)R 7 - N(R 7 )C(O)N(R 7 ) 2 , -OC(O)N(R 7 ) 2 , -N(R 7 )C(O)OR 7 , -C(O)OR 7 , -OC(O)R 7 , -S(O)R 7 , and Ci 6 alkyl, wherein the C1-6 alkyl, is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, and -NH2;
  • R 1 is a linker selected from:
  • C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR 7 , -SR 7 , -N(R 7 ) 2 , -C(O)R 7 , -C(O)N(R 7 ) 2 , -N(R 7 )C(O)R 7 -N(R 7 )C(O)N(R 7 ) 2 , - OC(O)N(R 7 ) 2 , -N(R 7 )C(O)OR 7 , -C(O)OR 7 , -OC(O)R 7 , and -S(O)R 7 ;
  • R 3 and R 4 are each independently selected from:
  • each R 5 is independently selected from: -OC(O)R 7 , -OC(O)N(R 7 ) 2 , -N(R 7 )C(O)R 7 -N(R 7 )C(O)N(R 7 ) 2 , - N(R 7 )C(O)OR 7 , -C(O)R 7 , -C(O)OR 7 , and -C(O)OR 7 ; each R 5 is independently selected from: -OC(O)R 7 , -OC(O)N(R 7 ) 2 , -N(R 7 )C(O)R 7 -N(R 7 )C(O)N(R 7 ) 2 , - N(R 7 )C(O)OR 7 , -C(O)R 7 , -C(O)OR 7 , and -C(O)OR 7 ;
  • 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.
  • z is 3 and Y is C.
  • Q is selected from C5-6 carbocycle optionally substituted with one or more substituents independently selected from halogen, -CN, -NO 2 , -OR 7 , -SR 7 , -N(R 7 ) 2 , -C(O)R 7 , -C(O)N(R 7 ) 2 , -N(R 7 )C(O)R 7 - N(R 7 )C(O)N(R 7 ) 2 , -OC(O)N(R 7 ) 2 , -N(R 7 )C(O)OR 7 , -C(O)OR 7 , -OC(O)R 7 , and -S(O)R 7 .
  • Q is selected from C5-6 carbocycle optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO 2 , and -NH 2 .
  • 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, -NO 2 , and -NH 2 .
  • Q is selected from phenyl.
  • Q is selected from cyclohexyl.
  • R 1 is selected from -OP(O)(OR 7 )O-, -SP(O)(OR 7 )O-, -OP(S)(OR 7 )O-, -OP(O)(SR 7 )O-, - OP(O)(OR 7 )S-, -OP(O)(O )O-, -SP(O)(O )O-, -OP(S)(O )O-, -OP(O)(S )O-, -OP(O)(O )S-, -OP(O)(OR 7 )NR 7 -, -OP(O)(N(R 7 ) 2 )NR 7 -, -OP(OR 7 )O-, -OP(N(R 7 ) 2 )O-, -OP(OR 7 )N(R 7 )-, and -OPN(R 7 ) 2 .
  • R 1 is selected from -OP(O)(OR 7 )O-, -SP(O)(OR 7 )O-, -OP(S)(OR 7 )O-, - OP(O)(SR 7 )O-, -OP(O)(OR 7 )S-, -OP(O)(O )O-, -SP(O)(O )O-, -OP(S)(O )O-, -OP(O)(S )O-, -OP(O)(S )O-, -OP(O)(O )S-, and -OP(OR 7 )O-.
  • R 1 is selected from -OP(O)(OR 7 )O-, -OP(S)(OR 7 )O-, - OP(O)(O )O-, -OP(S)(O )O-, -OP(O)(S )O-, and -OP(OR 7 )O-. In some embodiments, R 1 is selected from - OP(O)(OR 7 )O- and -OP(OR 7 )O-.
  • R 2 is selected from C1-3 alkyl substituted with one or more substituents independently selected from halogen, -OR 7 , -OC(O)R 7 , -SR 7 , -N(R 7 )2, -C(O)R 7 , and -S(O)R 7 .
  • R 2 is selected from C1-3 alkyl substituted with one or more substituents independently selected from -OR 7 , -OC(O)R 7 , -SR 7 , and -N(R 7 )2.
  • R 2 is selected from C1-3 alkyl substituted with one or more substituents independently selected from -OR 7 and - OC(O)R 7 .
  • R 3 is selected from halogen, -OR 7 , -SR 7 , -N(R 7 )2, -C(O)R 7 , -OC(O)R 7 , and -S(O)R 7 In some embodiments, R 3 is selected from -OR 7 -SR 7 , -OC(O)R 7 , and -N(R 7 )2. In some embodiments, R 3 is selected from -OR 7 - and -OC(O)R 7 .
  • R 4 is selected from halogen, -OR 7 , -SR 7 , -N(R 7 )2, -C(O)R 7 , -OC(O)R 7 , and -S(O)R 7 In some embodiments, R 4 is selected from -OR 7 -SR 7 , -OC(O)R 7 , and -N(R 7 )2 In some embodiments, R 4 is selected from -OR 7 - and -OC(O)R 7 .
  • R 5 is selected from -OC(O)R 7 , -OC(O)N(R 7 )2, -N(R 7 )C(O)R 7 -N(R 7 )C(O)N(R 7 )2, and -N(R 7 )C(O)OR 7 . In some embodiments, R 5 is selected from -OC(O)R 7 and -N(R 7 )C(O)R 7 .
  • each R 7 is independently selected from C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, and -SH.
  • 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;
  • R 1 is selected from -OP(O)(OR 7 )O-, -OP(S)(OR 7 )O-, -0P(0)(0 )0-, -OP(S)(O )0-, -OP(O)(S )0-, and - OP(OR 7 )O-;
  • R 2 is Ci alkyl substituted with -OH or -0C(0)CH3;
  • R 3 is -OH or -0C(0)C some embodiments, the compound comprises:
  • the oligonucleotide (J) is attached at a 5’ end or a 3’ end of the oligonucleotide.
  • the oligonucleotide comprises DNA.
  • the oligonucleotide comprises RNA.
  • the oligonucleotide comprises one or more modified intemucleoside linkages.
  • 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.
  • 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.
  • the compound binds to an asialoglycoprotein receptor.
  • the compound targets a hepatocyte.
  • 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.
  • 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. [00147] 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.
  • Some embodiments include the following, where J is the oligonucleotide:
  • J The structure in this compound attached to the oligonucleotide (J) may be referred to as “ETL17,” and is an example of a GalNAc moiety.
  • J may include one or more phosphates or phosphorothioates linking to the oligonucleotide.
  • J may include one or more phosphates linking to the oligonucleotide.
  • J may include a phosphate linking to the oligonucleotide.
  • J may include one or more phosphorothioates linking to the oligonucleotide.
  • J may include a phosphorothioate linking to the oligonucleotide.
  • Some embodiments include the following, where the phosphate or “5”’ indicates a connection to the oligonucleotide:
  • Some embodiments include the following, where the phosphate or “5”’ indicates a connection to the oligonucleotide:
  • 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.
  • Some embodiments include the following, where J is the oligonucleotide:
  • J The structure in this compound attached to the oligonucleotide (J) may be referred to as “ETL1,” and is an example of a GalNAc moiety.
  • J may include one or more phosphates or phosphorothioates linking to the oligonucleotide.
  • J may include one or more phosphates linking to the oligonucleotide.
  • J may include a phosphate linking to the oligonucleotide.
  • J may include one or more phosphorothioates linking to the oligonucleotide.
  • J may include a phosphorothioate linking to the oligonucleotide.
  • 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.
  • described herein is a compound (e.g., oligonucleotide) represented by Formula (III), (IV), or (V):
  • Q is selected from: C3-20 cyclic, heterocyclic or acyclic linker optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, -OR 7 , -SR 7 , -N(R 7 )2, -C(O)R 7 , - C(O)N(R 7 ) 2 , -N(R 7 )C(O)R 7 -N(R 7 )C(O)N(R 7 ) 2 , -OC(O)N(R 7 ) 2 , -N(R 7 )C(O)OR 7 , -C(O)OR 7 , -OC(O)R 7 , - S(O)R 7 , 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;
  • R 1 is a linker selected from: -O-, -S-, -N(R 7 )-, -C(O)-, -C(O)N(R 7 )-, -N(R 7 )C(O)-_ -N(R 7 )C(O)N(R 7 )-, -OC(O)N(R 7 )-, -N(R 7 )C(O)O-, -C(O)O-, -OC(O)-, -S(O)-, -S(O) 2 -, -OS(O) 2 -, -OP(O)(OR 7 )O-, - SP(O)(OR 7 )O-, -OP(S)(OR 7 )O-, -OP(O)(SR 7 )O-, -OP(O)(OR 7 )S-, -OP(O)(O-, -SP(O)(O )O-,
  • sugar moieties comprising the following structure, where J is an oligonucleotide:
  • J 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.
  • sugar moieties comprising the following structure, where J is an oligonucleotide:
  • J 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.
  • provided herein are sugar moieties comprising the following structure, where J is an oligonucleotide:
  • J The structure in this compound attached to the oligonucleotide (J) in some instances is referred to as “GluGalNAc,” and is an example of a GalNAc moiety.
  • J in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide.
  • J in some instances comprises one or more phosphates linking to the oligonucleotide.
  • J in some instances comprises a phosphate linking to the oligonucleotide.
  • J in some instances comprises one or more phosphorothioates linking to the oligonucleotide.
  • J in some instances comprises a phosphorothioate linking to the oligonucleotide.
  • sugar moieties comprising the following structure, where J and K are independently H, a GalNAc moiety or oligonucleotides:
  • 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.
  • GalNAc moieties are attached to the oligonucleotide.
  • J and K may in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide.
  • J and K in some instances comprises one or more phosphates linking to the oligonucleotide.
  • J and K in some instances comprises a phosphate linking to the oligonucleotide.
  • J and K in some instances comprises one or more phosphorothioates linking to the oligonucleotide.
  • J and K in some instances comprises a phosphorothioate linking to the oligonucleotide.
  • sugar moieties comprising the following structure, where R is an oligonucleotide:
  • 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.
  • sugar moieties comprising the following structure, where J is an oligonucleotide:
  • J 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.
  • 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.
  • sugar moieties comprising the following structure, where J is an oligonucleotide:
  • 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.
  • sugar moieties comprising the following structure, where J or K comprises an oligonucleotide:
  • GalNAc moieties referred to as “PyrGalNAc”, “PipGalNAc” and “TEG-GalNAc” are examples of GalNAc moieties.
  • 2-4 GalNAc moieties are attached oligonucleotide.
  • 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.
  • sugar moieties comprising the following structure, where J is an oligonucleotide:
  • 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.
  • sugar moieties comprising the following structure, where Nu is an oligonucleotide:
  • 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 to the oligonucleotide.
  • Nu in some instances comprises one or more phosphorothioates linking to the oligonucleotide.
  • Nu in some instances comprises a phosphorothioate linking to the oligonucleotide.
  • Nu in some instances comprises a phosphorothioate linking to the oligonucleotide.
  • 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.
  • 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’-NfsnsNfiiNfiiNfNfNfhNfiiNfnNfiiNfsnsn-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.
  • the sense strand comprises modification pattern 2S: 5 ’ -nsnsnnNfiiNfNfNfnnnnnnnnsnsn- 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.
  • the sense strand comprises modification pattern 3S: 5’-nsnsnnNfhNfiiNfimnnnnnnnsn-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.
  • the sense strand comprises modification pattern 4S: 5’-NfsnsNfhNfiiNfNfNfiiNfiiNfnNfiiNfsnsnN-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.
  • the sense strand comprises modification pattern 5S: 5’-nsnsnnnNfiiNfNfNfnnnnnnnnsnsnN-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.
  • the moiety in modification pattern 4S or 5S is a lipid moiety. In some embodiments, the moiety in modification pattern 4S or 5S is a sugar moiety.
  • the sense strand comprises modification pattern 6S: 5’-NfsnsNfiiNfiiNfnNfnNfhNfiiNfnNfiiNfsn-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.
  • the sense strand comprises modification pattern 7S: 5’-nsnsnnNfNfNfNfNfnnnnnnnsnsn-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.
  • the sense strand comprises modification pattern 8S: 5’-nsnsnnnnNfNfNfNfnnnnnnnnsn-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.
  • the sense strand comprises modification pattern 9S: 5’-nsnsnnnnnNfNfNfnnnnnnnsn-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.
  • the sense strand comprises modification pattern IOS: 5'- nsnsnnNfNfiiNfNfnnnnnnnnsnsn-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.
  • the sense strand comprises modification pattern 1 IS: 5'-nsnsnnnNfnnnNfnnnnnnnnsnsn-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.
  • 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.
  • 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.
  • the sense strand comprises modification pattern 14S: 5'-snnNfNfimnnNfimnnNfiiNfNfnnsn-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.
  • the sense strand comprises modification pattern 15S: 5'-snnNfiiNfnNfNfdNnNfNfnnNfnnnsnsn-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.
  • the sense strand comprises modification pattern 16S: 5'- snnnnNfnNfNfNfimnnnnnnsnsn-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.
  • the sense strand comprises modification pattern 17S: 5'-snnnnnNfNfNfNfnnnnnnnnsnsn-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.
  • the sense strand comprises modification pattern 18S: 5'-snnnnNfNfnNfNfnnnnnnnnsnsn-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.
  • the sense strand comprises modification pattern 19S: 5'-snnnnNfnnnNfnnnnnnnnsnsn-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.
  • the sense strand comprises modification pattern 20S: 5'-snnnnnNfNfNfNfimnnnnnnsnsn-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.
  • the sense strand comprises modification pattern 2 IS: 5'- snnnnnnNfNfNfNfimnnnnnsnsn-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.
  • 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.
  • the sense strand comprises modification pattern 23S: 5'-snnnnNfhNfNfdTnnnnnnnnsnsn-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.
  • the sense strand comprises modification pattern 24S: 5'- snnnnNfNfnnNfNfimnnnnnnsnsn-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.
  • the sense strand comprises modification pattern 25S: 5'-snnnnnNfNfhNfimnnnnnnnsnsn-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.
  • 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.
  • 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.
  • 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.
  • the sense strand comprises modification pattern 29S: 5'-snnnnnnnNfNfNfnnnnnnnsn- 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.
  • the sense strand comprises modification pattern 30S: 5'-snnnnmnNfNfNfimnnmnnnnnnsnsn-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.
  • the sense strand comprises modification pattern 3 IS: 5'-snnnnmnNfNfNfimnmnnnnnnsnsn-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.
  • the sense strand comprises modification pattern 32S: 5'-snnnnmnNfNfNfhtmnnnnnnnnsn-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.
  • the sense strand comprises modification pattern 33S: 5'-snnnnnmNfNfNfimnmnnnnnnsnsn-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.
  • the sense strand comprises modification pattern 34S: 5'-snnnnmnNfNfNfimnnnmnnnnsn-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.
  • the sense strand comprises modification pattern 35S: 5'-snnnnmnNfNfNfimnnnmnnnnnsn-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.
  • the sense strand comprises modification pattern 36S: 5'-snnnnmnNfNfNfimnntmnnnnnsnsn-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.
  • the sense strand comprises modification pattern 37S: 5'-snnnnmnNfNfNfimnnmnnnnnnsnsn-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.
  • the sense strand comprises modification pattern 38S: 5'- snnnnmNfiiNfNfNfimnmnnnnnnsn-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.
  • the sense strand comprises modification pattern 39S: 5'-snnnnmnNfNfNfimmnnnnnnnnsnsn-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.
  • 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.
  • the sense strand comprises modification pattern 4 IS: 5'- snnnnmnNfNfNfNfnnnmnnnnnnnsn-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.
  • 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.
  • the sense strand comprises modification pattern 43S: 5'-snnnnNfimNfNfNfimnnnnnsn-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.
  • the sense strand comprises modification pattern 44S: 5'- snnnnNfNfNfNfNfnnnnnnnnsnsn-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.
  • 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.
  • the sense strand comprises modification pattern 46S: 5'-snnnnmNfhNfNfNfnntmnnnnnnsnsn-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.
  • the sense strand comprises modification pattern 47S: 5'- snnnnmnNfNfNfNfnnntmnnnnnnnsn-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.
  • the sense strand comprises modification pattern 48S: 5'-snnnnmnNfNfNfimtmnnnnnnsnsn-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.
  • 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.
  • the sense strand comprises modification pattern 50S: 5'-snnnnnnNfNfNfNfnnnnnnnnsn- 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.
  • the sense strand comprises modification pattern 5 IS: 5'-snnnnNfiiNfiiNfhnnnnnnnnnsn-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.
  • the sense strand comprises modification pattern 52S: 5'- snnnnmnNfNfNfNfnnnnmnnnnnsn-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.
  • the sense strand comprises modification pattern 53S: 5'-snnnnnnNfNfNfnnnnnnnsn-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.
  • the sense strand comprises modification pattern 54S: 5'-snnnmnNfNfNfNfnnnmnnnnnnsn-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.
  • the sense strand comprises modification pattern 55S: 5'- snnnnNfnnNfNfNfimnnnnnnsnsn-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.
  • the sense strand comprises modification pattern 56S: 5'-snnnnNfNfNfNfimnnnnnnnsnsn-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.
  • the sense strand comprises modification pattern 57S: 5'-snnnnNfimNfNfhNfnnnnnnnsnsn-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.
  • 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.
  • the sense strand comprises modification pattern 59S: 5'-snnnnNfnNfNfdTnnnnnnnnsn-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.
  • the sense strand comprises modification pattern 60S: 5'-snnnnNfhNfiiNfNfnnnnnnnnsnsn-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.
  • the sense strand comprises modification pattern 6 IS: 5'-snnnnNfimNfNfimnnnnnnnsnsn- 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.
  • the sense strand comprises modification patem 62S: 5'-snnnnNfnnnNfNfnnnnnnnnsnsn-3'.
  • the sense strand comprises modification pattern 63S: 5'-snnnnnnNfNfNfimnnnnnnsnsn- 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.
  • 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.
  • the sense strand comprises modification pattern 65S: 5'- snnnnmNfiiNfNfNfimnmnnnnnnsn-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.
  • the sense strand comprises modification pattern 66S: 5'-snnnmnNfNfNfNfnnnmnnnnnnsn-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.
  • 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’-nsNfsnNfiiNfiiNfiiNfnnnNfnNfiiNfnsn-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.
  • 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.
  • the antisense strand comprises modification pattern 3 AS: 5’-nsNfsnnnNfnnnnnnnnNfiiNfnnnsn-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.
  • 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.
  • the antisense strand comprises modification pattern 5 AS: 5’-nsNfsnnnnnnnnnnNfhNfiinnsnsn-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.
  • 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.
  • the antisense strand comprises modification pattern 7AS: 5’-nsNfsnNfiiNfnNfiiNfiiNfnNfhNfnNfnsn-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.
  • the antisense strand comprises modification pattern 8 AS: 5’-nsNfsnnnnnnnnnnNfimnnnsnsn-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.
  • the antisense strand comprises modification pattern 9AS: 5’-nNfiiNfiiNfnNfiiNfhNfiiNfiiNfnNfnsn-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.
  • 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.
  • the antisense strand comprises modification pattern 1 IAS: 5'- nsNfsnNfnnNfnnNfnNfiiNfiiNfnsnsn-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.
  • 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.
  • the antisense strand comprises modification pattern HAS: 5'-nsNfsndTndNnNfnNfndNndTndNndTnsn-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.
  • 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.
  • 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.
  • 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.
  • the antisense strand comprises modification pattern 17AS: 5'- nsNfsnnnNfiiNfnNfnNfiiNfiiNfiiNfnsn-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.
  • the antisense strand comprises modification pattern 18AS: 5'-nsNfsnNfnNfimnNfiiNfhNfiiNfnNfnsn-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.
  • 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.
  • 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.
  • the antisense strand comprises modification pattern 21AS: 5'-nsNfsnnnNfiiNfnnnNfnNfiiNfiisnsn-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.
  • 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.
  • 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.
  • 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.
  • the sense strand comprises modification pattern 25 AS: 5'-nsNfsnnNfhNfimNfiiNfnNfiiNfiiNfnsn-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.
  • the sense strand comprises modification pattern 26AS: 5'- nsNfsnnNfnNfNfimnNfiiNfiiNfiiNfnsn-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.
  • the sense strand comprises modification pattern 27AS: 5'-nsNfsnNfhNfnNfnNfiiNfiiNfiiNfnnsn-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.
  • 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.
  • 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.
  • the sense strand comprises modification pattern 30AS: 5'-nsNfsnnNfiiNfNfnNfhNfiiNfiiNfnNfnsn-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.
  • 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.
  • the sense strand comprises modification pattern 32AS: 5'- nsNfsnnNfnNfNfiiNfimnNfiiNfiiNfnsn-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.
  • the sense strand comprises modification pattern 33AS: 5'-nsNfsnnnnNfimnnNfhNfiiNfiiNfnsn-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.
  • the sense strand comprises modification pattern 34AS: 5'-nsNfsnnNfhNfiiNfnnNfnNfiiNfiiNfnsn-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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the sense strand comprises modification pattern 41AS: 5'- nsNfsnNfnnnfimNfnnfnNfiiNfsn-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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the sense strand comprises pattern IOS and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, WAS, HAS, 12AS, I3AS.
  • 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.
  • the sense strand comprises pattern 12S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 10AS, HAS, 12AS, HAS.
  • the sense strand comprises pattern 13S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, WAS, HAS, 12AS, I3AS.
  • the sense strand comprises pattern 14S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, WAS, HAS, 12AS, I3AS.
  • the sense strand comprises pattern 15S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 10AS, HAS, 12AS, HAS.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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,
  • 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.
  • 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,
  • the antisense strand comprises pattern 3AS.
  • 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,
  • the antisense strand comprises pattern 4AS.
  • 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,
  • the antisense strand comprises pattern 5AS.
  • 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,
  • 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.
  • 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,
  • the antisense strand comprises pattern 8AS.
  • 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,
  • the antisense strand comprises pattern 9AS.
  • 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.
  • the sense strand comprises pattern IS, 2S, 3S, 4S,
  • 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.
  • 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.
  • 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,
  • the antisense strand comprises pattern 13AS.
  • the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S,
  • the antisense strand comprises pattern 14AS.
  • 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
  • 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,
  • 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,
  • 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,
  • the antisense strand comprises pattern 18AS.
  • the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S,
  • the antisense strand comprises pattern 19AS.
  • 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
  • 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.
  • 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.
  • 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,
  • the antisense strand comprises pattern 23AS.
  • the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S,
  • the antisense strand comprises pattern 24AS.
  • 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
  • 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.
  • 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.
  • 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,
  • the antisense strand comprises pattern 28AS.
  • the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S,
  • the antisense strand comprises pattern 29AS.
  • 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
  • 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.
  • 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.
  • 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,
  • the antisense strand comprises pattern 33AS.
  • the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S,
  • the antisense strand comprises pattern 34AS.
  • 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
  • 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.
  • 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.
  • 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,
  • the antisense strand comprises pattern 38AS.
  • the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, IOS, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S,
  • 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,
  • the antisense strand comprises pattern 40AS.
  • the sense strand comprises pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S,
  • 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.
  • 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 .
  • the sense strand or the antisense strand comprises modification pattern ASO 1 .
  • 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.
  • 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.
  • purines of the sense strand comprise 2’ -fluoro modified purines, and pyrimidines of the sense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines. In some embodiments, purines of the sense strand comprise 2’-O-methyl modified purines, and pyrimidines of the sense strand comprise a mixture of 2 ’-fluoro and 2’-O-methyl modified pyrimidines. In some embodiments, purines of the sense strand comprise 2’ -fluoro modified purines, and pyrimidines of the sense strand comprise 2’-O-methyl modified pyrimidines.
  • purines of the sense strand comprise 2’-O-methyl modified purines
  • pyrimidines of the sense strand comprise 2’-fluoro modified pyrimidines.
  • pyrimidines of the sense strand comprise 2 ’-fluoro modified pyrimidines
  • purines of the sense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines.
  • pyrimidines of the sense strand comprise 2’-O-methyl modified pyrimidines
  • purines of the sense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • pyrimidines of the antisense strand comprise 2 ’-fluoro modified pyrimidines. In some embodiments, pyrimidines of the antisense strand comprise 2’-O-methyl modified pyrimidines. In some embodiments, pyrimidines of the antisense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines. In some embodiments, all pyrimidines of the antisense strand comprise 2’-fluoro modified pyrimidines. In some embodiments, all pyrimidines of the antisense strand comprise 2’-O-methyl modified pyrimidines. In some embodiments, all pyrimidines of the antisense strand comprise a mixture of 2 ’-fluoro and 2’-O-methyl modified pyrimidines.
  • 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.
  • purines of the antisense strand comprise 2’-O-methyl modified purines
  • pyrimidines of the antisense strand comprise 2 ’-fluoro modified pyrimidines.
  • pyrimidines of the antisense strand comprise 2 ’-fluoro modified pyrimidines
  • purines of the antisense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines.
  • pyrimidines of the antisense strand comprise 2’-O-methyl modified pyrimidines
  • purines of the antisense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines.
  • 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. [00187] 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.
  • 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.
  • 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.
  • modified oligonucleotides may be an siRNA that includes modifications to the ribose rings, and phosphate linkages. The modifications may be in particular patterns that maximize cell delivery, stability, and efficiency.
  • the siRNA may also include a vinyl phosphonate and a hydrophobic group. These modifications may aid in delivery to a cell or tissue within a subject.
  • the modified oligonucleotide may be used in a method such as a treatment method or a method of reducing gene expression.
  • the oligonucleotide comprises a duplex consisting of 21 nucleotide single strands with base pairing between 19 of the base pairs.
  • 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.
  • the oligonucleotide is used to knock down a FGG mRNA or a target protein.
  • 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.
  • the sense strand of any of the siRNAs comprises siRNA with a particular modification pattern.
  • position 9 counting from the 5’ end of the sense strand may have a 2’F modification.
  • position 9 of the sense strand is a pyrimidine, then all purines in the sense strand have a 2’0Me modification.
  • 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.
  • both of these pyrimidines are the only two positions with a 2’F modification in the sense strand.
  • 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.
  • the sense strand of any of the siRNAs comprises a modification pattern which conforms to any or all of these sense strand rules.
  • position 9 of the sense strand 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.
  • any combination of 2’F modifications can be made that give three 2’F modifications in total.
  • all combinations of purines 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.
  • the sense strand of any of the siRNAs comprises a modification pattern which conforms to any or all of these sense strand rules.
  • position 9 of the sense strand can be a 2’deoxy.
  • 2’F and 2’OMe modifications may occur at the other positions of the sense strand.
  • the sense strand of any of the siRNAs comprises a modification pattern which conforms to these sense strand rules.
  • the sense strand of any of the siRNAs comprises a modification pattern which conforms to these sense strand rules.
  • 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
  • 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.
  • 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
  • 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; all pyrimidines comprise 2’-O-methyl modified pyr
  • 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 (i
  • 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; (ii)
  • 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 pur
  • a deoxy nucleoside may be included in the sense strand.
  • the sense strand includes the deoxy nucleoside.
  • the deoxy nucleoside may be at nucleoside position 9 of the sense strand.
  • the sense strand does not include a deoxy nucleoside.
  • the deoxy nucleoside of the sense strand may be otherwise unmodified.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 3 or 4 nucleoside substitutions, additions, or deletions.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 modifications or nucleoside modifications different from those in Table 82.
  • the siRNA may include some unmodified intemucleoside linkages or nucleosides.
  • 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 86.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 86 or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 86 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 86.
  • the siRNA may include the same intemucleoside linkage modifications or nucleoside modifications as those in Table 86.
  • the siRNA may include any different intemucleoside linkage modifications or nucleoside modifications different from those in Table 86.
  • the siRNA may include some unmodified intemucleoside linkages or nucleosides.
  • 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 92.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 92 or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 92 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 92.
  • the siRNA may include the same intemucleoside linkage modifications or nucleoside modifications as those in Table 92.
  • the siRNA may include any different intemucleoside linkage modifications or nucleoside modifications different from those in Table 92.
  • the siRNA may include some unmodified intemucleoside linkages or nucleosides.
  • 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 96.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 96 or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 96 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 96.
  • the siRNA may include the same intemucleoside linkage modifications or nucleoside modifications as those in Table 96.
  • the siRNA may include any different intemucleoside linkage modifications or nucleoside modifications different from those in Table 96.
  • the siRNA may include some unmodified intemucleoside linkages or nucleosides.
  • 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 100.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 100 or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 100 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 100.
  • the siRNA may include the same intemucleoside linkage modifications or nucleoside modifications as those in Table 100.
  • the siRNA may include any different intemucleoside linkage modifications or nucleoside modifications different from those in Table 100.
  • the siRNA may include some unmodified intemucleoside linkages or nucleosides.
  • 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 104.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 104 or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 104 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 104.
  • the siRNA may include the same intemucleoside linkage modifications or nucleoside modifications as those in Table 104.
  • the siRNA may include any different intemucleoside linkage modifications or nucleoside modifications different from those in Table 104.
  • the siRNA may include some unmodified intemucleoside linkages or nucleosides.
  • 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 108.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 108 or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 108 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 108.
  • the siRNA may include the same intemucleoside linkage modifications or nucleoside modifications as those in Table 108.
  • the siRNA may include any different intemucleoside linkage modifications or nucleoside modifications different from those in Table 108.
  • the siRNA may include some unmodified intemucleoside linkages or nucleosides.
  • 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 112.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 112 or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 112 or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 112.
  • the siRNA may include the same intemucleoside linkage modifications or nucleoside modifications as those in Table 112.
  • the siRNA may include any different intemucleoside linkage modifications or nucleoside modifications different from those in Table 112.
  • the siRNA may include some unmodified intemucleoside linkages or nucleosides.
  • 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 116.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 116 or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 116 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 116.
  • the siRNA may include the same intemucleoside linkage modifications or nucleoside modifications as those in Table 116.
  • the siRNA may include any different intemucleoside linkage modifications or nucleoside modifications different from those in Table 116.
  • the siRNA may include some unmodified intemucleoside linkages or nucleosides.
  • 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 120.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 120 or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 120 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 120.
  • the siRNA may include the same intemucleoside linkage modifications or nucleoside modifications as those in Table 120.
  • the siRNA may include any different intemucleoside linkage modifications or nucleoside modifications different from those in Table 120.
  • the siRNA may include some unmodified intemucleoside linkages or nucleosides.
  • 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 124.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 124 or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 124 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 124.
  • the siRNA may include the same intemucleoside linkage modifications or nucleoside modifications as those in Table 124.
  • the siRNA may include any different intemucleoside linkage modifications or nucleoside modifications different from those in Table 124.
  • the siRNA may include some unmodified intemucleoside linkages or nucleosides.
  • 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 165.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 165 or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 165 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 165.
  • the siRNA may include the same intemucleoside linkage modifications or nucleoside modifications as those in Table 165.
  • the siRNA may include any different intemucleoside linkage modifications or nucleoside modifications different from those in Table 165.
  • the siRNA may include some unmodified intemucleoside linkages or nucleosides.
  • 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 169.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 169 or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 169 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 169.
  • the siRNA may include the same intemucleoside linkage modifications or nucleoside modifications as those in Table 169.
  • the siRNA may include any different intemucleoside linkage modifications or nucleoside modifications different from those in Table 169.
  • the siRNA may include some unmodified intemucleoside linkages or nucleosides.
  • 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 175.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 175 or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 175 or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 175.
  • the siRNA may include the same intemucleoside linkage modifications or nucleoside modifications as those in Table 175.
  • the siRNA may include any different intemucleoside linkage modifications or nucleoside modifications different from those in Table 175.
  • the siRNA may include some unmodified intemucleoside linkages or nucleosides.
  • 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 176.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 176 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 176.
  • the siRNA may include the same intemucleoside linkage modifications or nucleoside modifications as those in Table 176.
  • the siRNA may include any different intemucleoside linkage modifications or nucleoside modifications different from those in Table 176.
  • the siRNA may include some unmodified intemucleoside linkages or nucleosides.
  • 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: 3591-3594.
  • the sense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 3591-3594, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the sense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 3591-3594, 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: 3591-3594.
  • the sense strand may include any different intemucleoside linkage modifications or nucleoside modifications different from those in SEQ ID NOS: 3591-3594.
  • the sense strand may include some unmodified intemucleoside linkages or nucleosides.
  • the sense strand may include GalNAcl or another GalNAc moiety (e.g., ETL17).
  • the sense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 3591. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3591, 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: 3591, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3591. The sense strand may include any different intemucleoside linkage modifications or nucleoside modifications different from those in SEQ ID NO:
  • the sense strand may include some unmodified intemucleoside linkages or nucleosides.
  • the sense strand may include GalNAcl or another GalNAc moiety (e.g., ETL17).
  • the sense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 3592. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3592, 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:
  • the sense strand comprises the nucleoside sequence of SEQ ID NO: 3592.
  • the sense strand may include any different intemucleoside linkage modifications or nucleoside modifications different from those in SEQ ID NO: 3592.
  • the sense strand may include some unmodified intemucleoside linkages or nucleosides.
  • the sense strand may include GalNAcl or another GalNAc moiety (e.g., ETL17).
  • the sense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 3593.
  • the sense strand comprises the nucleoside sequence of SEQ ID NO: 3593, 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: 3593, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3593.
  • the sense strand may include any different intemucleoside linkage modifications or nucleoside modifications different from those in SEQ ID NO:
  • the sense strand may include some unmodified intemucleoside linkages or nucleosides.
  • the sense strand may include GalNAcl or another GalNAc moiety (e.g., ETL17).
  • the sense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 3594. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3594, 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:
  • the sense strand comprises the nucleoside sequence of SEQ ID NO: 3594.
  • the sense strand may include any different intemucleoside linkage modifications or nucleoside modifications different from those in SEQ ID NO: 3594.
  • the sense strand may include some unmodified intemucleoside linkages or nucleosides.
  • the sense strand may include GalNAcl or another GalNAc moiety (e.g., ETL17).
  • 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: 3641-3676.
  • the sense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 3641-3676, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the sense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 3641-3676, and 3 or 4 nucleoside substitutions, additions, or deletions.
  • the sense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 3641-3676.
  • the sense strand may include any different intemucleoside linkage modifications or nucleoside modifications different from those in SEQ ID NOs: 3641-3676.
  • the sense strand may include some unmodified intemucleoside linkages or nucleosides.
  • the sense strand may include GalNAcl or another GalNAc moiety (e.g., ETL17).
  • the sense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 3651. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3651, 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: 3651, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3651. The sense strand may include any different intemucleoside linkage modifications or nucleoside modifications different from those in SEQ ID NO: 3651.
  • the sense strand may include some unmodified intemucleoside linkages or nucleosides.
  • the sense strand may include GalNAcl or another GalNAc moiety (e.g., ETL17).
  • the sense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 3652.
  • the sense strand comprises the nucleoside sequence of SEQ ID NO: 3652, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the sense strand comprises the nucleoside sequence of SEQ ID NO: 3652, and 3 or 4 nucleoside substitutions, additions, or deletions.
  • the sense strand comprises the nucleoside sequence of SEQ ID NO: 3652.
  • the sense strand may include any different intemucleoside linkage modifications or nucleoside modifications different from those in SEQ ID NO: 3652.
  • the sense strand may include some unmodified intemucleoside linkages or nucleosides.
  • the sense strand may include GalNAcl or another GalNAc moiety (e.g., ETL17).
  • the sense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 3654. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3654, 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: 3654, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3654. The sense strand may include any different intemucleoside linkage modifications or nucleoside modifications different from those in SEQ ID NO: 3594. The sense strand may include some unmodified intemucleoside linkages or nucleosides. The sense strand may include GalNAcl or another GalNAc moiety (e.g., ETL17).
  • the sense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 3675. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3675, 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: 3675, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3675. The sense strand may include any different intemucleoside linkage modifications or nucleoside modifications different from those in SEQ ID NO: 3675. The sense strand may include some unmodified intemucleoside linkages or nucleosides. The sense strand may include GalNAcl or another GalNAc moiety (e.g., ETL17).
  • 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: 3795-3802.
  • the sense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 3795-3802, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the sense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 3795-3802, and 3 or 4 nucleoside substitutions, additions, or deletions.
  • the sense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 3795-3802.
  • the sense strand may include any different intemucleoside linkage modifications or nucleoside modifications different from those in SEQ ID NOs: 3795-3802.
  • the sense strand may include some unmodified intemucleoside linkages or nucleosides.
  • the sense strand may include GalNAcl or another GalNAc moiety (e.g., ETL17).
  • the sense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 3795.
  • the sense strand comprises the nucleoside sequence of SEQ ID NO: 3795, 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: 3795, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3795.
  • the sense strand may include any different intemucleoside linkage modifications or nucleoside modifications different from those in SEQ ID NO: 3795. The sense strand may include some unmodified intemucleoside linkages or nucleosides.
  • the sense strand may include GalNAcl or another GalNAc moiety (e.g., ETL17).
  • 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: 3595-3598.
  • the antisense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 3595-3598, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the antisense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 3595-3598, and 3 or 4 nucleoside substitutions, additions, or deletions.
  • the antisense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 3595-3598.
  • the antisense strand may include any different intemucleoside linkage modifications or nucleoside modifications different from those in SEQ ID NOS: 3595-3598.
  • the antisense strand may include some unmodified intemucleoside linkages or nucleosides.
  • the antisense strand may include a GalNAc moiety.
  • the antisense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 3595. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3595, 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: 3595, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3595.
  • the antisense strand may include any different intemucleoside linkage modifications or nucleoside modifications different from those in SEQ ID NO: 3595.
  • the antisense strand may include some unmodified intemucleoside linkages or nucleosides.
  • the antisense strand may include a GalNAc moiety.
  • the antisense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 3596. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3596, 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: 3596, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3596.
  • the antisense strand may include any different intemucleoside linkage modifications or nucleoside modifications different from those in SEQ ID NO: 3596.
  • the antisense strand may include some unmodified intemucleoside linkages or nucleosides.
  • the antisense strand may include a GalNAc moiety.
  • the antisense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 3597.
  • the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3597, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3597, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3597.
  • the antisense strand may include any different intemucleoside linkage modifications or nucleoside modifications different from those in SEQ ID NO: 3597.
  • the antisense strand may include some unmodified intemucleoside linkages or nucleosides.
  • the antisense strand may include a GalNAc moiety.
  • the antisense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 3598. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3598, 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: 3598, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3598.
  • the antisense strand may include any different intemucleoside linkage modifications or nucleoside modifications different from those in SEQ ID NO: 3598.
  • the antisense strand may include some unmodified intemucleoside linkages or nucleosides.
  • the antisense strand may include a GalNAc moiety.
  • 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: 3677-3712.
  • the antisense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 3677-3712, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the antisense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 3677-3712, and 3 or 4 nucleoside substitutions, additions, or deletions.
  • the antisense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 3677-3712.
  • the antisense strand may include any different intemucleoside linkage modifications or nucleoside modifications different from those in SEQ ID NOs: 3677-3712.
  • the antisense strand may include some unmodified intemucleoside linkages or nucleosides.
  • the antisense strand may include a GalNAc moiety.
  • the antisense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 3687. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3687, 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: 3687, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3687.
  • the antisense strand may include any different intemucleoside linkage modifications or nucleoside modifications different from those in SEQ ID NO: 3687.
  • the antisense strand may include some unmodified intemucleoside linkages or nucleosides.
  • the antisense strand may include a GalNAc moiety.
  • the antisense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 3688.
  • the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3688, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3688, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3688.
  • the antisense strand may include any different intemucleoside linkage modifications or nucleoside modifications different from those in SEQ ID NO: 3688.
  • the antisense strand may include some unmodified intemucleoside linkages or nucleosides.
  • the antisense strand may include a GalNAc moiety.
  • the antisense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 3690. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3690, 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: 3690, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3690.
  • the antisense strand may include any different intemucleoside linkage modifications or nucleoside modifications different from those in SEQ ID NO: 3690.
  • the antisense strand may include some unmodified intemucleoside linkages or nucleosides.
  • the antisense strand may include a GalNAc moiety.
  • the antisense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 3747. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3747, 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: 3747, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3747.
  • the antisense strand may include any different intemucleoside linkage modifications or nucleoside modifications different from those in SEQ ID NO: 3747.
  • the antisense strand may include some unmodified intemucleoside linkages or nucleosides.
  • the antisense strand may include a GalNAc moiety.
  • 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: 3803-3808.
  • the antisense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 3803-3808, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the antisense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 3803-3808, and 3 or 4 nucleoside substitutions, additions, or deletions.
  • the antisense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 3803-3808.
  • the antisense strand may include any different intemucleoside linkage modifications or nucleoside modifications different from those in SEQ ID NOs: 3803-3808.
  • the antisense strand may include some unmodified intemucleoside linkages or nucleosides.
  • the antisense strand may include a GalNAc moiety.
  • the antisense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 3690.
  • the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3690, 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: 3690, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3690.
  • the antisense strand may include any different intemucleoside linkage modifications or nucleoside modifications different from those in SEQ ID NO: 3690. The antisense strand may include some unmodified intemucleoside linkages or nucleosides.
  • the antisense strand may include a GalNAc moiety.
  • 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: 3813-3843.
  • the sense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 3813-3843, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the sense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 3813-3843, and 3 or 4 nucleoside substitutions, additions, or deletions.
  • the sense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 3813-3843.
  • the sense strand may include any different intemucleoside linkage modifications or nucleoside modifications different from those in SEQ ID NOs: 3813-3843.
  • the sense strand may include some unmodified intemucleoside linkages or nucleosides.
  • the sense strand may include a GalNAc moiety.
  • 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: 4018-4019.
  • the sense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 4018-4019, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the sense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 4018-4019, and 3 or 4 nucleoside substitutions, additions, or deletions.
  • the sense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 4018-4019.
  • the sense strand may include any different intemucleoside linkage modifications or nucleoside modifications different from those in SEQ ID NOs: 4018-4019.
  • the sense strand may include some unmodified intemucleoside linkages or nucleosides.
  • the sense strand may include a GalNAc moiety.
  • 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: 3844-3878.
  • the antisense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 3844-3878, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the antisense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 3844-3878, and 3 or 4 nucleoside substitutions, additions, or deletions.
  • the antisense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 3844-3878.
  • the antisense strand may include any different intemucleoside linkage modifications or nucleoside modifications different from those in SEQ ID NOs: 3844-3878.
  • the antisense strand may include some unmodified intemucleoside linkages or nucleosides.
  • the antisense strand may include a GalNAc moiety.
  • 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: 4003-4017.
  • the antisense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 4003-4017, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the antisense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 4003-4017, and 3 or 4 nucleoside substitutions, additions, or deletions.
  • the antisense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 4003-4017.
  • the antisense strand may include any different intemucleoside linkage modifications or nucleoside modifications different from those in SEQ ID NOs: 4003-4017.
  • the antisense strand may include some unmodified intemucleoside linkages or nucleosides.
  • the antisense strand may include a GalNAc moiety.
  • the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an antisense oligonucleotide (ASO).
  • ASO comprises modification pattern ASO 1 : 5’-nsnsnsnsnsdNsdNsdNsdNsdNsdNsdNsdNsdNsdNsdNsnsnsnsn-3’ (SEQ ID NO: 3640), wherein “dN” is any deoxynucleotide, “n” is a 2’-O-methyl or 2 ’-O-methoxyethyl -modified nucleoside, and “s” is a phosphorothioate linkage.
  • the ASO comprises modification pattern IS, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 1 IS, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, WAS, HAS, 12AS, I 3AS.
  • the composition is a pharmaceutical composition. In some embodiments, the composition is sterile. In some embodiments, the composition further comprises a pharmaceutically acceptable carrier.
  • the pharmaceutically acceptable carrier comprises water. In some embodiments, the pharmaceutically acceptable carrier comprises a buffer. In some embodiments, the pharmaceutically acceptable carrier comprises a saline solution. In some embodiments, the pharmaceutically acceptable carrier comprises water, a buffer, or a saline solution. In some embodiments, the composition comprises a liposome. In some embodiments, the pharmaceutically acceptable carrier comprises liposomes, lipids, nanoparticles, proteins, protein-antibody complexes, peptides, cellulose, nanogel, or a combination thereof. II. METHODS AND USES
  • composition described herein are methods of administering a composition described herein to a subject. Some embodiments relate to use a composition described herein, such as administering the composition to a subject.
  • Some embodiments relate to a method of treating a disease or disorder (e.g., hearing disorder) in a subject in need thereof. Some embodiments relate to use of a composition described herein in the method of treatment. Some embodiments include administering a composition described herein to a subject with the disorder. In some embodiments, the administration treats the disorder in the subject. In some embodiments, the composition treats the disorder in the subject.
  • a disease or disorder e.g., hearing disorder
  • Some embodiments relate to use of a composition described herein in the method of treatment. Some embodiments include administering a composition described herein to a subject with the disorder. In some embodiments, the administration treats the disorder in the subject. In some embodiments, the composition treats the disorder in the subject.
  • the treatment comprises prevention, inhibition, or reversion of the disorder (e.g., hearing disorder) in the subject.
  • a composition described herein in the method of preventing, inhibiting, or reversing the disorder.
  • Some embodiments relate to a method of preventing, inhibiting, or reversing a disorder in a subject in need thereof.
  • Some embodiments include administering a composition described herein to a subject with the disorder.
  • the administration prevents, inhibits, or reverses the disorder in the subject.
  • the composition prevents, inhibits, or reverses the disorder in the subject.
  • Some embodiments relate to a method of preventing a disorder (e.g., hearing disorder) in a subject in need thereof. Some embodiments relate to use of a composition described herein in the method of preventing the disorder. Some embodiments include administering a composition described herein to a subject with the disorder. In some embodiments, the administration prevents the disorder in the subject. In some embodiments, the composition prevents the disorder in the subject.
  • a disorder e.g., hearing disorder
  • Some embodiments relate to use of a composition described herein in the method of preventing the disorder. Some embodiments include administering a composition described herein to a subject with the disorder. In some embodiments, the administration prevents the disorder in the subject. In some embodiments, the composition prevents the disorder in the subject.
  • Some embodiments relate to a method of inhibiting a disorder (e.g., hearing disorder) in a subject in need thereof. Some embodiments relate to use of a composition described herein in the method of inhibiting the disorder. Some embodiments include administering a composition described herein to a subject with the disorder. In some embodiments, the administration inhibits the disorder in the subject. In some embodiments, the composition inhibits the disorder in the subject.
  • a disorder e.g., hearing disorder
  • Some embodiments relate to use of a composition described herein in the method of inhibiting the disorder. Some embodiments include administering a composition described herein to a subject with the disorder. In some embodiments, the administration inhibits the disorder in the subject. In some embodiments, the composition inhibits the disorder in the subject.
  • Some embodiments relate to a method of reversing a disorder (e.g., hearing disorder) in a subject in need thereof. Some embodiments relate to use of a composition described herein in the method of reversing the disorder. Some embodiments include administering a composition described herein to a subject with the disorder. In some embodiments, the administration reverses the disorder in the subject. In some embodiments, the composition reverses the disorder in the subject.
  • a disorder e.g., hearing disorder
  • Some embodiments relate to use of a composition described herein in the method of reversing the disorder. Some embodiments include administering a composition described herein to a subject with the disorder. In some embodiments, the administration reverses the disorder in the subject. In some embodiments, the composition reverses the disorder in the subject.
  • the administration is systemic. In some embodiments, the administration is intravenous. In some embodiments, the administration is by injection.
  • a disorder can include a disease.
  • the disorder is a hearing disorder.
  • hearing disorders include idiopathic sudden sensorineural hearing loss (ISSNHL), noise-induced sensorineural hearing loss, hearing loss, sensorineural hearing loss, tinnitus, and conductive hearing loss.
  • the disorder may include hearing loss.
  • the disorder may include sensorineural hearing loss.
  • the disorder may include sudden hearing loss.
  • the disorder may include ISSNHL.
  • the disorder may include noise-induced hearing loss.
  • the disorder may include noise-induced sensorineural hearing loss.
  • the disorder may include tinnitus.
  • the disorder may include conductive hearing loss.
  • the disorder may be diagnosed with the use of a questionnaire or a scoring system. In some cases, the disorder is diagnosed according to a clinical hearing loss criteria. In some cases, the disorder is diagnosed by a healthcare professional (e.g., physician or the like).
  • a healthcare professional e.g., physician or the like.
  • the disorder comprises one or more disorders (e.g., any of the disorders disclosed herein). In some embodiments, the disorder comprises two disorders. In some embodiments, the disorder comprises three disorders. In some embodiments, the disorder comprises four disorders. In some embodiments, the disorder comprises five disorders.
  • Some embodiments of the methods described herein include treatment of a subject.
  • subjects include vertebrates, animals, mammals, dogs, cats, cattle, rodents, mice, rats, primates, monkeys, and humans.
  • the subject is a vertebrate.
  • the subject is an animal.
  • the subject is a mammal.
  • the subject is a dog.
  • the subject is a cat.
  • the subject is a cattle.
  • the subject is a mouse.
  • the subject is a rat.
  • the subject is a primate.
  • the subject is a monkey.
  • the subject is an animal, a mammal, a dog, a cat, cattle, a rodent, a mouse, a rat, a primate, or a monkey.
  • the subject is a human.
  • the subject is male. In some embodiments, the subject is female. In some embodiments, the subject is an adult (e.g., at least 18 years old). In some embodiments, the subject is 45 years old or greater. In some embodiments, the subject is 50 years old or greater. In some embodiments, the subject is 55 years old or greater. In some embodiments, the subject is 60 years old or greater. In some embodiments, the subject is 65 years old or greater. In some embodiments, the subject is 70 years old or greater. In some embodiments, the subject is 75 years old or greater. In some embodiments, the subject is 80 years old or greater. In some embodiments, the subject is 85 years old or greater.
  • the subject has a body mass index (BMI) of 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, or more, or a range defined by any two of the aforementioned integers.
  • BMI body mass index
  • the subject is overweight.
  • the subject has a BMI of 25 or more.
  • the subject has a BMI of 25- 29.
  • the subject is obese.
  • the subject has a BMI of 30 or more.
  • the subject has a BMI of 30-39.
  • the subject has a BMI of 40-50.
  • the subject has a BMI of 25-50.
  • the subject has a personal history with the disorder.
  • the subject has a familial history with the disorder.
  • the subject is at high risk of contracting the disorder.
  • the subject has a hearing disorder.
  • the subject has idiopathic sudden sensorineural hearing loss (ISSNHL).
  • the subject has noise- induced sensorineural hearing loss.
  • the subject has hearing loss.
  • the subject may have hyperfibrinogenemia.
  • the hearing loss may result from hyperfibrinogenemia.
  • the subject has sensorineural hearing loss.
  • the subject has tinnitus.
  • the subject has conductive hearing loss.
  • the subject may be deaf.
  • the subject may be dumb.
  • Some embodiments of the methods described herein include obtaining a baseline measurement from a subject.
  • the baseline measurement is a hearing disorder baseline measurement.
  • a baseline measurement is obtained from the subject prior to treating the subject.
  • baseline measurements include a baseline measurement of pure-tone audiometry, pure tone threshold, speech audiometry and speech reception threshold, tympanometry, Stapedius reflex measurements, German speech intelligibility test (Freiburgerptest), brainstem audiometry, or otoacoustic emissions.
  • the baseline measurement may include a baseline fibrinogen measurement, a baseline FGG mRNA measurement, or a baseline FGG protein measurement.
  • the baseline measurement is obtained directly from the subject. In some embodiments, the baseline measurement is obtained by observation of the subject. In some embodiments, the baseline measurement is obtained by questioning the subject. In some embodiments, the baseline measurement is obtained by the subject filling out a questionnaire.
  • the baseline measurement is a baseline audiometry measurement. In some embodiments, the baseline measurement is a baseline pure-tone audiometry measurement. In some embodiments, the baseline pure-tone audiometry measurement has a frequency of 125, 250, 500, 1000, 2000, 3000, 4000, 6000, or 8000 Hz. In some embodiments, the baseline-pure tone audiometry measurement has a frequency of 125, 250, 500, 1000, 2000, 3000, 4000, 6000, and 8000 Hz. In some embodiments, the baseline measurement is a baseline pure tone threshold measurement.
  • the baseline measurement is a baseline speech audiometry and speech reception threshold measurement.
  • the baseline speech audiometry and speech reception threshold measurement is a baseline speech recognition threshold.
  • the baseline speech audiometry and speech reception threshold measurement is a baseline spondee threshold.
  • the baseline speech audiometry and speech reception threshold measurement is a baseline speech detection threshold.
  • the baseline speech audiometry and speech reception threshold measurement is a baseline speech awareness threshold.
  • the baseline measurement is a baseline German speech intelligibility test (Freiburgerptest) measurement.
  • the baseline measurement is a baseline tympanometry measurement. In some embodiments, the baseline tympanometry measurement is measured using a tympanometer. In some embodiments, the baseline measurement is a baseline stapedius reflex measurement. In some embodiments, the dynamic changes that result from the contraction of the stapedius in response to stimuli of 500, 1000, 2000 or 4000 Hz, or a combination thereof, are measured. In some embodiments, the dynamic changes that result from the contraction of the stapedius in response to stimuli at intensities including or between 70 to 115 dB of sound pressure are measured. In some embodiments, the dynamic changes that result from the contraction of the stapedius in response to stimuli of 500, 1000, 2000 and 4000 Hz at intensities of 70 to 115 dB of sound pressure are measured.
  • the baseline measurement is a baseline brainstem audiometry measurement. In some embodiments, the baseline measurement is an absolute wave latency. In some embodiments, the baseline measurement is a baseline wave amplitude. In some embodiments, the baseline measurement is a baseline interwave interval between waves.
  • the baseline measurement is a baseline otoacoustic emission measurement.
  • the baseline measurement is a baseline level of fibrinogen. In some embodiments, the baseline measurement is a baseline level of circulating fibrinogen.
  • the disorder (e.g., baseline measurement) may be diagnosed or measured with the use of a questionnaire or a scoring system. In some cases, the disorder is diagnosed according to a clinical hearing loss criteria. In some cases, the disorder is diagnosed by a healthcare professional (e.g., physician or the like).
  • a healthcare professional e.g., physician or the like.
  • Baseline measurements may include a baseline FGG protein measurement, or a baseline FGG mRNA measurement.
  • Baseline measurements may include any one or more of the baseline measurements disclosed herein.
  • the baseline measurement is obtained directly from the subject. In some embodiments, the baseline measurement is obtained by observation, for example by observation of the subject or of the subject’s tissue. In some embodiments, the baseline measurement is obtained noninvasively using an imaging device. In some embodiments, the baseline measurement is obtained invasively using an imaging device.
  • the baseline measurement is obtained in a sample from the subject. In some embodiments, the baseline measurement is obtained in one or more histological tissue sections. In some embodiments, the baseline measurement is obtained by performing an assay such as an immunoassay, a colorimetric assay, or a fluorescence assay, on the sample obtained from the subject. In some embodiments, the baseline measurement is obtained by an immunoassay, a colorimetric assay, a fluorescence assay, or a chromatography (e.g., HPLC) assay. In some embodiments, the baseline measurement is obtained by PCR.
  • the baseline measurement is a baseline FGG protein measurement.
  • the baseline FGG protein measurement comprises a baseline FGG protein level.
  • the baseline FGG protein level is indicated as a mass or percentage of FGG protein per sample weight.
  • the baseline FGG protein level is indicated as a mass or percentage of FGG protein per sample volume.
  • the baseline FGG protein level is indicated as a mass or percentage of FGG protein per total protein within the sample.
  • the baseline FGG protein measurement is a baseline tissue FGG protein measurement.
  • the baseline FGG protein measurement is obtained by an assay such as an immunoassay, a colorimetric assay, or a fluorescence assay.
  • the baseline FGG protein level is measured in the whole body. In some embodiments, the baseline FGG protein level is measured in the brain. In some embodiments, the baseline FGG protein level is measured in the liver. In some embodiments, the baseline FGG protein level is measured in the blood.
  • the baseline measurement is a baseline FGG mRNA measurement.
  • the baseline FGG mRNA measurement comprises a baseline FGG mRNA level.
  • the baseline FGG mRNA level is measured in the liver.
  • the baseline FGG mRNA level is indicated as an amount or percentage of FGG mRNA per sample weight.
  • the baseline FGG mRNA level is indicated as an amount or percentage of FGG mRNA per sample volume.
  • the baseline FGG mRNA level is indicated as an amount or percentage of FGG mRNA per total mRNA within the sample.
  • the baseline FGG mRNA level is indicated as an amount or percentage of FGG mRNA per total nucleic acids within the sample. In some embodiments, the baseline FGG mRNA level is indicated relative to another mRNA level, such as an mRNA level of a housekeeping gene, within the sample. In some embodiments, the baseline FGG mRNA measurement is a baseline tissue FGG mRNA measurement. In some embodiments, the baseline FGG mRNA measurement is obtained by an assay such as a polymerase chain reaction (PCR) assay. In some embodiments, the PCR comprises quantitative PCR (qPCR). In some embodiments, the PCR comprises reverse transcription of the FGG mRNA.
  • PCR quantitative PCR
  • Some embodiments of the methods described herein include obtaining a sample from a subject.
  • the baseline measurement is obtained in a sample obtained from the subject.
  • the sample is obtained from the subject prior to administration or treatment of the subject with a composition described herein.
  • a baseline measurement is obtained in a sample obtained from the subject prior to administering the composition to the subject.
  • the sample is obtained from the subject in a fasted state.
  • the sample is obtained from the subject after an overnight fasting period.
  • the sample is obtained from the subject in a fed state.
  • the sample comprises a fluid.
  • the sample is a fluid sample.
  • the sample is a blood, plasma, or serum sample.
  • the sample comprises blood.
  • the sample is a blood sample.
  • the sample is a whole-blood sample.
  • the blood is fractionated or centrifuged.
  • the sample comprises plasma.
  • the sample is a plasma sample.
  • a blood sample may be a plasma sample.
  • the sample comprises serum.
  • the sample is a serum sample.
  • a blood sample may be a serum sample.
  • the sample is a CSF sample.
  • the sample includes a CSF sample. In some embodiments, the sample is a CNS sample. In some embodiments, the sample includes a CNS sample. In some embodiments, the sample includes a sinus fluid sample. In some embodiments, the sample includes an aural fluid sample.
  • the sample comprises a tissue.
  • the sample is a tissue sample.
  • the tissue comprises liver or brain tissue.
  • the baseline FGG mRNA measurement, or the baseline FGG protein measurement may be obtained in a brain or liver sample obtained from the patient.
  • the tissue comprises neural tissue.
  • the tissue comprises neuronal tissue.
  • the tissue comprises neurons.
  • the tissue comprises glial cells.
  • the tissue comprises epithelial cells.
  • the tissue comprises liver tissue. The liver may include hepatocytes.
  • the tissue comprises brain tissue.
  • the tissue comprises ear tissue.
  • the tissue comprises auditory tissue.
  • the tissue comprises cochlea.
  • the tissue comprises a nerve.
  • the tissue comprises an auditory nerve.
  • the tissue comprises brainstem.
  • the sample includes cells.
  • the sample comprises a cell.
  • the cell comprises a liver cell (e.g., hepatocyte), or a brain cell.
  • the cell is a liver cell.
  • the liver cell is a hepatocyte.
  • the cell is a brain cell.
  • the cell is a neuron.
  • the cell is an nerve cell.
  • the cell is a glial cell.
  • the cell is an epithelial cell.
  • the cell is a vasculature cell.
  • the cell is an auditory cell.
  • Some embodiments of the methods described herein include obtaining a measurement from a subject.
  • the measurement is a hearing disorder measurement.
  • a measurement is obtained from the subject prior to treating the subject.
  • Non-limiting examples of measurements include a measurement of pure-tone audiometry, pure tone threshold, speech audiometry and speech reception threshold, tympanometry, Stapedius reflex measurements, German speech intelligibility test (Freiburgerptest), brainstem audiometry, or otoacoustic emissions.
  • the measurement may include a fibrinogen measurement, a FGG mRNA measurement, or a FGG protein measurement.
  • the measurement indicates that the disorder has been treated. In some embodiments, the measurement indicates that the severity of the disorder has decreased. In some embodiments, the measurement indicates that the severity of a sign or symptom of the disorder has decreased. In some embodiments, the measurement indicates that the frequency of a sign or symptom of the disorder has decreased.
  • Some embodiments of the methods described herein include obtaining the measurement from a subject.
  • the measurement may be obtained from the subject after treating the subject.
  • the measurement is obtained in a second sample (such as a fluid or tissue sample described herein) obtained from the subject after the composition is administered to the subject.
  • the measurement is an indication that the disorder has been treated.
  • the measurement is obtained directly from the subject. In some embodiments, the measurement is obtained noninvasively using an imaging device. In some embodiments, the measurement is obtained in a second sample from the subject. In some embodiments, the measurement is obtained in one or more histological tissue sections. In some embodiments, the measurement is obtained by performing an assay on the second sample obtained from the subject. In some embodiments, the measurement is obtained by an assay, such as an assay described herein. In some embodiments, the assay is an immunoassay, a colorimetric assay, a fluorescence assay, a chromatography (e.g., HPLC) assay, or a PCR assay.
  • the assay is an immunoassay, a colorimetric assay, a fluorescence assay, a chromatography (e.g., HPLC) assay, or a PCR assay.
  • the measurement is obtained by an assay such as an immunoassay, a colorimetric assay, a fluorescence assay, or a chromatography (e.g., HPLC) assay.
  • the measurement is obtained by PCR.
  • the measurement is obtained by histology.
  • the measurement is obtained by observation.
  • additional measurements are made, such as in a third sample, a fourth sample, or a fifth sample.
  • the measurement is obtained within 1 hour, within 2 hours, within 3 hours, within 4 hours, within 5 hours, within 6 hours, within 12 hours, within 18 hours, or within 24 hours after the administration of the composition. In some embodiments, the measurement is obtained within 1 day, within 2 days, within 3 days, within 4 days, within 5 days, within 6 days, or within 7 days after the administration of the composition. In some embodiments, the measurement is obtained within 1 week, within 2 weeks, within 3 weeks, within 1 month, within 2 months, within 3 months, within 6 months, within 1 year, within 2 years, within 3 years, within 4 years, or within 5 years after the administration of the composition.
  • the measurement is obtained after 1 hour, after 2 hours, after 3 hours, after 4 hours, after 5 hours, after 6 hours, after 12 hours, after 18 hours, or after 24 hours after the administration of the composition. In some embodiments, the measurement is obtained after 1 day, after 2 days, after 3 days, after 4 days, after 5 days, after 6 days, or after 7 days after the administration of the composition. In some embodiments, the measurement is obtained after 1 week, after 2 weeks, after 3 weeks, after 1 month, after 2 months, after 3 months, after 6 months, after 1 year, after 2 years, after 3 years, after 4 years, or after 5 years, following the administration of the composition.
  • the composition reduces the measurement relative to the baseline measurement.
  • an adverse phenotype of a hearing disorder may be reduced upon administration of the composition.
  • the reduction is measured in a second sample obtained from the subject after administering the composition to the subject.
  • the reduction is measured directly in the subject after administering the composition to the subject.
  • the measurement is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline measurement.
  • the measurement is decreased by about 10% or more, relative to the baseline measurement.
  • the measurement is decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, relative to the baseline measurement. In some embodiments, the measurement is decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, relative to the baseline measurement. In some embodiments, the measurement is decreased by no more than about 10%, relative to the baseline measurement. In some embodiments, the measurement is decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100% relative to the baseline measurement. In some embodiments, the measurement is decreased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or by a range defined by any of the two aforementioned percentages.
  • the composition increases the measurement relative to the baseline measurement.
  • a protective hearing phenotype may be increased upon administration of the composition.
  • the increase is measured in a second sample obtained from the subject after administering the composition to the subject.
  • the increase is measured directly in the subject after administering the composition to the subject.
  • the measurement is increased by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline measurement.
  • the measurement is increased by about 10% or more, relative to the baseline measurement.
  • the measurement is increased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, relative to the baseline measurement. In some embodiments, the measurement is increased by about 100% or more, increased by about 250% or more, increased by about 500% or more, increased by about 750% or more, or increased by about 1000% or more, relative to the baseline measurement. In some embodiments, the measurement is increased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, relative to the baseline measurement. In some embodiments, the measurement is increased by no more than about 10%, relative to the baseline measurement.
  • the measurement is increased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100% relative to the baseline measurement. In some embodiments, the measurement is increased by no more than about 100%, increased by no more than about 250%, increased by no more than about 500%, increased by no more than about 750%, or increased by no more than about 1000%, relative to the baseline measurement.
  • the measurement is increased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 250%, 500%, 750%, or 1000%, or by a range defined by any of the two aforementioned percentages.
  • the measurement is an audiometry measurement.
  • the measurement is a pure-tone audiometry measurement.
  • the pure- tone audiometry measurement has a frequency of 125, 250, 500, 1000, 2000, 3000, 4000, 6000, or 8000 Hz.
  • the baseline-pure tone audiometry measurement has a frequency of 125, 250, 500, 1000, 2000, 3000, 4000, 6000, and 8000 Hz.
  • the measurement is a pure tone threshold measurement.
  • the audiometry measurement is improved by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline measurement.
  • the audiometry measurement is improved by about 10% or more, relative to the baseline audiometry measurement. In some embodiments, the audiometry measurement is improved by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, relative to the baseline audiometry measurement. In some embodiments, the audiometry measurement is improved by about 100% or more, improved by about 250% or more, improved by about 500% or more, improved by about 750% or more, or improved by about 1000% or more, relative to the baseline audiometry measurement. In some embodiments, the audiometry measurement is improved by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, relative to the baseline audiometry measurement.
  • the audiometry measurement is improved by no more than about 10%, relative to the baseline audiometry measurement. In some embodiments, the audiometry measurement is improved by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100% relative to the baseline audiometry measurement. In some embodiments, the audiometry measurement is improved by no more than about 100%, improved by no more than about 250%, improved by no more than about 500%, improved by no more than about 750%, or improved by no more than about 1000%, relative to the baseline audiometry measurement.
  • the audiometry measurement is improved by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 250%, 500%, 750%, or 1000%, or by a range defined by any of the two aforementioned percentages.
  • the measurement is a speech audiometry and speech reception threshold measurement.
  • the speech audiometry and speech reception threshold measurement is a speech recognition threshold.
  • the speech audiometry and speech reception threshold measurement is a spondee threshold.
  • the speech audiometry and speech reception threshold measurement is a speech detection threshold.
  • the speech audiometry and speech reception threshold measurement is a speech awareness threshold.
  • the measurement is a German speech intelligibility test (Freiburgerptest) measurement.
  • the speech audiometry and speech reception measurement is improved by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline measurement.
  • the speech audiometry and speech reception measurement is improved by about 10% or more, relative to the baseline speech audiometry and speech reception measurement. In some embodiments, the speech audiometry and speech reception measurement is improved by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, relative to the baseline speech audiometry and speech reception measurement. In some embodiments, the speech audiometry and speech reception measurement is improved by about 100% or more, improved by about 250% or more, improved by about 500% or more, improved by about 750% or more, or improved by about 1000% or more, relative to the baseline speech audiometry and speech reception measurement.
  • the speech audiometry and speech reception measurement is improved by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, relative to the baseline speech audiometry and speech reception measurement. In some embodiments, the speech audiometry and speech reception measurement is improved by no more than about 10%, relative to the baseline speech audiometry and speech reception measurement. In some embodiments, the speech audiometry and speech reception measurement is improved by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100% relative to the baseline speech audiometry and speech reception measurement.
  • the speech audiometry and speech reception measurement is improved by no more than about 100%, improved by no more than about 250%, improved by no more than about 500%, improved by no more than about 750%, or improved by no more than about 1000%, relative to the baseline speech audiometry and speech reception measurement. In some embodiments, the speech audiometry and speech reception measurement is improved by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 250%, 500%, 750%, or 1000%, or by a range defined by any of the two aforementioned percentages.
  • the measurement is a tympanometry measurement.
  • the tympanometry measurement is measured using a tympanometer.
  • the measurement is a stapedius reflex measurement.
  • the dynamic changes that result from the contraction of the stapedius in response to stimuli of 500, 1000, 2000 and 4000 Hz at intensities of 70 to 115 dB of sound pressure are measured.
  • the tympanometry measurement is improved by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline measurement.
  • the tympanometry measurement is improved by about 10% or more, relative to the baseline tympanometry measurement. In some embodiments, the tympanometry measurement is improved by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, relative to the baseline tympanometry measurement. In some embodiments, the tympanometry measurement is improved by about 100% or more, improved by about 250% or more, improved by about 500% or more, improved by about 750% or more, or improved by about 1000% or more, relative to the baseline tympanometry measurement.
  • the tympanometry measurement is improved by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, relative to the baseline tympanometry measurement. In some embodiments, the tympanometry measurement is improved by no more than about 10%, relative to the baseline tympanometry measurement. In some embodiments, the tympanometry measurement is improved by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100% relative to the baseline tympanometry measurement.
  • the tympanometry measurement is improved by no more than about 100%, improved by no more than about 250%, improved by no more than about 500%, improved by no more than about 750%, or improved by no more than about 1000%, relative to the baseline tympanometry measurement. In some embodiments, the tympanometry measurement is improved by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 250%, 500%, 750%, or 1000%, or by a range defined by any of the two aforementioned percentages.
  • the measurement is a brainstem audiometry measurement.
  • the measurement is an absolute wave latency.
  • the measurement is a wave amplitude.
  • the measurement is a interwave interval between waves.
  • the brain stem audiometry measurement is improved by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline measurement.
  • the brain stem audiometry measurement is improved by about 10% or more, relative to the baseline brain stem audiometry measurement.
  • the brain stem audiometry measurement is improved by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, relative to the baseline brain stem audiometry measurement. In some embodiments, the brain stem audiometry measurement is improved by about 100% or more, improved by about 250% or more, improved by about 500% or more, improved by about 750% or more, or improved by about 1000% or more, relative to the baseline brain stem audiometry measurement. In some embodiments, the brain stem audiometry measurement is improved by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, relative to the baseline brain stem audiometry measurement.
  • the brain stem audiometry measurement is improved by no more than about 10%, relative to the baseline brain stem audiometry measurement. In some embodiments, the brain stem audiometry measurement is improved by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100% relative to the baseline brain stem audiometry measurement. In some embodiments, the brain stem audiometry measurement is improved by no more than about 100%, improved by no more than about 250%, improved by no more than about 500%, improved by no more than about 750%, or improved by no more than about 1000%, relative to the baseline brain stem audiometry measurement.
  • the brain stem audiometry measurement is improved by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 250%, 500%, 750%, or 1000%, or by a range defined by any of the two aforementioned percentages.
  • the measurement is a otoacoustic emission measurement.
  • the otoacoustic emission measurement is improved by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline measurement.
  • the otoacoustic emission measurement is improved by about 10% or more, relative to the baseline otoacoustic emission measurement.
  • the otoacoustic emission measurement is improved by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, relative to the baseline otoacoustic emission measurement. In some embodiments, the otoacoustic emission measurement is improved by about 100% or more, improved by about 250% or more, improved by about 500% or more, improved by about 750% or more, or improved by about 1000% or more, relative to the baseline otoacoustic emission measurement.
  • the otoacoustic emission measurement is improved by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, relative to the baseline otoacoustic emission measurement. In some embodiments, the otoacoustic emission measurement is improved by no more than about 10%, relative to the baseline otoacoustic emission measurement. In some embodiments, the otoacoustic emission measurement is improved by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100% relative to the baseline otoacoustic emission measurement.
  • the otoacoustic emission measurement is improved by no more than about 100%, improved by no more than about 250%, improved by no more than about 500%, improved by no more than about 750%, or improved by no more than about 1000%, relative to the baseline otoacoustic emission measurement. In some embodiments, the otoacoustic emission measurement is improved by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 250%, 500%, 750%, or 1000%, or by a range defined by any of the two aforementioned percentages.
  • the measurement is a fibrinogen measurement. In some embodiments, the measurement is a measurement of circulating fibrinogen. In some embodiments, the composition reduces the fibrinogen measurement relative to the baseline fibrinogen measurement. In some embodiments, the composition reduces the circulating fibrinogen measurement relative to the baseline circulating fibrinogen measurement. In some embodiments, the fibrinogen measurement is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline fibrinogen measurement. In some embodiments, the fibrinogen measurement is decreased by about 10% or more, relative to the baseline fibrinogen measurement.
  • the fibrinogen measurement is decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, relative to the baseline fibrinogen measurement. In some embodiments, the fibrinogen measurement is decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, relative to the baseline fibrinogen measurement. In some embodiments, the fibrinogen measurement is decreased by no more than about 10%, relative to the baseline fibrinogen measurement.
  • the fibrinogen measurement is decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100% relative to the baseline fibrinogen measurement. In some embodiments, the fibrinogen measurement is decreased by 2.5%, 5%, 7.5%, 19%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or by a range defined by any of the two aforementioned percentages.
  • the measurement is an FGG protein measurement.
  • the FGG protein measurement comprises an FGG protein level.
  • the FGG protein level is a FGG protein level in the whole body.
  • the FGG protein level is a FGG protein level in the blood.
  • the FGG protein level is a FGG protein level in the brain.
  • the FGG protein level is a FGG protein level in the liver.
  • the FGG protein level is indicated as a mass or percentage of FGG protein per sample weight.
  • the FGG protein level is indicated as a mass or percentage of FGG protein per sample volume.
  • the FGG protein level is indicated as a mass or percentage of FGG protein per total protein within the sample.
  • the FGG protein measurement is a circulating FGG protein measurement.
  • the FGG protein measurement is obtained by an assay such as an immunoassay, a colorimetric assay, or a fluorescence assay.
  • the composition reduces the FGG protein measurement relative to the baseline FGG protein measurement. In some embodiments, the composition reduces circulating FGG protein levels relative to the baseline FGG protein measurement. In some embodiments, the composition reduces tissue (e.g., brain, liver, blood, or whole body) FGG protein levels relative to the baseline FGG protein measurement. In some embodiments, the reduced FGG protein levels are measured in a second sample obtained from the subject after administering the composition to the subject. In some embodiments, the FGG protein measurement is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline FGG protein measurement. In some embodiments, the FGG protein measurement is decreased by about 10% or more, relative to the baseline FGG protein measurement.
  • the FGG protein measurement is decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, relative to the baseline FGG protein measurement. In some embodiments, the FGG protein measurement is decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, relative to the baseline FGG protein measurement. In some embodiments, the FGG protein measurement is decreased by no more than about 10%, relative to the baseline FGG protein measurement.
  • the FGG protein measurement is decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100% relative to the baseline FGG protein measurement. In some embodiments, the FGG protein measurement is decreased by 2.5%, 5%, 7.5%, 19%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or by a range defined by any of the two aforementioned percentages. [00304] In some embodiments, the measurement is an FGG mRNA measurement. In some embodiments, the FGG mRNA measurement comprises an FGG mRNA level.
  • the FGG mRNA level is measured in the liver. In some embodiments, the FGG mRNA level is indicated as an amount or percentage of FGG mRNA per sample weight. In some embodiments, the FGG mRNA level is indicated as an amount or percentage of FGG mRNA per sample volume. In some embodiments, the FGG mRNA level is indicated as an amount or percentage of FGG mRNA per total mRNA within the sample. In some embodiments, the FGG mRNA level is indicated as an amount or percentage of FGG mRNA per total nucleic acids within the sample. In some embodiments, the FGG mRNA level is indicated relative to another mRNA level, such as an mRNA level of a housekeeping gene, within the sample. In some embodiments, the FGG mRNA measurement is obtained by an assay such as a PCR assay. In some embodiments, the PCR comprises qPCR. In some embodiments, the PCR comprises reverse transcription of the FGG mRNA.
  • the composition reduces the FGG mRNA measurement relative to the baseline FGG mRNA measurement.
  • the FGG mRNA measurement is obtained in a second sample obtained from the subject after administering the composition to the subject.
  • the composition reduces FGG mRNA levels relative to the baseline FGG mRNA levels.
  • the reduced FGG mRNA levels are measured in a second sample obtained from the subject after administering the composition to the subject.
  • the second sample is a liver sample.
  • the FGG mRNA measurement is reduced by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline v mRNA measurement.
  • the FGG mRNA measurement is decreased by about 10% or more, relative to the baseline FGG mRNA measurement. In some embodiments, the FGG mRNA measurement is decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, relative to the baseline FGG mRNA measurement. In some embodiments, the FGG mRNA measurement is decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, relative to the baseline FGG mRNA measurement. In some embodiments, the FGG mRNA measurement is decreased by no more than about 10%, relative to the baseline FGG mRNA measurement.
  • the FGG mRNA measurement is decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100%, relative to the baseline FGG mRNA measurement. In some embodiments, the FGG mRNA measurement is decreased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% or by a range defined by any of the two aforementioned percentages.
  • range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the disclosure. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.
  • determining means determining if an element is present or not (for example, detection). These terms can include quantitative, qualitative or quantitative and qualitative determinations. Assessing can be relative or absolute.
  • Detecting the presence of can include determining the amount of something present in addition to determining whether it is present or absent depending on the context.
  • a “subject” can be a biological entity containing expressed genetic materials.
  • the biological entity can be a plant, animal, or microorganism, including, for example, bacteria, viruses, fungi, and protozoa.
  • the subject can be a mammal.
  • the mammal can be a human.
  • the subject may be diagnosed or suspected of being at high risk for a disease. In some cases, the subject is not necessarily diagnosed or suspected of being at high risk for the disease.
  • the term “about” a number refers to that number plus or minus 10% of that number.
  • the term “about” a range refers to that range minus 10% of its lowest value and plus 10% of its greatest value.
  • treatment or “treating” are used in reference to a pharmaceutical or other intervention regimen for obtaining beneficial or desired results in the recipient.
  • beneficial or desired results include but are not limited to a therapeutic benefit and/or a prophylactic benefit.
  • a therapeutic benefit may refer to eradication or amelioration of symptoms or of an underlying disorder being treated.
  • a therapeutic benefit can be achieved with the eradication or amelioration of one or more of the symptoms associated with the underlying disorder such that an improvement is observed in the subject, notwithstanding that the subject may still be afflicted with the underlying disorder.
  • a prophylactic effect includes delaying, preventing, or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.
  • a subject at risk of developing a particular disease, or to a subject reporting one or more of the physiological symptoms of a disease may undergo treatment, even though a diagnosis of this disease may not have been made.
  • C x.y or “C x -C y ” when used in conjunction with a chemical moiety, such as alkyl, alkenyl, or alkynyl is meant to include groups that contain from x to y carbons in the chain.
  • Ci-ealkyl refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl and branched-chain alkyl groups that contain from 1 to 6 carbons.
  • C x.y alkenyl and C x.y alkynyl refer to substituted or unsubstituted unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond, respectively.
  • Carbocycle refers to a saturated, unsaturated or aromatic ring in which each atom of the ring is carbon.
  • Carbocycle includes 3- to 10-membered monocyclic rings, 5- to 12-membered bicyclic rings, 5- to 12-membered spiro bicycles, and 5- to 12-membered bridged rings.
  • Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated, and aromatic rings.
  • an aromatic ring e.g., phenyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene.
  • a bicyclic carbocycle includes any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits.
  • a bicyclic carbocycle further includes spiro bicyclic rings such as spiropentane.
  • a bicyclic carbocycle includes any combination of ring sizes such as 3-3 spiro ring systems, 4-4 spiro ring systems, 4-5 fused ring systems, 5-5 fused ring systems, 5-6 fused ring systems, 6-6 fused ring systems, 5-7 fused ring systems, 6-7 fused ring systems, 5- 8 fused ring systems, and 6-8 fused ring systems.
  • Exemplary carbocycles include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, naphthyl, and bicyclo [l.l.l]pentanyl.
  • aryl refers to an aromatic monocyclic or aromatic multicyclic hydrocarbon ring system.
  • the aromatic monocyclic or aromatic multicyclic hydrocarbon ring system contains only hydrogen and carbon and from five to eighteen carbon atoms, where at least one of the rings in the ring system is aromatic, i.e., it contains a cyclic, delocalized (4n+2) n-electron system in accordance with the Htickel theory.
  • the ring system from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin and naphthalene.
  • cycloalkyl refers to a saturated ring in which each atom of the ring is carbon.
  • Cycloalkyl may include monocyclic and polycyclic rings such as 3- to 10-membered monocyclic rings, 5- to 12-membered bicyclic rings, 5- to 12-membered spiro bicycles, and 5- to 12-membered bridged rings.
  • a cycloalkyl comprises three to ten carbon atoms.
  • a cycloalkyl comprises five to seven carbon atoms.
  • the cycloalkyl may be attached to the rest of the molecule by a single bond.
  • Examples of monocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Polycyclic cycloalkyl radicals include, for example, adamantyl, spiropentane, norbomyl (i.e., bicyclo[2.2.1]heptanyl), decalinyl, 7,7 dimethyl bicyclo[2.2.1]heptanyl, bicyclo [l. l.l]pentanyl, and the like.
  • Cycloalkenyl refers to a saturated ring in which each atom of the ring is carbon and there is at least one double bond between two ring carbons.
  • Cycloalkenyl may include monocyclic and polycyclic rings such as 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, and
  • a cycloalkenyl comprises five to seven carbon atoms.
  • the cycloalkenyl may be attached to the rest of the molecule by a single bond.
  • monocyclic cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.
  • halo or, alternatively, “halogen” or “halide,” means fluoro, chloro, bromo or iodo. In some embodiments, halo is fluoro, chloro, or bromo.
  • haloalkyl refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, for example, trifluoromethyl, dichloromethyl, bromomethyl, 2,2,2-trifluoroethyl, 1- chloromethyl -2 -fluoroethyl, and the like.
  • the alkyl part of the haloalkyl radical is optionally further substituted as described herein.
  • heterocycle refers to a saturated, unsaturated or aromatic ring comprising one or more heteroatoms.
  • exemplary heteroatoms include N, O, Si, P, B, and S atoms.
  • Heterocycles include 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, 5- to 12- membered spiro bicycles, and 5- to 12-membered bridged rings.
  • a bicyclic heterocycle includes any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits.
  • an aromatic ring e.g., pyridyl
  • a saturated or unsaturated ring e.g., cyclohexane, cyclopentane, morpholine, piperidine or cyclohexene.
  • a bicyclic heterocycle includes any combination of ring sizes such as 4-5 fused ring systems, 5-5 fused ring systems, 5-6 fused ring systems,
  • a bicyclic heterocycle further includes spiro bicyclic rings, e.g., 5 to 12-membered spiro bicycles, such as 2-oxa-6-azaspiro[3.3]heptane.
  • heteroaryl refers to a radical derived from a 5 to 18 membered aromatic ring radical that comprises two to seventeen carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur.
  • the heteroaryl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, wherein at least one of the rings in the ring system is aromatic, i.e., it contains a cyclic, delocalized (4n+2) n-electron system in accordance with the Htickel theory.
  • Heteroaryl includes fused or bridged ring systems.
  • the heteroatom(s) in the heteroaryl radical is optionally oxidized.
  • heteroaryl is attached to the rest of the molecule through any atom of the ring(s).
  • heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzoxazolyl, benzo [d]thiazolyl, benzothiadiazolyl, benzo[b][l,4]dioxepinyl, benzo[b][l,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzo
  • heterocycloalkyl refers to a saturated ring with carbon atoms and at least one heteroatom.
  • exemplary heteroatoms include N, O, Si, P, B, and S atoms.
  • Heterocycloalkyl may include monocyclic and polycyclic rings such as 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, 5- to 12-membered spiro bicycles, and 5- to 12-membered bridged rings.
  • the heteroatoms in the heterocycloalkyl radical are optionally oxidized.
  • One or more nitrogen atoms, if present, are optionally quatemized.
  • heterocycloalkyl is attached to the rest of the molecule through any atom of the heterocycloalkyl, valence permitting, such as any carbon or nitrogen atoms of the heterocycloalkyl.
  • heterocycloalkyl radicals include, but are not limited to, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl,
  • heterocycloalkenyl refers to an unsaturated ring with carbon atoms and at least one heteroatom and there is at least one double bond between two ring carbons. Heterocycloalkenyl does not include heteroaryl rings. Exemplary heteroatoms include N, O, Si, P, B, and S atoms.
  • Heterocycloalkenyl may include monocyclic and polycyclic rings such as 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, and 5- to 12-membered bridged rings.
  • a heterocycloalkenyl comprises five to seven ring atoms.
  • the heterocycloalkenyl may be attached to the rest of the molecule by a single bond.
  • Examples of monocyclic cycloalkenyls include, e.g., pyrroline (dihydropyrrole), pyrazoline (dihydropyrazole), imidazoline (dihydroimidazole), triazoline (dihydrotriazole), dihydrofuran, dihydrothiophene, oxazoline (dihydrooxazole), isoxazoline (dihydroisoxazole), thiazoline (dihydrothiazole), isothiazoline (dihydroisothiazole), oxadiazoline (dihydrooxadiazole), thiadiazoline (dihydrothiadiazole), dihydropyridine, tetrahydropyridine, dihydropyridazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyrazine,
  • substituted refers to moieties having substituents replacing a hydrogen on one or more carbons or substitutable heteroatoms, e.g., an NH or NH2 of a compound. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, i.e., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.
  • substituted refers to moieties having substituents replacing two hydrogen atoms on the same carbon atom, such as substituting the two hydrogen atoms on a single carbon with an oxo, imino or thioxo group.
  • substituted is contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non -aromatic substituents of organic compounds.
  • the permissible substituents can be one or more and the same or different for appropriate organic compounds.
  • a "derivative" polypeptide or peptide is one that is modified, for example, by glycosylation, pegylation, phosphorylation, sulfation, reduction/alkylation, acylation, chemical coupling, or mild formalin treatment.
  • a derivative may also be modified to contain a detectable label, either directly or indirectly, including, but not limited to, a radioisotope, fluorescent, and enzyme label.
  • thymine may be interchanged with uracil (U), or vice versa.
  • U uracil
  • some sequences in the sequence listing may recite Ts, but these may be replaced with Us in some embodiments.
  • the uracil may be replaced with thymine.
  • the thymine may be replaced with uracil.
  • an oligonucleotide such as an siRNA comprises or consists of RNA.
  • the oligonucleotide may include of DNA.
  • the oligonucleotide may include 2’ deoxyribonucleotides.
  • An ASO may comprise or consist of DNA.
  • Nf refers to a 2’-fluoro-modified nucleoside
  • dN e.g., dA, dC, dG, dT, or dU
  • n e.g., a, c, g, t, or u
  • s refers to a phosphorothioate linkage.
  • a pyrimidine may include cytosine (C), thymine (T), or uracil (U).
  • a pyrimidine may include C or U.
  • a pyrimidine may include C or T. Where a pyrimidine is referred to, it may indicate a nucleoside or nucleotide comprising a pyrimidine.
  • a purine may include guanine (G), inosine (I), adenine (A). Where a purine is referred to, it may indicate a nucleoside or nucleotide comprising a purine.
  • Example 1 Functional variants in FGG demonstrate protective associations for hearing disorders
  • Both variants may be hypomorphic or loss-of-fiinction variants that result in a decrease in the abundance or activity of the FGG gene product and therefore of fibrinogen.
  • a FGG gene burden test which aggregated carriers of rsl48685782 and rs6063 was also evaluated.
  • Example 2 Bioinformatic selection of sequences in order to identify therapeutic siRNAs to downmodulate expression of FGG mRNA
  • Screening sets were defined based on bioinformatic analysis.
  • Therapeutic siRNAs were designed to target human FGG, and the FGG sequence of at least one toxicology-relevant species; in this case, non-human primates (NHP) including rhesus and cynomolgus monkeys.
  • Drivers for the design of the screening set were predicted specificity of the siRNAs against the transcriptome of the relevant species as well as cross-reactivity between species.
  • Predicted specificity in human, rhesus monkey, cynomolgus monkey, mouse, rat, rabbit, dog, gerbil, Syrian hamster, Chinese hamster, guinea pig, and naked mole rat was determined for sense (S) and antisense (AS) strands.
  • siRNAs with high specificity and a low number of predicted off-targets provide a benefit of increased targeting specificity.
  • siRNA sequences within the seed region were analyzed for similarity to seed regions of known miRNAs.
  • siRNAs can function in a miRNA like manner via base-pairing with complementary sequences within the 3’-UTR of mRNA molecules. The complementarity typically encompassed the 5’-bases at positions 2-7 of the miRNA (seed region).
  • siRNA strands containing natural miRNA seed regions can be avoided. Seed regions identified in miRNAs from human, mouse, rat, rhesus monkey, dog, rabbit and pig are referred to as “conserved”. Combining the “specificity score” with miRNA seed analysis yielded a “specificity category”. This was divided into categories 1-4, with 1 having the highest specificity and 4 having the lowest specificity. Each strand of the siRNA was assigned to a specificity category.
  • siRNAs in these subsets were selected based on the ability to recognize at least the human, cynomolgus monkey, rhesus monkey FGG sequences. Therefore, the siRNAs in these subsets may be used to target human FGG in a therapeutic setting.
  • siRNA sequences derived from human FGG mRNA (ENST00000404648, SEQ ID NO: 3621) without consideration of specificity or species cross-reactivity was 1742 (sense and antisense strand sequences included in SEQ ID NOS: 1-3484).
  • Subset A includes 319 siRNAs whose base sequences are shown in Table 3.
  • siRNAs in subset A were selected to have the following characteristics: • Cross-reactivity: With 19mer in human FGG mRNA, with 17mer/19mer in NHP FGG
  • miRNA seeds AS+SS strand: seed region not conserved in human, mouse, and rat and not present in >4 species
  • Off-target frequency ⁇ 30 human off-targets matched with 2 mismatches in antisense strand
  • siRNA target sites do not harbor SNPs with a MAF > 1% (pos. 2-18)
  • siRNA sequences in subset A were selected for more stringent specificity to yield subset
  • Subset B includes 318 siRNAs whose base sequences are shown in Table 4.
  • siRNAs in subset B were selected to have the following characteristics:
  • miRNA seeds AS+SS strand: seed region not conserved in human, mouse, and rat and not present in >4 species
  • Off-target frequency ⁇ 20 human off-targets matched with 2 mismatches in antisense strand
  • siRNA target sites do not harbor SNPs with a MAF > 1% (pos. 2-18)
  • subset B The siRNA sequences in subset B were further selected for absence of seed regions in the AS strand that are identical to a seed region of known human miRNA to yield subset C.
  • Subset C includes 221 siRNAs whose base sequences are shown in Table 5.
  • siRNAs in subset C have the following characteristics:
  • AS+SS strand seed region not conserved in human, mouse, and rat and not present in >4 species.
  • AS strand seed region not identical to seed region of known human miRNA
  • Off-target frequency ⁇ 30 human off-targets matched with 2 mismatches by antisense strand
  • siRNA target sites do not harbor SNPs with a MAF > 1% (pos. 2-18)
  • siRNA sequences in subset C were also selected for absence of seed regions in the AS or
  • Subset D includes 147 siRNAs whose base sequences are shown in Table 6.
  • siRNAs in subset D were selected to have the following characteristics:
  • AS+SS strand seed region not conserved in human, mouse, and rat and not present in >4 species.
  • AS+SS strand seed region not identical to seed region of known human miRNA
  • Off-target frequency ⁇ 20 human off-targets matched with 2 mismatches by antisense strand
  • siRNA target sites do not harbor SNPs with a MAF > 1% (pos. 2-18)
  • Subset E includes 53 siRNAs.
  • the siRNAs in subset E include siRNAs from subset A and additional siRNAs that were tested in vitro (see, e.g., Table 7).
  • the sense strand of any of the siRNAs of subset E comprises siRNA with a particular modification pattern.
  • position 9 counting from the 5’ end of the of the sense strand is has the 2’F modification.
  • a “2’F modification” is denoted, it is intended to mean that a 2’F is included.
  • position 9 of the sense strand is a pyrimidine, then all purines in the sense strand have the 2’0Me modification.
  • a “2’0Me modification” is denoted, it is intended to mean that a 2’0Me is included.
  • the sense strand of any of the siRNAs of subset E comprises a modification pattern which conforms to these sense strand rules (Table 8A).
  • the antisense strand of any of the siRNAs of subset E comprises modification pattern 9AS (Table 8A).
  • the siRNAs in subset E may comprise any other modification pattem(s).
  • Nf (Af, Cf, Gf, Uf, or Tf) is a 2’-fluoro-modified nucleoside
  • n (a, c, g, u, or t) is a 2’-0-methyl modified nucleoside
  • s is a phosphorothioate linkage.
  • any siRNA among any of subsets A-E may comprise any modification pattern described herein. If a sequence is a different number of nucleotides in length than a modification pattern, the modification pattern may still be used with the appropriate number of additional nucleotides added 5’ or 3’ to match the number of nucleotides in the modification pattern. For example, if a sense or antisense strand of the siRNA among any of subsets A-E comprises 19 nucleotides, and a modification pattern comprises 21 nucleotides, UU may be added onto the 5’ end of the sense or antisense strand.
  • Subset G contains 131 siRNAs whose base sequences are shown in Table 8B.
  • siRNAs in subset G had the following characteristics:
  • Off-target frequency ⁇ 30 human off-targets matched with 2 mismatches in antisense strand
  • siRNA target sites do not harbor SNPs with a MAF > 1% (pos. 2-18)
  • Example 3 Screening FGG siRNAs for activity in Hep 3B2.1-7 cells in culture
  • FGG siRNAs cross reactive for at least human and non-human primates will be assayed for FGG mRNA knockdown activity in cells in culture.
  • Hep 3B2.1-7 cells ATCC® catalog# HB-8064
  • EMEM media VWR catalog# 76000-922
  • the FGG siRNAs will be individually transfected into Hep 3B2.
  • RNA will be harvested from each well and cDNA prepared using TaqMan® Fast Advanced Cells-to-CTTM Kit (ThermoFisher, catalog# A35374) according to the manufacturer’s instructions.
  • the level of FGG mRNA from each well will be measured in triplicate by biplex real-time qPCR on a QuantStudio 6 Pro instrument (Applied Biosystems) using TaqMan Gene Expression Assay for human FGG (ThermoFisher, assay# Hs00241037_ml).
  • the level of PPIA mRNA will be measured using TaqMan Gene Expression Assay (ThermoFisher, assay# Hs99999904_ml) and used to determine relative FGG mRNA levels in each well using the delta-delta Ct method. All data will be normalized to relative FGG mRNA levels in untreated Hep 3B2.1-7 cells. Identification of siRNAs targeting FGG that reduce FGG expression is anticipated.
  • the IC50 values for knockdown of FGG mRNA by select FGG siRNAs will be determined in Hep 3B2.1-7 cells.
  • the siRNAs will be assayed individually in triplicate at 30 nM, 10 nM, 3 nM, 1 nM and 0.3 nM, 0.1 nM and 0.03 nM.
  • Hep 3B2.1-7 cells (ATCC® catalog# HB-8064) will be seeded in 96- well tissue culture plates at a cell density of 7,500 cells per well in EMEM media (VWR catalog# 76000- 922) supplemented with 10% fetal bovine serum and incubated overnight in a water-jacketed, humidified incubator at 37°C in an atmosphere without supplemental carbon dioxide.
  • the FGG siRNAs will be individually transfected using 0.3 pL Lipofectamine RNAiMax (Fisher, catalog# 13778150) in 5 pl Opti- MEM (Thermo Fisher, catalog# 31985070) per well. After incubation for 48 hours at 37°C, total RNA will be harvested from each well and cDNA prepared using TaqMan® Fast Advanced Cells-to-CTTM Kit (ThermoFisher, Catalog# A35374) according to the manufacturer’s instructions.
  • the level of FGG mRNA from each well will be measured in triplicate by biplex real-time qPCR on a QuantStudio 6 Pro instrument (Applied Biosystems) using TaqMan Gene Expression Assay for human FGG (ThermoFisher, assay# Hs00241037_ml).
  • the level of PPIA mRNA will be measured using TaqMan Gene Expression Assay (ThermoFisher, assay# Hs99999904_ml) and used to determine relative FGG mRNA levels in each well using the delta-delta Ct method. All data will be normalized to relative FGG mRNA levels in untreated Hep 3B2.1-7 cells. Curve fit will be accomplish using the [inhibitor] vs. response (three parameters) function in GraphPad Prism software.
  • Example 5 ASO-mediated knockdown of FGG in HEPG2 cell line
  • the HEPG2 cells are seeded at 150,000 cells/mL into a Falcon 24-well tissue culture plate (ThermoFisher Cat. No. 353047) at 0.5 mb per well.
  • the FGG ASO and negative control ASO master mixes are prepared.
  • the FGG ASO master mix contains 350 pl of Opti-MEM (ThermoFisher Cat. No. 4427037 - sl288 Lot No. AS02B02D) and 3.5 pl of a FGG ASO (10 pM stock).
  • the negative control ASO master mix contains 350 pl of Opti-MEM and 3.5 pl of negative control ASO (ThermoFisher Cat. No. 4390843, 10 uM stock).
  • 3 pl of TransIT-X2 (Minis Cat. No. MIR-6000) is added to each master mix.
  • cells are washed with 50 pl using cold IX PBS and lysed by adding 49.5 pl of Lysis Solution and 0.5 pl Dnase I per well and pipetting up and down 5 times and incubating for 5 minutes at room temperature.
  • the Stop Solution (5 pl/well) is added to each well and mixed by pipetting up and down five times and incubating at room temperature for 2 minutes.
  • the reverse transcriptase reaction is performed using 22.5 pl of the lysate according to the manufacturer’s protocol. Samples are stored at -80 °C until real-time qPCR is performed in triplicate using TaqMan Gene Expression Assays (Applied Biosystems FAM/FGG using a BioRad CFX96 Cat. No. 1855195).
  • a decrease in FGG mRNA expression in the HEPG2 cells is expected after transfection with the FGG ASO compared to FGG mRNA levels in HEPG2 cells transfected with the non-specific control ASO 48 hours after transfection.
  • There is an expected decrease in the amount of FGG secreted protein measured by quantifying the amount of FGG protein in media of HEPG2 cells transfected with the FGG ASO relative to the amount of FGG protein in media of HEPG2 cells transfected with a non-specific control ASO 48 hours after transfection.
  • mice were injected subcutaneously with 100 pl of sterile PBS
  • Group 2 mice were subcutaneously injected with 200 pg of ETD01592 (sense strand SEQ ID NO: 3591; antisense strand SEQ ID NO: 3595) in 100 pl of sterile PBS
  • Group 3 mice were subcutaneously injected with 200 pg ETD01593 (sense strand SEQ ID NO: 3592; antisense strand SEQ ID NO: 3596) in 100 pl of sterile PBS
  • Group 4 mice were subcutaneously injected with 200 pg of ETD01594 (sense strand SEQ ID NO: 3593; antisense strand SEQ ID NO: 3597) in 100 pl PBS
  • Group 5 mice were subcutaneously injected with 200 pg of ETD01595 (sense strand SEQ ID NO: 3594; antisense strand SEQ ID NO: 3598) in 100 pl PBS.
  • RNA from the liver lysate was purified on a Maxwell RSC 48 platform (Promega Corporation) according to the manufacturer’s recommendations.
  • the relative level of FGG mRNA in each liver sample was assessed by RT-qPCR on a QuantStudio 6 Pro instrument (Applied Biosystems) using TaqMan assays for mouse FGG (ThermoFisher, assay# Mm00513575_ml) and the mouse housekeeping gene PPIA (ThermoFisher, assay# Mm02342430_g I ). and then normalized to the mean value of the control mice (Group 1) using the delta-delta Ct method.
  • mice treated ETD01592 (Group 2), ETD01593 (Group 3), ETD01594 (Group 4), or ETD01595 (Group 4) showed decreased liver FGG mRNA levels compared with mice injected with PBS (Group 1).
  • the results of the plasma fibrinogen analyses are shown in Table 10.
  • Animals treated with ETD01592 (Group 2), ETD01593 (Group 3), ETD01594 (Group 4), or ETD01595 (Group 5) showed decreased plasma fibrinogen levels as measured by the Clauss method or by ELISA compared with mice injected with PBS (Group 1).
  • the results from the clinical chemistry indicated all the siRNAs were generally well tolerated (Table 11).
  • Table 9 Day 10 FGG mRNA liver levels in mice treated with siRNAs targeting FGG
  • Example 7 Determining the activity of siRNAs targeting FGG in mice at low dose levels
  • mice in Group 1 were injected subcutaneously with 100 pl of sterile PBS
  • mice in Groups 2 and 3 were subcutaneously injected with 20 pg or 60 pg of ETD01592, respectively (sense strand SEQ ID NO: 3591; antisense strand SEQ ID NO: 3595) in 100 pl of sterile PBS
  • mice in Groups 4 and 5 were subcutaneously injected with 20 pg or 60 pg of ETD01593, respectively (sense strand SEQ ID NO: 3592; antisense strand SEQ ID NO: 3596) in 100 pl of sterile PBS
  • mice in Groups 6 and 7 were subcutaneously injected with 20 pg or 60 pg of ETD01594, respectively (sense strand SEQ ID NO: 3593; antisense strand SEQ ID NO: 3597) in 100 pl PBS, and mice in Groups 8
  • RNA from the liver lysate was purified on a Maxwell RSC 48 platform (Promega Corporation) according to the manufacturer’s recommendations.
  • the relative level of FGG mRNA in each liver sample was assessed by RT-qPCR on a QuantStudio 6 Pro instrument (Applied Biosystems) using TaqMan assays for mouse FGG (ThermoFisher, assay# Mm00513575_ml) and the mouse housekeeping gene PPIA (ThermoFisher, assay# Mm02342430_g I ). and then normalized to the mean value of the control mice (Group 1) using the delta-delta Ct method.
  • mice treated with 20 pg ETD01592, ETD01593, ETD01594, or ETD01595 showed decreased liver FGG mRNA levels compared with mice injected with PBS.
  • Animals treated with 60 pg ETD01592, ETD01593, ETD01594, or ETD01595 showed decreased liver FGG mRNA levels compared with mice injected with 20 pg of those siRNAs or with mice injected with PBS.
  • the results of the plasma fibrinogen ELISA are shown in Table 13.
  • mice treated with 20 pg ETD01592, ETD01593, ETD01594, or ETD01595 showed decreased plasma fibrinogen protein levels compared with mice injected with PBS.
  • Animals treated with 60 pg ETD01592, ETD01593, ETD01594, or ETD01595 showed decreased plasma fibrinogen protein levels compared with mice injected with 20 pg of those siRNAs or with mice injected with PBS.
  • the results of the PT and aPTT measurements in animals treated with 20 pg and 60 pg ETD01592, ETD01593, ETD01594, or ETD01595 are shown in Table 14. The results from the clinical chemistry indicate that all the siRNAs were generally well tolerated at these dose levels (Table 15).
  • Example 8 Screening FGG siRNAs for activity in Huh7 cells in culture

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